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+ Adaptive substance, creative regeneration: Mainstream science, repression, and creativity +

+ +

+ "I intend to show you how neo-Darwinism has been invalidated within science itself, as an + explanation of how life on earth has evolved and is evolving. It is nevertheless still perpetrated by + the academic establishment, if only because it serves so well to promote genetic engineering, a + technology that has the potential to destroy all life on earth. Furthermore, neo-Darwinism reinforces a + worldview that undermines all moral values and prevents us from the necessary shift to holistic, + ecological sciences that can truly regenerate the earth and revitalize the human spirit." + + Mae-Wan Ho + http://www.i-sis.org.uk/paris.php +

+

+

+

+

+ More than 50 years have been wasted in one of the most important and fundamental branches of science and + medicine, for reasons that are highly ideological and political. Rather than studying the regeneration of + organs and tissues, and recognizing its obvious importance in healing as well as in understanding the nature + of life, much of the last century was devoted to the defamation of the researchers who were making real + process in the field. Despite many demonstrations that regeneration can occur in adult mammals, students + were taught that it happens only in lower vertebrates. I think it's important to look closely at the + ideology responsible for this great loss. +

+ +

+ Warburg and Szent-Gyorgyi, in thinking about cancer, emphasized that growth is the primordial function of + all cells, and that the differentiated functions of complex organisms involve restraints of that primitive + function, imposed by a system that has developed through time. +

+

+ Seen with this orientation, regeneration is the spontaneous result of the disappearance of restraint. The + reproduction of a whole plant from a twig, or clone, was a process known for thousands of years. Any part of + the plant contains the information needed for making a whole plant. More than thirty years ago, cells from a + tumor were added to the cells of a normal embryo, and the animal that matured from the embryo-tumor mix was + normal, and had traits of both lineages, showing that the tumor cells had retained the genetic information + of a complete healthy organism, and just needed a different environment in which to realize their full + potential. +

+

+ One of the currents of medical thinking, from classical times through Paracelsus to homeopathy and + naturopathy, has been a confidence in the capacity of the organism to heal itself. But "modern" medicine has + arrogated to itself the "healing power," with terrible results, mitigated only by their occasional reluctant + acceptance of fragments of sane organismic thinking, such as recognizing the importance of nutrition, or of + keeping sewage out of the drinking water. Research into methods to support the organism's natural + restorative powers has been ridiculed and suppressed. +

+

+ We are immersed in the propaganda of modern medicine, and part of that propaganda involves the confabulation + of a history of science that supports their practice and their ideology. The real history of science won't + be found in science textbooks. +

+ +

+ "I intend to show you how neo-Darwinism has been invalidated within science itself, as an explanation of how + life on earth has evolved and is evolving. It is nevertheless still perpetrated by the academic + establishment, if only because it serves so well to promote genetic engineering, a technology that has the + potential to destroy all life on earth. Furthermore, neo-Darwinism reinforces a worldview that undermines + all moral values and prevents us from the necessary shift to holistic, ecological sciences that can truly + regenerate the earth and revitalize the human spirit." Mae-Wan Ho + http://www.i-sis.org.uk/paris.php +

+

+ Mainstream medical treatments are based on some fundamentally absurd scientific ideas. The advent of + experimental animal cloning and the industrialization of genetic engineering have undercut the most + important biological doctrines of the 20th century, but the processes of critical thinking haven't made + headway against most of the traditional medical stereotypes. Cloning shows that all cells are potential + "stem cells," but this fact co-exists with the Hayflick doctrine, that says, essentially, that no cell is a + stem cell. +

+

+ The ideology of culturally significant "intellectuals"--scientists, professors, neurobiologists, linguists, + philosophers, oncologists, geneticists--in the US is deeply influenced by the dualism and mechanistic + materialism of Rene DesCartes. +

+ +

+ The denial that animals can think or understand language, the claim that babies or animals don't feel pain, + or that heart cells and brain cells can't divide, or that somatic cells lack the genetic capacity to be + cloned, or that they are intrinsically mortal, limited to a maximum of 50 cell divisions--these absurdities + of 20th century biology and medicine all resulted from an abject commitment to the mechanistic doctrine of + matter and life promoted or invented by DesCartes. +

+

+ I doubt that DesCartes really invented anything, because, by the evidence of his writing, he wasn't an + intelligent man, but he placed himself politically in such a way that his arguments were acceptable to many + influential people, and they continue to be acceptable to authoritarian and elitist factions even today. +

+

+ In the 16th and 17th century the cultures of England, Holland, and France were increasingly dominated by + business interests. People who had money to invest wanted to see the world as an orderly, predictable place, + and they found that many of the ideas of the ancient Greeks were useful. Mathematics was needed to calculate + interest rates, insurance premiums, and, for the military, the trajectories of missiles. In an orderly + world, allowance for a little random variation helped to save the perfection of the general rule. +

+

+ In this environment, theological thinking began retrenching its doctrine, to make it more acceptable to the + increasingly powerful commercial people. The clockwork universe of DesCartes' time, in which a perfect world + that operated according to perfect natural laws had been divinely created, gradually became theologically + acceptable during the 18th and 19th centuries. In the 18th century, the Deists were the most famous + embodiment of the idea, and then in the 19th century their place was taken by the Catastrophists, who + claimed that the fossils which seemed to show evolutionary change of species actually represented species + that had been created along with those now existing, but that had been destroyed by catastrophes, such as + Noah's flood. By the end of the 19th century, the president of an American university recognized that + theological compromises could prevent his undergraduates from rejecting religion entirely, and forbade + sermons against evolution. +

+ +

+ There were many biologists who insisted that evolution of new species was analogous to the development of an + individual, and that both revealed an adaptive capacity of the living substance. In this view, the adaptive + growth of an individual in a new environment revealed novel solutions to new problems, and showed an innate + inventiveness and intelligence in the process of growth and adaptation. The appearance of new species was + thought to represent the same sorts of adaptive processes. +

+

+ Erasmus Darwin (grandfather of Charles) was an evolutionist of this sort, but because of political and + theological pressure, he kept relatively quiet about his beliefs. There was an underground culture, in which + an evolutionary view of the world was accepted, but these views were seldom published, because of + increasingly stringent censorship. Because of censorship, poetry, letters, and diaries, rather than academic + and scholarly works, give us the true picture of 18th century and early 19th century scientific culture. +

+

+ The scientists who wanted their work to be acceptable to those in power found ways to work with the + Cartesian mechanical view of the world, building on the Deists' compromise, which had succeeded in removing + the supernatural from nature. As the fossil evidence of evolution became inescapable, around the time of + Charles Darwin's work, those who wanted to bring evolution into the mainstream of culture found that the + Catastrophism of the creationists could be adapted to their purposes, with only slight modification. +

+

+ The doctrine of Thomas Malthus, who argued that war, famine, and disease were beneficial for those who + survived, by decreasing the competition for limited resources, became a near equivalent to the catastrophic + floods that the creationists had invoked to explain the geological record that contained evidence of many + extinct animals. The doctrine of Malthus, like that of the Catastrophists, made loss, deletion, and + destruction into a central device for explaining the history of the world. +

+

+ Both of the Darwins had accepted the idea that many biological changes were adaptive, rather than random, + but the new practical compromise doctrine introduced the idea that changes were just "random variations." + The essentially mechanical nature of the world was preserved, because "chance" occurrences could be dealt + with, and didn't involve anything supernatural. The function of the environment wasn't to add + anything to life (that would have been to assert that there were creative powers other than those of the + Creator), but simply to eliminate the inferior individuals that appeared as the result of random + changes. +

+

+ Gregor Mendel applied the principle of chance to explaining the inheritance of certain traits, and showed + that "traits" were passed on unchanged, even when they weren't visible. His ideas were published and were + acceptable to the scientific mainstream of his time. Traits were determined by "factors" that were passed + on, unchanged, from parents, and biological variation was explained by varied mixing of factors which in + themselves were unaffected by the organism or the environment. Genetic determinism was safely compatible + with creationism. +

+ +

+ Shortly after Mendel's death, August Weismann began a campaign to put a stop to the claims of those who, + like the Darwins and Lamarck, saw adaptive development of organisms as an essential part of the evolution of + species. +

+

+ Weismann was essentially a propagandist, and his first fame was the result of "disproving" Lamarck by + cutting the tails off more than 1500 mice, and observing that their offspring were born with tails. The + reason the inheritance of acquired traits was impossible, he said, was that the "germ line" was perfectly + isolated from the rest of the organism. The differentiated tissues of the body were produced by the + selective loss of information from the nuclei of cells in the embryo. The cells of the germ line were + immortal and contained all the information needed to produce an organism, but no other cell of the organism + was complete. +

+

+ Complexity was produced by deletion, and this was the basis for arguing that, if even the development of an + individual was nothing but a passive unfolding of inherited properties, much like unpacking a trunkful of + clothes, then there could be no adaptively acquired traits, and certainly no inheritance of something which + didn't exist. Changes in an individual were simply accidents, such as having a tail amputated, and so the + whole issue of the origin of complexity was safely left to a primordial creation. +

+ +

+ Weismann and his arguments were famous in Europe and the US, and formed the background for the ideas known + as neo-Darwinism. His "isolation of the germ line" was the earliest version of the Central Dogma of + molecular biology, namely, that information flows only from DNA to RNA to protein. His doctrine, of + complexification through deletion, is the epitome of the greatest dogma of modern times, expressed in + doctrines from Catastrophism through the second law of thermodynamics and the theory of the Big Bang, down + to Hayflick's Doctrine of the mortality of somatic cells. All these are consequences of the Cartesian and + Deistic separation of intelligence from matter. +

+

+ Regeneration is one of the most vivid examples of the intelligence of living substance. +

+

+ Given a natural tendency of cells to multiply, the interesting thing about regenerative healing is the + question of why the new growth of tissue sometimes differentiates to fit appropriately into its + surroundings, but sometimes fails to differentiate, becoming a tumor. +

+

+ With aging, the regenerative process declines, and the process of tissue rebuilding slows. Against a + background of reduced regenerative ability, tissue growth sometimes produces tumors, rather than renewed + healthy tissue. When tumors are grafted onto the amputated tail stump of a salamander, which has good + regenerative ability, the tumor is transformed into a tail, by its envirornment, or morphogenic field. The + "cancer problem" is essentially the problem of understanding the organizing forces of the organism. The + aging problem is another aspect of the same problem. +

+ +

+ Traditionally, biologists had studied anatomy, physiology, embryology or development, and taxonomy or the + classification of organisms. The growth of knowedge early in the 20th century was suddenly seeming to + confirm the physiological, adaptive view of organisms that Lamarck had held. C.M. Child, Joseph Needham, + Alexander Gurwitsch, and L.V. Polezhaev were demonstrating the primacy of a formative process in biology. + Polezhaev and Vladimir Filatov were studying practical means of stimulating regeneration as a medical + technique. +

+

+ Until the beginning of the second world war, the study of regeneration and the pattern-forming processes in + embryology were the liveliest parts of biological research. Gestalt psychology was being developed at the + same time, with a similar emphasis on patterns and wholes. +

+

+ But Weismannism and neo-Darwinism, largely embodied in the person of the geneticist T.H. Morgan, + deliberately set out to kill that line of biological research. Gestalt psychology was similarly eliminated + by the Behaviorists. +

+

+ One of Morgan's closest associates, his student and colleague A.H. Sturtevant, said that "Morgan's + objectives, what he was trying to get at in general in his biological work was to produce mechanistic + interpretations of biological phenomena. One of the things that irritated him most was any suggestion of + purpose in biological interpretation. He always had some reservations about the idea of natural selection, + because it seemed to him to open the door to interpretations of biological phenomena in terms of purpose. He + could be talked into the conclusion that there was nothing that wasn't strictly mechanistic about this + interpretation, but he never liked it. And you had to talk him into it again every few months." (Sturtevant, + A. H., Genetics, Vol. 159, 1-5, September 2001, Copyright 2001, Reminiscences of T. H. Morgan.) +

+ +

+ Whatever his motives, Morgan was known to have prevented his students (including C.M. Child) from publishing + work that supported a holistic view of the organism. After Morgan's death, there was an intense and + widespread campaign to suppress any approach to biology other than the "new synthesis," neo-Darwinism, with + its doctrine of mechanistic genetic determinism and its doctrine of random variation. A developmental + biologist, J.M. Opitz (1985), commented that "in one of the most astounding developments in Western + scientific history, the gradient-field, or epimorphic field concept, as embodied in normal ontogeny and + as studied by experimental embryologists, seems to have simply vanished from the intellectual patrimony + of Western biologists." + +

+

+ Formative processes are necessarily multidimensional, and that makes calculation and analysis very complex. + To a great extent, the geneticists were motivated to study bacterial genes, rather than vertebrate embryos, + by the principle that motivated the drunk to look for his car keys under the street lamp, even though that + wasn't where he lost them, because the light made it easier to look there. +

+

+ Bacteria are easy to study because they lack the complexity that makes it hard to study an embryo or an + animal. The language used in genetics textbooks shows not only that bacteria are treated by geneticists as + if they were one or two dimensional, but that the concepts developed for bacterial genetics have been + extrapolated to use in describing complex organisms: "Genes interact to establish the body + axis in Drosophila. Homeotic Genes control pattern formation along the anterior-posterior + body axis." (Essentials of Genetics, M. Cummings and W. Klug, Prentice Hall, 2004.) +

+ +

+ One of the basic distinctions in embryology is in the way the cells divide after the egg is fertilized. + Oysters and earthworms have spiral cleavage, sea urchins and people have radial cleavage. Several decades + ago an experimenter was transferring a nucleus from an egg of an animal with radial cleavage, I think a sea + urchin, into the enucleated egg of a snail, with spiral cleavage. The nucleus transplanted across such a + great difference in phyla didn't sustain maturation of the animal, but it did permit development to proceed + for several rounds of cell division, and the pattern of cell division, or cleavage, and embryonic + development always followed the pattern of the phylum to which the egg cytoplasm belonged, never the pattern + of the phylum from which the nucleus was derived. The genes in the nucleus, obviously, weren't directing the + basic pattern formation of the embryo. +

+

+ One-dimensional bacterial genetics can be used to "explain" multidimensional systems, but it can't be + expected to make useful predictions. +

+

+ The idea of complexity, or of multidimensionality, has often been analyzed in terms of "fields," by analogy + with a magnetic field, as some property, or properties, that extend beyond any individual part, giving some + coherence to the parts. Lamarck was concerned with understanding ensembles of particles and cells, but in + his time electricity and heat were the only principles that physics provided that helped to illuminate the + nature of living organisms. At the end of the 19th century, though, the physicist J.C. Bose was noticing + that all of the properties of life that had interested Lamarck and Buffon--irritability, sensation, + contraction, memory, etc.--had their close analogs in non-living substances. Bose, who invented the radio + detector that was the core of Marconi's apparatus, found that, in the presence of an electromagnetic field, + particles of a substance, such as finely powdered metal filings, cohered into a unified whole. An otherwise + invisible, undetectable "field" which in Lamarck's time might have been known as one of the "subtle fluids," + was able to organize a myriad of inert particles into a unified whole. +

+

+ In the early 1920s, Bungenberg de Jong and A.I. Oparin showed how solutions of organic substances could + spontaneously organize themselves into complex systems, with differentiated parts. A Russian embryologist, + Alexander Gurwitsch, found that the parts of an organ or embryo could exert their stimulating or organizing + influence on other cells even through a piece of glass, and by using different types of filter, he + identified ultraweak ultraviolet rays as a medium of communication between cells. F.-A. Popp and others are + currently studying the integrating functions of ultraweak light signals. Guenter Albrecht-Buehler (who has + an interesting website called Cell Intelligence) is investigating the role of pulsed infrared signals in + cell communication. +

+

+ Electrical fields produced by cells, tissues, and organisms have been shown to influence cellular metabolism + and physiology, and to influence growth patterns. Closely associated with cellular electrical fields are + fields or gradients of pH and osmolarity, and all of these fields are known to affect the activity of + enzymes, and so to create environments or fields of particular chemical concentrations. +

+

+ A phenomenon that was well known in the 1930s, when developmental fields were still a familiar part of + scientific discussion, was the "cancer field." Before a cancer developed in a particular area, the area + showed progessive changes, away from normal function and structure, toward the cancer physiology. +

+

+ In the embryonic state, damaged tissues regenerate quickly. The metabolism of an embryo or fetus is highly + oxidative, converting glucose rapidly to carbon dioxide and water. Both carbon dioxide and water are + important regulators of cellular metabolism and function, and the concentrations of both of them decrease + systematically with maturity and aging. Both are involved with the most basic aspects of cellular + sensitivity, responsiveness, and organization. +

+ +

+ To resume the scientific tradition that has "simply vanished," I think we have to recover our ability to + think about organisms generally, leaving aside as many of the concepts of genetics as possible (such as + "gene," "operon," "receptor"; "the gene" has never been more than an ideological artifact), because they so + often falsify the most important issues. The organization of tissues and organs, and their functional + properties, should be the focus of attention, as they were for Lamarck around 1800, and for Johanes Muller, + who in 1840 saw cancer as a problem on the level of tissue, rather than cells. For Lamarck, sensitivity and + movement were the essential properties of the living substance, and J. C. Bose showed reasons for believing + that the characteristics of life were built on related properties of matter itself. +

+

+ Sensitivity, the ability to respond appropriately to the environment, is probably a missing factor in the + development of a tumor. The ability to become quiescent, to quietly participate in the ensemble of cells, is + an essential feature of the sensitivity and responsiveness of the cells of complex organisms. The factors + that support organized appropriate functioning are the factors that help cells to inhibit the excitatory + state. If the keys of an accordion or organ didn't spring back after the musician pressed them, the + instrument would be unplayable. In extreme physiological states, such as epilepsy or malignant hyperthermia, + nerves or muscles become incapable of relaxing. Insomnia and muscle cramps are milder degrees of a defective + relaxation process. Excitoxicity and inflammation describe less generalized cases of a similar process, in + which there is an imbalance between excitation and the restorative ability to stop the excitation. Prolonged + excitation, resulting in excessive fatigue, can cause a cell to disintegrate, in the process of cell death + called apoptosis, "falling away." +

+ +

+ In the experiments of Polezhaev and Filatov, the products of cell disintegration were found to stimulate the + birth of new cells (possibly by blocking a signal that restrains cell division). This process has been found + in every organ that has been examined appropriately. It amounts to a "streaming regeneration" of the + organism, analogous to the progressive creation of Lamarck's view. G. Zajicek has demonstrated an orderly + "streaming" renewal in several organs, and even the oocytes (which in the Weismannian dogma were formed at a + very early stage during embryonic development, and were perfectly isolated from the cells of the mature + body) have recently been shown to be continually regenerated in adult ovaries. +

+

+ "Stem" cells turn out to be ubiquitous, and the failure of regeneration and restoration seems to be + situational. In the 1950s a magazine article described the regeneration of a finger-tip when the wound was + kept enclosed. Decades later, friends (one a child, the other a man in his forties) had accidental + amputations of a finger-tip, down to the cuticle so that no visible nail remained. The boy's mother fitted + his finger with the tube from a ballpoint pen, and the man used an aluminum cigar tube as his "bandage." + Within a few weeks, their fingers had regenerated to their normal shape and length. I think the closed + environment allows the healing tissues to be exposed to a high concentration of carbon dioxide, in + equilibrium with the carbon dioxide in the capillaries, and to a humid atmosphere, regulated by the osmotic + or vapor pressure of the living tissues. +

+ +

+ Under ordinary conditions, the creation of cells and the dissolution of cells should be exactly balanced. + The coordination of these processes requires a high degree of coherence in the organism. +

+

+ Simple increase of water in the vicinity of a cell increases its tendency to multiply, as well as its + excitability, and hypertonicity restrains cell division, and reduces excitability. Carbon dioxide, besides + helping proteins to release water, appears to increase the ability of proteins and cells to respond to + morphogenetic fields. Carbon dioxide is the most universal agent of relaxation, restoration, and + preservation of the ability of cells to respond to signals. Progesterone is another very general agent of + restorative inhibition. +

+

+ The study of regeneration and "stem cells" is helping to illuminate the general process of aging, and to + provide very practical solutions for specific degenerative diseases, as well as providing a context for more + appropriate treatment of traumatic tissue injury. +

+

+ In aging, the growth and regenerative processes are slowed. There is some evidence that even cell death is + slower in old age, at least in some tissues. Since animals with the highest metabolic rate live the longest, + the slowing rate of metabolism during aging probably accounts for those changes in the rate of cell renewal. + The continually streaming regeneration of tissues is part of the adaptive process, and it is probably + intensified by stress. +

+

+ The ability to sleep deeply decreases in old age, as a generalized inflammatory, excitatory state of stress + develops. With progressive weakening of restorative cellular relaxation (inhibition), cells become more + susceptible to disintegration. It's well established that bone loss occurs almost entirely during the night, + and since the catabolic hormones generally affect soft tissues as well as bones, the atrophy of soft tissues + ("sarcopenia") of aging is also probably a process that occurs mostly during the night. Mediators of + inflammation are at their highest during the night (Cutolo and Masi, 2005). But during the period of growth, + the length of bones seems to increase mostly during the night (Noonan, et al., 2004). My interpretation of + this is that the stress of darkness accelerates biological processes, whether the process is mainly + constructive or mainly destructive. +

+ +

+ The effect of light supports efficient oxidative energy production, which supports the protective inhibitory + processes, by increasing ATP and CO2, and decreases the inflammatory mediators that intensify stress. If + organized cellular luminescence is required for a proper balance, then the random luminescence produced by + lipid peroxidation (which may be more intense at night--Diaz-Munoz, et al., 1985), might be an important + factor in disrupting the balanced streaming of regeneration. Free radicals, whatever their source, absorb a + broad spectrum of radiation, and would block luminous signals of all frequencies. Isoprene, produced mainly + at night (Cailleux and Allain, 1989), is another ultraviolet absorber that might account for nocturnal + regulatory disorders. +

+

+ The age pigment, lipofuscin, is known to contribute to degenerative diseases, but the nature of its toxicity + has never been established. Its absorptive and fluorescent properties would be very likely to interfere with + mitogenetic and morphogenetic radiation. Polyunsaturated fats are the main component of lipofuscin, and + these fats in themselves can absorb ultraviolet light. When those fats are present in the skin, exposure to + ultraviolet light accelerates the aging of the skin. Free fatty acids often increase during the night, under + the influence of hormones such as adrenaline and growth hormone. +

+

+ A single night of poor sleep probably causes significant anatomical damage to the streaming cellular systems + that will be repaired over the next few days if a high level of energy metabolism can be combined with a + sufficient amount of deep sleep. The things that optimize energy and sleep form the background for + supporting the restorative processes. Salt, glycine, carbon dioxide, progesterone, thyroid hormone and sugar + all contribute to preserving the organism's energetic reserves by reducing inappropriate excitation. +

+

+ Lamarck's idea that organs developed or regressed according to their use or disuse was often attacked by + followers of the Weismann-Morgan genetic dogma. In their view, the influence of the environment was limited + to either preventing or permitting the realization of "the genetic potential." Once that predefined + potential had been unfolded, the finite and mortal nature of the somatic cells didn't allow for any + significant changes, except for depletion and death. One of the high points of Weismannian biology came with + the publication of an article in Science, around 1970, that proposed to explain learning in terms of the + lifelong loss of brain cells, beginning in humans around the age of 18 months, with a daily loss of 100,000 + cells, which would record experience by selective deletion, the way punching holes in cards had been used to + enter data into computers. I was present to witness "world class biologists" taking that idea very + seriously. +

+ +

+ As Sturtevant mentioned in the quotation above, T.H. Morgan couldn't accept any attribution of + purposefulness to organisms. In his genetic dogma, changes were only random, and people who denied that were + denounced as "teleological" (or metaphysical) thinkers. Changes occurred by deletion, not by meaningful + addition. +

+

+ One of Pavlov's students, P.K. Anokhin, developed the concept of the Functional System in the 1930s, to + explain the purposive behavior of animals. In the 1950s, Anokhin integrated the endocrinology of stress and + adaptation into the concept, and F.Z. Meerson continued the work, concentrating on the metabolic and + structural changes that protect the heart during stress. The simplest view of the conditional reflex + involves the adaptation of an animal to an external signal, identifying it as the occasion for a particular + action. Analyzing the Functional System starts with the need of the animal, for example for food, and + examines the processes that are involved in satisfying that need, including nerve cells, a sense of hunger, + knowledge of what things are edible, the muscles needed to get the food, and the digestive apparatus for + assimilating it. +

+

+ When an understanding of stress physiology is combined with the idea of functional systems, the adaptive + meaning of the use or disuse of certain organs is given a concrete basis. Cortisol mobilizes amino acids + from muscles that are idle, and makes them available for the synthesis of proteins in the muscles, nerves, + or glands that are activated in adapting to the stress. The London taxi drivers whose hippocampus grows as + they learn the locations of the streets are very good examples of the processes described by Meerson, + Anokhin, and Lamarck, in which the use of an organ in meeting a need contributes to the development of that + organ. The balance between growth and regression is shifted during adaptive behavior. +

+

+ Exercise physiologists, without mentioning functional systems, have recently discovered some principles that + extend the discoveries of Meerson and Anokhin. They found that "concentric" contraction, that is, causing + the muscle to contract against resistance, improves the muscle's function, without injuring it. (Walking up + a mountain causes concentric contractions to dominate in the leg muscles. Walking down the mountain injures + the muscles, by stretching them, forcing them to elongate while bearing a load; they call that eccentric + contraction.) Old people, who had extensively damaged mitochondrial DNA, were given a program of concentric + exercise, and as their muscles adapted to the new activity, their mitochondrial DNA was found to have become + normal. +

+ +

+ There are probably the equivalents of constructive "concentric" activity and destructively stressful + "eccentric" activity in the brain. For example, "rote learning" is analogous to eccentric muscle + contraction, and learning by asking questions is "concentric." "No bird soars too high, if he soars with his + own wings." Any activity that seems "programmed" probably stifles cellular energy and cellular intelligence. +

+ +

+ When activity is meaningful, and is seen to be meeting a felt need, the catabolic and anabolic systems + support and strengthen the components of the functional system that has been activated. Everything we do has + an influence on the streaming renewal of the adaptive living substance. +

+

+ There are many therapeutic techniques that could be improved by organized research, for example, + investigating the interactions of increasing carbon dioxide, reducing atmospheric pressure, supplementing + combinations of salt and other minerals, balancing amino acids and sugars, and varying light exposure and + types of activity. The dramatic results that have occasionally been demonstrated (and then suppressed and + forgotten) are just a hint of the possibilities. +

+

+ If we keep our thoughts on the living substance, the pervasive ideologies lose their oppressive power. +

+

REFERENCES

+

+ Chronobiol Int. 2004;21(6):937-47. Postprandial metabolic profiles following meals and snacks eaten + during simulated night and day shift work. +

+

+

+ Anokhin P.K. System mechanisms of higher nervous activity. + Moscow, Nauka, 1979. (In Russian). +

+

+ Life Sci. 1989;44(24):1877-80. Isoprene and sleep. Cailleux A, Allain P. Isoprene is one of + the main constituents of endogenous origin in exhaled human breath. The concentration of isoprene seems to + vary with states of sleep and wakefulness, increasing during sleep and decreasing sharply just after + awakening. Thus, isoprene may be involved in in sleep upholding. +

+ +

+ Exp Neurol. 1978 May 15;60(1):41-55. Evidence of normal mitosis with complete cytokinesis in central nervous + system neurons during sustained depolarization with ouabain. Cone CD Jr, Cone CM. +

+

+ Nat New Biol. 1973 Nov 28;246(152):110-1. Stimulation of DNA synthesis in CNS neurones by sustained + depolarisation. Stillwell EF, Cone CM, Cone CD Jr. +

+

+ J Natl Cancer Inst. 1971 Mar;46(3):655-63. Intercellular transfer of toxic components after laser + irradiation. May JF, Rounds DE, Cone CD. +

+

+ J Theor Biol. 1971 Jan;30(1):151-81. Unified theory on the basic mechanism of normal mitotic control + and oncogenesis. Cone CD Jr. +

+

+ Oncology. 1971;25(2):168-82. Control of somatic cell mitosis by simulated changes in the + transmembrane potential level. Cone CD Jr, Tongier M Jr. +

+ +

+ Acta Cytol. 1969 Oct;13(10):576-82. Autosynchrony and self-induced mitosis in sarcoma cell + networks. Cone CD Jr. +

+

+ Ann N Y Acad Sci. 1980;339:115-31. Ionically mediated induction of mitogenesis in CNS + neurons. Cone CD Jr. +

+

+ Science. 1976 Apr 9;192(4235):155-8. Induction of mitosis in mature neurons in central nervous + system by sustained depolarization. Cone CD Jr, Cone CM. DNA synthesis and mitosis have been + induced in vitro in fully differentiated neurons from the central nervous system by depolarization with a + variety of agents that produce a sustained rise in the intracellular sodium ion concentration and a decrease + in the potassium ion concentration. Depolarization was followed in less than 1 hour by an increase in RNA + synthesis and in 3 hours by initiation of DNA synthesis. Apparently normal nuclear mitosis ensued, but + cytokinesis was not completed in most cells; this resulted in the formation of binucleate neurons. The + daughter nuclei each contained the same amount of DNA as the diploid preinduction parental neurons; this + implies that true mitogenic replication was induced. +

+ +

+ Ann N Y Acad Sci. 1974;238:420-35. The role of the surface electrical transmembrane potential in + normal and malignant mitogenesis. Cone CD Jr. +

+

+ Ann N Y Acad Sci. 1974;238:451-6. Panel discussion: The role of electrical potential at the cellular + level in growth and development. Becker RO, Cone CD, Jaffe LF, Parsegian VA, Pohl HA, Weiss L. +

+

+ J Cell Physiol. 1973 Dec;82(3):373-86. Contact inhibition of division: involvement of the electrical + transmembrane potential. Cone CD Jr, Tongier M Jr. +

+ +

+ J Theor Biol. 1971 Jan;30(1):183-94. Maintenance of mitotic homeostasis in somatic cell + populations. Cone CD Jr. +

+

+ Oncology. 1970;24(6):438-70. Variation of the transmembrane potential level as a basic mechanism of + mitosis control. Cone CD Jr. +

+

+ Trans N Y Acad Sci. 1969 Apr;31(4):404-27. Electroosmotic interactions accompanying mitosis + initation in sarcoma cells in vitro. + + Cone CD Jr. +

+ +

+ Rheum Dis Clin North Am. 2005 Feb;31(1):115-29, ix-x. Circadian rhythms and arthritis. + Cutolo M, Masi AT. +

+

+ Neuroscience. 1985 Dec;16(4):859-63. Day-night cycle of lipid peroxidation in rat cerebral cortex + and their relationship to the glutathione cycle and superoxide dismutase activity. Diaz-Munoz + M, Hernandez-Munoz R, Suarez J, Chagoya de Sanchez V. Lipoperoxidation, glutathione cycle components and + superoxide dismutase activity show a day-night rhythm in the cerebral cortex of the rat. The highest + lipoperoxidative activity is observed during the night (20.00-04.00 h). + + The enhancement in lipoperoxidation occurs concurrently with a decrease in glutathione peroxidase activity, + an increase in superoxide dismutase activity and an increase in the double bonds in the brain cortex lipid + fraction. The changes described in this paper seem to be related to a succession of light and dark periods, + or to fasting and feeding periods. We propose that those fluctuations could act as a physiological + oscillator with an important role in modulating the membrane properties of the nerve cell. +

+

+ Brain Res. 1977 Mar 4;123(1):137-45. Daily variations of various parameters of serotonin metabolism + in the rat brain. + II. Circadian variations in serum and cerebral tryptophan levels: lack of correlation with 5-HT + turnover. + Hery F, Chouvet G, Kan JP, Pujol JF, Glowinski J. Rats submitted to regular 12 h cycles of light + and darkness for three weeks were sacrificed at various times of the day. 5-HT, 5-HIAA and tryptophan levels + were estimated in the fronto-parietal cerebral cortex. Tyrosine and free and total tryptophan levels in + serum were estimated in parallel. Significant circadian variations in 5-HT and 5-HIAA levels were found in + cerebral tissues. The peaks of 5-HIAA levels were dectected during the lignt and dark periods respectively, + the maximal fluctuations being seen between 17.00 h and 21.00 h, two times separating the light off. + Important significant circadian variations in free and total serum tryptophan levels were + also observed. In both cases, the maximal levels were found during the middle of the dark + phase after the peak of 5-HIAA levels. The circadian rhythm of tyrosine levels in serum was in + opposite phase with that of tryptophan (free or total). The diurnal changes in tryptophan content in + cerebral tissues seemed thus related to those found in serum. Taking in consideration results obtained in + previous studies 16,17 carried out in similar experimental conditions, it was concluded that the parallel + increase in serum free tryptophan and in tissues 5-HIAA levels seen during the night were not related to a + stimulation of 5-HT turnover. Indeed 5-HT synthesis is minimal at this time16. +

+ +

+ Kryukov V.I. An attention model based on the principle of dominanta + + // Proceedings in Nonlinear Science. Neurocomputers and Attention. I: Neurobiology, Synchronization, + and Chaos. 1989. Ed. by A.Y. Holden and V.I. Kryukov, pp. 319-351. +

+

+ Endocrinol Exp. 1976 Jun;10(2):131-7. Diurnal variation in the effect of melatonin on plasma and + muscle free fatty acid levels in the pigeon. John TM, George JC. Pigeons maintained on standard + diet and held under 12 h daily photo-period in a controlled environmental room, were given intravenous + injections of melatonin. A low dose (1.25 mg/kg body weight) of melatonin when given in the middle of the + scotophase, produced a significant increase in plasma FFA when estimated at 20 min and 90 min + post-injection, whereas no significant change was seen with injections given in the middle of the + photophase. No significant change in muscle FFA level was obtained either during the photophase or the + scotophase when estimated at 90 min postinjection. With a higher dose (5 mg/kg body weight) of + melatonin given in the scotophase, on the other hand, a significant increase in both plasma as well as + muscle FFA levels was obtained at 90 min post-injection but there was no effect on plasma FFA at 20 min + or 90 min post-injection in the photophase and at 20 min in the scotophase. It is concluded + that + melatonin has a lipid mobilizing action in the pigeon when administered during the scotophase. +

+

+ Exp Brain Res. 2001 Feb;136(3):313-20. Enhanced neurogenesis after transient global ischemia in the + dentate gyrus of the rat. Kee NJ, Preston E, Wojtowicz JM. "Certain insults such as epileptic + seizures and ischemia are known to enhance the rate of neuronal production. We analyzed this phenomenon + using the temporary occlusion of the two carotid arteries combined with arterial hypotension as a method to + induce ischemia in rats. We measured the rate of cell production and their state of differentiation with a + mitotic indicator, bromodeoxyuridine (BrdU), in combination with the immunohistochemical detection of + neuronal markers. One week after the ischemic episode, the cell production in dentate gyrus was increased + two- to threefold more than the basal level seen in control animals. + Two weeks after ischemia, over 60% of these cells became young neurons as determined by colabeling with + BrdU and a cytoplasmic protein (CRMP-4) involved in axonal guidance during development. Five weeks after + the ischemia, over 60% of new neurons expressed calbindin, a calcium-binding protein normally expressed + in mature granule neurons. In addition to more cells being generated, a greater proportion of + all new cells remained in the differentiated but not fully mature state during the 2- to 5-week period after + ischemia." "The results support the hypothesis that survival of dentate gyrus after ischemia is linked with + enhanced neurogenesis. Additional physiological stimulation after ischemia may be exploited to stimulate + maturation of new neurons and to offer new therapeutic strategies for promoting recovery of neuronal + circuitry in the injured brain." +

+

+ Am J Cardiol. 1998 Dec 17;82(12A):24U-28U; discussion 39U-41U. Clinical profiles of plain versus + sustained-release niacin (Niaspan) and the physiologic rationale for nighttime dosing. Knopp + RH. Niacin is the oldest and most versatile agent in use for the treatment of dyslipidemia. It has + beneficial effects on low-density lipoprotein cholesterol; high-density lipoprotein cholesterol; the + apolipoproteins B and A-I constituting these fractions; triglyceride; and lipoprotein(a). Together, these + benefits lead to a diminished incidence of coronary artery disease among niacin users. The chief constraints + against niacin use have been flushing, gastrointestinal discomfort, and metabolic effects including + hepatotoxicity. Time-release niacin has been developed in part to limit flushing, and now a nighttime + formulation (Niaspan) has been developed that assists in containing this untoward effect. In a pivotal + metabolic study, bed-time administration of 1.5 g time-release niacin was shown to have the same beneficial + effects as 1.5 g plain niacin in 3 divided doses and to be well tolerated. Previous studies suggest + that bedtime niacin administration diminishes lipolysis and release of free fatty acids to the + liver; this, in turn, leads to an abolition of the usual diurnal increase in plasma triglyceride, which may + result in diminished formation and secretion of triglyceride in the very-low-density lipoprotein fraction. +

+ +

+ J Pediatr Orthop. 2004 Nov-Dec;24(6):726-31. Growing pains: are they due to increased growth during + recumbency as documented in a lamb model? + + Noonan KJ, Farnum CE, Leiferman EM, Lampl M, Markel MD, Wilsman NJ. +

+

+ Cell Tissue Kinet. 1977 Nov;10(6):557-68. Circadian rhythms of presumptive stem cells in three + different epithelia of the mouse. Potten CS, Al-Barwari SE, Hume WJ, Searle J. +

+

+ Physiol Res. 1995;44(4):249-56. Circadian and circaannual oscillations of tissue lipoperoxides in + rats. Solar P, Toth G, Smajda B, Ahlers I, Ahlersova E. Circadian and circaannual oscillations + of tissue lipid peroxides (LPO) were studied in young male Wistar rats. The concentration of + malondialdehyde, one of LPO degradation products, was measured at 3-h intervals during 24 hours in rats, + adapted to light:dark 12:12 h regimen in the course of the year. LPO in the liver, thymus and bone marrow + oscillated rhythmically in the course of the day and year. Circadian oscillations in all tissues were + two-peaked, with zeniths at various times of the light and dark parts of the day. In the liver and thymus, + the highest mesors were found during the winter, in the bone marrow during the spring. The + same holds for amplitude values, with the exception of the bone marrow which exhibited the highest values + during the summer. The reason for the LPO oscillations is probably resulting from the changing ratio of pro- + and anti-oxidative capacities in various tissues during the day and the year. +

+ +

+ Biofizika. 1976 Jul-Aug;21(4):688-91. [Circadian rhythms of ultraweak chemiluminescence of bean + roots] Sul'tsman FM, Petrusevich IuM, Tarusov BN. Circadian rhythms of ultra-weak + chemoluminescence of bean roots were investigated. It was found that under periodical change of light and + darkness and without subsequent illumination a periodical change of spontaneous chemoluminescence of bean + roots was observed. (The study of antiradical activity of the substances extracted from the root showed the + dependence of this activity on illumination conditions. +

+

+ Ukr Biokhim Zh. 1977 Sep-Oct;49(5):64-9. [Effect of "carbostimulin", vitamin D 3 and their mixture on bone + tissue regeneration] [Article in Ukrainian] Taran TT, Guly MF, Mykhajlovskyj VO, Dvornykova PD, Fanak MM, + Vorobjov NA. "Healing of the bone injury in rabbits was studied as affected by carbostimulin and its mixture + with vitamin D3. Some biochemical indexes: the content of sialic acids, calcium and citric acid in blood + serum of the animals, intensity of 14C incorporation from NaH14CO3 into the regenerated bone tissue and its + proteins as well as histological studies, data, evidence for a positive effect of the mentioned preparations + on the bone substance regeneration in the animals under experiment." +

+

+ Biofizika. 1961;6(4):490-2. [Study on ultra-weak spontaneous luminescence of animal cells.] + Tarusov BN, Polivoda AI, Zhuravlev AI. +

+ +

+ Biofizika. 1961;6(4):83-5. Study of the faint spontaneous luminescence of animal cells. + Tarusov BN, Polivoda AI, Zhuravlev AI. +

+

+ Vopr Med Khim. 1977 May-Jun;(3):375-81. [Free fatty acids and cholesterol as possible participants + in lipid oxidation radical reactions in animal tissues] [Article in Russian] Terekhova SF, + Burlakova EB, Elizarova TI. Alterations in concentration of free fatty acids, free cholesterol, native + antioxidants as well as in the antioxidative activity were studied in lipids of mice liver tissue and small + intestinal mucosa. The intensity of free radical reactions in lipids of animal tissues was affected directly + by administration of synthetic inhibitors of the reactions. The inverse correlation was observed between the + alteration in concentrations of native antioxidants and free fatty acids as well as between the + antioxidative activity of lipids and amount of free cholesterol in them. Free fatty acids appears to + be the constant participants in the system of free radical oxidation of lipids, while cholesterol can + center the system under distinct level of these reactions intensity. +

+

+ Ukhtomsky A.A. Dominanta as factor of behavior // Collected works. + + Leningrad, 1950. Vol.1, pp.293-315. +

+

+ Biofizika. 1974 Mar-Apr;19(2):295-9. + [Formation of pigments of lipid nature in animal tissues during neoplastic growth and irradiation] + + Vertushkov VT, Ivanov II, Tarusov BN. +

+

+ Biofizika. 1967 Jul-Aug;12(4):739-41. [Antioxidative activity of blood serum fractions during + malignant degeneration studied by inhibition of chemiluminescence] + + Zakarian AE, Tarusov BN. +

+

+ Biofizika. 1966;11(5):919-21. [Inhibition of chemiluminescence of the blood plasma in malignant + growth] [Article in Russian] Zakarian AE, Tarusov BN. +

+ +

+ © Ray Peat 2008. All Rights Reserved. www.RayPeat.com +

+ + diff --git a/raypeat-articles/processed/cholesterol-longevity.html b/raypeat-articles/processed/cholesterol-longevity.html new file mode 100644 index 0000000..3924bb7 --- /dev/null +++ b/raypeat-articles/processed/cholesterol-longevity.html @@ -0,0 +1,469 @@ + + Cholesterol, longevity, intelligence, and health. + +

+ Cholesterol, longevity, intelligence, and health. +

+ + + The biological meaning of cholesterol is just starting to be explored. Everything that doctors know about + cholesterol is wrong. New information about cholesterol is clarifying important issues in physiology and + pathology. + + + Medical magazines and television stations like to propagate the idea that cholesterol is bad stuff, and as a + result, that cliche is known to almost every American. Recent journal articles have promoted the idea that "the + lower the serum cholesterol is, the better" it is for the health of the patient. The theory that heart disease + is "caused by cholesterol" has gone through several stages, and most recently the use of the "statin" drugs has + revived it in a radical way. One consistent theme for fifty years has been that people should eat more + polyunsaturated fat and less saturated fat, to lower their cholesterol, and to avoid butter, cream, eggs, and + "red meat," because they contain both saturated fat and cholesterol. Often, medical attention is focused on the + fats in the atheroma, rather than on the whole disease process, including clotting factors, vascular spasms, + heart rhythm, viscosity of the blood, deposition of calcium and iron in blood vessels, and the whole process of + inflammation, including the reactions to absorbed bowel toxins. Almost 100 years ago, some experiments in Russia + showed that feeding rabbits cholesterol caused them to develop atherosclerosis, but subsequent experiments + showed that rabbits are unusual in responding that way to cholesterol, and that even rabbits don't develop + atherosclerosis from cholesterol if they are given a supplement of thyroid (Friedland, 1933). By 1936, it was + clear that hypercholesterolemia in humans and other animals was caused by hypothyroidism, and that + hypothyroidism caused many diseases to develop, including cardiovascular disease and cancer. There was already + more reason at that time to think that the increased cholesterol was a protective adaptation than to think that + it was maladaptive. The strange idea that cholesterol causes atherosclerosis was revived in the 1950s when the + vegetable oil industry learned that their polyunsaturated oils lowered serum cholesterol. (Many other toxins + lower cholesterol, but that is never mentioned.) The industry began advertising their oils as "heart + protective," and they enlisted some influential organizations to help in their advertising: The + American Dietetic Association, the American Heart Association, the US Dept. of Agriculture and FDA, and the AMA. + Besides the early rabbit research, which didn't make their case against cholesterol and might actually have had + implications harmful to their argument (since Anitschkow had used vegetable oil as solvent for his cholesterol + feedings), the oil industry helped to create and promote a large amount of fraudulent and unscientific work. The + death rate from heart disease in the United States began increasing early in the twentieth century, and it + reached its peak from about 1950 to 1975, and then began declining. During the decades in which the death rate + was rising, consumption of animal fat was decreasing, and the use of vegetable oil was increasing. In the + southern European countries that have been said to show that eating very little animal fat prevents heart + disease, the trends after the second world war have been the opposite--they have been eating more animal fat + without an increase in heart disease. The correspondence between heart disease and consumption of saturated fat + and cholesterol is little more than advertising copy. If people were looking for the actual causes of heart + disease, they would consider the factors that changed in the US during the time that heart disease mortality was + increasing. Both increases in harmful factors, and decreases in protective factors would have to be considered. + The consumption of manufactured foods, pollution of air and water, the use of lead in gasoline, cigarette + smoking, increased medicalization and use of drugs, psychosocial and socioeconomic stress, and increased + exposure to radiation--medical, military, and industrial--would be obvious things to consider, along with + decreased intake of some protective nutrients, such as selenium, magnesium, and vitamins. But those harmful + factors all had their defenders: Who defends socioeconomic stress? All of the social + institutions that fail to alleviate it. In 1847, Rudolph Virchow was sent to Poland to study the health + situation there, and when he returned, the highly regarded anatomist, physiologist and pathologist announced + that the Poles wouldn't have a health problem if the government would stop oppressing them, and institute + economic reforms to alleviate their poverty. The reforms weren't made, and Virchow lost his job. Other harmful + factors, such as seed oils, degraded foods, and radiation, have specific, very well organized and powerful + lobbies to defend them. Despite the growing knowledge about the dangers of polyunsaturated fats, many medical + articles are still advocating the "official" heart protective diet (e.g., "... + diets using nonhydrogenated unsaturated fats as the predominant form of dietary fat," Hu and Willet, 2002). Some + dogs alertly look at the thing a person is pointing at, other dogs just sniff the pointing finger. The + publicists who disregard the complete nutritional and ecological situation, to focus on cholesterol and fat in + the diet, are like the finger sniffers. Recent articles in the medical and lipids journals are praising the 1950 + work of J. W. Gofman, and the 1914 rabbit studies of N. N. Anitschkow, as the research that revealed cholesterol + to be the cause of heart disease. Anitschkow and his co-workers, however, understood that their experiment + hadn't explained human heart disease, and John Gofman, about 50 years after publishing his work on the + lipoproteins, has done some large studies that could be crucial in disproving the doctrine that has become + almost a national religion. He has shown that mortality from both heart disease and cancer corresponds very + closely to the population's exposure to medical services, and specifically to medical radiation. During the peak + years of heart disease mortality, medical x-rays gave very large doses of radiation with each exposure, and the + population was also exposed to radioactive fallout from atomic bomb testing (explosions from 1945 to 1963 + produced a peak of heavy fallout that persisted through the 'sixties and into the 'seventies). Around 1971, + someone noticed that the commercial cholesterol being used in feeding experiments was oxidized, that is, it + wasn't really cholesterol. Comparing carefully prepared, unoxidized cholesterol with the oxidized degraded + material, it was found that dietary cholesterol wasn't necessarily atherogenic (Vine, et al., 1998). Dietitians + often recommend eating poached salmon, rather than "red meat," to lower cholesterol. Experimenters have measured + the toxic oxidized cholesterol in different foods prepared in a variety of ways. Steaming salmon produced + several times as much oxidized cholesterol as frying it, because of the longer cooking time that allowed the + polyunsaturated fatty acids to break down, producing toxins such as acrolein and free radicals that oxidize the + cholesterol and other components of the fish. The toxic cholesterol content of the steamed salmon was much + higher than that of beef cooked at a high temperature. When oxidized polyunsaturated oils, such as corn oil or + linoleic acid, are added to food, they appear in the blood lipids, where they accelerate the formation of + cholesterol deposits in arteries (Staprans, et al., 1994, 1996). Stress accelerates the oxidation of the + polyunsaturated fatty acids in the body, so people who consume unsaturated vegetable oils and fish will have + some oxidized cholesterol in their tissues. The constant turnover of cholesterol in the tissues tends to lower + the proportion of the toxic oxidized degradation products of cholesterol, but in hypothyroidism, the use of + cholesterol is slowed, allowing the toxic forms to accumulate. Many antioxidant nutrients act like a thyroid + supplement did in the 1934 rabbit experiments, preventing atherosclerosis even when extra toxic cholesterol is + given to the animals. People who eat seafood get much more selenium in their diet than people who eat nothing + from the sea, and selenium is one of the extremely protective nutrients that prevent atherosclerosis in animal + experiments with excess cholesterol. It is well established that several antioxidant nutrients are protective + factors in heart disease. The medical establishment has expended a great amount of money and time in the last 60 + years fighting the use of vitamin E or selenium for treating or preventing heart disease, though many physicians + now take vitamin E themselves. But people who study free radical chemistry recognize that polyunsaturated fats + are highly susceptible to oxidation, and that saturated fats tend to slow their degradation, acting to some + extent as antioxidants. Several experiments and observations have shown that cholesterol itself can protect + against damaging oxidation of polyunsaturated fats, protecting DNA and other vital components of the cell. A + consistent program to prevent the oxidation of cholesterol would have to include all of the vitamins and + minerals that are involved in antioxidant defense, avoidance of nutrients that exacerbate the destructive + oxidations, and an effort to normalize the hormones and other factors, such as carbon dioxide, that have + protective effects against free radical oxidation. A low level of cholesterol might increase susceptibility to + the oxidants. The steroids in general, especially those produced in large amounts, progesterone and DHEA, are + important parts of the antioxidant defenses. Cholesterol, either that produced internally by the cell, or taken + in from the blood stream, is the precursor for all the steroids in the body. Several of the major steroid + hormones are antiinflammatory, and cholesterol itself is antiinflammatory. (Mikko, et al., 2002; Kreines, et + al., 1990). Cholesterol also protects against radiation damage, and many forms of toxin (saponins, cobra venom, + chloroform--W.G. MacCallum, + A Text-book of + Pathology, 1937, Saunders Co.; many more recent studies show that it protects blood cells against + hemolysis--breakdown of red blood cells--caused by heat and other harmful agents; e.g., Dumas, et al., 2002, + Velardi, et al., 1991). Cholesterol, vitamin E, progesterone, and vitamin D are considered to be "structural + antioxidants," that prevent oxidation partly by stabilizing molecular structures. One of the basic functions of + cholesterol seems to be the stabilization of mitochondria, preventing their destruction by stress. Serious + stress lowers ATP, magnesium, and carbon dioxide. When ATP and intracellular magnesium are decreased, + cholesterol synthesis increases. During stress, free fatty acids are released from the tissues, and circulating + in the bloodstream they are highly susceptible to oxidation. They contribute to the formation of the age + pigment, lipofuscin, which is an oxygen-wasting substance that's found in the atheroma plaques in the damaged + blood vessels. Iron and calcium accumulation adds to the tissue damage. The hemolysis which is promoted by + polyunsaturated fats and an imbalance of antioxidants and oxidants, releases iron and heme into the blood + stream. The incidence of atherosclerosis is increased when the body iron stores are high (Kiechl, et al., 1997), + probably because of its role in lipid peroxidation and lipofuscin formation. Especially when the lining of the + blood vessel is too permeable, because of the influence of polyunsaturated fats, prostaglandins, estrogen, etc., + the heme and iron will enter the endothelial cells, where the iron will catalyze the formation of free radicals, + and the heme will be broken down by the enzyme heme oxygenase, into biliverdin, iron, and carbon monoxide, which + can contribute to the oxidative stress of the cells. Carbon monoxide makes the blood vessel lining more + permeable, allowing fats and fibrinogen to enter the cells (Allen, et al., 1988). Although cholesterol is + protective against oxidative and cytolytic damage, the chronic free radical exposure will oxidize it. During the + low cholesterol turnover of hypothyroidism, the oxidized variants of cholesterol will accumulate, so cholesterol + loses its protective functions. When the metabolic pathways of the steroid hormones were being worked out, an + experimenter perfused an isolated ovary with blood. When the amount of cholesterol in the blood pumped into the + ovary was increased, the amount of progesterone in the blood leaving the ovary increased proportionately. In the + healthy organism, cholesterol is constantly being synthesized, and constantly converted into steroid hormones, + and, in the liver, into the bile salts that are secreted to emulsify fats in the intestine. Thyroid hormone and + vitamin A are used in the process of converting cholesterol into pregnenolone, the immediate precursor of + progesterone and DHEA. Anything that interfered with these processes would be disastrous for the organism. The + supply of cholesterol, thyroid and vitamin A must always be adequate for the production of steroid hormones and + bile salts. When stress suppresses thyroid activity, increased cholesterol probably compensates to some extent + by permitting more progesterone to be synthesized. In very young people, the metabolic rate is very high, and + the rapid conversion of cholesterol into pregnenolone, DHEA, and progesterone usually keeps the level of + cholesterol in the blood low. In the 1930s, a rise in the concentration of cholesterol was considered to be one + of the most reliable ways to diagnose hypothyroidism (1936 Yearbook of Neurology, Psychiatry, and + Endocrinology, E.L. Sevringhaus, editor, Chicago, p. 533). With aging, the metabolic rate declines, and + the increase of cholesterol with aging is probably a spontaneous regulatory process, supporting the synthesis of + the protective steroids, especially the neurosteroids in the brain and retina. Many people refer to the + structural importance of cholesterol for "membranes," and often imply that the membranes are just at the surface + of the cell (the plasma membrane). But in fact cholesterol is found in the nucleus in the chromosomes, bound to + DNA and in the nuclear matrix that governs the activation of genes, and in the mitotic spindle, which regulates + separation of the chromosomes during cell division: without sufficient cholesterol, cells + divide irregularly, producing aneuploid daughter cells (i.e., they have an abnormal number of chromosomes). + Aneuploidy is now coming to be recognized as an essential feature of cancer cells. A significant amount of + cholesterol was recently discovered to bind to hemoglobin, suggesting that it will be found in association with + many other types of protein, when it occurs to anyone to look for it. Osmotic regulation, which is closely + involved in cell division and other functions, appears to require cholesterol synthesis. Around 1985, a big + study in Hungary showed that lowering cholesterol with drugs caused a huge increase in the cancer death rate. + Hundreds of publications appeared in the U.S. saying that wasn't possible, because low cholesterol is good, the + lower the better. The extreme increase in cancer mortality in the Hungarian study was probably the result of the + drug that was commonly used at that time to lower cholesterol, but the pattern of mortality in that study was + approximately the same pattern seen in any group with very low cholesterol. In the last 20 years, there have + been many studies showing that lowering cholesterol increases mortality, especially from cancer and suicide, and + that people with naturally low cholesterol are more likely to die from cancer, suicide, trauma, and infections + than people with normal or higher than average cholesterol. The increased mortality from accidents and suicide + when cholesterol is lowered is reminiscent of the problems seen in progesterone deficiency, and it's very likely + that a deficiency of the neurosteroids accounts for it. A deficiency of progesterone and other neurosteroids + (the steroids synthesized by the nerves themselves) causes depression of mood and impaired learning ability, + among other neurological changes. As was the case with cancer, the pharmaceutical industry continues to deny + that their anticholesterol drugs cause suicide, depression, and dementia, but there is a large amount of + evidence from human as well as animal studies showing that mood and intelligence are depressed by lowering + cholesterol. Simply injecting cholesterol into animals can improve their learning ability. In the Framingham + heart study of 1894 people extending over a period of about 20 years, people with cholesterol naturally in the + "desirable" range, below 200 mg.%, scored lower on "verbal fluency, attention/concentration, abstract reasoning, + and a composite score measuring multiple cognitive domains" than those with higher cholesterol (Elias, et al., + 2005). +
+ + The next step in studies of this sort should be to see how the combination of extra thyroid with adequate + cholesterol influences longevity. The rising cholesterol that commonly occurs with aging is probably only + partial compensation for declining thyroid function, and by optimizing all of the protective factors, radical + changes in the aging process may be possible. In the roundworm C. elegans, which is now a very popular animal + for testing aging theories, because its genes and cells have been thoroughly "mapped," it was recently found + that adding a gene that simply allows it to synthesize cholesterol, rather than depending on food for its + sterols, increased its life span by as much as 131% (Lee, et al., 2005). That would be like increasing the human + lifespan to about 175 years. These worms are also more resistant than normal to radiation and heat stress. The + cells of the thymus are extremely sensitive to radiation and other stressors, and their enrichment with + cholesterol inhibits lipid peroxidation, DNA degradation, and death in response to radiation (Posokhov, et al., + 1992). Many high altitude regions of the world have high levels of background radiation, from minerals as well + as cosmic rays, so it has been dogmatically believed that mortality from cancer and heart disease would increase + with altitude, but the reverse is true. Because oxygen at lower pressure displaces less carbon dioxide from the + blood, the body is able to retain more carbon dioxide at high altitude. Carbon dioxide protects against free + radicals, and also helps to deliver oxygen to tissues, to maintain efficient energy production, and to prevent + cellular stress. One study found 18 times higher incidence of hypertension in low altitude populations than in + high altitude people (Fiori, et al., 2000). For many years, these principles have been applied in treating + atherosclerosis and other degenerative diseases, in high altitude health resorts. Even a short period of hypoxic + treatment can improve the body's ability to eliminate atherogenic lipid peroxides, possibly by improving the + stress-resistant functions of the liver (Meerson, et al., 1988; Aleshin, et al., 1993; Kitaev, et al., 1999). I + think editors of medical journals generally see themselves as the purveyors of enlightenment, i.e., as the + pushers of the stylish and prestigious doctrines. (Selectivity of evidence to serve the received doctrine is the + commonest form of scientific dishonesty.) But because their mental framework is culturally narrow, they + sometimes publish things which later could turn out to be embarrassing (if inconsistency could embarrass such + types). The recent discovery that the size of the LDL particle is a predominant factor in the development of + atherosclerosis is one of those things that the editors and medical professors should find embarrassing. Smaller + lipoprotein particles have a greater surface area exposed to the oxidative factors in the serum, and so are more + rapidly degraded into toxic substances. People with larger LDL particles are remarkably resistant to heart + disease, and the drug companies are looking for a way to turn their lipoproteins into products. But the + conditions that govern the size of the LDL particles are physically and chemically reasonable, and are causing + confusion among the doctinaire. There have been several studies in India showing that consumption of butter and + ghee is associated with a low incidence of heart disease; for example, according to one study, people in the + north eat 19 times more fat (mostly butter and ghee) than in the south, yet the incidence of heart disease is + seven times higher in the south. A study in Sweden found that the fatty acids in milk products are associated + with larger LDL particles (Sjogren, et al., 2004). In a 35 day study, when butter (20% of the calories) was + compared to various kinds of margarine (with more trans fatty acids) in a similar quantity, the LDL particles + were bigger on the butter diet (Mauger, et al., 2003). But in a study of the habitual diet of 414 people, large + LDL particles were found to be correlated with increased intake of protein, animal fat, and trans fatty acids + (Kim and Campos, 2003). In a study of the effect of dietary cholesterol on the atherogenicity of the blood + lipids, 52 people were given either an egg diet (with 640 mg. of extra cholesterol per day) or a placebo diet + for 30 days. Those whose LDL increased the most on the high cholesterol diet had the largest LDL particle size + (Herron, et al., 2004). They concluded that "these data indicate that the consumption of a high-cholesterol diet + does not negatively influence the atherogenicity of the LDL particle." A similar study in Mexico found that + "Intake of 2 eggs/d results in the maintenance of LDL:HDL and in the generation of a less atherogenic LDL in + this population of Mexican children" (Ballesteros, et al., 2004). The estrogen industry tried to get into the + heart disease business several times over the last half century, and they are still trying, but the issue of + estrogen's harmful effects on LDL particle size is getting some attention. Estrogen clearly decreases the size + of the LDL particles (Campos, et al., 1997). The LDL particles also get smaller at menopause, and in polycystic + ovary syndrome, and in preeclamptic pregnancies, all of which involve a low ratio of progesterone to estrogen. + But there are still journals publishing claims that estrogen will protect against heart disease, by reducing the + atherogenic response in increasingly mysterious ways. Occasionally, people have argued not only that estrogen is + the factor that protects women against heart attacks, but that androgens predispose men to heart disease. One of + their arguments has been that androgens lower HDL, the "good" form of cholesterol. However, there are many + studies that show that testosterone and DHEA (Arad, et al., 1989) are protective against atherosclerosis. The + LDL particle size is increased by androgens, and postprandial triglyceridemia is decreased (Hislop, et al., + 2001). The studies in the 1930s that showed the protective effects of thyroid hormone against atherosclerosis + and heart disease have sometimes been interpreted to mean that the thyroid is protective because + it lowers the cholesterol, but since cholesterol is protective, rather than harmful, something else explains the + protective effect. Ever since the time of Virchow, who called atherosclerosis arteritis + deformans, + the inflammatory nature of the problem has been clear to those who aren't crazed by the anticholesterol cult. We + are all subject to a variable degree of inflammatory stimulation from the endotoxin absorbed from the intestine, + but a healthy liver normally prevents it from reaching the general circulation, and produces a variety of + protective factors. The HDL lipoprotein is one of these, which protects against inflammation by binding + bacterial endotoxins that have reached the bloodstream. (Things that increase absorption of endotoxin--exercise, + estrogen, ethanol--cause HDL to rise.) Chylomicrons and VLDL also absorb, bind, and help to eliminate + endotoxins. All sorts of stress and malnutrition increase the tendency of endotoxin to leak into the + bloodstream. Thyroid hormone, by increasing the turnover of cholesterol and its conversion into the protective + steroids, is a major factor in keeping the inflammatory processes under control. In hypothyroidism, the + pituitary secretes more TSH to activate the thyroid gland, but TSH itself has a variety of pro-inflammatory + actions. The C-reactive protein (CRP), which is recognized as a factor contributing to atherosclerosis, is + increased in association with TSH. CRP activates mast cells, which are found in the atheroma plaques, to produce + a variety of pro-inflammatory substances, including histamine. The belief that cells are controlled by a plasma + membrane, and that cholesterol's main function is to participate in that membrane, has led to a culture that + treats cholesterol physiology with little curiosity. A different perspective on the cell starts with a + recognition of the lipophilic nature of the structural proteins (not "membrane proteins," but things like + cytoskeleton-cytoplasmic ground substance, spindle, centrosome-centrioles, nuclear matrix, etc.), with which + lipids interact. Modifying an extremely complex system, the living substance, cholesterol participates in + complexity, and must be investigated with subtlety. I suspect that the physiological meaning of cholesterol has + to do with movement, stability, differentiation, memory, and sensitivity of the parts of the cells, that is, + with everything physiological. The functions of cholesterol parallel the functions of other sterols in plants + and other types of organism. Its functions have been refined and extended with the development of other + steroids, such as progesterone, as biological requirements have evolved, but cholesterol is still at the center + of this system. To deliberately interfere with its synthesis, as contemporary medicine does, reveals a terrible + arrogance. Many participants in the cholesterol-lowering cult believe that they have succeeded in hijacking our + science culture, but when the patents on another generation of their drugs have expired, the cult could begin to + fade away. + +

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+ + © Ray Peat Ph.D. 2007. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/co2.html b/raypeat-articles/processed/co2.html new file mode 100644 index 0000000..6375214 --- /dev/null +++ b/raypeat-articles/processed/co2.html @@ -0,0 +1,564 @@ + + Protective CO2 and aging + +

+ Protective CO2 and aging +

+ +

+

+ The therapeutic effects of increasing carbon dioxide are being more widely recognized in recent years. Even + Jane Brody, the NY Times writer on health topics, has favorably mentioned the use of the Buteyko method for + asthma, and the idea of "permissive hypercapnia" during mechanical ventilation, to prevent lung damage from + excess oxygen, has been discussed in medical journals. But still very few biologists recognize its role as a + fundamental, universal protective factor. I think it will be helpful to consider some of the ways carbon + dioxide might be controlling situations that otherwise are poorly understood. +

+ +

+ The brain has a high rate of oxidative metabolism, and so it forms a very large proportion of the carbon + dioxide produced by an organism. It also governs, to a great extent, the metabolism of other tissues, + including their consumption of oxygen and production of carbon dioxide or lactic acid. Within a particular + species, the rate of oxygen consumption increases in proportion to brain size, rather than body weight. + Between very different species, the role of the brain in metabolism is even more obvious, since the resting + metabolic rate corresponds to the size of the brain. For example, a cat's brain is about the size of a + crocodile's, and their oxygen consumption at rest is similar, despite their tremendous difference in body + size. +

+

+ Stress has to be understood as a process that develops in time, and the brain (especially the neocortex and + the frontal lobes) organizes the adaptive and developmental processes in both the spatial and temporal + dimensions. The meaning of a situation influences the way the organism responds. For example, the stress of + being restrained for a long time can cause major gastrointestinal bleeding and ulcerization, but if the + animal has the opportunity to bite something during the stress (signifying its ability to fight back, and + the possibility of escape) it can avoid the stress ulcers. +

+

+ The patterning of the nervous activity throughout the body governs the local ability to produce carbon + dioxide. When the cortex of the brain is damaged or removed, an animal becomes rigid, so the cortex is + considered to have a "tonic inhibitory action" on the body. But when the nerves are removed from a muscle + (for example, by disease or accident), the muscle goes into a state of constant activity, and its ability to + oxidize glucose and produce carbon dioxide is reduced, while its oxidation of fatty acids persists, + increasing the production of toxic oxidative fragments of the fatty acids, which contributes to the muscle's + atrophy. +

+

+ The organism's intentions, expectations, or plans, are represented in the nervous system as a greater + readiness for action, and in the organs and tissues controlled by the nerves, as an increase or decrease of + oxidative efficiency, analogous to the differences between innervated and denervated muscles. This pattern + in the nervous system has been called "the acceptor of action," because it is continually being compared + with the actual situation, and being refined as the situation is evaluated. The state of the organism, under + the influence of a particular acceptor of action, is called a "functional system," including all the + components of the organism that participate most directly in realizing the intended adaptive action. +

+

+ The actions of nerves can be considered anabolic, because during a stressful situation in which the + catabolic hormones of adaption, e.g., cortisol, increase, the tissues of the functional system are + protected, and while idle tissues may undergo autophagy or other form of involution, the needs of the active + tissues are supplied with nutrients from their breakdown, allowing them to change and, when necessary, grow + in size or complexity. +

+ +

+ The brain's role in protecting against injury by stress, when it sees a course of action, has a parallel in + the differences between concentric (positive, muscle shortening) and eccentric (negative, lengthening under + tension) exercise, and also with the differences between innervated and denervated muscles. In eccentric + exercise and denervation, less oxygen is used and less carbon dioxide is produced, while lactic acid + increases, displacing carbon dioxide, and more fat is oxidized. Prolonged stress similarly decreases carbon + dioxide and increases lactate, while increasing the use of fat. +

+

+ Darkness is stressful and catabolic. For example, in aging people, the morning urine contains nearly all of + the calcium lost during the 24 hour period, and mitochondria are especially sensitive to the destructive + effects of darkness. Sleep reduces the destructive catabolic effects of darkness. During the + rapid-eye-movement (dreaming) phase of sleep, breathing is inhibited, and the level of carbon dioxide in the + tissues accumulates. In restful sleep, the oxygen tension is frequently low enough, and the carbon dioxide + tension high enough, to trigger the multiplication of stem cells and mitochondria. +

+

+ Dreams represent the "acceptor of action" operating independently of the sensory information that it + normally interacts with. During dreams, the brain (using a system called the Ascending Reticular Activating + System) disconnects itself from the sensory systems. I think this is the nervous equivalent of + concentric/positive muscle activity, in the sense that the brain is in control of its actions. The active, + dreaming phase of sleep occurs more frequently in the later part of the night, as morning approaches. This + is the more stressful part of the night, with cortisol and some other stress hormones reaching a peak at + dawn, so it would be reasonable for the brain's defensive processes to be most active at that time. The + dreaming process in the brain is associated with deep muscle relaxation, which is probably associated with + the trophic (restorative) actions of the nerves. +

+

+ In ancient China the Taoists were concerned with longevity, and according to Joseph Needham (Science and + Civilization in China) their methods included the use of herbs, minerals, and steroids extracted + from the urine of children. Some of those who claimed extreme longevity practiced controlled breathing and + tai chi (involving imagery, movement, and breating), typically in the early morning hours, when stress + reduction is most important. As far as I know, there are no studies of carbon dioxide levels in + practitioners of tai chi, but the sensation of warmth they typically report suggests that it involves + hypoventilation. +

+

+ In the 1960s, a Russian researcher examined hospital records of measurements of newborn babies, and found + that for several decades the size of their heads had been increasing. He suggested that it might be the + result of increasing atmospheric carbon dioxide. +

+ +

+ The experiences and nutrition of a pregnant animal are known to affect the expression of genes in the + offspring, affecting such things as allergies, metabolic rate, brain size, and intelligence. Miles Storfer + (1999) has reviewed the evidence for epigenetic environmental control of brain size and intelligence. The + main mechanisms of epigenetic effects or "imprinting" are now known to involve methylation and acetylation + of the chromosomes (DNA and histones). +

+

+ Certain kinds of behavior, as well as nutrition and other environmental factors, increase the production and + retention of carbon dioxide. The normal intrauterine level of carbon dioxide is high, and it can be + increased or decreased by changes in the mother's physiology. The effects of carbon dioxide on many + biological processes involving methylation and acetylation of the genetic material suggest that the + concentration of carbon dioxide during gestation might regulate the degree to which parental imprinting will + persist in the developing fetus. There is some evidence of increased demethylation associated with the low + level of oxygen in the uterus (Wellman, et al., 2008). A high metabolic rate and production of carbon + dioxide would increase the adaptability of the new organism, by decreasing the limiting genetic imprints. +

+

+ A quick reduction of carbon dioxide caused by hyperventilation can provoke an epileptic seizure, and can + increase muscle spasms and vascular leakiness, and (by releasing serotonin and histamine) contribute to + inflammation and clotting disorders. On a slightly longer time scale, a reduction of carbon dioxide can + increase the production of lactic acid, which is a promoter of inflammation and fibrosis. A prolonged + decrease in carbon dioxide can increase the susceptibility of proteins to glycation (the addition of + aldehydes, from polyunsaturated fat peroxidation or methylglyoxal from lactate metabolism, to amino groups), + and a similar process is likely to contribute to the methylation of histones, a process that increases with + aging. Histones regulate genetic activity. +

+

+ With aging, DNA methylation is increased (Bork, et al., 2009). I suggest that methylation stabilizes + and protects cells when growth and regeneration aren't possible (and that it's likely to increase when + CO2 isn't available). + + + Hibernation (Morin and Storey, 2009) and sporulation (Ruiz-Herrera, 1994; Clancy, et al., 2002) appear to + use methylation protectively. +

+

+ Parental stress, prenatal stress, early life stress, and even stress in adulthood contribute to "imprinting + of the genes," partly through methylation of DNA and the histones. +

+

+ Methionine and choline are the main dietary sources of methyl donors. Restriction of methionine has many + protective effects, including increased average (42%) and maximum (44%) longevity in rats (Richie, et al., + 1994). Restriction of methyl donors causes demethylation of DNA (Epner, 2001). + The age accelerating effect of methionine might be related to disturbing the methylation balance, + inappropriately suppressing cellular activity. Besides its effect on the methyl pool, methionine inhibits + thyroid function and damages mitochondria. +

+

+ The local concentration of carbon dioxide in specific tissues and organs can be adjusted by nervous and + hormonal activation or inhibition of the carbonic anhydrase enzymes, that accelerate the oonversion of CO2 + to carbonic acid, H2CO3. The activity of carbonic anhydrase can determine the density and strength of the + skeleton, the excitability of nerves, the accumulation of water, and can regulate the structure and function + of the tissues and organs. +

+

+ Ordinarily, carbon dioxide and bicarbonate are thought of only in relation to the regulation of pH, and only + in a very general way. Because of the importance of keeping the pH of the blood within a narrow range, + carbon dioxide is commonly thought of as a toxin, because an excess can cause unconsciousness and acidosis. + But increasing carbon dioxide doesn't necessarily cause acidosis, and acidosis caused by carbon dioxide + isn't as harmful as lactic acidosis. +

+ +

+ Frogs and toads, being amphibians, are especially dependent on water, and in deserts or areas with a dry + season they can survive a prolonged dry period by burrowing into mud or sand. Since they may be buried 10 or + 11 inches below the surface, they are rarely found, and so haven't been extensively studied. In species that + live in the California desert, they have been known to survive 5 years of burial without rainfall, despite a + moderately warm average temperature of their surroundings. One of their known adaptations is to produce a + high level of urea, allowing them to osmotically absorb and retain water. (Very old people sometimes have + extremely high urea and osmotic tension.) +

+

+ Some laboratory studies show that as a toad burrows into mud, the amount of carbon dioxide in its tissues + increases. Their skin normally functions like a lung, exchanging oxygen for carbon dioxide. If the toad's + nostrils are at the surface of the mud, as dormancy begins its breathing will gradually slow, increasing the + carbon dioxide even more. Despite the increasing carbon dioxide, the pH is kept stable by an increase of + bicarbonate (Boutilier, et al., 1979). A similar increase of bicarbonate has been observed in hibernating + hamsters and doormice. +

+

+ Thinking about the long dormancy of frogs reminded me of a newspaper story I read in the 1950s. Workers + breaking up an old concrete structure found a dormant toad enclosed in the concrete, and it revived soon + after being released. The concrete had been poured decades earlier. +

+

+ Although systematic study of frogs or toads during their natural buried estivation has been very limited, + there have been many reports of accidental discoveries that suggest that the dormant state might be extended + indefinitely if conditions are favorable. Carbon dioxide has antioxidant effects, and many other stabilizing + actions, including protection against hypoxia and the excitatory effects of intracellular calcium and + inflammation (Baev, et al., 1978, 1995; Bari, et al., 1996; Brzecka, 2007; Kogan, et al., 1994; Malyshev, et + al., 1995). +

+

+ When mitochondria are "uncoupled," they produce more carbon dioxide than normal, and the mitochondria + produce fewer free radicals. Animals with uncoupled mitochondria live longer than animals with the ordinary, + more efficient mitochondria, that produce more reactive oxidative fragments. One effect of the high rate of + oxidation of the uncoupled mitochondria is that they can eliminate polyunsatured fatty acids that might + otherwise be integrated into tissue structures, or function as inappropriate regulatory signals. +

+ +

+ Birds have a higher metabolic rate than mammals of the same size, and live longer. Their tissues contain + fewer of the highly unsaturated fatty acids. Queen bees, which live many times longer than worker bees, have + mainly monounsaturated fats in their tissues, while the tissues of the short-lived worker bees, receiving a + different diet, within a couple of weeks of hatching will contain highly unsaturated fats. +

+

+ Bats have a very high metabolic rate, and an extremely long lifespan for an animal of their size. While most + animals of their small size live only a few years, many bats live a few decades. Bat caves usually have + slightly more carbon dioxide than the outside atmosphere, but they usually contain a large amount of + ammonia, and bats maintain a high serum level of carbon dioxide, which protects them from the otherwise + toxic effects of the ammonia. +

+

+ The naked mole rat, another small animal with an extremely long lifespan (in captivity they have lived up to + 30 years, 9 or 10 times longer than mice of the same size) has a low basal metabolic rate, but I think + measurements made in laboratories might not represent their metabolic rate in their natural habitat. They + live in burrows that are kept closed, so the percentage of oxygen is lower than in the outside air, and the + percentage of carbon dioxide ranges from 0.2% to 5% (atmospheric CO2 is about 0.038). The temperature and + humidity in their burrows can be extremely high, and to be very meaningful their metabolic rate would have + to be measured when their body temperature is raised by the heat in the burrow. +

+

+ When they have been studied in Europe and the US, there has been no investigation of the effect of altitude + on their metabolism, and these animals are native to the high plains of Kenya and Ethiopia, where the low + atmospheric pressure would be likely to increase the level of carbon dioxide in their tissues. Consequently, + I doubt that the longevity seen in laboratory situations accurately reflects the longevity of the animals in + their normal habitat. +

+

+ Besides living in a closed space with a high carbon dioxide content, mole rats have another similarity to + bees. In each colony, there is only one female that reproduces, the queen, and, like a queen bee, she is the + largest individual in the colony. In beehives, the workers carefully regulate the carbon dioxide + concentration, which varies from about 0.2% to 6%, similar to that of the mole rat colony. A high carbon + dioxide content activates the ovaries of a queen bee, increasing her fertility. +

+

+ Since queen bees and mole rats live in the dark, I think their high carbon dioxide compensates for the lack + of light. (Both light and CO2 help to maintain oxidative metabolism and inhibit lactic acid formation.) Mole + rats are believed to sleep very little. During the night, normal people tolerate more CO2, and so breathe + less, especially near morning, with increased active dreaming sleep. +

+ +

+ A mole rat has never been known to develop cancer. Their serum C-reactive protein is extremely low, + indicating that they are resistant to inflammation. In humans and other animals that are susceptible to + cancer, one of the genes that is likely to be silenced by stress, aging, and methylation is p53, a + tumor-suppressor gene. +

+

+ If the intrauterine experience, with low oxygen and high carbon dioxide, serves to "reprogram" cells to + remove the accumulated effects of age and stress, and so to maximize the developmental potential of the new + organism, a life that's lived with nearly those levels of oxygen and carbon dioxide might be able to avoid + the progressive silencing of genes and loss of function that cause aging and degenerative diseases. +

+

+ Several diseases and syndromes are now thought to involve abnormal methylation of genes. Prader-Willi + sydrome, Angelman's syndrome, and various "autistic spectrum disorders," as well as post-traumatic stress + disorder and several kinds of cancer seem to involve excess methylation. +

+

+ Moderate methionine restriction (for example, using gelatin regularly in the diet) might be practical, but + if increased carbon dioxide can activate the demethylase enzymes in a controlled way, it might be a useful + treatment for the degenerative diseases and for aging itself. +

+

+ The low carbon dioxide production of hypothyroidism (e.g., Lee and Levine, 1999), and the respiratory + alkalosis of estrogen excess, are often overlooked. An adequate supply of calcium, and sometimes + supplementation of salt and baking soda, can increase the tissue content of CO2. +

+ +

REFERENCES

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+ Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E621-7. Uncoupling protein-2 regulates lifespan in + mice. Andrews ZB, Horvath TL. +

+

+ Fiziol Zh SSSR 1978 Oct;64(10):1456-62. [Role of CO2 fixation in increasing the body's resistance to + acute hypoxia]. Baev VI, Vasil'ev VV, Nikolaeva EN. In rats, the phenomenon of considerable + increase in resistance to acute hypoxia observed after 2-hour stay under conditions of gradually increasing + concentration of CO2, decreasing concentration of O2, and external cooling at 2--3 degrees seems to be based + mainly on changes in concentration of CO2 (ACCORDINGLY, PCO2 and other forms of CO2 in the blood). The high + resistance to acute hypoxia develops as well after subcutaneous or i.v. administration of 1.0 ml of water + solution (169.2 mg/200 g) NaHCO2, (NH4)2SO4, MgSO4, MnSO4, and ZnSO4 (in proportion: 35 : 5 : 2 : 0.15 : + 0.15, resp.) or after 1-hour effect of increased hypercapnia and hypoxia without cooling. +

+ +

+ Fiziol Zh Im I M Sechenova 1995 Feb;81(2):47-52. + [The unknown physiological role of carbon dioxide]. Baev VI, Vasil'eva IV, L'vov SN, Shugalei + IV [The data suggests that carbon dioxide is a natural element of the organism antioxidant defence system. + ion poisoning]. +

+

+ Stroke. 1996 Sep;27(9):1634-9; discussion 1639-40. Differential effects of short-term hypoxia and + hypercapnia on N-methyl-D-aspartate-induced cerebral vasodilatation in piglets. Bari F, Errico + RA, Louis TM, Busija DW. +

+

+ Vojnosanit Pregl. 1996 Jul-Aug;53(4):261-74. [Carbon dioxide inhibits the generation of active forms + of oxygen in human and animal cells and the significance of the phenomenon in biology and + medicine] [Article in Serbian] Boljevic S, Kogan AH, Gracev SV, Jelisejeva SV, Daniljak IG. +

+ +

+ J Exp Biol. 1979 Oct;82:357-65. Acid-base relationships in the blood of the toad, Bufo marinus. III. + The effects of burrowing. + + Boutilier RG, Randall DJ, Shelton G, Toews DP. +

+

+ Acta Neurobiol Exp (Wars). 2007;67(2):197-206. Role of hypercapnia in brain oxygenation in + sleep-disordered breathing. Brzecka A. Adaptive mechanisms may diminish the detrimental effects + of recurrent nocturnal hypoxia in obstructive sleep apnea (OSA). The potential role of elevated carbon + dioxide (CO2) in improving brain oxygenation in the patients with severe OSA syndrome is discussed. CO2 + increases oxygen uptake by its influence on the regulation of alveolar ventilation and ventilation-perfusion + matching, facilitates oxygen delivery to the tissues by changing the affinity of oxygen to hemoglobin, and + increases cerebral blood flow by effects on arterial blood pressure and on cerebral vessels. Recent clinical + studies show improved brain oxygenation when hypoxia is combined with hypercapnia. Anti-inflammatory and + protective against organ injury properties of CO2 may also have therapeutic importance. These biological + effects of hypercapnia may improve brain oxygenation under hypoxic conditions. This may be especially + important in patients with severe OSA syndrome. +

+

+ Ageing Res Rev. 2009 Oct;8(4):268-76. Epub 2009 Apr 1. The role of epigenetics in aging and + age-related diseases. Calvanese V, Lara E, Kahn A, Fraga MF. +

+ +

+ Rev Esp Geriatr Gerontol. 2009 Jul-Aug;44(4):194-9. Epub 2009 Jul 3. + [Effect of restricting amino acids except methionine on mitochondrial oxidative stress.] + [Article in Spanish] Caro P, G"mez J, S"nchez I, L"pez-Torres M, Barja G. +

+

+ Cell Metab. 2007 Jan;5(1):21-33. A central thermogenic-like mechanism in feeding regulation: an + interplay between arcuate nucleus T3 and UCP2. + Coppola A, Liu ZW, Andrews ZB, Paradis E, Roy MC, Friedman JM, Ricquier D, Richard D, Horvath TL, Gao XB, + Diano S. +

+

+ Ter Arkh. 1995;67(3):23-6. [Changes in the sensitivity of leukocytes to the inhibiting effect of CO2 + on their generation of active forms of oxygen in bronchial asthma patients] Daniliak IG, Kogan + AKh, Sumarokov AV, Bolevich S. +

+ +

+ Cell Metab. 2007 Dec;6(6):497-505. Respiratory uncoupling in skeletal muscle delays death and + diminishes age-related disease. Gates AC, Bernal-Mizrachi C, Chinault SL, Feng C, Schneider JG, + Coleman T, Malone JP, Townsend RR, Chakravarthy MV, Semenkovich CF. +

+

+ Endocr Pract. 2009 Jun 2:1-13. + Fibrotic Appearance of Lungs in Severe Hypothyroidism is Reversible with Thyroxine Replacement. + George JT, Thow JC, Rodger KA, Mannion R, Jayagopal V. +

+

+ J Bioenerg Biomembr. 2009 Jun;41(3):309-21. Epub 2009 Jul 25. Effect of methionine dietary + supplementation on mitochondrial oxygen radical generation and oxidative DNA damage in rat liver and + heart. + + + Gomez J, Caro P, Sanchez I, Naudi A, Jove M, Portero-Otin M, Lopez-Torres M, Pamplona R, Barja G. +

+

+ Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7612-7. Increased tricarboxylic acid cycle flux in rat + brain during forepaw stimulation detected with 1H[13C]NMR. + Hyder F, Chase JR, Behar KL, Mason GF, Siddeek M, Rothman DL, Shulman RG. +

+

+ Can J Neurol Sci. 1979 May;6(2):105-12. The effects of partial chronic denervation on forearm + metabolism. Karpati G, Klassen G, Tanser P. +

+

+ Biull Eksp Biol Med. 1994 Oct;118(10):395-8. + [CO2--a natural inhibitor of active oxygen form generation by phagocytes] Kogan AKh, Manuilov + BM, Grachev SV, Bolevich S, Tsypin AB, Daniliak IG. +

+ +

+ Izv Akad Nauk Ser Biol. 1997 Mar-Apr;(2):204-17. + [Carbon dioxide--a universal inhibitor of the generation of active oxygen forms by cells (deciphering + one enigma of evolution)] + + Kogan AKh, Grachev SV, Eliseeva SV, Bolevich S. +

+

+ Vopr Med Khim. 1996 Jul-Sep;42(3):193-202. + [Ability of carbon dioxide to inhibit generation of superoxide anion radical in cells and its biomedical + role] Kogan AKh, Grachev SV, Eliseeva SV, Bolevich S. +

+

+ Dokl Akad Nauk. 1996 May;348(3):413-6. [New evidence for the inhibitory action of CO2 on generation + of superoxide anion radicals by phagocytes in various tissues. (Mechanism of bio- and eco-effects of + CO2)] + Kogan AKh, Grachev SV, Bolevich S, Eliseeva SV. +

+ +

+ Biull Eksp Biol Med. 1996 Apr;121(4):407-10. [Carbon dioxide gas inhibition of active forms of + oxygen generation by cells in the internal organs and its biological significance] Kogan AKh, + Grachev SV, Eliseeva SV. +

+

+ Fiziol Cheloveka. 1995 Jul-Aug;21(4):128-36. [CO2--a natural inhibitor of the generation of active + species of oxygen in phagocytes] Kogan AKh, Manuilov BM, Grachev SV, Bolevich S, Tsypin AB, + Daniliak IG. +

+

+ Patol Fiziol Eksp Ter. 1995 Jul-Sep;(3):34-40. [Comparative study of the effect of carbon dioxide on + the generation of active forms of oxygen by leukocytes in health and in bronchial asthma] Kogan + AKh, Bolevich S, Daniliak IG. +

+ +

+ Can J Anaesth. 1999 Feb;46(2):185-9. Acute respiratory alkalosis associated with low minute + ventilation in a patient with severe hypothyroidism. + Lee HT, Levine M. Tl128@columbia.edu PURPOSE: + Patients with severe hypothyroidism present unique challenges to anesthesiologists and demonstrate much + increased perioperative risks. Overall, they display increased sensitivity to anesthetics, higher incidence + of perioperative cardiovascular morbidity, increased risks for postoperative ventilatory failure and other + physiological derangements. The previously described physiological basis for the increased incidence of + postoperative ventilatory failure in hypothyroid patients includes decreased central and peripheral + ventilatory responses to hypercarbia and hypoxia, muscle weakness, depressed central respiratory drive, and + resultant alveolar hypoventilation. These ventilatory failures are associated most frequently with severe + hypoxia and carbon dioxide (CO2) retention. The purpose of this clinical report is to discuss an interesting + and unique anesthetic presentation of a patient with severe hypothyroidism. CLINICAL FEATURES: We describe + an unique presentation of ventilatory failure in a 58 yr old man with severe hypothyroidism. He had + exceedingly low perioperative respiratory rate (3-4 bpm) and minute ventilation volume, and at the same time + developed primary acute respiratory alkalosis and associated hypocarbia (P(ET)CO2 approximately 320-22 + mmHg). CONCLUSION: Our patient's ventilatory failure was based on unacceptably low minute ventilation and + respiratory rate that was unable to sustain adequate oxygenation. His profoundly lowered basal metabolic + rate and decreased CO2 production, resulting probably from severe hypothyroidism, may have resulted in + development of acute respiratory alkalosis in spite of concurrently diminished minute ventilation. +

+

+ Anal Bioanal Chem. 2008 Jan;390(2):679-88. Epub 2007 Oct 27. The structural modification of DNA + nucleosides by nonenzymatic glycation: an in vitro study based on the reactions of glyoxal and + methylglyoxal with 2'-deoxyguanosine. + Li Y, Cohenford MA, Dutta U, Dain JA. +

+ +

+ Biull Eksp Biol Med. 1995 Jun;119(6):590-3. [Adaptation to high altitude hypoxia facilitates a + limitation of lipid peroxidation activation in inflammation and stress] [Article in Russian] + + Malyshev VV, Vasil'eva LS, Belogorov SB, Nefedova TV. +

+

+ Am J Physiol Regul Integr Comp Physiol. 2007 Sep;293(3):R1159-68. Epub 2007 Jun 20. Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS + production. Muller FL, Song W, Jang YC, Liu Y, Sabia M, Richardson A, Van Remmen H. +

+

+ Radiobiologiia. 1984 Jan-Feb;24(1):29-34. [Enzyme activity of glutamic acid metabolism and the Krebs + cycle in the brain of rats laser-irradiated against a background of altered adrenoreceptor function] + [Article in Russian] + + + Pikulev AT, Dzhugurian NA, Zyrianova TN, Lavrova VM, Mostovnikov VA. +

+

+ Rejuvenation Res.2007 Dec12; :18072884, Exploring Overlooked Natural Mitochondria-Rejuvenative + Intervention: The Puzzle of Bowhead Whales and Naked Mole Rats. + + Prokopov A.F. +

+

+ Proceedings of the Japan Academy. Ser. B: Physical and Biological Sciences Vol.78, No.10(2002)pp.293-298. + DNA methylation and Lamarckian inheritance, + Sano H. +

+

+ Biol Chem. 2009 Nov;390(11):1145-53. The epigenetic bottleneck of neurodegenerative and psychiatric + diseases. + Sananbenesi F, Fischer A. The orchestrated expression of genes is essential for the development and + survival of every organism. In addition to the role of transcription factors, the availability of genes for + transcription is controlled by a series of proteins that regulate epigenetic chromatin remodeling. The two + most studied epigenetic phenomena are DNA methylation and histone-tail modifications. Although a large body + of literature implicates the deregulation of histone acetylation and DNA methylation with the pathogenesis + of cancer, recently epigenetic mechanisms have also gained much attention in the neuroscientific community. + In fact, a new field of research is rapidly emerging and there is now accumulating evidence that the + molecular machinery that regulates histone acetylation and DNA methylation is intimately involved in + synaptic plasticity and is essential for learning and memory. Importantly, dysfunction of epigenetic gene + expression in the brain might be involved in neurodegenerative and psychiatric diseases. In particular, it + was found that inhibition of histone deacetylases attenuates synaptic and neuronal loss in animal models for + various neurodegenerative diseases and improves cognitive function. In this article, we will summarize + recent data in the novel field of neuroepigenetics and discuss the question why epigenetic strategies are + suitable therapeutic approaches for the treatment of brain diseases. +

+ +

+ Ukr Biokhim Zh 1994 Jan-Feb;66(1):109-12. [Protective effect of sodium bicarbonate in nitrite ion + poisoning]. Shugalei IV, L'vov SN, Baev VI, Tselinskii IV +

+

+ Am J Respir Crit Care Med. 2000 Mar;161(3 Pt 1):891-8. + Modulation of release of reactive oxygen species by the contracting diaphragm. + Stofan DA, Callahan LA, DiMarco AF, Nethery DE, Supinski GS. +

+

+ Ecology: Vol. 50, No. 3, pp. 492-494. Carbon Dioxide Retention: A Mechanism of Ammonia Tolerance in + Mammals. Studier EM and Fresquez AA. +

+ +

+ Sci Signal. 2009 Mar 31;2(64): pe17. Reversing DNA methylation: new insights from neuronal + activity-induced Gadd45b in adult neurogenesis. + + Wu H, Sun YE. Neurogenesis in the adult mammalian brain involves activity-dependent expression of genes + critical for the proliferation of progenitors and for neuronal maturation. A recent study suggests that the + stress response gene Gadd45b (growth arrest and DNA-damage-inducible protein 45 beta) can be transiently + induced by neuronal activity and may promote adult neurogenesis through dynamic DNA demethylation of + specific gene promoters in adult hippocampus. These results provide evidence supporting the provocative + ideas that active DNA demethylation may occur in postmitotic neurons and that DNA methylation-mediated + dynamic epigenetic regulation is involved in regulating long-lasting changes in neural plasticity in + mammalian brains. +

+

+ Patol Fiziol Eksp Ter. 2005 Apr-Jun;(2):13-5. [The effect of the NMDA-receptor blocker MK-801 on + sensitivity of the respiratory system to carbon dioxide] + Tarakanov IA, Dymetska A, Tarasova NN. +

+

+ Life Sci. 1997;61(5):523-35. Effect of acidotic challenges on local depolarizations evoked by + N-methyl-D-aspartate in the rat striatum. Urenjak J, Zilkha E, Gotoh M, Obrenovitch TP. + "Hypercapnia reduced NMDA-evoked responses in a concentration-dependent manner, with 7.5 and 15 % CO2 in the + breathing mixture reducing the depolarization amplitude to 74 % and 64 % of that of the initial stimuli, + respectively. Application of 50 mM NH4+ progressively reduced dialysate pH, and a further acidification was + observed when NH4+ was discontinued. Perfusion of NMDA after NH4+ application evoked smaller depolarizations + (56 % of the corresponding control, 5 min after NH4+ removal), and this effect persisted for over 1 h." + "Together, these results demonstrate that extracellular acidosis, such as that associated with excessive + neuronal activation or ischemia, inhibits NMDA-evoked responses in vivo." +

+ +

+ Arch Int Physiol Biochim. 1977 Apr;85(2):295-304. Glutamate and glutamine in the brain of the + neonatal rat during hypercapnia. Van Leuven F, Weyne J, Leusen I. +

+

+ Pediatrics 1995 Jun;95(6):868-874. Carbon dioxide protects the perinatal brain from hypoxic-ischemic + damage: an experimental study in the immature rat. Vannucci RC, Towfighi J, Heitjan DF, + Brucklacher RM +

+

+ Pediatr Res 1997 Jul;42(1):24-29. Effect of carbon dioxide on cerebral metabolism during + hypoxia-ischemia in the immature rat. + + Vannucci RC, Brucklacher RM, Vannucci SJ +

+ +

+ Sci. Signal., 31 March 2009 Vol. 2, Issue 64, p. pe17, Reversing DNA Methylation: New Insights from + Neuronal Activity-Induced Gadd45b in Adult Neurogenesis + Wu H, Sun YI +

+ + Copyright 2011. Raymond Peat, P.O. Box 5764, Eugene OR 97405. All Rights Reserved. www.RayPeat.comNot for + republication without written permission. + + diff --git a/raypeat-articles/processed/edema-heart-failure-hypertension-sarcopenia.html b/raypeat-articles/processed/edema-heart-failure-hypertension-sarcopenia.html new file mode 100644 index 0000000..aaaad13 --- /dev/null +++ b/raypeat-articles/processed/edema-heart-failure-hypertension-sarcopenia.html @@ -0,0 +1,776 @@ + + + +

+ +

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+ When energy fails: + Edema, heart failure, hypertension, sarcopenia, etc.  +

+
+
+
+ More than 100 years ago the idea of + a morphogenetic field was proposed by A.G. Gurwitsch, as a way to explain the orderly movements + of cells in embryos and growing tissues, and to understand the principles that cause cells to + change appropriately when their location in the organism changes. For 30 years, the concept + guided research in embryology, but also led to important discoveries in the biology of cancer, + aging, wound repair, and other important areas. But by the late 1940s, a more abstract approach + to biology, based on the gene doctrine of Mendel and Weismann, took charge of academic and + governmental biological research. This ideology at first said that organisms are determined by + unchanging units of inheritance, "genes," and later when genes were found to be susceptible to + mutation, the changes were said to be always random. The Central Dogma of the ideology was that + any meaningful, adaptive changes that occur in an organism can't influence the genes. For many + years, adaptive changes were said to be nothing but changes in the size or function of existing + cells, because the cells of the major organs of the body were supposed to be created before + birth, or in infancy.  +
+
+
+ Besides the purely ideological + commitment to the theory of genes, there were other influences that contributed to the culture + of Molecular Biology. People learned histology from slides or pictures made by killing, + hardening, dehydrating, and slicing parts of organisms. Biochemists studied the chemistry of + life mainly by grinding cells or tissues, and extracting water soluble materials to study the + actions of enzymes on various materials. These unrealistic artifacts filled the textbooks and + the minds of generations of biologists and physicians. The culture of molecular biology used + these artifacts to create theories of embryology and physiology, and holistic ideas such as the + developmental field were disregarded. +
+
+
+ The mental image of a living + organism that has been created by that culture is simply wrong. The concept of a developmental + field is essential for understanding embryology, because things that exist on a scale bigger + than molecules and cells govern the functions of the molecules and cells, and the principles of + embryology don't arbitrarily stop operating at birth, but can be seen to continue operating + during maturity and aging. The interactions of cells with their environment are different at + different stages of life, but there are commonalities that are extremely important. +
+
+
+ The processes that govern the + pregnant woman's blood circulation, in sustaining the development of a fetus, are very similar + to the processes that govern anyone's blood circulation, providing for the maintenance and + renewal of all the body's organs. The common problems of pregnancy involving the circulatory + system can provide insights into the problems of the various organs that have been the focus of + the medical specialties, and to some basic medical issues, including aging, obesity, and + inflammation. +
+
+
+ The development of a fertilized egg + into an embryo consumes energy at a very high rate, and the way the embryo develops depends on a + continuously adequate supply of oxygen and sugar, and other nutrients. The intense flow of + energy through each stage of a developing structure shapes the following stage. The necessary + energy and materials are provided abundantly by the mother's blood. When the development has + advanced far enough to make life possible outside the uterus, energy will be used more slowly, + for growth, maintenance, and renewal of tissues.  +
+
+
+ Failure to renew cells and tissues + leads to the loss of function and substance. Bones and muscles get weaker and smaller with + aging. Diminished bone substance, osteopenia, is paralleled, at roughly the same rate, by the + progressive loss of muscle mass, sarcopenia (or myopenia). The structure of aging tissue + changes, with collagen tending to fill the spaces left by the disappearing cells. It's also + common for fat cells to increase, as muscle cells disappear. +
+
+
+ When conditions are ideal, as during + healthy development in the uterus, tissue damage is corrected by the multiplication of cells to + replace any that were lost. But when conditions are less perfect, injuries are imperfectly + repaired, usually with highly collagenous scar tissue bridging the area that was destroyed. + During this imperfect repair, there is inflammation, which apparently exists to the extent that + the substances needed for regeneration are lacking. For example, when oxygen is lacking, lactic + acid is likely to be produced, along with increases of pro-inflammatory regulators such as + histamine and serotonin, leading to the loss of many important proteins and functions, and the + over-production of collagen instead. +
+
+
+ Since cellular renewal of tissues, + in a healthy individual, is a constant process, we can think of the metabolic rate of a healthy + adult as just what is needed to sustain this constant, limited sort of regeneration, but not + quite intense enough to produce scarless healing of a wound (without special + intervention). +
+
+
+ If something reduces the systemic + ability to produce energy, there will be a gap between the available energy and the energy + needed for the constant turnover of cells in each tissue and organ, and a generalized + inflammation will develop. The replacement of cells will be slowed, and the organism will + mobilize the processes used for producing scar tissue, producing an excess of collagen, filling + the spaces left by the lost cells. +
+
+
+ We are susceptible to many things + that interfere with energy production---the substitution of iron for copper in the respiratory + enzyme, the absorption of endotoxin, the accumulation of PUFA, a deficiency of thyroid hormone, + the formation of increased amounts of nitric oxide, serotonin, and histamine, etc. Different + environments will condition the way the defensive mechanisms of inflammation are + produced.  +
+
+
+ Toxemia of pregnancy, or + preeclampsia, is a state of generalized inflammation, and some of the causes and remedies are + known. Despite the predominance of crazy genetic theories of preeclampsia in 20th century + medical literature, there was clear evidence (reviewed by Tom Brewer, Douglas Shanklin, and Jay + Hodin) that it was caused by malnutrition, and that it could be cured by adequate protein, salt, + and calcium.    +
+
+
+ The old medical practice of + restricting salt intake during pregnancy was an important factor in causing it, so it's + interesting to look at the effects of salt restriction as a treatment for hypertension. +
+
+
+ The pregnant woman's blood volume + expands, to permit the supply of energy to match the needs of the embryo. If the blood volume + doesn't increase, or if it decreases, as in pregnancy toxemia, her blood pressure will increase. + Typically, the decrease of blood volume is accompanied by an increase in the extracellular + fluid, edema, resulting from leakage of fluid through the walls of the capillaries, and albumin + appears in the urine as it leaks through the capillaries in the kidneys. The amount of blood + pumped by the heart, however, is increased in toxemia (Hamilton, 1952), showing that the + increased blood pressure is at least partially compensating for the smaller volume of + blood.  +
+
+
+ A similar situation, reduced blood volume and edema, can be seen (Tarazi, 1976) in "essential hypertension," the + "unexplained" high blood pressure that occurs more often with increasing age and + obesity. At the beginning of "essential hypertension," the amount of blood pumped is usually + greater than normal. +
+
+
+ In both situations, preeclampsia and + essential hypertension, there is an increased amount of aldosterone, an adrenal steroid which + allows the kidneys to retain sodium, and to lose potassium and ammonium instead. A restriction + of salt in the diet causes more aldosterone to be produced, and increased salt in the diet + causes aldosterone to decrease. One effect of aldosterone is to increase the production of a + substance called vascular endothelial growth factor, VEGF, or vascular permeability factor, + which causes capillaries to become leaky, and causes new blood vessels to grow. +
+
+
+ While increased salt in + the diet tends to lower both aldosterone and VEGF, reducing the leakiness of blood + vessels, sodium also has a direct effect that tends to prevent the leakage of + water and albumin out of the blood vessels, helping to maintain the blood volume which is needed + to perfuse the kidneys, preventing them from producing signals to increase blood pressure and + aldosterone. There is a large amount of albumin in the blood serum, and sodium ions associate + with the negative electrical charges on the albumin molecule. This association causes the + complex of albumin and sodium to attract a large amount of water, that is to exert osmotic or + oncotic pressure. This oncotic pressure causes any excess extracellular water to be attracted + into the blood vessels, preventing edema while maintaining the blood volume. When there is too + little sodium, the albumin molecule itself easily leaves the blood stream along with the + water. +
+
+
+ Instead of considering the + significance of sodium's effects on albumin, aldosterone, and VEGF, textbooks have often talked + about the factors that "pump" sodium, and factors that specifically regulate the movement of + water. Experiments in which an excess of aldosterone is combined with a high salt intake produce + increased blood pressure, and--by invoking various genes--salt is said to cause hypertension in + certain people. This reasoning is hardly different from the reasoning of the drug companies in + the 1950s who said that since women with toxemia have hypertension and edema, they should be + treated with a diuretic and a low salt diet, to eliminate water and to reduce blood + pressure. +
+
+
+ The physiological loss of sodium + occurs when energy metabolism fails, as indiabetes, hypothyroidism, hyperestrogenism, + and starvation. What these conditions have in common is an increased level of + free fatty acids in the blood. Increased free fatty acids impair the use of glucose. The + consumption of carbohydrate, like an increase of thyroid hormone, insulin, or progesterone, + increases the retention of sodium; fructose is the most effective carbohydrate (Rebello, et al., + 1983).  +
+
+
+ The loss of sodium is often + accompanied by the retention of water, reducing the osmotic pressure of the body fluids. The + leakiness of blood vessels allows the extracellular fluid volume to increase, as understood in + the standard definition of edema. However, when this fluid is hypo-osmotic, it will enter cells, + causing them to swell. Cell swelling excites cells (Ayus, et al., 2008; Baxter, et al., 1991), + and can kill them if they are unable to produce enough energy to restore their original volume, + by measures including the excretion of amino acids and potassium.  Both low sodium + (hyponatremia) and low osmotic pressure stimulate the adrenergic nervous system. +
+
+
+ The increase of adrenalin,f caused + by a deficiency of sodium, is one of the factors that can increase blood pressure; if the + tissues's glycogen stores are depleted, the adrenalin will mobilize free fatty acids from the + tissues, which tends to inhibit energy production from glucose, and to increase leakiness. After + I had read Tom Brewer's work on preventing or curing preeclampsia with added salt, I realized + that the premenstrual syndrome involved some of the features of preeclampsia (edema, insomnia, + cramps, hypertension, salt craving), so I suggested to a friend that she might try salting her + food to taste, instead of trying to restrict salt to "prevent edema." She immediately noticed + that it prevented her monthly edema problem. For several years, all the women who tried it had + similarly good results, and often mentioned that their sleep improved. I mentioned this to + several people with sleep problems, and regardless of age, their sleep improved when they ate as + much salt as they wanted. Around that time, several studies had shown that salt restriction + increases adrenalin, and one study showed that most old people on a low sodium diet suffered + from insomnia, and had unusually high adrenalin. When they ate a normal amount of salt, their + adrenalin was normalized, and they slept better. +
+
+
+ It's very common for physicians who + are aware of progesterone's "anti-aldosterone" activity to think that both estrogen and + progesterone are responsible for the increased risk of sodium loss in women, especially during + pregnancy, but Hans Selye demonstrated that progesterone will normalize sodium retention even + when there is no aldosterone at all, following removal of the adrenal glands. It is estrogen + which is responsible for the dangerous loss of sodium.       +
+
+
+ The ratio of estrogen to + progesterone--regardless of age or gender--is an important factor in regulating minerals and + water, cell energy metabolism, and blood pressure. The ratios of many other regulatory + substances (including serotonin/dopamine, glucagon/insulin, and + aldosterone/cortisol+progesterone) vary according to the quality of the individual's level of + adaptation to the environment. Improving the environment can shift the ratio in the direction of + restoration, rather than mere survival. +
+
+
+ Gershom Zajicek and his colleagues + have demonstrated an organized renewal of tissues, in which new cells are born with the division + of stem cells, and "stream" away from their origin as they mature, and finally are shed or + dissolved. A few studies have demonstrated a similar kind of migration of new cells in the brain + (Eriksson, et al., 1998; Gould, et al., 1999), a process which differs by the absence of + systematic dissolution of mature brain cells. While Zajicek has demonstrated the conversion of + one kind of cell, such as a pancreatic ductal epithelial or acinar cell into insulin-secreting + beta cells, other researchers have shown that after injury to the pancreas beta cells can be + formed from glucagon-secreting alpha cells, as well as from other beta cells.  +
+
+
+ Stress, increasing the need for + energy, increases the formation of cortisol and free fatty acids when glucose isn't available, + and those--while they provide alternative sources of energy--interfere with the ability to + produce energy from glucose. Free fatty acids and cortisol can cause the insulin-secreting beta + cells to die. Glucose, and insulin which allows glucose to be used for energy production, while + it lowers the formation of free fatty acids, promotes the regeneration of the beta-cells. + Although several research groups have demonstrated the important role of glucose in regeneration + of the pancreas, and many other groups have demonstrated the destructive effect of free fatty + acids on the beta cells, the mainstream medical culture still claims that "sugar causes + diabetes." +
+
+
+ In the adrenal glands, renewing + cells stream from the capsule on the surface of the gland toward the center of the gland. The + first cells to be produced in a regenerating gland are those that produce aldosterone, the next + in the stream are the cortisol producing cells, and the last to be formed are the cells that + produce the sex hormones, the androgens including DHEA, and progesterone. In aging, after the + age of thirty, the renewal slows, but the dissolution of the sex hormone zone continues, so the + proportion shifts, increasing the ratio of the aldosterone and cortisol producing cells to the + layer that produces the protective androgens and progesterone (Parker, et al., 1997). +
+
+
+ Even before aldosterone was + identified, progesterone's role in regulating the salts, water, and energy metabolism was known, + and after the functions of aldosterone were identified, progesterone was found to protect + against its harmful effects, as it protects against an excess of cortisol, estrogen, or the + androgens. New anti-aldosterone drugs are available that are effective for treating hypertension + and heart failure, and their similarity to progesterone is recognized. +
+
+
+ While stress typically causes the + adrenal glands to produce cortisol, extreme stress, as described by Hans Selye, damages the + adrenal cortex, and can cause the cells to die, leading to the death of the animal. There is + evidence that it is the breakdown of unsaturated fatty acids that causes damage to the adrenal + cortex in extreme stress. Although many factors influence the production of the adrenal + steroids, arachidonic acid, even without being converted to prostaglandins, is an important + activator of aldosterone synthesis. Adrenalin, produced in response to a lack of glucose, + liberates free fatty acids from the tissues, so when the tissues contain large amounts of the + polyunsaturated fatty acids, the production of aldosterone will be greater than it would be + otherwise.  +
+
+
+ The continuing accumulation of + polyunsaturated fats in the tissues is undoubtedly important in the changing relationship + between the pancreas and the adrenal glands in aging. Aspirin, which is antilipolytic, + decreasing the release of free fatty acids, as well as inhibiting their conversion to + prostaglandins, lowers the production of stress-induced aldosterone, and helps to lower blood + pressure, if it's taken in the evening, to prevent the increase of free fatty acids during the + night. Aspirin increases insulin sensitivity. A low salt diet increases the free fatty acids, + leading to insulin resistance, increasing free fatty acids in the blood, and contributing to + atherosclerosis (Prada, et al., 2000; Mrnka, et al., 2000; Catanozi, et al., 2003; Garg, et al., + 2011). +
+
+
+ The same factors that support or + interfere with cellular renewal in the pancreas and adrenal glands have similar effects in the + bones, skin, skeletal and heart muscle, nervous system, liver, and other organs. In every case, + the local circulation of blood is influenced by both local and systemic factors. The loss of + control over the water in the body is the result of energy failure, and hypertension is one of + the adaptations that helps to preserve or restore energy production.  +
+
+
+ Lowering inflammation and the + associated excess of free fatty acids in the blood, and improving the ability to oxidize + glucose, will lower blood pressure while improving tissue renewal, but lowering blood pressure + without improving energy production and use will create new problems or intensify existing + problems. After 40 years the medical profession quietly retreated from their catastrophic + approach to pregnancy toxemia, but in the more general problem of essential hypertension, the + mistaken ideology is being preserved, even as less harmful treatments are introduced. That + ideology prevents a comprehensive and rational approach to the problems of stress and + aging. +
+
+
+               +     

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+ Gynecol Endocrinol. 2005 + Nov;21(5):243-7. Drospirenone in the treatment of severe premenstrual cerebral + edema in a woman with antiphospholipid syndrome, lateral sinus thrombosis, situs inversus + and epileptic seizures. Vujovic S, Zidverc J, Stojanovic M, Penezic Z, Ivovic + M, Dukic V, Drezgic M. +
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+ J Hypertens. 1988 + Jun;6(6):471-9. Mechanism of action of ketanserin: studies on cardiovascular + reactivity in essential and diabetes-associated hypertension. Waser M, Ziegler + WH, Beretta-Piccoli C. "Ketanserin treatment administered over a period of 8 weeks, decreased + arterial pressure in patients with essential hypertension and, to a lesser extent, in diabetics, + but not in normal subjects." +
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+ Aust J Exp Biol Med Sci. 1976 + Feb;54(1):71-8. Regulation of aldosterone in the guinea-pig--effect of oestrus + cycle, pregnancy and sodium status. Whipp GT, Wintour EM, Coghlan JP, Scoggins + BA. Compared with a moderate Na intake, salt loading suppressed aldosterone levels and Na + restriction raised them. +
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+ J Clin Invest. 1972 + Oct;51(10):2645-52. Studies of the control of plasma aldosterone concentration in + normal man. 3. Response to sodium chloride infusion. Williams GH, Tuck ML, + Rose LI, Dluhy RG, Underwood RH. +
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+ Diabet. Research. 13:121-125, + 1990. Streaming Pancreas : Islet cell kinetics. Zajicek G, Arber N. + Schwartz-Arad D, Ariel I. +
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+ Path. Res. Pract. + 188:410-412,1992. Time dimension in histopathology, Zajicek + G  +
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+ Zajicek G. Streaming + Organism: The Tissue Automat. in: Computing with Biological Metaphors. Ed. R. + Paton.Chapman & Hall London, 1994. +
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+ Methods of Inform. Med. + 26:1-2,1987.  The time dimension in histology. Zajicek G. +
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+
+ + © Ray Peat Ph.D. 2013. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/epilepsy-progesterone.html b/raypeat-articles/processed/epilepsy-progesterone.html new file mode 100644 index 0000000..62e2509 --- /dev/null +++ b/raypeat-articles/processed/epilepsy-progesterone.html @@ -0,0 +1,563 @@ + + Epilepsy and Progesterone + +

+ Epilepsy and Progesterone +

+

+ The length of the life-span, and of the period of youth or immaturity, is closely associated with the size + of the brain, and the brain has a very high rate of metabolism. When something interferes with this very + high metabolic rate, the consequences may be instantanteous,* or developmental, or chronic and degenerative, + or even transgenerational. The issue of epilepsy centers on questions of brain metabolism, and so it has all + of those dimensions. +

+

+ As I discuss the mechanisms known to predispose a person to epilepsy, I will emphasize the centrality of + oxidative energy production, and show how "stroke," "stress," "hyperactivity," "dementia," and other brain + syndromes are related to "epilepsy." (Similar processes are being studied in the heart and other tissues; + eventually, we might have a general language that will make it easier to understand the parallels in the + various kinds of "seizure" in any organ.) +

+

+ As an old term, "epilepsy" has aquired a burden of pseudoscientific ideas, covering old superstitions with + an overlay of new superstitions. [Hereditary epilepsy has been discussed in countless textbooks and medical + journals, but I think a much better case could be made for the inheritance of a tendency to offer stupid + genetic explanations.] "Hereditary epilepsy" and "idiopathic epilepsy" are seriously pathogenic terms; + "brain scar" sometimes has a factual basis, but most often the term is an evasion of understanding. +

+ +

+ As long as we realize that the essential meaning of the word is "something that grabs you," "epilepsy" is a + convenient way to refer to a cluster of convulsive states, fainting spells, night-terrors and nightmares, + and strange sensations. +

+

+ Seizures can be caused by lack of glucose, lack of oxygen, vitamin B6 deficiency, and magnesium deficiency. + They are more likely to occur during the night, during puberty, premenstrually, during pregnancy, during the + first year of life, and can be triggered by hyperventilation, running, strong emotions, or unusual sensory + stimulation. Water retention and low sodium increase susceptibility to seizures. When I was in high school, + our dog found and ate a pint of bacon grease, and shortly afterward had a convulsive seizure. I knew of + veterinarians who treated seizures in dogs with a vermifuge, so it seemed obvious that a metabolic + disturbance, especially if combined with intestinal irritation, could cause fits. +

+

+ It was undoubtedly such observations that led some physicians to advocate removal of the colon as treatment + for epilepsy. Pregnancy and the menstrual cycle have been recognized as having something to do with + seizures, but when seizures occurred only during pregnancy, they were classified as nonepileptic, and when + they had a clear premenstrual occurrence, they were likely to be classified as "hysterical fits," to be + treated with punishment. +

+

+ It has been observed that all "recognized" anti-seizure drugs are teratogenic, and women who are taking such + drugs are told that pregnancy might kill them if they stop the drug, but that their babies will have a + greatly increased risk of birth defects if they take the drugs during pregnancy. This is why a better + understanding of epilepsy is very important. Old therapies are mainly important for the insight they can + give into the nature of the physiological problem. Some of the well established clinical-laboratory + observations (F. Mora, and C. S. Babel, for example) give strong hints as to the physiological problem, for + example, low albumin, high prealbumin, low magnesium and high calcium all suggest hypothyroidism. (Problems + with the bowel, liver, and sex hormones are highly associated with hypothyroidism, both as causes and as + effects.) Water retention was so clearly involved in seizures that increased water intake was used as a + diagnostic procedure. (R. Grinker) Unfortunately, animal experiments showed that water intoxication + increased susceptibility to seizures even in normal individuals. Low sodium content in the body fluids also + predisposed to seizures, so that someone with hyponatremia (low blood sodium) would be more susceptible to + induction of a seizure by excessive water intake. (Excessive water uptake is still recognized as a factor in + seizures, but now it is seen as part of a complex process, involving energy, hormones, and transmitter + substances. E.g., Kempski; Chan.) +

+

+ Hypothyroid people tend to lose sodium easily, and unopposed estrogen increases water retention, without an + equivalent sodium retention, so low thyroid, high estrogen people have two of the conditions (edema and + hyponatremia) known to predispose to seizures. Another outstanding feature of seizures of various sorts is + that they are most likely to occur at night, especially in the early pre-dawn hours. Low blood sugar and + high adrenalin predominate during those hours. Hypoglycemia, in itself, like oxygen deprivation, is enough + to cause convulsions. +

+

+ Progesterone and thyroid promote normal energy production, and their deficiency causes a tendency toward + hypoglycemia, edema and instability of nerves. +

+

+ Twenty years ago, a woman who was considered demented visited me. From the age of 21, she had been + increasingly disabled by premenstrual migraines. When she was 35 she was a school teacher, and during the + summer a neurologist told her that dilantin would help her headaches, because "migraine is similar to + epilepsy." Although she told the neurologist that the drug made her "too stupid to teach school," he offered + her no alternatives, and didn't mention that sudden withdrawal from the drug could trigger a seizure. When + classes started she discontinued the dilantin and had a seizure. The neurologist said the seizure proved + that migraines were a form of epilepsy. At the age of 52, she spent about 20 hours a day in bed, and + couldn't go outside by herself, because she would get lost. After using a little progesterone for a few + days, she stopped having seizures, discontinued her drugs, and was able to work. When she returned to + graduate school, she got straight As, and earned her masters' degree in gerontology. But she had lost 17 + years because the drug industry had covered up the role of the hormones in epilepsy, migraine, and the + perimenstrual syndrome. +

+ +

+ The most popular anticonvulsant drugs are both neurotoxic and teratogenic, that is, they damage the + patient's brain, and greatly increase the incidence of birth defects. The Nazis justified their horrible + medical experiments as "science," but the effects of epilepsy medicine in the last half century have been + similar in effect, grander in scale, and without any scientific justification. +

+

+ Besides the specific promotional efforts of the drug industry and their branch of government, there is a + broader situation that makes their work easier. It is a culture of goony ideas, that ultimately emanates + from the academic elite, which (since Descartes, and before) places "thought" above evidence. In biology, + "genes" and "membranes" are confused ideas that are used to justify actions that aren't based on evidence. + For the Nazis, "cultural degeneracy" was a medical-biological-political category based on that style of + thinking. In the United States, "genes" for epilepsy, hyperactivity, language development, IQ, eclampsia, + etc., are "found" at Harvard/MIT/Stan- ford/Yale/Univ. of California, etc., by an elite whose wits have been + dulled by environmental deprivation, that is, by a lack of criticism. +

+

+ By manipulating the diet and environment, animals can be made more or less seizure-prone, and it happens + that the changes that affect the brain affect all other organs, in ways that are now fairly well understood. + Examining the cellular events associated with a seizure is useful for therapy and prevention of seizures, + but the same methods are helpful for many other conditions. It is now clearly established that stress can + cause brain damage, as well as other diseases. Now that our public health establishment has eliminated + smoking from public places, maybe they can find a way to reduce stress and disease by removing morons from + positions of power. +

+

+ Excitotoxicity, in its simplest sense, is the harmful cellular effect (death or injury) caused by an + excitatory transmitter such as glutamate or aspartate acting on a cell whose energetic reserves aren't + adequate to sustain the level of activity provoked by the transmitter. Once an excitotoxic state exists, the + consequences of cell exhaustion can increase the likelihood that the condition will spread to other cells, + since any excitation can trigger a complex of other excitatory processes. As calcium enters cells, potassium + leaves, and enzymes are activated, producing free fatty acids (linoleic and arachidonic, for example) and + prostaglandins, which activate other processes, including lipid peroxidation and free radical production. + Protein kinase C (promoted by unsaturated fats and estrogen) facilitates the release of excitatory amino + acids. (See J. W. Phillis and M. H. O'Regan, "Mechanisms of glutamate and aspartate release in the ischemic + rat cerebral cortex," Br. Res. 730(1-2), 150-164, 1996.) Estrogen supports acetylcholine release, which + leads to increased extracellular potassium and excitatory amino acids. (See R. B. Gibbs, et al., "Effects of + estrogen on potassium-stimulated acetylcholine release in the hippocampus and overlying cortex of adult + rats," Br. Res. 749(1), 143-146, 1997.) +

+ +

+ Estrogen also stimulates the production of free radicals. Calcium, free radicals, and unsaturated free fatty + acids impair energy production, decreasing the ability to regulate potassium and calcium. The increased + estrogen associated with seizures is associated with reduced serum calcium (Jacono and Robertson, 1987). + Feedback self-stimulation of free radicals, free fatty acids, and prostaglandins create a bias toward + increased excitation. +

+

+ Ammonia is produced by stimulated nerves, and normally its elimination helps to eliminate and control the + excitotoxic amino acids, glutamate and aspartate. The production of urea consumes aspartic acid, converting + it to fumaric acid, but this requires carbon dioxide, produced by normal mitochondrial function. A + deficiency of carbon dioxide would reduce the delivery of oxygen to the brain by constricting blood vessels + and changing hemoglobin's affinity for oxygen (limiting carbon dioxide production), and the failure to + consume aspartate (in urea synthesis) and glutamate (as alpha-ketoglutarate) and aspartate (as oxaloacetate) + in the Krebs cycle, means that as energy becomes deficient, excitation tends to be promoted. This helps to + explain the fact that seizures can be induced by hypoxia. (Balloonists and mountain climbers at extremely + high elevations have mentioned suffering from severe insomnia. The mechanisms of excitotoxicity are probably + involved in other forms of insomnia, too.) Antioxidants help to control seizures, by reducing the excitatory + contribution of free radicals and lipid peroxidation. Since excitation can promote the toxic forms of + oxidation, many surprising substances turn out to have an "antioxidant" function. Magnesium, sodium + (balancing calcium and potassium), thyroid and progesterone (increasing energy production), and in some + situations, carbon dioxide. Aspirin, by inhibiting prostaglandin synthesis (and maybe other mechanisms) + often lowers free radical production. Adenosine seems to have a variety of antioxidant functions, and one + mechanism seems to be its function as an antiexcitatory transmitter. One of estrogen's excitant actions on + the brain probably involves its antagonism to adenosine (Phillis and O'Regan, 1988). +

+

+ Albumin, besides maintaining blood volume and preventing edema, serves to protect respiration, by binding + free fatty acids. Estrogen blocks the liver's ability to produce albumin, and increases the level of + circulating free fatty acids. Free fatty acids cause brain edema. This is probably another aspect of + estrogen's contribution to seizure susceptibility. Magnesium sulfate has been used for generations in India + to treat eclampsia and "toxemia" of pregnancy, and its effectiveness is gradually coming to be recognized in + the U.S. Increasingly, magnesium deficiency is recognized as a factor that increases susceptibility to + seizures. (Valenzuela and Benardo, 1995; Slandley, et al., 1995). Hypothyroidism reduces the ability of + cells to retain magnesium. Thyroid does many things to protect against seizures. It keeps estrogen and + adrenal hormones low, and increases production of progesterone and pregnenolone. It facilitates retention of + magnesium and of sodium, and prevents edema in a variety of ways. +

+ +

+ Progesterone, because of its normal anesthetic function (which prevents the pain of childbirth when its + level is adequate), directly quiets nerves, and in this way suppresses many of the excitotoxic processes. It + has direct effects on mitochondria, promoting energy production, and it facilitates thyroid hormone + functions in various ways. It promotes the elimination of estrogen from tissues, and is a "diuretic" in + several benign ways, that are compatible with maintenance of blood volume. It antagonizes the + mineralocorticoids and the glucocorticoids, both of which promote seizures. (Roberts and Keith, 1995.) The + combination of hypoglycemia with elevation of cortisone probably accounts for the nocturnal incidence of + seizures. +

+

+ If progesterone's antiepileptic effectiveness were not enough (and it is very effective even in irrational + pharmaceutical formulations), the fact that it reduces birth defects, and promotes brain development and + nerve repair should assure its general use in women with a history of seizures, until it is established that + they are no longer "epileptic." Although thyroid, progesterone, and a high quality protein diet will + generally correct the epilepsy problem, it is important to mention that the involvement of unsaturated fats + and free radicals in seizure physiology implies that we should minimize our consumption of the unsaturated + fats. Even years after eliminating them from the diet, their release from tissue storage can prolong the + problem, and during that time the use of vitamin E is likely to reduce the intensity and frequency of + seizures. Coconut oil lowers the requirement for vitamin E, and reduces the toxicity of the unsaturated fats + (see Cleland, et al.), favoring effective respiration and improving thyroid and progesterone production. + Endotoxin formed in the bowel can block respiration and cause hormone imbalances contributing to instability + of the nerves, so it is helpful to optimize bowel flora, for example with a carrot salad; a dressing of + vinegar, coconut oil and olive oil, carried into the intestine by the carrot fiber, suppresses bacterial + growth while stimulating healing of the wall of the intestine. The carrot salad improves the ratio of + progesterone to estrogen and cortisol, and so is as appropriate for epilepsy as for premenstrual syndrome, + insomnia, or arthritis. +

+

NOTES:

+ +

+ When the brain loses its oxygen supply, consciousness is lost immediately, before there is much decrease in + the ATP concentration. This has led to the proposal of interesting "electronic" ideas of consciousness, but + there is another way of viewing this. While ATP constitutes a kind of reservoir of cellular energy, the flow + of carbon dioxide through the brain cell is almost the mirror image of the flow of oxygen. Oxygen scarcity + leads directly to carbon dioxide scarcity. The "sensitive state," consciousness, might require the presence + of carbon dioxide as well as ATP, to sustain a cooperative, semi-stable, state of the cytoplasmic proteins. + The ability of ordinary light to trigger a conformation change in the hemoglobin-carbon monoxide-carbon + dioxide system shows how sensitive a system with only a few elements can be. At the other extreme from + consciousness, there is the evidence that carbon dioxide is essential for even the growing/living state of + protozoa, algae, and bacteria.(O. Rahn, 1941.) +

+

+ O. Rahn, "Protozoa need carbon dioxide for growth," Growth 5, 197-199, 1941. "On page 113 of this volume, + the statement of Valley and Rettger that all bacteria need carbon dioxide for growth had been shown to apply + to young as well as old cells." "...it is possible...to remove it as rapidly as it is produced, and under + these circumstances, bacteria cannot multiply." +

+

REFERENCES

+ +

+ E. Tauboll, et al., "The progesterone metabolite 5-alpha-pregnan-3-alpha-ol-20-one reduces K+-induced GABA + and glutamate release from identified nerve terminals in rat hippocampus--a semiquantitative + immunocytochemical study," Brain Research 623(2), 329-333, 1993. +

+

+ E. Tauboll and S. Lindstrom, similar article in Epilepsy Research 14(1), 17-30, 1993. +

+

+ G. K. Herkes, et al., "Patterns of seizure occurrence in catamenial epilepsy," Epilepsy Research 15(1), + 47-52, 1993. (Seizures are more frequent at ovulation, during the two days before menstruation, and during + menstruation.) +

+

+ M. S. Myslobodsky, "Proconvulsant and anticonvulsant effects of stress--the role of neuroactive steroids," + Neuroscience & Biobehavioral Reviews 17(2_, 129-139, 1993. (Discusses steroid-induced sedation, + excitatory steroids, stress and epilepsy, GABA and respiratory functions, and asymmetric brain injury.) +

+ +

+ P. Berbel, et al., "Organization of auditory callosal connections in hypothyroid adult rats," European J. of + Neuroscience 5(11), 1465-1478, 1993.(Changes in cortical connectivity related to epilepsy associated with + early hypothyroidism.) +

+

+ D. A. Marks and B. L. Ehrenberg, "Migraine-related seizures in adults with epilepsy, with EEG correlation," + Neurology 43(12), 2475-2483, 1993. ("Patients with catamenial epilepsy and patients with migraine with aura + were at an increased risk for an association between..." migraine and epilepsy.) +

+

+ R. D. Brinton, "The neurosteroid 3-alpha-hydroxy-5-alpha-pregnan-20-one induces cytoarchitectural regression + in cultured fetal hippocampal neurons," J. of Neuroscience 145(5 part 1), 2763-2774, 1994. J. W. Phillis and + M. H. O'Regan, "Effects of estradiol on certain cortical neurons and their responses to adenosine," Br. Res. + Bull. 20(2), 151-155, 1988. +

+

+ J. O. McNamara, "Human hypoxia and seizures: Effects and interactions," Advances in Neurology 26, S. Fahn, + et al., eds., Raven Press, N.Y., 1979. (Seizures can cause hypoxia, etc.) +

+

+ M. R. Liebowitz, et al., "Lactate provocation of panic attacks: 2. Biochemical and physiological findings." + Arch. Gen. Psychiatry 42(7), 709-719, 1985. "Before receiving lactate, patients showed higher heart rates + than controls and also signs of hyperventilation." R. H. Mattson, et al., "Treatment of seizures with + medroxyprogesterone acetate: Preliminary report," Neurology 34, 1255-7, 1984. M. W. Newmark, et al, + "Catamenial epilepsy: A review," Epilepsia 21, 281-300, 1980. +

+ +

+ J. W. Phillis and M. H. O'Regan, "Effects of estradiol on cerebral cortex neurons and their responses to + adenosine," Br. Res. Bull. 20(2), 151-155, 1966. (Antagonism to endogenous adenosine may account for the + excitant actions of estradiol in the brain.) +

+

+ J. W. Phillis, et al., "Acetylcholine output from the ischemic rat cerebral cortex: Effects of adenosine + agonists," Br. Res. 613(2), 337-340, 1993. (Acetylcholine enhances excitotoxicity, could contribute to + ischemic brain injury.) +

+

+ T. Backstrom, "Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual + cycle," Acta Neurol. Scand. 54, 321-347, 1976. (Seizures are more frequent at menstruation and ovulation.) + T. Backstrom, et al., "Effects of intravenous progesterone infusion on the epilepsy discharge frequency in + women with partial epilepsy," Acta Naurol. Scan. 69(4), 240-248, 1984. +

+ +

+ A. W. Zimmerman, "Hormones and epilepsy," Neurol. Clin. 4(4), 853-861, 1985. "Progesterone appears to be + especially effective in treating seizures." J. Bauer, et al., "Catamenial seizures--an analysis," Nervenarzt + 66(10), 760-769, 1995. "...when anticonvulsants have failed to suppress seizures, progesterone or + progesterone-derivates have been administered with success." R. H. Mattson, et al., "Seizure frequency and + the menstrual cycle: a clinical study," Epilepsia 22, 242, 1981. J. Logothetis, et al., "The role of + estrogens in catamenial exacerbation of epilepsy," Neurology (Minneap) 9, 352-360, 1959. J Laidlaw, + "Catamenial epilepsy," Lancet 2, 1235-7, 1956. S. Landgren and O. Selstam, "Interaction between + 17-beta-oestradiol and 3alpha-hydroxy-5alpha pregnane- 20-one in the control of neuronal excitability in + slices from the hippocampus in vitro of guinea-pigs and rats," Acta Physiologica Scandinavica 154(2), + 165-176, 1995. C. A. Frye, "The neurosteroid 3 alpha, 5 alpha-THP has antiseizure and possible + neuroprotective effects in an animal model of epilepsy," Brain Research 696(1-2), 113-120, 1995. +

+

+ G. K. Herkes, "Drug treatment of catamenial epilepsy," CNS Drugs 3(4), 260-266, 1995. (Mentions use of + diuretics, progesterone, and the very high incidence of premenstrucal seizure, and of abnormal menstrual + cycles in women with epilepsy.) +

+

+ E. Spiegel and H. Wycis, "Anticonvulsant effects of steroids," J. Lab. Clin. Med. 33, 945-957, 1947. +

+ +

+ G. Holmes, "Anticonvulsant effect of hormones on seizures in animals," 265-268, in: R. Porter, R. H. + Mattson, A. Ward, and M. Dam, eds., Advances in Epileptology, 15th Epilepsy International Symposium, New + York, Raven Press, 1984. +

+

+ H. W. Zimmerman, et al., "Medroxyprogesterone acetate in the treatment of seizures associated with + menstruation," J. Pediatr. 83, 959-963, 1973. R. H. Mattson, et al., "Medroxy-progesterone treatment of + women with uncontrolled seizures," Epilepsia 22, 242, 1981. A. Rosenfield, et al., "The Food and Drug + Administration and medroxyprogesterone acetate: What are the issues?" JAMA 249, 2922-2928. 1983. V. + Valenzuela and L. S. Benardo, "An in vitro model of persistent epileptiform activity in neocortex," Epilepsy + Research 21(3), 195-204, 1995. C. A. Slandley, et al., "Magnesium sulfate reduces seizures induced by + central administration of the excitatory amino acid N-methyl-D-aspartate in rats," Hypertension in Pregnancy + 14(2), 235-244, 1995. ("Magnesium is a physiological blocker of the NMDA receptor.") M. Simonale, et al., + "Adenosine JA(1) receptors in the rat brain in the kindled model of epilepsy," Eur. J. of Pharmac. 265(3), + 121-124, 1994. (Adenosine has potent anticonvulsive effects in various seizure models.) P. S. Timiras and H. + F. Hill, Chapter 43, in Antiepileptic Drugs: Mechanisms of Action, ed. by G. H. Glaser, et al, Raven Press, + N.Y., 1980. (Estrogens increase cortical excitability, lower convulsive thresholds, and are clearly + associated with certain cases of petit mal epilepsy. "The mechanisms of this so-called 'catamenial' epilepsy + are unknown. Water retention and electrolyte changes in the brain...have been implicated..." + "...acetazolamide (diamox), a carbonic anhydrase inhibitor and diuretic, is successful in the treatment of + many cases of these seizures, and in refractory cases progestational agents are effective." "...seizures + were more severe and frequent during the estrogen-dominated preovulatory phase of the menstrual cycle than + in the progesterone-dominated postovulatory phase." "...ACTH may trigger epileptic convulsions by increasing + intracellular sodium concentration throughout the body." "Progesterone can effectively reduce the frequency + and severity of intractable seizures associated with menstruation..." "Considering the markedly + proconvulsant effects of estrogens, it is surprising that the differential effects of sex hormones on + central neurotransmitter mechanisms have been only sparingly investigated." "...estradiol decreases + monoamine oxidase activity and increases choline acetyltransferase activity in various brain regions." + "...hypothyroidism in perinatal animals has striking suppressant effects on GABA metabolism and also causes + a persistent lowering of electroconvulsive threshold.") +

+ +

+ P. S. Timiras and H. F. Hill, "Antiepileptic drugs," Chapter 43; E. Roberts, "Epilepsy and antiepileptic + drugs: A speculative synthesis," Chapter 44, in Antiepileptic Drugs: Mechanisms of Action, ed. by G. H. + Glaser, et al., Raven Press, New York, 1980. E. V. Nikushkin, et al.,"Relationship between peroxidation and + phospholipase hydrolysis of lipids in synaptosomes," B.E.B.M.107(2)183-186, 1989. Free unsaturated fatty + acids are liberated in nerve endings and contribute to lipid peroxidation in epileptic seizures. P. A. Long, + et al., "Importance of abnormal glucose tolerance (hypoglycemia and hyperglycemia) in the aetiology of + pre-eclampsia," Lancet 1, 923-925, 1977. +

+

+ M. M. Singh, "Carbohydrate metabolism in pre-eclampsia," Br. J. Obstet. Gynaecol. 83, 124-131, 1976. +

+ +

+ N. A. Ziboh, et al., Prostaglandins 5, 233, 1974. (Eicosatrienoic (20:3 n-9) acid is a potent inhibitor of + prostaglandin synthetase.) C. Galli and C. Spagnuolo, "The release of brain free fatty acids during + ischaemia in essential fatty acid-deficient rats," J. of Neurochemistry 26, 401-404, 1976. +

+

+ B. Meldrum, "Excitatory amino acids and anoxic-ischemic brain damage," Trends Neurosci. 8, 47-48, 1985. +

+

+ B. Halliwell, "Oxidants and human disease: Some new concepts," FASEB J. 1, 358-364, 1987. "...injury to the + brain causes release of metal ions that stimulate lipid peroxidation." "..lipid peroxidation...could be + important in spreading injury to adjacent cells...." P.H. Chan, et al., "Effects of excitatory + neurotransmitter amino acids on swelling of rat brain cortical slices," J. Neurochem. 33, 1309, 1979. P. H. + Chan and R. A. Fishman, "Alterations of membrane integrity and cellular constituents by arachidonic acid in + neuroblastoma and glioma cells," Brain Res. 248, 151, 1982. +

+

+ T. O. Kokate, et al., "Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic + seizures and status epilepticus in mice," Neuropharmacology 35(8), 1049-1056, 1996. (With a second dose, + "complete protection from the...limbic seizures and status epilepticus was obtained.") J. W. Phillis, et + al., "Effect of adenosine receptor agonist on spontaneous and K+-evoked acetylcholine release from the in + vivo rat cerebral cortex," Brain Res. 605(2), 293-297, 1993. +

+

+ J. W. Phillis, et al., "Acetylcholine output from the ischemic rat cerebral cortex: Effectss of adenosine + agonists," Brain Res. 613(2), 337-340, 1993. (Acetylcholine enhances excitotoxic depolarization, + intracellular calcium levels, and neural degeneration, and could contribute to ischemic brain injury. +

+ +

+ R. L. Grief, "Thyroid status influences calcium ion accumulation and retention by rat liver mitochondria," + Proc. Soc. Exp. Biol. & Med. 189(1), 39-44, 1988. +

+

+ L. G. Cleland, et al., "Effects of dietary n-9 eicosatrienoic acid on the fatty acid composition of plasma + lipid fractions and tissue plasma lipids," Lipids 31(8), 829-837, 1996. "Dietary enrichment with ETrA + warrants further investigation for possible beneficial effects in models of inflammation and autoimmunity, + as well as in other conditions in which mediators derived from n-6 fatty acids can affect homeostasis + adversely." A. A. Starkov, et al., "Regulation of the energy coupling in mitochondria by some steroid and + thyroid hormones," Bioch. Biophys. Acta 1318(1-2), 173-183, 1997. (Thyroid and progesterone improve + respiratory efficiency, lowering oxygen consumption which restoring energy production.) R. B. Gibbs, et al., + "Effects of estrogen on potassium stimulated acetylcholine release in the hippocampus and overlying cortex + of adult rats," Brain Res. 749(1), 143-146, 1997. (Increased response.) I. V. Gusakov, et al., + "Investigation of the role of free-radical processes in epilepsy and epileptogenesis," Bull. Exp. Biol. + & Medicine 117(2), 206, 1994. +

+

+ B. K. Shakenova, "A new treatment of epilepsy resistant to traditional antiseizure pharmacotherapy," Bull. + Exp. Biol. & Medicine 117(2), 227, 1994. (Antihypoxant with antioxidant activity.) R. N. Rzaev and M. N. + Aliev, "The use of antioxidants in the treatment of tic-accompanied hyperkineses in children," Bull. Exp. + Biol. & Medicine 117(2), 222, 1994. +

+ +

+ D. A. Sutkovoi and N. I. Lisyanyi, "Relationship between the kinetics of lipid peroxidation and autoimmune + reactions after craniocerebral injury," Bull. Exp. Biol. & Medicine 117(2), 2, 1994. Winfried G. + Rossmanith, "Gonadotropin secretion during aging in women: Review article," Exp. Gerontology 30(3/4) + 369-381, 1995. "...major functional derangements, primarily at a hypothalamic rather than a pituitary site, + have been determined as concomitants of aging in women." "...aging may impair the negative feedback + sensitivity to ovarian sex steroids...." Hormonal changes at menopause "may represent the sum of functional + aberrations that were initiated much earlier in life...." "...prolonged estrogen exposure facilitates the + loss of hypothalamic neurons...." +

+ +

+ J. R. Brawer, et al., "Ovary-dependent degeneration in the hypothalamic arcuate nucleus," Endocrinology 107, + 274-279, 1980. J. Herbert and S. Zuckerman, "Ovarian stimulation from cerebral lesion in ferrets," J. + Endocrinology 17(4), 433-443, 1958. G. C. Desjardins, "Estrogen-induced hypothalamic beta-endorphin neuron + loss: A possible model of hypothalamic aging," Exp. Gerontology 30(3/4), 253-267, 1995. "This loss of opioid + neurons is prevented by treatment with antioxidants indicating that it results from estradiol-induced + formation of free radicals." "...this beta-endorphin cell loss is followed by a compensatory upregulation of + mu opioid receptors in the vicinity of LHRH cell bodies." Resulting supersensitivity of the cells results + "in chronic opioid suppression of the pattern of LHRH release, and subsequently that of LH." The neurotoxic + effects of estradiol cause a "cascade of neuroendocrine aberrations resulting in anovulatory acyclicity." + Treatment with an opiod antagonist "reversed the cystic morphology of ovaries and restored normal ovarian + cycles" in estrogen-treated rats. G. B. Melis, et al., "Evidence that estrogens inhibit LH secretion through + opioids in postmenopausal women using naloxone," Neuroendocrinology 39, 60-63, 1984. +

+

+ H. J. Sipe, et al., "The metabolism of 17 beta-estradiol by lactoperoxidase: A possible source of oxidative + stress in breast cancer," Carcinogenesis 15(11), 2637-2643, 1994. "...molecular oxygen is consumed by a + sequence of reactions initiated by the glutathione thiyl radical. ...the estradiol phenoxyl radical + abstracts hydrogen from...NADH to generate the NAD radical." "...the futile metabolism of micromolar + quantities of estradiol catalyzes the oxidation of much greater concentrations of biochemical reducing + cofactors, such as glutathione and NADH, with hydrogen peroxide produced as a consequence." S. Santagati, et + al., "Estrogen receptor is expressed in different types of glial cells in culture," J. Neurochem. 63(6), + 2058-2064, 1994. "...in all three types of glial cell analyzed in almost equal amounts..." D. X. Liu and L. + P. Li, "Prostaglandin F-2 alpha rises in response to hydroxyl radical generated in vivo," Free Radical Biol. + Med. 18(3), 571-576, 1995. "Free radicals and some free fatty acids, such as arachidonic acid + metabolites...may form a feedback loop in which generation of one type leads to formation of the other." + "Prostaglandin F-2 alpha dramatically increased in response to hydroxyl radical generation...." J. Owens and + P. A. Schwartzkroin, "Suppression of evoked IPSPs by arachidonic acid and prostaglandin F-2 alpha," Brain + Res. 691(1-2), 223-228, 1995. "These findings suggest that high levels of AA and its metabolites may bias + neurons towards excitation." [Estrogen appears to support this excitatory system at every level, while + prostaglandin F2 alpha alters steroid balance, by suppressing progesterone synthesis.] J. G. Liehr, et al., + "4-hydroxylation of estradiol by human uterine myometrium and myoma microsomes: Implications for the + mechanism of uterine tumorigenesis," Proc Natl Acad Sci USA 92(20), 9220-9224, 1995. "... elicits biological + activities distinct from estradiol, most notably an oxidant stress response induced by free radicals + generated by metabolic redox cycling reactions." +

+

+ J. G. Liehr and D. Roy, "Free radical generation by redox cycling of estrogens," Free Rad. Biol. Med. 8, + 415-423, 1990. P. Aschheim, "Resultats fournis par la greffe heterochrone des ovaires dan l'etude de la + regulation hypothalamo-hypophyso-ovarienne de la ratte senile," Gerontologia 10, 65-75, 1964/65. "Our last + experiment, grafting ovaries...into senile rats which had been castrated (ovariectomized) when young, and + its result, the appearance of estrous cycles, seems explicable by this hypothesis. Everything happens as if + the long absence of ovarian hormones... had kept the cells of the hypothalamus in the state of youth. It's + as if the messages of the circulating steroids fatigued the hypothalamic memory." "What are the factors that + cause this diminution of the hypothalamic sensitivity...? Kennedy incriminates a decrease in the cellular + metabolism in general...." +

+

+ P. Ascheim, "Aging in the hypothalamic-hypophyseal-ovarian axis in the rat," pp. 376-418 in: A. V. Everitt + and J. A. Burgess, editors, Hypothalamus, Pituitary and Aging, C. C. Thomas, Springfield, 1976. C. A. Frye + and J. D. Sturgis, "Neurosteroids affect spatial reference, working, and long-term memory of female rats," + Neurobiol. Learn. Memory 64(1), 83-96, 1995. [Female rats take longer to acquire a spatial task during + behavioral estrus.] (CA Frye, boston univ., dept biol, behavioral neurosci lab, boston 02215) + "Estrus-associated decrements in a water maze task are limited to acquisition," Physiol. Behav. 57(1), 5-14, + 1995. +

+

+ C. A. Kristensen, et al., "Effect of estrogen withdrawal on energy-rich phosphates and prediction of + estrogen-dependence monitored by in vivo 31P magnetic resonance spectoscopy of four human breast cancer + xenografts," Cancer Research 55(8), 1664-1669, 1995. This is a very important confirmation of the idea that + estrogen, by blocking energy, constrains cell function. +

+

+ A. J. Roberts and L. D. Keith, "Corticosteroids enhance convulsion susceptibility via central + mineralocorticoid receptors," Psychoneuroendocrinology 20(8), 891-902, 1995. ("...increase corticosterone + levels are associated with increased severity of ethanol, pentobarbitol, and diazepam withdrawal. Further + work with chemical convulsants suggests that mineralocorticoid receptors mediate excitatory effects of + corticosteroids on convulsion susceptibility. The circadian rhythm in convulsion susceptibility varies with + the circadian rhythm of plasma corticosterone levels and MR binding." "...MR are substantially bound at rest + and maximally occupied during the circadian peak in corticosteroid levels and during stressor exposure, + these receptors are implicated in the maintenance of and in changes in the arousal state of animals.") L. + Murri, et al., "Neuroendocrine evaluation in catamenial epilepsy," Funct. Neurol. 1(4) 399-403, 1986. "Our + data showed a reduction of luteal phase progesterone secretion; an imbalanced secretion of ovarian steroids + plays a role in the catamenial exacerbation of epilepsy." S. Bag, et al., "Pregnancy and epilepsy," J. + Neurol. 236(5), 311-313, 1989. +

+

+ "Patients with increased seizure frequency had significantly higher oestrogen levels, lower level of + progesterone...." "...abortions and status epilepticus had high serum oestrogen levels." M. I. Balabolkin, + et al., "The role of the female sex hormones in the pathogenesis of catamenial epileptic seizures," Ter. + Arkh. 66(4), 68-71, 1994. "...a tendency to deficient luteal phase and relative hyperestrogenemia in all the + cycle phases." C. A. Guerreiro, "Ovulatory period and epileptic crisis," Arq. Neuropsiquiatr. 49(2), + 198-203, 1991. "We think the estrogen peak is probably the main cause of the increased frequency of + epileptic seizures during the ovulatory period." +

+ +

+ U. Bonuccelli, et al., "Unbalanced progesterone and estradiol secretion in catamenial epilepsy," Epilepsy + Res. 3(2), 100-106, 1989. (Luteal secretion ratio, progesterone to estrogen, was significantly reduced in + patients versus controls.) +

+

+ T. Backstrom, "Epilepsy in women," Experientia 32(2), 248-249, 1976. "...a significant positive correlation + between estrogen/progesterone ratio and scores of fits." +

+

+ A. G. Herzog, "Hormonal changes in epilepsy," Epilepsia 36(4), 323-326, 1995. A. G. Herzog, "Progesterone + therapy in women with partial and secondary generalized seizures," Neurology 45(9), 1660-1662, 1995. A. G. + Herzog, "Reproductive endocrine considerations and hormonal therapy for women with epilepsy," Epilepsia + 32(Suppl.6), S27-33, 1991. "Seizure frequency varies with the serum estradiol to progesterone ratio." "... + propensity for onset at menarch and exacerbation of seizures during the months or years leading up to + menopause..." polycystic ovarian syndrome and hypogonadotropic hypogonadism are significantly + overrepresented among women with epilepsy. +

+

+ R.H. Mattson and J. A. Cramer, "Epilepsy, sex hormones, and antiepileptic drugs," Epilepsia 26(Suppl. 1), + S40-51, 1985. There were fewer seizures during the luteal phase but they increased when the progesterone + level declined. +

+

+ J.J. Jacono and J. M. Robertson, "The effects of estrogen, progesterone, and ionized calcium on seizures + during the menstrual cycle of epileptic women," Epilepsia 28(5), 571-577, 1987. A positive relation of serum + estrogen and seizures, negative relation between serum ionized calcium and seizures, and negative relation + between serum estrogen and calcium. F. E. Jensen, et al., "Epileptogenic effect of hypoxia in the immature + rodent brain," Ann. Neurol. 29(6),629-836, 1991. E. C. Wirrell, et al., "Will a critical level of + hyperventilation-induced hypocapnia always induce an absence seizure?" Epilepsia 37(5), 459-462, 1996. A. + Nehlig, et al., "Absence seizures induce a decrease in cerebral blood flow: Human and animal data," J. + Cereb. Blood Flow Metab. 16(1), 147-155, 1996. +

+ +

+ Some clinical laboratory findings in epilepsy: Folic acid, serum decrease, R. E. Davis, et al., "Serum + pyridoxal, folate, and vitamin B12 levels in institutionalized epileptics," Epilepsia 16, 463-8, 1975. +

+

+ Serum GGT, constantly elevated. Ewen and Griffiths, "Gamma-glutamyl transpeptidase: Elevated activities in + certain neurologic diseases," Am. J. Clin. Pathol. 59, 2-9, 1973. +

+

+ IgA, CSF decreased, F. Mora, et al. +

+

+ Iron-binding capacity, total, serum decrease. F. Mora, et al. Magnesium, serum, decreased; between seizures. + C S Babel, et al Prealbumin, CSF, increased, the only protein to increase in epileptics. F. Mora, et al. +

+

+ Pyridoxine, serum, sometimes decreased. R. L. Searcy, Diagnostic Biochemistry, McGraw-Hill, 1969. +

+ +

+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com +

+ + diff --git a/raypeat-articles/processed/estriol-des-ddt.html b/raypeat-articles/processed/estriol-des-ddt.html new file mode 100644 index 0000000..376ce3a --- /dev/null +++ b/raypeat-articles/processed/estriol-des-ddt.html @@ -0,0 +1,460 @@ + + Estriol, DES, DDT, etc. + +

+ Estriol, DES, DDT, etc. +

+
+

+ A review of the use of estrogens reported in J.A.M.A. (only up to 1987) found nearly 200 different + "indications" for its use. (Palmlund, 1996.) Using the conservative language of that journal, such use + could be said to constitute wildly irresponsible "empirical" medical practice. More appropriate language + could be used. +

+ +

+ Pollution of the environment and food supply by estrogenic chemicals is getting increased attention. + Early in the study of estrogens, it was noticed that soot, containing polycyclic aromatic hydrocarbons, + was both estrogenic and carcinogenic. Since then, it has been found that phenolics and chlorinated + hydrocarbons are significantly estrogenic, and that many estrogenic herbicides, pesticides, and + industrial by-products persist in the environment, causing infertility, deformed reproductive organs, + tumors, and other biological defects, including immunodeficiency. In the Columbia River, a recent study + found that about 25% of the otters and muskrats were anatomically deformed. +

+ +

+ Estrogenic pollution kills birds, panthers, alligators, old men, young women, fish, seals, babies, and + ecosystems. Some of these chemicals are sprayed on forests by the US Department of Agriculture, where + they enter lakes, underwater aquifers, rivers, and oceans. Private businesses spray them on farms and + orchards, or put them into the air as smoke or vapors, or dump them directly into rivers. Homeowners put + them on their lawns and gardens. +

+ +

+ Natural estrogens, from human urine, enter the rivers from sewage. Many tons of synthetic and + pharmaceutical estrogens, administered to menopausal women in quantities much larger than their bodies + ever produced metabolically, are being added to the rivers. +

+ +

+ In the same way that weak estrogens in the environment may become hundreds of times more estrogenic by + synergistic interactions (J. A. McLachlan, et al., Science, June 7, 1996), combinations of + natural, medical, dietary, and environmental estrogens are almost certain to have unexpected results. + The concept of a "protective estrogen" is very similar to the idea of "protective mutagens" or + "protective carcinogens," though in the case of estrogens, their promoters don't even know what the + normal, natural functions of estrogen are. + +

+ +

+ In November, 1995, an international conference was held to study the problem of "Environmental + endocrine-disrupting chemicals," and to devise strategies for increasing public awareness of the + seriousness of the problem. Their "Statement from the work session" says "New evidence is especially + worrisome because it underscores the exquisite sensitivity of the developing nervous system to chemical + perturbations that result in functional abnormalities." "This work session was convened because of the + growing concern that failure to confront the problem could have major economic and societal + implications." "We are certain of the following: Endocrine-disrupting chemicals can undermine + neurological and behavioral development and subsequent potential of individuals...." + "Because the endocrine system is sensitive to perturbation, it is a likely target for disturbance." + "Man-made endocrine-disrupting chemicals range across all continents and oceans. They are found in + native populations from the Arctic to the tropics, and, because of their persistence in the body, can be + passed from generation to generation." "...many endocrine-disrupting contaminants, even if less + potent than the natural products, are present in living tissue at concentrations millions of times + higher than the natural hormones." "The developing brain exhibits specific and often narrow + windows during which exposure to endocrine disruptors can produce permanent changes in its structure and + function." +

+ +

+ In spite of this increased exposure to estrogens, there is a new wave of advertising of estrogenic + substances, based on the idea that weak estrogens will provide protection against strong estrogens. The + environmental background of estrogenic pollution already provides a continuous estrogenic exposure. In + the 1940s, Alexander Lipshuts demonstrated that a continuous, weak estrogenic stimulus was immensely + effective in producing, first fibromas, then cancer, in one organ after another, and the effect was not + limited to the reproductive system. How is it possible that the idea of "protection" from a weak + estrogen seems convincing to so many? Isn't this the same process that we saw when the nuclear industry + promoted Luckey's doctrine of "radiation hormesis," literally the claim that "a little radiation is + positively good for us"? +

+ +

+ DES (diethyl stilbestrol) is one of the most notorious estrogens, because studies in humans revealed + that its use during pregnancy not only caused cancer, miscarriages, blood clots, etc., in the women who + used it, but also caused cancer, infertility, and deformities in their children, and even in their + grandchildren. (But those transgenerational effects are not unique to it.) +

+ +

+ Besides the absurd use of DES to prevent miscarriages, around 1950 it was also used to treat + vulvovaginitis in little girls, for menstrual irregularity at puberty, to treat sterility, dysfunctional + bleeding, endometriosis, amenorrhea, oligomenorrhea, dysmenorrhea, migraine headaches, nausea and + vomiting, and painful breast engorgement or severe bleeding after childbirth. +

+ +

+ DES is a "weak" estrogen, in the sense that it doesn't compete with natural estrogens for the "estrogen + receptors." (Estriol binds more strongly to receptors than DES does: "Cytosolic and nuclear estrogen + receptors in the genital tract of the rhesus monkey," J. Steroid Bioch. 8(2), 151-155, 1977.) Pills + formerly contained from 5 to 250 mg. of DES. The 1984 PDR lists doses for hypogonadism and + ovarian failure as 0.2 to 0.5 mg. daily. In general, dosage of estrogens decreased by a factor of 100 + after the 1960s. +

+ +

+ An aggressively stupid editorial by Alvin H. Follingstad, from the Jan. 2, 1978, issue of JAMA, pages + 29-30, "Estriol, the forgotten estrogen?" is being circulated to promote the use of estriol, or the + phytoestrogens. It argues that women who secrete larger amounts of estriol are resistant to cancer. +

+ +

By some tests, estriol is a "weak estrogen," by others it is a powerful estrogen.

+ +

+ When estriol was placed in the uterus of a rabbit, only 1.25 mcg. was sufficient to prevent implantation + and destroy the blastocyst. (Dmowski, et al., 1977.) Since the effect was local, the body weight of the + animal doesn't make much difference, when thinking about the probable effect of a similar local + contentration of the hormone on human tissues. The anti-progestational activity of estriol and estradiol + are approximately the same. (Tamotsu and Pincus, 1958.) +

+ +

+ When 5 mg. of estriol was given to women intravaginally, this very large dose suppressed LH within 2 + hours, and suppressed FSH in 5 hours. Given orally, 8 mg. had similar effects on LH and FSH after 30 + days, and also had an estrogenic effect on the vaginal epithelium.. These quick systemic effects of a + "weak estrogen" are essentially those of a strong estrogen, except for the size of the dose. (Schiff, et + al., 1978.) +

+ +

When administered subcutaneously, estriol induced abortions and stillbirths (Velardo, et al.)

+ +

+ Another indication of the strength of an estrogen is its ability to cause the uterus to enlarge. Estriol + is slightly weaker, in terms of milligrams required to cause a certain rate of uterine enlargement, than + estradiol. (Clark, et al., 1979.) But isn't the important question whether or not the weak estrogen + imitates all of the effects of estradiol, including carcinogenesis and blood clotting, in addition to + any special harmful effects it might have? +

+ +

+ When added to long-term culture of human breast cancer cells, estriol stimulated their growth, and + overcame the antiestrogenic effects of tamoxifen, even at concentrations hundreds of times lower than + that of tamoxifen. "The data do not support an antiestrogenic role for estriol in human breast cancer." + (Lippman, et al., 1977.) +

+ +

+ Studies of the urinary output of estriol/estradiol in women with or without breast cancer do not + reliably show the claimed association between low estriol/estradiol and cancer, and the stimulating + effect of estriol on the growth of cancer cells suggests that any alteration of the estrogen ratio is + likely to be a consequence of the disease, rather than a cause. The conversion of estradiol to + other estrogens occurs mainly in the liver, in the non-pregnant woman, as does the further metabolism of + the estrogens into glucuronides and sulfates. The hormonal conditions leading to and associated with + breast cancer all affect the liver and its metabolic systems. The hydroxylating enzymes are also + affected by toxins. Hypothyroidism (low T3), low progesterone, pregnenolone, DHEA, etiocholanolone, and + high prolactin, growth hormone, and cortisol are associated with the chronic high estrogen and breast + cancer physiologies, and modify the liver's regulatory ability. +

+ +

+ The decreased output of hormones when the fetal-placental system is dying is a natural consequence, + since the placenta produces hormones, and during pregnancy converts estradiol to estriol. Since + estradiol in excess kills the fetus, its conversion by the placenta to estriol is in accord with the + evidence showing that estriol is the more quickly excreted form. (G. S. Rao, 1973.) The conversion of + 16-hydroxy androstenedione and 16-hydroxy-DHEA into estriol by the placenta (Vega Ramos, 1973) would + also cause fetal exhaustion or death to result in lower estriol production. But a recent observation + that a surge of estriol production precedes the onset of labor, and that its premature occurrence can + identify women at risk of premature delivery (McGregor, et al., 1995) suggests that the estriol surge + might reflect the mother's increased production of adrenal androgens during stress. (This would be + analogous to the situation in the polycystic ovary syndrome, in which excessive estradiol drives the + adrenals to produce androgens.) +

+ +

+ Estetrol, which has one more hydroxyl group than estriol, is a "more sensitive and reliable indicator of + fetal morbidity than estriol during toxemic pregnancies," because it starts to decrease earlier, or + decreases more, than estriol. (Kundu, et al., 1978.) This seems to make it even clearer that the decline + of estriol is a consequence, not a cause, of fetal sickness or death. +

+ +

+ A 1994 publication (B. Zumoff, "Hormonal profiles in women with breast cancer," Obstet. Gynecol. + Clin. North. Am. (U.S.) 21(4), 751-772) reported that there are four hormonal features in women + with breast cancer: diminished androgen production, luteal inadequacy, increased + 16-hydroxylation of estradiol, and increased prolactin. The 16-hydroxylation converts estradiol into + estriol. +

+ +

+ A new technique for radiographically locating a hormone-dependent breast cancer is based on the fact + that estriol-sulfate is a major metabolite of estradiol. The technique showed the tumor to have about a + six times higher concentration of estriol-sulfate than liver or muscle. (N. Shimura, et al., "Specific + imaging of hormone-dependent mammary carcinoma in nude mice with [131I]-anti-estriol 3-sulfate + antibody," Nucl. Med. Biol. (England) 22(5), 547-553, 1995.) +

+ +

+ Another association of elevated conversion of estradiol to estriol with disease was found to occur in + men who had a myocardial infarction, compared to controls who hadn't. (W. S. Bauld, et al., 1957.) +

+ +

+ The estrogens in clover have been known for several decades to have a contraceptive action in sheep, and + other phytoestrogens are known to cause deformities in the genitals, feminization of men, and anatomical + changes in the brain as well as functional masculinization of the female brain. (Register, et al., 1995; + Levy, et al, 1995; Clarkson, et al., 1995; Gavaler, et al., 1995.) The effects of the phytoestrogens are + very complex, because they modify the sensitivity of cells to natural estrogens, and also modify the + metabolism of estrogens, with the result that the effects on a given tissue can be either pro-estrogenic + and anti-estrogenic. For example, the flavonoids, naringenin, quercetin and kaempherol (kaempherol is an + antioxidant, a phytoestrogen, and a mutagen) modify the metabolism of estradiol, causing increased + bioavailability of both estrone and estradiol. (W. Schubert, et al., "Inhibition of 17-beta-estradiol + metabolism by grapefruit juice in ovariectomized women," Maturitas (Ireland) 30(2-3), 155-163, + 1994.) +

+ +

+ Why do plants make phytoestrogens? There is some information indicating that these compounds evolved to + regulate the plants' interactions with other organisms--to attract bacteria, or to repel insects, for + example, rather than just as pigment-forming materials. (Baker, 1995.) The fact that some of them bind + to our "estrogen receptors" is probably misleading, because of their many other effects, including + inhibiting enzyme functions involved in the regulation of steroids and prostaglandins. Their + biochemistry in animals is much more complicated than that of natural estrogens, which is itself so + complicated that we can only guess what the consequences might be when we change the concentration and + the ratio of substances in that complex system. (See quotation from Velardo, et al., page 6) +

+ +

+ These "natural" effects in sheep were forerunners of the observed estrogenic effects in wild animals, + caused by pollutants. Twenty-five years ago I reviewed many of the issues of estrogen's toxicity, and + the ubiquity of estrogenic substances, and since then have regularly spoken about it, but I haven't + concentrated much attention on the phytoestrogens, because we can usually just choose foods that are + relatively free of them. They are so often associated with other food toxins--antithyroid factors, + inhibitors of digestive enzymes, immunosuppressants, etc.--that the avoidance of certain foods is + desirable. Recently an advocate of soybeans said "if they inhibit the thyroid, why isn't there an + epidemic of hypothyroidism in Asia?" I happened to hear this right after seeing newspaper articles about + China's problem with 100,000,000 cretins; yes, Asia has endemic hypothyroidism, and + beans are widely associated with hypothyroidism. +

+ +

+ When I first heard about clover-induced miscarriages in sheep, I began reading about the subject, + because it was relevant to the work I was doing at that time on reproductive aging. Sheep which are + adapted to living at high altitude, where all animals have reduced fertility, have an adaptive type of + hemoglobin, with a greater affinity for oxygen. Fetal hemoglobin, in animals at sea-level, has a great + affinity for oxygen, making it possible for the fetus to get enough oxygen, despite its insulation from + the mother's direct blood supply. The high-altitude-tolerant sheep have hemoglobin which is able to + deliver sufficient oxygen to the uterus to meet the needs of the embryo/fetus, even during relative + oxygen-deprivation. These sheep are able to sustain pregnancy while grazing on clover. It seemed evident + that estrogen and high altitude had something in common, namely, oxygen deprivation, and it also seemed + evident that these sheep provided the explanation for estrogen's abortifacient effects. +

+ +

+ Estrogen's effects, ranging from shock to cancer, all seem to relate to an interference with the use of + oxygen. Different estrogens have different affinities for various tissues, and a given substance is + likely to have effects other than estrogenicity, and the presence of other substances will modify the + way a tissue responds, but the stressful shift away from oxidative production of energy is the factor + that all estrogens have in common. Otherwise, how could suffocation and x-irradiation have estrogenic + effects? +

+ +

+ Pharmaceutical misrepresentations regarding the estrogens rank, in terms of human consequences, with the + radiation damage from fall-out from bomb tests and reactor-leaks, with industrial pollution, with + degradation of the food supply--with genocide, in fact. +

+ +

+ Advertising gets a bad name when it can't be distinguished from mass murder. At a certain point, we + can't afford to waste our time making subtle distinctions between ignorance and malevolence. If we begin + pointing out the lethal consequences of "stupid" or quasi-stupid commer- cial/governmental policies, the + offenders will have the burden of proving that their actions are the result of irresponsible ignorance, + rather than criminal duplicity. From the tobacco senators to the chemical/pharmaceutical/food/energy + industries and their agents in the governmental agencies, those who do great harm must be held + responsible. +

+ +

+ The idea of corporate welfare, in which public funds are given in massive subsidies to rich + corporations, is now generally recognized. Next, we have to increase our consciousness of corporate + responsibility, and that ordinary criminal law, especially RICO, can be directly applied to + corporations. It remains to be seen whether a government can be made to stop giving public funds to + corporations, and instead, to begin enforcing the law against them--and against those in the agencies + who participated in their crimes. +

+ +

+ In the U.S., the death penalty is sometimes reserved for "aggravated homicide." If those who kill + hundreds of thousands for the sake of billions of dollars in profits are not committing aggravated + homicide, then it must be that no law written in the English language can be objectively interpreted, + and the legal system is an Alice in Wonderland convenience for the corporate state. +

+ +

Copyright: Raymond Peat, PhD 1997

+

PO Box 5764 Eugene, OR 97405

+ +

 

+

REFERENCES

+

+ Dr. Bernard Weiss, Dept. of Environmental Medicine, University of Rochester School of Medicine, + Rochester, NY. and 17 others, work session on environmental endocrine-disrupting chemicals, Nov. 5-10, + 1995. +

+

+ Isaac Schiff, et al., "Effects of estriol administration on the hypogonadal woman," Fertil. Steril. + 30(3), 278-282, 1978. +

+

+ N. P. J. Kundu, et al., "Sequential determination of serum human placental lactogen, estriol, and + estetrol for assessment of fetal morbidity," Obstet. Gynecol. 52(5), 513-520, 1978. +

+

+ M. E. Lieberman, et al., "Estrogen control of prolactin synthesis in vitro," P.N.A.S. (USA) 75(12), + 5946-5949, 1978. +

+

+ Marc Lippman, et al., "Effects of estrone, estradiol and estriol on hormone-responsive human breast + cancer in long term tissue culture," Cancer Res. 37(6), 1901-1907, 1977. +

+

+ W. P. Dmowski, et al., "Effect of intrauterine estriol on reproductive function in the rabbit," Fertil. + Steril. 28(3), 262-8, 1977. +

+

+ W. S. Bauld, et al, "Abnormality of estrogen metabolism in human subjects with myocardial infarction," + Canadian Jour. Biochem. and Physiol. 35(12), 1277-1288, 1957. (The conversion of estradiol to + estriol was higher in men with previous myocardial infarction than in controls.) +

+

+ R. A. Edgren and D. W. Calhoun, "Interaction of estrogens on the vaginal smear of spayed rats," Am. + J. Physiol. 189(2), 355-357, 1957. "Employing the vaginal smear as an index of effect, + combinations of various estrogenic substances were tested for interaction. Studies were concentrated at + the approximate 50% response level." "These data are interpreted as indicating simple additive + relationships among the compounds tested." "Curiously then, estrogens that showed inhibitory + interrelationships when tested on uterine growth had simple additive interactions when tested on + the vaginal smears." "...it seems reasonable to postulate that a given hormone combination may evoke + differing levels of response in different target organs, and particularly, that increase of one + component may increase response at one site while decreasing it at another. Many steroids...are + present in the mammalian circulation during various phases of the sex cycle and are known to modify + the effects of any given estrogen. This hormonal multiplicity apparently constitutes an + estrogen-buffering system and supports the hypothesis that sexual responses depend '...upon a rather + precise hormonal homeostasis.'" +

+

+ R. C. Merrill, "Estriol: A review," Physiol. Revs. 38(3), 463-480, 1958. "...estriol + itself is a potent estrogen, contrary to the usual conception of its being just a metabolite of the + more potent estrone and estradiol. Although ordinarily less effective than estrone and + estradiol in promoting vaginal cornification, estriol, under optimum conditions, approaches their + effectiveness for this purpose. Estriol is more potent than estrone or estradiol in causing + establishment and opening of the vaginal orifice, in promoting imbibition of uterine fluid, in + increasing lactic dehydrogenase activity in the uterus, and in stimulating mitotic activity in the + epidermis of the mouse ear. The activity of estriol is of the same order of magnitude as that of estrone + and estradiol in other estrogenic actions, such as to promote uterine growth at low concentrations + (although less effective at high doses), to increase beta-glucuronidase and reduced diphosphopyridine + nucleotide oxidase activity in the uterus, to reduce motility of the uterus in vivo, and to stimulate + ovarian growth, body weight, phagocytosis of carbon by reticuloendothelial cells, ciliary movements of + the buccopharyngeal mucose of the frog, and new bone formation. The fibromatogenic activity of estriol + in the guinea pig is much less than that of estrone or estradiol. Recent experiments suggest and partly + verify the hypothesis that estriol stimulates the cervix, vagina and vulva more effectively than estrone + or estradiol, whereas the latter are much more effective on the corpus uteri." +

+

+ T. Miyake and G. Pincus, "Anti-progestational activity of estrogens in rabbit endometrium," Proc. + Soc. Exptl. Biol. and Med. 99(2) 478-482, 1958. "The anti-progestational activity of 4 + estrogens--estrone, estradiol, estriol, and stilbestrol--administered subcutaneously with progesterone + into Clauberg rabbits has been demonstrated...." "The anti-progestational activities of these + estrogens are approximately the same." "...estrogen may depress reactivity of the + endometrium to progesterone rather than neutralize or inactivate progesterone in the body." +

+

+ J. T. Velardo, et al., "Effect of various steroids on gestation and litter size in rats," Fertility + and Sterility 7(4), 301-311, 1956. "...certain metabolites of estrogenic and progestative + substances that were previously considered to be 'weak' or inert may well play a role in the + reproductive process." "We have been impressed with the probability that any endocrine + receptor-organ response is not accomplished by the independent action of one hormone alone. It + appears more likely that such response is the physiological expression of the sum total of the + biologic hormones and their metabolites in concert on the receptor organs." "The effect of + estriol on the birth rate of these rats was more dramatic." "...when estriol was used before mating, it + reduced the litter size to 66 per cent of the controls." "However, when the same dose was employed from + the day of mating and daily thereafter beyond the time of usual implantation, 6 days later, a reduction + of live births to 33 per cent of the controls was produced. In this experiment the medication was + withheld until after ovulation had presumably occurred. The presence of placental scars and an increased + incidence of abortions and stillbirths argues against the possibility that the fertile ova have been + 'locked' by the estrogen in the tubes." "...the incidence of placental scars, abortions, and stillbirths + further bears witness to the possibility that the steroids employed interfered with the optimum + differentiation of progestational endometrial changes, rather than affecting any suppression of + ovulatory mechanisms." +

+

+ B. Register, et al., "Effect of neonatal exposure to diethylstilbestrol, coumestrol, and beta-sitosterol + on pituitary responsiveness and sexually dimorphic nucleus volume," P.S.E.B.M. 208, 72, 1995. +

+

+ J. R. Levy, et al., "Effect of prenatal exposure to the phytoestrogen genistein on sexual + differentiation in rats," P.S.E.B.M. 208, 60, 1995. +

+

+ B.D. Lyn-Cook, et al., "Methylation profile and amplification of proto-oncogenes in rat pancreas induced + with phytoestrogens," PSEBM 208, 116, 1995. +

+

+ J. S. Gavaler, et al., "Phytoestrogen congeners of alcoholic beverages: Current status,: PSEBM + 208, 98, 1995. +

+

+ A. I. Nwannenna, et al., "Clinical changes in ovariectomized ewes exposed to phytoestrogens and + 17beta-estradiol implants," PSEBM 208, 92, 1995. +

+

+ P. L. Whitten, et al., "Influence of phytoestrogen diets on estradiol action in the rat uterus," + Steroids 59, 443-449, 1994. "Coumestrol did not antagonize the uterotrophic action of estradiol + when administered either prior to, or jointly with, E2 treatment, or when administered orally or + parenterally." "These findings contradict the assumption that all phytoestrogens are necessarily + antiproliferative agents...." +

+

+ M. E. Baker, "Endocrine activity of plant-derived compounds: An evolutionary perspective," + PSEBM 208, 131, 1995. +

+

+ I. Palmlund, "To cell from environment," Chapter 19 in Cellular and Molecular Mechanisms of Hormonal + Carcinogenesis, published by Wiley-Liss. +

+

+ J. H. Clark, et al., "Nuclear binding of the estrogen receptor: Heterogeneity of sites and uterotropic + response," Steroid Hormone Receptor Systems, page 17, 1979. +

+

+ P. Vega Ramos, et al., "Formation of oestriol from C19, 16-oxygenated steroids by microsomal + preparations of human placenta," Res. on Steroids, vol. V, page 79, Proc. of the Fifth Meeting + of the International Study Group for Steroid Hormones, edited by M. Finkelstein, et al., 1973. +

+

G. S. Rao, "Enzymes in steroid metabolism," Res. on Steroids, vol. V, page 175, 1973.

+

+ L. H. Carter and C. B. Harrington, Administrative Law and Politics HarperCollins, 1991. + "Capture occurs when agencies informally promote the very interests they are officially responsible for + regulating." In 1925, Coolidge's appointment of "anti-public" W. E. Humphrey to the FTC led some of its + former supporters to call for the abolition of the FTC. +

+

+ + "If nearly a century of regulatory history tells us anything, it is that the rules-making agencies + of government are almost invariably captured by the industries which they are established to + control." Robert Heilbroner, In the Name of Profit, 1972, p. 239. "Federal economic + regulation was generally designed by the regulated interest to meet its own end, and not those of the + public or the commonweal." Gabriel Kolko, The Triumph of Conservatism: A Reinterpretation of + American History, 1900-1916, 1963. +

+

+ "It is a given in the modern doctrine of most tort laws that the existence of potential liability if + anything encourages citizens to use greater thoughtfulness and care in their daily actions, and no + obvious reasons suggest the same dynamic should not affect public officials." Adm. Law. & Pols., p. + 404. "That Congress decided, after the passage of the Fourteenth Amendment, to enact legislation + specifically requiring state officials to respond in federal court for their failures to observe the + constitutional limitations on their powers is hardly a reason for excusing their federal counterparts + for the identical constitutional transgressions." "In situations of abuse, an action for damages + against the responsible official can be an important means of vindicating constitutional + guarantees...." Justice White, Butz v. Economou, p. 409, Adm. Law & Pols. + +

+
+ + diff --git a/raypeat-articles/processed/estrogen-age-stress.html b/raypeat-articles/processed/estrogen-age-stress.html new file mode 100644 index 0000000..45dea46 --- /dev/null +++ b/raypeat-articles/processed/estrogen-age-stress.html @@ -0,0 +1,1006 @@ + + Estrogen and brain aging in men and women: Depression, energy, stress + +

+ Estrogen and brain aging in men and women: Depression, energy, stress +

+ +

+

+ Although the incidence of Alzheimer's disease is 2 or 3 times as high among women as among men, there is a + major campaign under way to convince the public that taking estrogen supplements will prevent the disease. + Estrogen is now mainly promoted to prevent osteoporosis (another problem that is more common in women) and + heart disease (which is more common in men). +

+

+ This substance, which came into medical use as "the female hormone" for the treatment of "female problems," + especially for improving fertility, and then for preventing fertility as the oral contraceptive, is now + being aimed primarily at the post-reproductive population, for problems that are essentially unrelated to + femininity. It is, in fact, being presented to the public as something to prevent major age-related + conditions. +

+ +

+ Brain degeneration, like osteoporosis, takes years to develop. Analysis of letters written by young women, + for example, showed limited mental functioning in those who many years later developed Alzheimer's disease, + and young women who have small bones are the ones most likely to develop osteoporosis later. + It seems clear that the course of degenerative aging processes is set in young adulthood (or even + earlier), and that it is never too early to be concerned with correcting processes that are going in the + wrong direction. (See Walker, et al., 1988, and Smith, et al., 1992.) +

+

+ In "The Biological Generality of Progesterone" (1979) I proposed that the life-long trajectory of energy + production and longevity was strongly influenced by prenatal nutrition and progesterone. This idea was based + on work by people such as Marion Diamond, who showed that prenatal progesterone enlarges the cortex of the + brain, and that estrogen makes it smaller, and Leonell Strong, who showed that a treatment that lowered the + estrogen function in a young mouse could produce cancer-free offspring for several generations. Strong's + work was very encouraging, because it showed that biological problems that had been "bred in" over many + generations could be corrected by some simple metabolic treatments. +

+

+ Seeing these profoundly toxic long-range effects of estrogen, which shaped the animal's growth, development, + function, and even its heredity, made it important to learn how estrogen works, because such fundamental + changes covering the whole range of biology, produced by a simple little molecule, promised to reveal + interesting things about the nature of life. +

+

+ Aging is an energy problem, and in the brain, which has extremely high energy requirements, interference + with the energy supply quickly causes cells to die. +

+

+ I believe that estrogen's "principle," in all of its actions, is to interfere with the respiratory mode of + energy production. This is an integrating principle that explains estrogen's immediate, direct effects on + cells and organisms, which aren't explained by the idea that it acts on the genes through a specific + "estrogen receptor." (It's hard to imagine, for example, how the "estrogen receptor" doctrine could explain + the fact that a single injection of estrogen can kill a large portion of brain cells.) It explains why + estrogen causes cells to take up water, allowing calcium to enter, activating various enzymes and cell + division. On the organismic level, it explains why estrogen mimics "shock," releasing histamine and + activating the nervous and glandular stress response system. The inefficiency of metabolism which doesn't + use oxygen in the normal way causes glucose to be used rapidly, and this in itself is enough to trigger the + release of pituitary ACTH and adrenal cortisol. The ACTH, and related hormones, liberate free fatty acids, + which cells take up instead of glucose, and this (in the so-called Randall cycle) further limits the body's + ability to oxidize glucose. +

+

+ People have spoken of "cascades" in relation to the adrenal glucocorticoids (e.g., cortisol) and estrogen, + leading to cell damage, but really both of these hormonal cascades have to be seen as part of a more general + collapse of adaptive systems, as a result of both chronic and immediate inadequacies of energy production. +

+

+ Estrogen activates the adrenal stress reaction by way of the hypothalamus and pituitary, by direct + actions on the adrenal glands, and by a variety of indirect effects, such as the increase of free fatty + acids. It activates the excitotoxic glutamic acid pathway, and interferes with protective adenosine + inhibition of nerves. It has both direct and indirect ways of promoting the formation of nitric oxide + and carbon monoxide. These, and other estrogen-promoted factors, quickly and seriously interfere with + mitochondrial respiration. Many of these effects contribute to increased intracellular calcium and free + radical production, contributing to both the excitatory excess and the energy deficit. +

+ +

+ The biochemical details of these cascades are mainly interesting because they show how many different kinds + of stress converge on a few physiological processess--mitochondrial energy production, cellular excitation, + and intercellular communication--which, when damaged thousands of times, lead to the familiar states of old + age. These few functions, damaged by an infinite variety of stresses, have their own complexly adaptive ways + of deteriorating, producing the various degenerative diseases. +

+

+ This perspective brings dementia, heart failure, autoimmunity, immunodeficiency and other diseases of aging + together, in ways that allow generalized therapeutic and preventive approaches. +

+

+ The antistress, antiestrogen approaches become fundamental to prevention of aging. +

+

+ The pro-estrogenic nature of the unsaturated fatty acids is probably the biggest barrier to the radical + elimination of degenerative diseases. Various saturated fatty acids, including butyric, octanoic, and + palmitic, have protective effects on mitochondrial respiration. +

+

+ Progesterone is the basic brain-protective antiestrogen. It works to protect the brain at many + levels (preventing lipid peroxidation, exitotoxicity, nitric oxide damage, energy deficit, edema, etc.) + and it promotes repair and recovery. +

+

+ Progesterone in most cases has effects opposite to estrogen's, improving mitochondrial energy production + while preventing excessive excitation. Along with pregnenolone, progesterone is recognized as a neurosteroid + with anti-excitotoxic actions, with the ability to promote repair and regeneration of the nervous system. + (Roof, Stein, Faden; Schumacher, et al.; Baulieu.) +

+ +

+ The use of aspirin, which reduces inflammation and inhibits the formation of neurotoxic prostaglandins, is + known to be associated with a lower incidence of Alzheimer's disease, and in other contexts, it offers + protection against estrogen. Naloxone, the antiendorphin, has been found to reverse some of the cumulative + effects of stress, restoring some pituitary and ovarian function, and it promotes recovery after brain + injury; in a variety of ways, it corrects some of estrogen's toxic effects. +

+

+ Adenosine helps to maintain brain glycogen stores, which are lost in stress and aging. Vitamin B12 protects + against nitric oxide, and improves alertness. +

+

+ Pyruvic acid has brain-protective effects, apparently through its decarboxylation (producing carbon dioxide) + rather than through its use as an energy source, since other ketoacids are similarly protective. (The + ketoacids occur in some natural foods.) The directly brain-protective effect of carbon dioxide offers many + clues that should be interpreted in relation to estrogen's toxicity, since many of their effects on nerves + are opposite. + Estrogen blocks the production of energy while it stimulates nerve cells to use energy more rapidly, and + carbon dioxide promotes the production of energy, while restraining the excitation which expends energy. + + + The presence of carbon dioxide is an indicator of proper mitochondrial respiratory functioning. +

+

+ Pharmaceutical blockers of glutamic acid transmission, and of calcium and sodium uptake, prevent some + deterioration following brain injury, but the most physiological way to protect against those toxic + processes is to maintain metabolic energy at a high level. Magnesium, which is protective against excitatory + damage and is a calcium antagonist, tends to be retained in proportion to the activity of thyroid hormone. +

+

+ As I have discussed previously, progesterone alone has brought people out of post-epileptic dementia and + senile dementia, but it is reasonable to use a combined physiological approach, including thyroid. +

+

+ Besides providing new insights into biological energy and aging, the recognition that estrogen activates the + stress hormone system--the pituitary-adrenal system--also provides clear insights into other problems, such + as the polycystic ovary syndrome, hirsutism, adrenal hyperplasia, Cushing's disease, etc. +

+

REFERENCES

+ +

+ [The references are clustered into groups, showing estrogen's indirect toxicity through its activation of + the adrenal hormones, its direct brain-toxicity, and some of the interactions between these and fats, nitric + oxide, etc.] +

+

.

+

+ Stress 1996 Jul;1(1):1-19 + Stress, Glucocorticoids, and Damage to the Nervous System: The Current State of Confusion. + Sapolsky RM Department of Biological Sciences, Stanford University, Stanford, CA 94305. An extensive + literature demonstrates that glucocorticoids (GCs), the adrenal steroids secreted during stress, can + have a broad range of deleterious effects in the brain. The actions occur predominately, but not + exclusively, in the hippocampus, a structure rich in corticosteroid receptors and particularly sensitive + to GCs. The first half of this review considers three types of GC effects: a) GC-induced atrophy, in + which a few weeks' exposure to high GC concentrations or to stress causes reversible atrophy of + dendritic processes in the hippocampus; b) GC neurotoxicity where, over the course of months, GC + exposure kills hippocampal neurons; c) GC neuroendangerment, in which elevated GC concentrations at the + time of a neurological insult such as a stroke or seizure impairs the ability of neurons to survive the + insult. The second half considers the rather confusing literature as to the possible mechanisms + underlying these deleterious GC actions. Five broad themes are discerned: a) that GCs induce a + metabolic vulnerability in neurons due to inhibition of glucose uptake; b) that GCs exacerbate various steps + in a + damaging cascade of glutamate excess, calcium mobilization and oxygen radical generation. In a review a + number of years ago, I concluded that these two components accounted for the deleterious GC effects. + Specifically, the energetic vulnerability induced by GCs left neurons metabolically compromised, and + less able to carry out the costly task of containing glutamate, calcium and oxygen radicals. More recent + work has shown this conclusion to be simplistic, and GC actions are shown to probably involve at least + three additional components: c) that GCs impair a variety of neuronal defenses against neurologic + insults; d) that GCs disrupt the mobilization of neurotrophins; e) that GCs have a variety of + electrophysiological effects which can damage neurons. + The relevance of each of those mechanisms to GC-induced atrophy, neurotoxicity and + neuroendangerment is considered, as are the likely interactions among them. +

+ +

+ J Clin Endocrinol Metab 1996 Oct;81(10):3639-43 Short-term estradiol treatment enhances + pituitary-adrenal axis and sympathetic responses to psychosocial stress in healthy young men. + Kirschbaum C, Schommer N, Federenko I, Gaab J, Neumann O, Oellers M, Rohleder N, Untiedt A, Hanker J, Pirke + KM, Hellhammer DH Center for Psychobiological, University of Trier, Germany. + Evidence from animal studies and clinical observations suggest that the activity of the + pituitary-adrenal axis is under significant influence of sex steroids. The present study investigated + how a short term elevation of estradiol levels affects ACTH, cortisol, norepinephrine, and heart rate + responses to mental stress in healthy men. + In a double blind study, 16 men received a patch delivering 0.1 mg estradiol/day transdermally, and + age- and body mass index-matched control subjects received a placebo patch. Twenty-four to 48 h later, they + were exposed to a brief psychosocial stressor (free speech and mental arithmetic in front of an audience). + In response to the psychosocial stressor, ACTH, cortisol, norepinephrine, and heart rate were increased in + both experimental groups (all P < 0.0001). However, the + estradiol-treated subjects showed exaggerated peak ACTH (P < 0.001) and cortisol (P < 0.002) + responses compared to the placebo group. Also, the norepinephrine area under the response curve was + greater in the estradiol group + + (P < 0.05). Although heart rate responses differences failed to reach statistical significance, they, + too, tended to be larger in the estradiol group. Neither mood ratings before or after the stressor, nor + ratings of the perception of the stressor could explain the observed endocrine response differences. In + conclusion, short term estradiol administration resulted in hyperresponses of the pituitary-adrenal + axis and norepinephrine to psychosocial stress in healthy young men independent of psychological + effects, + as assessed in this study. +

+ +

+ J Appl Physiol 1996 Mar;80(3):931-9 + Treadmill exercise training and estradiol increase plasma ACTH and prolactin after novel + footshock. White-Welkley JE, Warren GL, Bunnell BN, Mougey EH, Meyerhoff JL, Dishman RK "We + examined whether rats that were treadmill exercise trained (Tr) or chronically immobilized (CI) had similar + responses by the hypothalamic-pituitary-adrenal (HPA) cortical axis to acute stress and whether the HPA + responses interacted with the hypothalamic-pituitary-gonadal (HPG) axis." "[ACTH] and + [prolactin] after + footshock were higher in Tr rats with E2 compared with CI and sedentary rats without E2; + recovery levels for sedentary animals were higher after Run compared with Im. The elevation in + [corticosterone] from minute 1 to 15 of recovery was higher after the familiar Run and Im conditions. Our + findings are consistent with an increased responsiveness of the HPA axis to novel footshock after treadmill + exercise training that is additionally modulated by the HPG axis." +

+

+ Endocrinology 1992 Sep;131(3):1261-9. + Chronic estrogen-induced alterations in adrenocorticotropin and corticosterone secretion, and + glucocorticoid receptor-mediated functions in female rats. Burgess LH, Handa RJ "The effect of + estrogen (E) on the hypothalamic-pituitary-adrenal axis was investigated in female Sprague-Dawley rats." + "...the ACTH and CORT secretory responses to ether stress could be suppressed by exogenous RU 28362 (a + specific glucocorticoid receptor agonist; 40 micrograms/100 g BW for 4 days) in OVX controls (P less than + 0.05), but not in E-treated animals. These data suggest that E can impair glucocorticoid + receptor-mediated delayed or slow negative feedback." "Thus, E + treatment results in a loss of the glucocorticoid receptor's ability to autoregulate; this suggests that + E may cause a functional impairment of the glucocorticoid receptor even though receptor binding appears + normal. These findings suggest that hyperactivation of the hypothalamic-pituitary-adrenal axis after + stress in E-treated rats is due in part to impaired glucocorticoid receptor-mediated slow negative + feedback." + +

+

+ Am J Physiol 1994 Jul;267(1 Pt 1):E32-8 Lesions of hypothalamic paraventricular nuclei do not + prevent the effect of estradiol on energy and fat balance. + + Dagnault A, Richard D. "Plasma levels of corticosterone and ACTH were higher in E2-treated rats than + in animals receiving the placebo treatment. The present results provide evidence that the hypothalamic + PVH is not an essential neuroanatomical structure in the effects of E2 on energy and fat balances." + +

+

+ Fertil Steril 1994 Oct;62(4):738-43 + Ovarian suppression reduces clinical and endocrine expression of late-onset congenital adrenal + hyperplasia due to 21-hydroxylase deficiency. + Carmina E, Lobo RA "OBJECTIVE: To determine the effectiveness of GnRH-agonist (GnRH-a) treatment in women + with late onset congenital adrenal hyperplasia." "CONCLUSIONS: Suppression of the ovary with GnRH-a + treatment was beneficial in these patients with late-onset congenital adrenal hyperplasia. An ovarian + influence on the clinical and biochemical findings of the disorder is suggested." +

+

+ Life Sci 1995;57(9):833-7. + Effects of sex hormones on the steroidogenic activity of dispersed adrenocortical cells of the rat + adrenal cortex. Nowak KW, Neri G, Nussdorfer GG, Malendowicz LK "The effect of 17 + beta-estradiol and testosterone on glucocorticoid secretion were studied in vitro by using dispersed inner + adrenocortical cells obtained from gonadectomized female and male rats. Independently of the sex of animals, + estradiol enhanced basal, but not ACTH-stimulated corticosterone (B) secretion; conversely, testosterone + inhibited ACTH-stimulated, but not basal B output." "Testosterone inhibited by about 30% ACTH-stimulated + PREG production and by about 54% total post-PREG secretion (B was decreased to 56% of the control value, and + other steroid hormones were below the limit of sensitivity of our assay system). These findings indicate + that sex hormones directly affect rat adrenocortical secretion, + mainly by acting on the rate-limiting step of steroidogenesis (i.e. the conversion of cholesterol to + PREG); moreover, they suggest that testosterone is also able depress the activity of the enzymes + operating distally to cholesterol side-chain cleavage." + +

+ +

+ J Endocrinol 1995 Feb;144(2):311-21 + The influence of ovarian steroids on hypothalamic-pituitary-adrenal regulation in the female + rat. Carey MP, Deterd CH, de Koning J, Helmerhorst F, de Kloet ER "The present study examined + the association between hypothalamic- pituitary-adrenal (HPA) and hypothalamic-pituitary-ovarian axes. HPA + activity determined by plasma levels of adrenocorticotropin (ACTH) and corticosterone (B) was assessed in + intact female rats as a function of oestrous cycle stage under resting conditions and after exposure to a 20 + min restraint stress. To delineate the roles of oestradiol and progesterone in HPA axis modulation, plasma + concentrations of ACTH and B were determined in ovariectomised (OVX) animals treated with oestradiol and/or + progesterone under resting conditions and during exposure to the stress of a novel environment. The effects + of these steroid treatments on the transcription and/or binding properties of the two corticosteroid + receptors, the mineralocorticoid (MR) and glucocorticoid (GR) receptors, were also examined in hippocampal + tissue, (i) Fluctuations in basal and + stress-induced plasma ACTH and B concentrations were found during the oestrous cycle with highest levels + at late pro-oestrus. (ii) In OVX steroid-replaced animals, basal and stress-induced activity was + enhanced in oestradiol and oestradiol plus progesterone-treated animals compared with OVX controls." + + "In conclusion, we find that sex steroids modulate HPA activity and + suggest that the observed effects of these steroids on hippocampal MR may underlie their concerted + mechanism of action in inducing an enhanced activity at the period of late pro-oestrus." + +

+

+ J Clin Endocrinol Metab 1995 Feb;80(2):603-7 The impact of estrogen on adrenal androgen sensitivity + and secretion in polycystic ovary syndrome. Ditkoff EC, Fruzzetti F, Chang L, Stancyzk FZ, Lobo + RA "Adrenal hyperandrogenism is a common feature of patients with polycystic ovary syndrome (PCO). + + + This may be due to enhanced adrenal sensitivity to ACTH. + Because enhanced ovarian androgen secretion does not appear to explain this phenomenon, we explored the + role of estrogen in inducing enhanced adrenal sensitivity, in that a state of relative hyperestrogenism + exists in PCO." + "Steroid ratio + responses to oCRH suggested that 17,20-desmolase activity (delta maximum change in the ratio of + A4/17-hydroxyprogesterone) was lowered with estrogen suppression and increased again after transdermal + E2 administration." "In conclusion, these data provide + evidence that estrogen is at least one factor that influences adrenal androgen sensitivity in PCO and + may help explain the frequent finding of adrenal hyperandrogenism in this syndrome." + +

+

+ Endocrinology 1993 Nov;133(5):2284-91 + Estrogen and hydroxysteroid sulfotransferases in guinea pig adrenal cortex: cellular and subcellular + distributions. Whitnall MH, Driscoll WJ, Lee YC, Strott CA "The high concentration of EST + immunoreactivity in nuclei suggests that EST may play a role in modulating the + ability of active estrogens to regulate gene expression in ACTH-responsive cells. The distribution of + HST labeling suggests that sulfonation of adrenocortical 3-hydroxysteroids takes place largely within + smooth endoplasmic reticulum in the zona reticularis in adult guinea pigs." + +

+ +

+ J Clin Endocrinol Metab 1993 Sep;77(3):754-8. Interaction of insulin-like growth factor-II and + estradiol directs steroidogenesis in the human fetal adrenal toward dehydroepiandrosterone sulfate + production. + + Mesiano S, Jaffe RB +

+

+ J Clin Endocrinol Metab 1993 Aug;77(2):494-7. Estradiol stimulates cortisol production by adrenal + cells in estrogen-dependent primary adrenocortical nodular dysplasia. + Caticha O, Odell WD, Wilson DE, Dowdell LA, Noth RH, Swislocki AL, Lamothe JJ, Barrow R. Adrenal glands from + a patient with ACTH-independent Cushing's syndrome, whose symptoms worsened during pregnancy and oral + contraceptive use, were cultured in different concentrations of estradiol. Estradiol stimulated cortisol + secretion in a dose-response manner in the absence of ACTH." . "This is the first description of estradiol + stimulation of cortisol production by cultured adrenal cells in ACTH-independent Cushing's syndrome." +

+

+ Endocrinology 1992 Nov;131(5):2430-6 + Effects of gonadectomy and sex hormone therapy on the endotoxin-stimulated hypothalamo-pituitary-adrenal + axis: evidence for a neuroendocrine-immunological sexual dimorphism. Spinedi E, Suescun MO, + Hadid R, Daneva T, Gaillard RC "Bacterial lipopolysaccharide (LPS) stimulates the + hypothalamo-pituitary-adrenal axis by a mechanism involving the release of cytokines, which activate the + CRH-ACTH system and, as a result, increase glucocorticoid secretion. + In the present study we investigated the possibility that endogenous sex hormones modulate the in vivo + endotoxin-stimulated adrenal and immune responses in adult BALB/c mice." "Our results indicate + that 1) + randomly cycling female mice have significantly more pronounced corticosterone secretion than males 2 h + after endotoxin + + injection, although the tumor necrosis factor responses were similar....". +

+

+ J Neurosci Res 1995 Oct 1;42(2):228-35 + Activation of the hypothalamo-anterior pituitary corticotropin- releasing hormone, adrenocorticotropin + hormone and beta-endorphin systems during the estradiol 17 beta-induced plasma LH surge in the + ovariectomized monkey. Kerdelhue B, Jones GS, Gordon K, Seltman H, Lenoir V, Melik + Parsadaniantz S, Williams RF, Hodgen GD. "These results suggest that there + may be a marked activation of the hypothalamo-anterior pituitary-adrenal axis during the negative and + positive feedback phases of the E2B-induced LH surge in the ovariectomized monkey." + +

+

+ Biol Reprod 1995 Nov;53(5):996-1002 + Activation of the baboon fetal pituitary-adrenocortical axis at midgestation by estrogen: responsivity + of the fetal adrenal gland to adrenocorticotropic hormone in vitro. Berghorn KA, Albrecht ED, + Pepe G.J. +

+

+ Fertil Steril 1996 May;65(5):950-3 + Ovarian hyperstimulation augments adrenal dehydro- epiandrosterone sulfate secretion. Casson + PR, Kristiansen SB, Umstot E, Carson SA, Buster JE. +

+

+ Hinyokika Kiyo 1997 Apr;43(4):275-8 + [A case of concurrent bilateral adrenocortical adenoma causing Cushing's syndrome]. Koga F, + Sumi S, Umeda H, Maeda S, Honda M, Hosoya Y, Yano M, Konita A, Suzuki S, Yoshida K. "All 14 previously + reported cases of bilateral adrenocortical adenoma (BAA) causing Cushing's syndrome as well as the present + case were + concurrent and dominant in females of reproductive age. This suggests that some cofactors other than + ACTH, such as estrogen, contribute to the pathogenesis of BAA." + +

+ +

+ Endocrinology 1991 Nov;129(5):2503-11 + Variations in the hypothalamic-pituitary-adrenal response to stress during the estrous cycle in the + rat. Viau V, Meaney MJ. "In cycling rats, we found significantly higher peak ACTH (P + less than 0.01) and B (P less than 0.05) responses to stress during proestrus + + compared to the estrous and diestrous phases." "In response to + stress, ACTH levels were higher (P less than 0.01) in the E' group compared to the EP' and O' groups. + + + Although the peak B response was similar in all groups, the E' and EP' groups secreted more B after the + termination of stress than did the O' group. Within the 20 min stress period, + ACTH levels in the E' group were significantly (P less than 0.05) higher at 5, 10, and 15 min after the + onset of stress, compared to the EP' and O' groups. Plasma B levels were significantly higher in the E' + group at 5 and 10 min (P less than 0.05 and P less than 0.01, respectively) compared to the EP' and O' + group. beta-endorphin-like immunoreactive responses to restraint stress were also significantly higher + in the E' group compared to the EP' (P less than 0.05) and O' (P less than 0.01) groups. In + contrast to the effect seen at 24 h, ACTH responses to stress 48 h after E2 injection in the E' group were + comparable to O' animals. There was no effect of E2 on ACTH clearance, whereas B clearance was enhanced in + E' treated animals vs. O'-treated animals. These results indicate that the HPA axis in the female rat is + most sensitive to stress during proestrous. Such enhanced HPA responses to stress are limited to the early + portion of proestrous, as progesterone appears to inhibit the facilitatory effects of estrogen on + ACTH release during stress. + + + Taken together, these results suggest an ovarian influence on both activational and inhibitory components of + HPA activity." +

+

+ Semin Reprod Endocrinol 1997 May;15(2):137-57 Adrenal involvement in polycystic ovary syndrome. + + Gonzalez F. "Whereas 17,20 lyase hyperactivity diagnosed by defined criteria in response to pharmacological + ACTH may be an intrinsic genetic defect, increases in 17,20 lyase activity and adrenal androgen + hyper-responsiveness to ACTH in response to physiological ACTH may be promoted by the functional + elevation of estrogen of ovarian origin in PCOS. + The latest in vitro data suggest the estrogen may elicit its effect on the adrenal cortex through a + receptor mediated mechanism." +

+

+ Metabolism 1997 Aug;46(8):902-7. + Mild adrenal and ovarian steroidogenic abnormalities in hirsute women without hyperandrogenemia: does + idiopathic hirsutism exist? Escobar-Morreale HF, Serrano-Gotarredona J, Garcia-Robles R, Sancho + J, Varela C "Basal and ACTH-stimulated 17OHP and delta 4-A, and stimulated DHEA concentrations were + reduced with ovarian suppression, but their net increment and ratio to the increase of F in + response to ACTH remained unchanged, + reflecting the ovarian contribution to the secretion of these steroids.". +

+

+ Am J Physiol 1997 Apr;272(4 Pt 2):R1128-34. + Modulation of ovine fetal adrenocorticotropin secretion by androstenedione and 17beta-estradiol. Saoud CJ, Wood CE "Parturition in sheep is initiated by increases in activity of the fetal + hypothalamic-pituitary-adrenal axis. We + have previously reported that cortisol negative feedback efficacy is decreased at the end of gestation. + The present study was designed to test the hypothesis that + increasing plasma estrogen and/or androgen concentrations in the fetus might increase plasma + adrenocorticotropic hormone (ACTH) concentration, either by stimulating ACTH secretion or by altering + the negative feedback + effect of cortisol on ACTH." "We conclude that increased fetal cortisol and ACTH secretion at the end of + gestation may be due to the combined effects of the gonadal steroids in that + estradiol increases basal plasma ACTH secretion while androstenedione reduces cortisol negative feedback + efficacy." + +

+ +

+ J Clin Endocrinol Metab 1998 Sep;83(9):3083-8. + Menstrual abnormalities in women with Cushing's disease are correlated with hypercortisolemia rather + than raised circulating androgen levels. Lado-Abeal J, Rodriguez-Arnao J, Newell-Price JD, + Perry LA, Grossman AB, Besser GM, Trainer PJ. +

+

+ Eur J Endocrinol 1998 Apr;138(4):430-5. + Hypothalamo-pituitary-adrenal axis and adrenal function before and after ovariectomy in premenopausal + women. De Leo V, la Marca A, Talluri B, D'Antona D, Morgante G + The hypothalamo-pituitary-adrenal (HPA) axis is modulated by sex hormones. Few data exist on the + relation between acute estrogen deficit and HPA axis response to corticotropin-releasing hormone + (CRH). The effects of a sudden drop in estradiol levels on basal and CRH-stimulated levels of + ACTH, cortisol, testosterone, androstenedione and 17-hydroxyprogesterone (17-OHP) were assessed in nine + premenopausal women (44-48 years of age), before and after ovariectomy. The CRH test was performed before + and 8 days after ovariectomy. + A significant reduction in ACTH and adrenal steroids but not in cortisol response to CRH was observed + after ovariectomy. + + + The ratio of deltamax androstenedione/17-OHP after CRH stimulation was substantially the same before and + after ovariectomy, whereas deltamax 17-OHP/cortisol was significantly lower in + ovariectomized women showing increased 21- and 11beta-hydroxylase activity. The results show + that the acute estrogen deficit induces changes in the HPA xis characterized by reduced stimulated + secretion of ACTH and steroids but normal stimulated cortisol production. +

+

+ Biokhimiia 1987 Sep;52(9):1501-11 + [Activation of lipolysis and ketogenesis in tumor-bearing animals as a reflection of chronic stress + states]. [Article in Russian] Chekulaev VA, Shelepov VP, Pasha-zade GR, Shapot VS In order to + elucidate the peculiarities of brain metabolism in tumour-bearing organisms, the arterio-venous (A-V) + content of glucose, acetoacetate (Ac-Ac), beta-hydroxybutyrate (beta-HB) and non-esterified fatty acids + (NEFA) in growing Zajdela ascite hepatoma (ZAH) and solid hepatoma 27 (H-27) was compared. Analysis of + metabolic patterns of healthy, starving and fed recipients (ZAH and H-27) revealed the inadequacy of the + concepts on anorexia as being the cause of carbohydrate-lipid metabolic disturbances. In tumour-bearing + organisms lipolysis and ketogenesis reflect the tumour-induced chronic stress. Absorption + of beta-HB and release of Ac-Ac by brain were observed at all stages of malignant growth. This is + probably due to a partial switch-over of brain metabolism to non-carbohydrate energy sources. + Besides, certain stages of tumour growth are associated with active assimilation of NEFA by + brain. A correlation between the A-V difference with respect to glucose and Ac-Ac as well as + between the glucose and NEFA contents was established. It was assumed that the A-V difference in glucose is + the main regulator of ketone body metabolism. +

+ +

+ R. Sanchez Olea, et al., + "Inhibition by polyunsaturated fatty acids of cell volume regulation and osmolyte fluxes in + astrocytes," Amer. J. of Physiology--cell physiology 38(1), C96-C102, 1995. "...potent + blockers of regulatory volume decrease and of the swelling-activated efflux of taurine, + D-aspartate, inositol, and I-125 (used as marker of Cl). + ...oleic and ricinoleic acids and saturated fatty acids were ineffective." "...polyunsaturated fatty + acids directly inhibit the permeability pathways correcting cell volume after swelling in cultured + astrocytes." +

+

+ P. H. Chan and R. A. Fishman, "Brain edema: Induction in cortical slices by polyunsaturated fatty + acids," Science 201, 358-369, 1978. "This cellular edema was specific, since + neither saturated fatty acids nor a fatty acid containing a single double bond had such effect." +

+

+ Endocrinology 1992 Aug;131(2):662-8 Estradiol selectively regulates agonist binding sites on the + N-methyl-D-aspartate receptor complex in the CA1 region of the hippocampus. Weiland NG. + Laboratory of Neuroendocrinology, Rockefeller University. + "Estradiol alters cognitive function and lowers the threshold for seizures in women and laboratory + animals. Both of these activities are modulated by the excitatory neurotransmitter glutamate in the + hippocampus. To assess the hypothesis that estradiol increases the sensitivity of the hippocampus to + glutamate activation by increasing glutamate binding sites, the densities of N-methyl-D-aspartate (NMDA) + agonist sites...." "Two days of estradiol treatment increased the density of NMDA agonist, but + not of competitive nor noncompetitive NMDA antagonist binding sites exclusively in the CA1 region of the + hippocampus." + "The increase in NMDA agonist sites with ovarian hormone treatment should result in an increase in the + sensitivity of the hippocampus to glutamate activation which may mediate some of the effects of + estradiol on learning and epileptic seizure activity." +

+ +

+ J Neurochem 1994 Sep;63(3):953-62 + Corticosterone regulates heme oxygenase-2 and NO synthase transcription and protein expression in rat + brain. Weber CM, Eke BC, Maines MD."We suggest that glucocorticoid-mediated deficits in + hippocampal functions may reflect their negative effect on messenger-generating systems." + +

+

+ Gen Pharmacol 1993 Nov;24(6):1383-6 + Changes in microtubular tau protein after estrogen in a cultured human neuroblastoma cell line. + Lew GM. "4. The estrogen (10(-7) M) also caused a 31% reduction in the total number of + cells." +

+

+ Rodriguez, P; Fernandez-Galaz, C; Tejero, A. Controlled neonatal exposure to estrogens: A suitable + tool for reproductive aging studies in the female rat. + + Biology of Reproduction, v.49, n.2, (1993): 387-392. +

+

+ O'Rourke, M T; Lipson, S F; Ellison, P T. Ovarian function in the latter half of the reproductive + lifespan. American Journal of Human Biology, v.8, n.6, (1996): 751-759. +

+

+ Schumacher, M; Robel, P; Baulieu, E-E. Development and regeneration of the nervous system: A role + for neurosteroids. Developmental Neuroscience, v.18, n.1-2, (1996): 6-21. +

+

+ Life Sci 1996;58(17):1461-7 The endogenous estrogen metabolite 2-methoxyestradiol induces apoptotic + neuronal cell death in vitro. Nakagawa-Yagi Y, Ogane N, Inoki Y, Kitoh N. "We examined the + effects of 2-methoxyestradiol, a metabolite of estradiol, on cell death in retinoic acid (RA)-differentiated + neuroblastoma SH-SY5Y cell cultures. Cell death was induced by 2-methoxyestradiol in a + concentration- dependent manner." [Provides evidence] + "...for an endogenous neuroactive steroid metabolite in the etiology of some neurodegenerative + diseases." +

+

+ Recent Prog Horm Res 1997;52:279-303 + Aging of the female reproductive system: a window into brain aging. + Wise PM, Kashon ML, Krajnak KM, Rosewell KL, Cai A, Scarbrough K, Harney JP, McShane T, Lloyd JM, Weiland NG + "The menopause marks the permanent end of fertility in women. It was once thought that the + exhaustion of ovarian follicles was the single, most important explanation for the transition to the + menopause. Over the past decade, this perception has gradually changed with the realization that there + are multiple pacemakers of reproductive senescence. We will present evidence that lends credence to the + hypothesis that the central nervous system is a critical pacemaker of reproductive aging and that + changes at this level contribute to the timing of the menopause." +

+

+ Neuroendocrinology 1989 Nov;50(5):605-612 + N-methyl-aspartic acid lesions of the arcuate nucleus in adult C57BL/6J mice: a new model for + age-related lengthening of the estrous cycle. + May PC, Kohama SG, Finch CE. "We report a new effect of the excitotoxin N-methyl-aspartic acid (NMA) on + adult mice. Besides confirming cell loss in the arcuate nucleus of animals treated as adults, we also + observed lengthened estrous cycles. Cycling female C57BL/6J mice were treated with subcutaneous injections + of NMA and estrous cycles monitored for 30 days. NMA treatment lengthened average estrous cycle length by 1 + day, to 5.6 days." + "Consistent with the regional pattern of cell loss, little specific binding of any glutamatergic ligand + was observed in the VMN. NMA caused weight gain in all age groups." "The transition from 4-day to 5- and + 6-day estrous cycles produced by NMA treatment mimics the early age-related changes in estrous cycle + patterns in rodents." This new model will be useful in analyzing the contributions of + neuroendocrine changes in the arcuate nucleus to reproductive senescence." +

+

+ Pathologic effect of estradiol on the hypothalamus. Brawer JR; Beaudet A; Desjardins GC; + Schipper HM. Biol Reprod, 1993 Oct, 49:4, 647-52. "In addition to its multiple physiological actions, we + have shown that estradiol is also selectively cytotoxic to beta-endorphin neurons in the hypothalamic + arcuate nucleus. The mechanism underlying this neurotoxic action appears to involve the conversion of + estradiol to catechol estrogen and subsequent oxidation to o-semiquinone free radicals. The + estradiol-induced loss of beta-endorphin neurons engenders a compensatory increment in mu opioid binding in + the medial preoptic area rendering this region supersensitive to residual beta-endorphin or to other + endogenous opioids. The consequent persistent opioid inhibition results in a cascade of neuroendocrine + deficits that are ultimately expressed as a chronically attenuated plasma LH pattern to which the ovaries + respond by becoming anovulatory and polycystic. This neurotoxic action of estradiol may contribute to a + number of reproductive disorders in humans and in animals in which aberrant hypothalamic function is a major + component." +

+

+ Vitamin E protects hypothalamic beta-endorphin neurons from estradiol neurotoxicity. + Desjardins GC; Beaudet A; Schipper HM; Brawer JR. Endocrinology, 1992 Nov, 131:5, 2482-4 "Estradiol + valerate (EV) treatment has been shown to result in the destruction of 60% of beta-endorphin neurons in + the hypothalamic arcuate nucleus." +

+

+ Estrogen-induced hypothalamic beta-endorphin neuron loss: a possible model of hypothalamic + aging. + Desjardins GC; Beaudet A; Meaney MJ; Brawer JR. Exp Gerontol, 1995 May-Aug, 30:3-4, 253-67 Over the course + of normal aging, all female mammals with regular cycles display an irreversible arrest of cyclicity at + mid-life. Males, in contrast, exhibit gametogenesis until death. + Although it is widely accepted that exposure to estradiol throughout life contributes to reproductive + aging, a unified hypothesis of the role of estradiol in reproductive senescence has yet to + emerge. + + Recent evidence derived from a rodent model of chronic estradiol-mediated accelerated reproductive + senescence now suggests such a hypothesis. It has been shown that chronic estradiol exposure results in the + + destruction of greater than 60% of all beta-endorphin neurons in the arcuate nucleus + while leaving other neuronal populations spared. This loss of opioid neurons is prevented by + treatment with antioxidants indicating that it results from estradiol-induced formation of free + radicals. Furthermore, we have shown that this beta-endorphin cell loss is followed by a compensatory + upregulation of mu opioid receptors in the vicinity of LHRH cell bodies. The increment in mu + opioid receptors presumably renders the opioid target cells supersensitive to either residual beta-endorphin + or other endogenous mu ligands, such as met-enkephalin, thus resulting in chronic opioid suppression + of the pattern of LHRH release, and subsequently that of LH. Indeed, prevention of the + neuroendocrine effects of estradiol by antioxidant treatment also + prevents the cascade of neuroendocrine aberrations resulting in anovulatory acyclicity. The + loss of beta-endorphin neurons along with the paradoxical opioid supersensitivity which ensues, provides a + unifying framework in which to interpret the diverse features that characterize the reproductively senescent + female. +

+

+ The 21-aminosteroid antioxidant, U74389F, prevents estradiol-induced depletion of hypothalamic + beta-endorphin in adult female rats. Schipper HM; Desjardins GC; Beaudet A; Brawer JR. Brain + Res, 1994 Jul 25, 652:1, 161-3 + "A single intramuscular injection of 2 mg estradiol valerate (EV) results in neuronal degeneration and + beta-endorphin depletion in the hypothalamic arcuate nucleus of adult female rats." +

+ +

+ J Neurochem 1998 Sep;71(3):1187-93 + Energy dependency of glucocorticoid exacerbation of gp120 neurotoxicity. + Brooke SM, Howard SA, Sapolsky RM "The HIV envelope glycoprotein, gp120, a well documented neurotoxin, may + be involved in AIDS-related dementia complex. gp120 works through an NMDA receptor- and calcium-dependent + mechanism to damage neurons. We have previously demonstrated that both natural and synthetic glucocorticoids + (GCs) exacerbate gp120-induced neurotoxicity and calcium mobilization in hippocampal mixed cultures. GCs, + steroid hormones secreted during stress, are now shown to work in conjunction with gp120 to decrease ATP + levels and to work synergistically with gp120 to decrease the mitochondrial potential in hippocampal + cultures. + Furthermore, energy supplementation blocked the ability of GCs to worsen gp120's effects on neuronal + survival and calcium mobilization. A GC-induced reduction in glucose transport in hippocampal + neurons, as previously documented, may contribute to this energetic dependency. These results may have + clinical significance, considering the common treatment of severe cases of Pneumocystis carinii pneumonia, + typical of HIV infection, with large doses of synthetic GCs." +

+

+ Acta Otolaryngol Suppl (Stockh) 1990;476:32-6. Glutamate neurotoxicity in the cochlea: a possible + consequence of ischaemic or anoxic conditions occurring in ageing. + Pujol R, Rebillard G, Puel JL, Lenoir M, Eybalin M, Recasens M. +

+ +

+ Br J Pharmacol 1996 Jan;117(1):189-95. + Metabotropic glutamate receptors, transmitter output and fatty acids: studies in rat brain slices. + Lombardi G, Leonardi P, Moroni F. "The requirement of both unsaturated fatty acids and 1S,3R-ACPD + in the facilitation of transmitter exocytosis may play an important role in the regulation of synaptic + plasticity." +

+

+ Adv Exp Med Biol 1992;318:147-58 + A role for the arachidonic acid cascade in fast synaptic modulation: ion channels and transmitter uptake + systems as target proteins. + Volterra A, Trotti D, Cassutti P, Tromba C, Galimberti R, Lecchi P, Racagni G. "Recent evidence indicates + that arachidonic acid (AA) and its metabolites play a fast messenger role in synaptic modulation in the + CNS." "Other types of K+ channels in vertebrate excitable cells have been found to be + sensitive to arachidonic acid, lipoxygenase products, and polyunsaturated fatty acids (PUFA). In the + mammalian CNS, arachidonic acid is released upon stimulation of N-methyl-D-aspartate (NMDA)-type + glutamate receptors." "Polyunsaturated fatty acids mimic arachidonate with a rank of potency parallel to + the degree of unsaturation. Since the effect of glutamate on the synapses is terminated by diffusion and + uptake, a slowing of the termination process may potentiate glutamate synaptic efficacy. However, + excessive extracellular accumulation of glutamate may lead to neurotoxicity." + +

+ +

+ J Neurochem 1999 Jan;72(1):129-38. Transient inhibition of glutamate uptake in vivo induces + neurodegeneration when energy metabolism is impaired. + + Sanchez-Carbente MR, Massieu L. + "Impairment of glutamate transport during ischemia might be related to the elevation of the extracellular + concentration of glutamate and ischemic neuronal damage. Additionally, impairment of energy metabolism in + vivo leads to neurodegeneration apparently mediated by a secondary excitotoxic mechanism. In vitro + observations show that glucose deprivation and inhibition of energy metabolism exacerbate the toxic effects + of glutamate." + "Our results show that glutamate uptake inhibition leads to marked neuronal damage in energy-deficient + rats but not in intact animals...." +

+

+ J Neurochem 1998 Nov;71(5):1993-2005. + Glia modulate NMDA-mediated signaling in primary cultures of cerebellar granule cells. + Beaman-Hall CM, Leahy JC, Benmansour S, Vallano ML "Nordihydroguaiaretic acid, a lipoxygenase inhibitor, + blocked NMDA-mediated toxicity in astrocyte-poor cultures, raising the possibility + that glia effectively reduce the accumulation of highly diffusible and toxic arachidonic acid + metabolites in neurons. Alternatively, glia may alter neuronal development/phenotype in a + manner that selectively reduces susceptibility to NR-mediated toxicity." +

+ +

+ J Neurosci 1997 Dec 1;17(23):9060-7. Pyruvate protects neurons against hydrogen peroxide-induced + toxicity. + + Desagher S, Glowinski J, Premont J. "Pyruvate strongly protected neurons against both H2O2 added to + the external medium and H2O2 endogenously produced through the redox cycling of the experimental quinone + menadione. The neuroprotective effect of pyruvate appeared to result rather from the ability of + alpha-ketoacids to undergo nonenzymatic decarboxylation in the presence of H2O2 than from an improvement + of energy metabolism. Indeed, several other alpha-ketoacids, including alpha-ketobutyrate, which is not + an energy substrate, reproduced the neuroprotective effect of pyruvate. In contrast, lactate, a neuronal + energy substrate, did not protect neurons from H2O2." "Together, these results indicate that + pyruvate efficiently protects neurons against both exogenous and endogenous H2O2. Its low toxicity and its + capacity to cross the blood-brain barrier open a new therapeutic perspective in brain pathologies in which + H2O2 is involved." +

+

+ J Neurosci 1998 Jan 1;18(1):156-63. Neuroprotective effects of creatine and cyclocreatine in animal + models of Huntington's disease. + Matthews RT, Yang L, Jenkins BG, Ferrante RJ, Rosen BR, Kaddurah-Daouk R, Beal MF + . + +

+ +

+ M. C. Diamond, Enriching Heredity: The Importance of the Environment on the Anatomy of the + Brain. Free Press, N.Y., 1988. +

+

+ C. Finch and L. Hayflick, Handbook of the Biology of Aging. + Van Nostrand Reinhold, N.Y., 1977. +

+

+ Swanson RA Physiologic coupling of glial glycogen metabolism to neuronal activity in brain. + Can J Physiol Pharmacol, 1992, 70 Suppl:, S138-44. Brain glycogen is localized almost exclusively to glia, + where it undergoes continuous utilization and resynthesis. We have shown that glycogen utilization increases + during tactile stimulation of the rat face and vibrissae. + Conversely, decreased neuronal activity during hibernation and anesthesia is accompanied by a marked + increase in brain glycogen content. These observations support a link between neuronal activity + and glial glycogen metabolism. The energetics of glycogen metabolism suggest that glial glycogen is + mobilized to meet increased metabolic demands of glia rather than to serve as a substrate for neuronal + activity. An advantage to the use of glycogen may be the potentially faster generation of ATP from glycogen + than from glucose. Alternatively, glycogen could be utilized if glucose supply is transiently insufficient + during the onset of increased metabolic activity. Brain glycogen may have a dynamic role as a buffer + between the abrupt increases in focal metabolic demands that occur during normal brain activity and the + compensatory changes in focal cerebral blood flow or oxidative metabolism. +

+ +

+ "Free fatty acids activate the hypothalamic-pituitary-adrenocortical axis in rats." + + Widmaier EP; Rosen K; Abbott B. Endocrinology, + + 1992 Nov, 131:5, 2313-8. "Intravenous administration of Intralipid 10% increases blood levels of essential + free fatty acids." "Since corticosterone, the final secretory product of the rat + hypothalamic-pituitary-adrenocortical (HPA) axis, is also lipolytic, we tested the hypothesis that FFA would + inhibit the HPA axis." "At 60 min, plasma ACTH levels were significantly elevated to over 1500 pg/ml in + Intralipid-infused rats, but were unchanged in saline controls. This dose of Intralipid increased + corticosterone levels by nearly 20-fold at 120 min. At 180 min, corticosterone levels were still + significantly greater than those in saline controls. Lower doses of Intralipid also + significantly elevated both FFA and corticosterone levels, but by 180 min, levels of both were similar to + those in controls." "The results suggest that high circulating FFA levels activate, rather than inhibit, the + HPA axis in rats. Since stress activates glucocorticoid production and + increases FFA levels due to lipolysis, it is possible that FFA and the HPA axis constitute a previously + unrecognized positive feedback loop." +

+

+ "Impairment of glucose disposal by infusion of triglycerides in humans: role of glycemia," + + Felley CP; Felley EM; van Melle GD; Frascarolo P; J"quier E; Felber JP, Am J Physiol, 1989 Jun, 256:6 Pt 1, + E747-52. "These results suggest the existence of physiological regulatory mechanisms by which 1) the + rise in plasma free fatty acid inhibits both oxidative and nonoxidative glucose disposal, and 2) the + rise in glycemia stimulates predominantly nonoxidative glucose disposal." +

+

+ Nature 1998 Jan 15;391(6664):281-5. Prostaglandins stimulate calcium-dependent glutamate release in + astrocytes. + Bezzi P, Carmignoto G, Pasti L, Vesce S, Rossi D, Rizzini BL, Pozzan T, Volterra A. + Astrocytes in the brain form an intimately associated network with neurons. They respond to + neuronal activity and synaptically released glutamate by raising intracellular calcium concentration + ([Ca2+]i), which could represent the start of back-signalling to neurons. + Here we show that coactivation of the AMPA/kainate and metabotropic glutamate receptors (mGluRs) on + astrocytes stimulates these cells to release glutamate through a Ca2+-dependent process mediated by + prostaglandins. Pharmacological inhibition of prostaglandin synthesis prevents glutamate release, + whereas application of prostaglandins (in particular PGE2) mimics and occludes the releasing action of + GluR agonists. PGE2 promotes Ca2+-dependent glutamate release from cultured astrocytes and also from + acute brain slices under conditions that suppress neuronal exocytotic release. + When applied to the CA1 hippocampal region, PGE2 induces increases in [Ca2+]i both in astrocytes + and in neurons. The [Ca2+]i increase in neurons is mediated by glutamate released from astrocytes, because + it is abolished by GluR antagonists. + Our results reveal a new pathway of regulated transmitter release from astrocytes and outline the + existence of an integrated glutamatergic cross-talk between neurons and astrocytes in situ that may play + critical roles in synaptic plasticity and in neurotoxicity. + +

+

+ Prog Neurobiol 1998 Jan;54(1):99-125. Microglia as effector cells in brain damage and repair: focus + on prostanoids and nitric oxide. + Minghetti L, Levi G. + "The present article deals with two classes of compounds that activated microglial cells can produce in + large amounts: prostanoids (that derive from arachidonic acid through the cyclooxygenase pathway), and + nitric oxide (that is synthesized from arginine by nitric oxide synthase). Prostanoids and nitric oxide have + a number of common targets, on which they may exert similar or opposite actions, and have a crucial role in + the regulation of inflammation, immune responses and cell viability. Their synthesis can massively increase + when the inducible isoforms of cyclooxygenase and nitric oxide synthase are expressed." +

+

+ In Vitro Cell Dev Biol Anim 1998 Mar;34(3):265-74. Prostaglandins act as neurotoxin for + differentiated neuroblastoma cells in culture and increase levels of ubiquitin and beta-amyloid. + Prasad KN, La Rosa FG, Prasad JE. + + "Although chronic inflammatory reactions have been proposed to cause neuronal degeneration associated with + Alzheimer's disease (AD), the role of prostaglandins (PGs), one of the secretory products of inflammatory + reactions, in degeneration of nerve cells has not been studied. Our initial observation that PGE1-induced differentiated neuroblastoma (NB) cells degenerate in vitro more rapidly than those inducedby + RO20-1724, an inhibitor of cyclic nucleotide phosphodiesterase, has led us to postulate that PGs act as + a neurotoxin. This study has further investigated the effects of PGs on differentiated NB cells + in culture. Results showed that PGA1 was more effective than PGE1 in causing degeneration of differentiated + NB cells as shown by the cytoplasmic vacuolation and fragmentation of soma, nuclei, and neurites. Because + increased levels of ubiquitin and beta-amyloid have been implicated in causing neuronal degeneration, we + studied the effects of PGs on the levels of these proteins during degeneration of NB cells in vitro...." + "Results showed that PGs increased the intracellular levels of ubiquitin and beta-amyloid prior to + degeneration, whereas the degenerated NB cells had negligible levels of these proteins. These data + suggest that PGs act as external neurotoxic signals which increase levels of ubiquitin and + beta-amyloid that represent one of the intracellular signals for initiating degeneration of nerve cells." +

+

+ Brain Res Bull 1998 Apr;45(6):637-40. + The fatty acid composition of maternal diet affects the response to excitotoxic neural injury in + neonatal rat pups.Valencia P, Carver JD, Wyble LE, Benford VJ, Gilbert-Barness E, Wiener DA, + Phelps C + Fatty acids and their derivatives play a role in the response to neural injury. The effects of + prenatal and postnatal dietary fatty acid composition on excitotoxic neural injury were investigated in + neonatal rat pups." +

+ +

+ Proc Soc Exp Biol Med 1998 Nov;219(2):120-5. Prostaglandins as putative neurotoxins in Alzheimer's + disease. Prasad KN, Hovland AR, La Rosa FG, Hovland PG. + "Chronic inflammatory reactions in the brain appear to be one of the primary etiological factors in the + pathogenesis of Alzheimer's disease (AD). This is supported by the fact that the secretory products of + inflammatory reactions, which include cytokines, complement proteins, adhesion molecules, and free radicals, + are neurotoxic. We have recently reported that prostaglandins (PGs), which are also released during + inflammatory reactions, cause rapid degenerative changes in differentiated murine neuroblastoma cells (NB) + in culture." "The mechanisms underlying Abeta-induced neuronal degeneration have been under intense + investigation, and several mechanisms of action have been proposed. We postulate that PG-induced elevation + of Abeta may lead to an increased binding of Abeta to the 20S proteasome, resulting in a reduction of 20S + proteasome-mediated degradation of ubiquitin-conjugated proteins. This is predicted to lead to an increase + in an accumulation of abnormal proteins, which ultimately contribute to neuronal degeneration and death. + Based on our hypothesis and on studies published by others, we propose that a combination of nonsteroidal + anti-inflammatory drugs, which inhibit the synthesis of PGs, and antioxidant vitamins, which quench free + radicals and both of which have been recently reported to be of some value in AD treatment when + used-individually, may be much more effective in the prevention and treatment of AD than the individual + agents alone." +

+

+ Mol Chem Neuropathol 1998 May;34(1):79-101. Effects of EGb 761 on fatty acid reincorporation during + reperfusion following ischemia in the brain of the awake gerbil. + + + Rabin O, Drieu K, Grange E, Chang MC, Rapoport SI, Purdon AD. +

+

+ Regulation of arcuate nucleus synaptology by estrogen. Leedom L; Lewis C; Garcia-Segura LM; + Naftolin F. Ann N Y Acad Sci, 1994 Nov 14, 743:, 61-71 "Estrogen modulates the synaptology of the + hypothalamic arcuate nucleus during sexual differentiation of the rat brain in both males and females. In + + males, testosterone of gonadal origin is converted to estrogen in the brain by an enzyme, + aromatase, which is also present in females. The exposure of the male's hypothalamus to relatively high + levels of estrogen (following a perinatal testosterone surge) leads to the development of a pattern of + synaptogenesis + which does not support an estrogen-induced gonadotrophin surge in the adult. In female rats, + hypothalamic development occurs with permissively low levels of estrogen, enabling a + midcycle estrogen-induced gonadotrophin surge and ovulation in adulthood. During adult reproductive life in + female rats, circulating estrogen modulates the synaptology of the arcuate nucleus. The most + physiological example of this is the 30-50% loss of axosomatic synapses following the preovulatory + estrogen surge on diestrus-proestrus. + + Studies on post-synaptic membranes of the arcuate nucleus reveal sex differences in membrane organization + and protein content which are estrogen-dependent. + Estrogen apparently stimulates endocytosis of areas of post-synaptic membrane that are dense with small + intramembranous protein particles, resulting in a reduction in the number of small intramembranous + particles. This also appears to be the physiologic mechanism of neuronal changes in females during the + estrus cycle. Repeated exposure to preovulatory levels of estrogen may lead to an age-related + decline in reproductive capacity in female rats. Aging females lose the estrogen-induced gonadotrophin surge + responsible for ovulation. This loss of function may result from a cumulative estrogen effect during + the repeated ovarian cycles which results in a reorganization of the synaptology on which + regulates the estrogen-induced gonadotrophin surge." ". . .recent research has shown that GABA, the + monoamines, and several neuropeptides are participants in the estrogen-sensitive network which regulates + GNRH secretion. In this regard, present work shows estrogen-induced changes in GABA and dopamine synapses in + the arcuate nucleus." +

+

+ 17 beta Estradiol-induced increase in brain dopamine D-2 receptor: antagonism by MIF-1. + + Rajakumar G; Chiu P; Chiu S; Johnson RL; Mishra RK Department of Psychiatry, + Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada. Peptides, 1987 Nov-Dec, 8:6, + 997-1002 Animal behavioral and neurochemical studies implicate dopaminergic systems + in the neurological sequelae induced by estrogen. In the present study, we demonstrated for the + first time that MIF-1, a neuropeptide unrelated to classical dopamine agonists, when given prior to, + concurrently with, and after 17 beta-estradiol, antagonized significantly the estrogen-induced increase in + the density of dopamine D-2 receptor both in the striatum and the mesolimbic area of male + rat brain. The current findings have implications for the prophylactic and therapeutic potential for MIF-1 + in extrapyramidal motor disorders caused by estrogen imbalance in humans. +

+

+ Eur J Clin Invest 1984 Dec;14(6):431-4 + Effect of ovulation on haem metabolism in rabbits. Lindahl J, Werner B, Lerner R. "To + investigate the origin of the cyclic changes in the rate of endogenous carbon-monoxide production (nCO) + during the menstrual cycle, haem turnover was determined before and after chorion gonadotropic + hormone-induced ovulation in six female rabbits. 14C-labelled delta-aminolevulinic acid and glycine were + administered and the excretion rate of 14CO (A14CO) was measured for determination of hepatic + and + bone-marrow haem turnover, respectively." + ". . . nCO was increased 34% (P less than 0.05) during the post-ovulation period. As the increase in + 'unassigned' haem turnover was small and may be unaccompanied by a contemporary increase in bilirubin/CO + production, it was concluded that the increase in nCO during the post-ovulation period essentially + depends on increased destruction of circulating red cells in the rabbit." +

+ +

+ J Neurotrauma 1993 Winter;10(4):373-84. + Beneficial effect of the nonselective opiate antagonist naloxone hydrochloride and the + thyrotropin-releasing hormone (TRH) analog YM-14673 on long-term neurobehavioral outcome following + experimental brain injury in the rat. + + McIntosh TK, Fernyak S, Hayes RL, Faden AI +

+

+ J Neurosci 1990 Nov;10(11):3524-30. + Opiate antagonist nalmefene improves intracellular free Mg2+, bioenergetic state, and neurologic outcome + following traumatic brain injury in rats. + + Vink R, McIntosh TK, Rhomhanyi R, Faden AI. "Treatment of CNS trauma with the opiate antagonist naloxone + improves outcome, though the mechanisms of action remain speculative." +

+

+ Brain Res 1989 Mar 20;482(2):252-60. + Magnesium protects against neurological deficit after brain injury. + + McIntosh TK, Vink R, Yamakami I, Faden AI. +

+

+ Adv Neurol 1988;47:531-46. + Role of thyrotropin-releasing hormone and opiate receptor antagonists in limiting central nervous system + injury. Faden AI. "Opiate antagonists, including receptor antagonists and physiologic + antagonists, have been shown to produce beneficial effects in a variety of models of CNS injury and in a + variety of species. Opiate antagonists improve spinal cord blood flow, electrical conduction of the spinal + cord, pathological changes, and motor recovery following traumatic spinal cord injury in cats. TRH appears + to be superior to naloxone in this regard, although direct comparisons between receptor-selective opiate + receptor antagonists and TRH have not been made." +

+

+ Exp Neurol 1994 Sep;129(1):64-9.Progesterone facilitates cognitive recovery and reduces secondary + neuronal loss caused by cortical contusion injury in male rats. Roof RL, Duvdevani R, Braswell + L, Stein DG. +

+

+ Exp Neurol 1996 Apr;138(2):246-51. + Progesterone rapidly decreases brain edema: treatment delayed up to 24 hours is still effective. Roof RL, Duvdevani R, Heyburn JW, Stein DG. +

+

+ Mol Chem Neuropathol 1997 May;31(1):1-11. + Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Roof + RL, Hoffman SW, Stein DG. +

+

+ Jiang N, et al. Progesterone is neuroprotective after transient middle cerebral artery occlusion in + male rats. Brain Res. 1996 Sep 30;735(1):101-7. +

+

+ Roof RL, et al. Progesterone rapidly decreases brain edema: treatment delayed up to 24 hours is + still effective. Exp Neurol. 1996 Apr;138(2):246-51. +

+ +

+ Duvdevani R, et al. Blood-brain barrier breakdown and edema formation following frontal cortical + contusion: does hormonal status play a role? J Neurotrauma. 1995 Feb;12(1):65-75. +

+

+ Exp Neurol 1997 Dec;148(2):453-63. + Endogenous repair after spinal cord contusion injuries in the rat. + + Beattie MS, Bresnahan JC, Komon J, Tovar CA, Van Meter M, Anderson DK, Faden AI, Hsu CY, Noble LJ, Salzman + S, Young W. + "In addition to signs of regeneration, we noted evidence for the proliferation of cells located in the + ependymal zone surrounding the central canal at early times following contusion injuries." +

+ + © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/estrogen-osteoporosis.html b/raypeat-articles/processed/estrogen-osteoporosis.html new file mode 100644 index 0000000..00a11bc --- /dev/null +++ b/raypeat-articles/processed/estrogen-osteoporosis.html @@ -0,0 +1,254 @@ + + Estrogen and Osteoporosis + +

+ Estrogen and Osteoporosis +

+ + The government declared victory in the war on cancer, though the age-specific death rate from cancer keeps + increasing. In the equally well publicized effort to prevent disability and death from osteoporosis, no one is + declaring victory, because the only trend in its incidence that has been reported is an increase. The + estrogen-promoting culture tells us that this is because of the aging of the population, but the age corrected + numbers still show a great increase--for example, in Finland between 1970 and 1995, the number of women (for a + given population of women older than 60) breaking their forearm because of osteoporosis more than doubled + (Palvanen, et al., 1998). That this happened during a time when the use of estrogen had become much more common + doesn't present a good argument for the protective effects of estrogen treatment. (And during this period there + was a large increase in the consumption of estrogenic soy products.) Recently our local newspaper had a story at + the bottom of the front page reporting that lean women who used estrogen and synthetic progestins had an 80% + higher rate of breast cancer. Several days later, across the top of the front page, there was a rebuttal + article, quoting some doctors including a "world class expert on hormone replacement therapy" and a woman who + has taken Premarin for forty years and urges everyone to take it. The "protection against osteoporosis" and + against heart disease, they said, must be weighed against a trifle such as the 80% increase in cancer. It + appeared that the newspaper was apologizing for reporting a fact that could make millions of women nervous. (Jan + 26, Register-Guard). Medical magazines, like the mass media, don't like to miss any opportunity to inform the + public about the importance of using estrogen to prevent osteoporosis. Their attention to the bone-protective + effect of progesterone has been noticeably less than their mad campaign to sell estrogen, despite the evidence + that progesterone can promote bone rebuilding, rather than just slowing its loss. Although I have spoken about + progesterone and osteoporosis frequently in the last 25 years, I have only occasionally considered what estrogen + does to bones; generally, I described estrogen as a stress-promoting and age-promoting hormone. In the 1970s, + pointing out progesterone's protective antagonism to excessive amounts of other hormones, and that the catabolic + glucocorticoids tend to increase with aging, I began referring to progesterone as the "anticatabolic" hormone + that should be used to prevent stress-induced atrophy of skin, bones, brain, etc. A former editor of Yearbook of + Endocrinology had reviewed a series of studies showing that excess prolactin can cause osteoporosis. Then, he + presented a group of studies showing how estrogen promotes the secretion of prolactin, and can cause + hyperprolactinemia. In that review, he wryly wondered how something that increases something that causes + osteoporosis could prevent osteoporosis. Women have a higher incidence of osteoporosis than men do. Young women + have thinner more delicate bones than young men. The women who break bones in old age are generally the women + who had the thinnest bones in youth. Menstrual irregularities, and luteal defects, that involve relatively high + estrogen and low progesterone, increase bone loss. Fatter women are less likely to break bones than thinner + women. Insulin, which causes the formation of fat, also stimulates bone growth. Estrogen however, increases the + level of free fatty acids in the blood, indicating that it antagonizes insulin (insulin decreases the level of + free fatty acids), and the fatty acids themselves strongly oppose the effects of insulin. Estrogen dominance is + widely thought to predispose women to diabetes. Between the ages of 20 and 40, there is a very considerable + increase in the blood level of estrogen in women. However, bone loss begins around the age of 23, and progesses + through the years when estrogen levels are rising. Osteoarthritis, which involves degeneration of the bones + around joints, is strongly associated with high levels of estrogen, and can be produced in animals with estrogen + treatment. Thirty years ago, when people were already claiming that estrogen would prevent or cure osteoporosis, + endocrinologists pointed out that there was no x-ray evidence to support the claim. Estrogen can cause a + positive calcium balance, the retention of more calcium than is excreted, and the estrogen promoters argued that + this showed it was being stored in the bones, but the endocrine physiologists showed that estrogen causes the + retention of calcium by soft tissues. There are many reasons for not wanting calcium to accumulate in the soft + tissues; this occurs normally in aging and stress. Then, it was discovered that, although estrogen doesn't + improve the activity of the cells that build bone, it can reduce the activity of the cells that remove bone, the + osteoclasts. The osteoclast is a type of phagocytic cell, and is considered to be a macrophage, the type of cell + that can be found in any organ, which can eat any sort of particle, and which secretes substances (cytokines, + hormone-like proteins) that modify the functions of other cells. When estrogen was found to impair the activity + of this kind of cell, there wasn't much known about macrophage cytokines. With the clear evidence that estrogen + inhibits the osteoclasts without activating the bone-building osteoblasts, estrogen was said to "prevent bone + loss," and from that point on we never heard again about estrogen promoting a positive calcium balance. Calcium + retention by soft tissues has come to be an accepted marker of tissue aging, tissue damage, excitotoxicity, and + degeneration. Positive calcium balance had been the essence of the argument for using estrogen to prevent + osteoporosis: "Women are like chickens, estrogen makes them store calcium in their bones." But if everyone now + recognizes that calcium isn't being stored in bones, it's better for the estrogen industry if we forget about + the clearly established positive calcium balance produced by estrogen. The toxic effects of excessive + intracellular calcium (decreased respiration and increased excitation) are opposed by magnesium. Both thyroid + and progesterone improve magnesium retention. Estrogen dominance is often associated with magnesium deficiency, + which can be an important factor in osteoporosis (Abraham and Grewal, 1990; Muneyyirci-Delale, et al., 1999). As + part of the campaign to get women to use estrogen, an x-ray (bone density) test was devised which can supposedly + measure changes in the mineral content of bone. However, it happens that fat and water interfere with the + measurements. Estrogen changes the fat and water content of tissues. By chance, the distortions produced by fat + and water happen to be such that estrogen could appear to be increasing the density of a bone, when it is really + just altering the soft tissues. Ultrasound measurements can provide very accurate measurements of bone density, + without the fat and water artifacts that can produce misleading results in the x-ray procedure, and don't expose + the patient to radiation, but the ultrasound method is seldom used. In recent years, there has been quite a lot + of research into the effects of the macrophage cytokines. Immune therapy for cancer was considered quackery when + Lawrence Burton identified some substances in blood serum that could cause massive tumors in rodents to + disappear in just a few hours. One of the serum factors was called Tumor Necrosis Factor, TNF. An official + committee was formed to evaluate his work, but it reported that there was nothing to it. A member of the + committee later became known as "the authority" on tumor necrosis factor, which was thought to have great + potential as an anticancer drug. However, used by itself, TNF killed only a few cancers, but it damaged every + organ of the body, usually causing the tissues to waste away. Other names, lymphotoxin and cachectin, reflected + its toxic actions on healthy tissues. Aging involves many changes that tend to increase the inflammatory + reaction, and generally the level of TNF increases with aging. Although cancer, heart failure, AIDS, and extreme + hormone deficiency (from loss of the pituitary or thyroid gland, for example) can cause cachexia of an extreme + and rapid sort, ordinary aging is itself a type of cachexia. Progeria, or premature aging, is a kind of wasting + disease that causes a child's tissues (including bones) to atrophy, and to change in many of the ways that would + normally occur in extreme old age. Recent studies have found that both men and women lose minerals from their + bones at the rate of about 1% per year. Although men have lower estrogen in youth than women do, their bones are + much heavier. During aging, as their bones get thinner, men's estrogen levels keep rising. Besides having weaker + bones, old people have weaker muscles, and are more likely to injure themselves in a fall because their muscles + don't react as well. Muscle loss occurs at about the rate of 1% per year. Women's muscles, like their bones, are + normally smaller than men's, and estrogen contributes significantly to these differences. TNF can produce very + rapid loss of tissue including bone, and in general, it rises with aging. Some of the people who like to say + that "osteoporosis is caused by estrogen deficiency" know about the destructive actions of TNF, and argue that + it rises at menopause "because of estrogen deficiency." There are very good reasons for rejecting that argument; + the experiments sometimes seem to have been designed purely for propaganda purposes, using toxic levels of + estrogen for a specific result. One researcher noted that the effects of estrogen on cells in vitro are + biphasic: Low doses increased TNF, high doses decreased TNF. Everyone knows that unphysiologically high doses + (50 or 100 or more times above the physiological level of around 0.25 micrograms per liter) of estrogen are + toxic to cells, producing functional and structural changes, and even rapid death. So, when a researcher who + wants to show estrogen's "bone protective" effect of lowering TNF adds a lethal dose of estrogen to his cell + culture, he can conclude that "estrogen inhibits TNF production." But the result is no more interesting than the + observation that a large dose of cyanide inhibits breathing. TNF is produced by endotoxin, and estrogen + increases the amount of endotoxin in the blood. Even without endotoxin, though, estrogen can stimulate the + production of TNF. Lactic acid and unsaturated fats and hypoxia can stimulate increased formation of TNF. + Estrogen increases production of nitric oxide systemically, and nitric oxide can stimulate TNF formation. How + does TNF work, to produce tissue damage and wasting? It causes cells to take up too much calcium, which makes + them hypermetabolic before it kills them. It increases formation of nitric oxide and carbon monoxide, blocking + respiration. TNF can cause a 19.5 fold increased in the enzyme which produces carbon monoxide (Rizzardini, et + al., 1993), which blocks respiration. All of the normal conditions associated with high estrogen also are found + to involve increased production of TNF, and treatment of animals with estrogen clearly increases their TNF. + Premature ovarian failure (with low estrogen levels) leads to reduced TNF, as does treatment with antiestrogens. + If bone resorption is significantly regulated by TNF, then it should be concluded that increased estrogenic + influence will tend to produce osteoporosis. Tamoxifen, which has some estrogenic effects, including the + inhibition of osteoclasts, can kill osteoclasts when the dose is high enough. The inhibition of osteoclast + activity by either estrogen or tamoxifen is probably a toxic action, that has been characterized as "beneficial" + by the estrogen industry simply because they didn't have any better argument for getting women to use their + products. Some types of dementia, such as Alzheimer's disease, involve a life-long process of degeneration of + the brain, with an inflammatory component, that probably makes them comparable to osteoporosis and + muscle-wasting. (In the brain, the microglia, which are similar to macrophages, and the astrocytes, can produce + TNF.) The importance of the inflammatory process in Alzheimer's disease was appreciated when it was noticed that + people who used aspirin regularly had a low incidence of that dementia. Aspirin inhibits the formation of TNF, + and aspirin has been found to retard bone loss. In the case of osteoporosis (A. Murrillo-Uribe, 1999), as in + Alzheimer's disease, the incidence is two or three times as high in women as in men. In both Alzheimer's disease + and osteoporosis, the estrogen industry is arguing that the problems are caused by a suddenly developing + estrogen deficiency, rather than by prolonged exposure to estrogen. Similar arguments were made fifty years ago + regarding the nature of the menopause itself--that it was caused by a sudden decrease in estrogen production. + The evidence that has accumulated in the last forty years has decisively settled that argument: Menopause is the + result of prolonged exposure to estrogen. (Even one large dose destroys certain areas in the brain, and chronic, + natural levels damage the nerves that regulate the pituitary. Overactivity of the pituitary leads to many other + features of aging.) The links between estrogen and TNF appear to be essential factors in aging and its diseases. + Each of these substances has its constructive, but limited, place in normal physiology, but as excitatory + factors, they must operate within the appropriate constraints. The basic constraint is that resources, including + energy and oxygen, must be available to terminate their excitatory actions. Adequate oxygen, a generous supply + of carbon dioxide, saturated fats, thyroid, and progesterone restrain TNF, while optimizing other cytokines and + immune functions, including thymic protection. In the development of the organism and its adaptive functions, + there are patterned processes, functional systems, that can clarify the interactions of growth and atrophy. The + respiratory production of energy and carbon dioxide, and the respiratory defect in which lactic acid is + produced, correspond to successful adaptation, and to stressful/excitotoxic maladaptation, respectively. + Excitotoxicity, and Meerson's work on the protective functions of the antistress hormones, have to be understood + in this framework. This framework integrates the understanding of cancer metabolism with the other stress + metabolisms, and with the metabolism of normal growth. Unsaturated fats, iron, and lactic acid are closely + related to the actions and regulation of TNF, and therefore they strongly influence the nature of stress and the + rate of aging. The fact that cancer depends on the presence of polyunsaturated fats probably relates to the + constructive and destructive actions of TNF: The destructive effects such as multiple organ failure/congestive + heart failure/shock-lung, etc., apparently involve arachidonic acid and its metabolites, which are based on the + so-called essential fatty acids. When oxygen and the correct nutrients are available, the hypermetabolism + produced by TNF could be reparative (K. Fukushima, et al., 1999), rather than destructive. Stimulation in the + presence of oxygen produces carbon dioxide, allowing cells to excrete calcium and to deposit it in bones, but + stimulation in the absence of oxygen produces lactic acid and causes cellular calcium uptake. It is in this + context that the therapeutic effects of saturated fats, carbon dioxide, progesterone, and thyroid can be + understood. They restore stability to a system that has been stimulated beyond its capacity to adapt without + injury. + +

REFERENCES

 + + J Reprod Med 1990 May;35(5):503-7. A total dietary program emphasizing magnesium instead of calcium. Effect on + the mineral density of calcaneous bone in postmenopausal women on hormonal therapy. Abraham GE, Grewal H. J + Immunol 1999 Feb 15;162(4):2154-61. Increased TNF-alpha-induced apoptosis in lymphocytes from aged humans: + changes in TNF-alpha receptor expression and activation of caspases. Aggarwal S, Gollapudi S, Gupta S. Mech + Ageing Dev 1995 Oct 13;84(2):113-26. Cytokine production and lymphocyte subpopulations in aged humans. An + assessment during nocturnal sleep. Born J, Uthgenannt D, Dodt C, Nunninghoff D, Ringvolt E, Wagner T, Fehm HL. + "While monocyte counts were unchanged in the elderly production of IL-1 beta and TNF-alpha mainly derived from + these cells, was enhanced (p < 0.05). Results indicate a state of enhanced responsiveness of the T cell + compartment and of monocytes in aged which may compensate for the substantial decrease in T cells." Eur J Appl + Physiol 1999 Oct;80(5):452-60 Impact of three different types of exercise on components of the inflammatory + response. Brenner IK, Natale VM, Vasiliou P, Moldoveanu AI, Shek PN, Shephard RJ. J Surg Res 1994 + Jul;57(1):65-8. Dietary fish oil enhances macrophage production of nitric oxide. Chaet MS, Garcia VF, Arya G, + Ziegler MM. "In group A, BAM from animals fed omega 3 produced significantly more NO . . . and TNF . . . than + BAM from omega 6-fed animals." "These data demonstrate that PUFA influence BAM production of NO and TNF. Changes + in the omega 6-derived prostanoids may account for the differences in TNF production, but these data suggest + that PGE2 and PGI2 are not responsible for the observed differences in NO production." J Immunol 1996 Feb + 15;156(4):1525-30. Age-associated differences in TNF-alpha and nitric oxide production in endotoxic mice. + Chorinchath BB, Kong LY, Mao L, McCallum RE. Am J Physiol 1999 Sep;277(3 Pt 1):G671-7. Estriol sensitizes rat + Kupffer cells via gut-derived endotoxin. Enomoto N, Yamashina S, Schemmer P, Rivera CA, Bradford BU, Enomoto A, + Brenner DA, Thurman RG Scand J Gastroenterol 1999, Mar; 34(3):291-6. Lipopolysaccharide- and proinflammatory + cytokine-induced energy production in intestinal and colonic epithelial cell lines. Fukushima K, Sasaki I, + Takahashi K, Naito H, Matsuno S. Mech Ageing Dev 1995 Sep 29;84(1):39-54 Age-related enhancement of tumor + necrosis factor (TNF) production in mice. Han D, Hosokawa T, Aoike A, Kawai K "We previously reported that + systemic production of TNF increases with aging. The present study of TNF production at the cellular level in + mice indicated (1) that TNF production per macrophage increased with aging, and (2) that the number of T and B + cells involved in the production of TNF in the presence of macrophages also increased at least up to middle + age." J Clin Endocrinol Metab 1996 Feb;81(2):513-8. Cytokine production in the bone marrow microenvironment: + failure to demonstrate estrogen regulation in early postmenopausal women. Kassem M, Khosla S, Spelsberg TC, + Riggs BL Fertil Steril 1999 May;71(5):869-72. Serum ionized magnesium and calcium in women after menopause: + inverse relation of estrogen with ionized magnesium. Muneyyirci-Delale O, Nacharaju VL, Dalloul M, Altura BM, + Altura BT. Ginecol Obstet Mex 1999 May;67:227-33. [Osteoporosis in Mexican postmenopausal women. Magnitude of + the problem. Multicenter study]. Murrillo-Uribe A, Deleze-Hinojosa M, Aguirre E, Villa A, Calva J, Cons F, + Briseno A, Gonzalez G, Morales J, Pena H, Guerrero G, Orozco J, Morales G, Elizondo J. Hepatology 1997 + Dec;26(6):1538-45. Dietary saturated fatty acids down-regulate cyclooxygenase-2 and tumor necrosis factor alfa + and reverse fibrosis in alcohol-induced liver disease in the rat. Nanji AA, Zakim D, Rahemtulla A, Daly T, Miao + L, Zhao S, Khwaja S, Tahan SR, Dannenberg AJ. "The data indicate that a diet enriched in saturated fatty acids + (groups 3 and 4) effectively reverses alcohol-induced liver injury, including fibrosis. The therapeutic effects + of saturated fatty acids may be explained, at least in part, by reduced endotoxemia and lipid peroxidation, + which in turn result in decreased levels of TNF-alpha and Cox-2." Eur J Epidemiol 1998 Feb;14(2):159-64. Secular + trends in the osteoporotic fractures of the distal humerus in elderly women. Palvanen M, Kannus P, Niemi S, + Parkkari J. Biochem J 1993 Mar 1;290 ( Pt 2):343-7. Cytokine induction of haem oxygenase mRNA in mouse liver. + Interleukin 1 transcriptionally activates the haem oxygenase gene. Rizzardini M, Terao M, Falciani F, Cantoni L. + Nitric Oxide 1997;1(6):453-62..Effects of female hormones (17beta-estradiol and progesterone) on nitric oxide + production by alveolar macrophages in rats. Robert R, Spitzer JA. Nitric Oxide 1997;1(6):453-62.. Effects of + female hormones (17beta-estradiol and progesterone) on nitric oxide production by alveolar macrophages in rats. + Robert R, Spitzer JA. J Gerontol A Biol Sci Med Sci 1998 Jan;53(1):M20-6. Monocyte cytokine production in an + elderly population: effect of age and inflammation. Roubenoff R, Harris TB, Abad LW, Wilson PW, Dallal GE, + Dinarello CA. "OBJECTIVE: To determine the association among aging, inflammation, and cytokine production by + peripheral blood mononuclear cells." "We examined production of interleukin-1 beta (IL-1 beta), tumor necrosis + factor-alpha (TNF-alpha), IL-1 receptor antagonist (IL-1Ra), and IL-6 in 711 elderly participants in the + Framingham Heart Study (mean age, 79 y) and 21 young healthy volunteers (mean age, 39 y)." CONCLUSION: + "Production of IL-6 and IL-1Ra--but not IL-1 beta or TNF-alpha--was increased in the elderly compared to + healthy, young subjects. The increase in IL-6 also correlated with increased production of CRP, a marker of + inflammation. However, IL-1Ra was increased in the elderly independently of CRP production. Although limited by + the small control group, these data suggest that dysregulation of some inflammatory cytokines occurs with age, + but the role of inflammation in aging remains unclear." J Gerontol A Biol Sci Med Sci 1998 Jan;53(1):M20-6. + MMonocyte cytokine production in an elderly population: effect of age and inflammation. Roubenoff R, Harris TB, + Abad LW, Wilson PW, Dallal GE, Dinarello CA. Br J Cancer Suppl 1996 Jul;27:S133-5. The influence of oxygen and + carbon dioxide tension on the production of TNF alpha by activated macrophages. Sampson LE, Chaplin DJ. Mech + Ageing Dev 1997 Feb;93(1-3):87-94. Calorie restriction inhibits the age-related dysregulation of the cytokines + TNF-alpha and IL-6 in C3B10RF1 mice. Spaulding CC, Walford RL, Effros RB. "TNF-alpha and IL-6 are generally + increased in the sera of aged humans and mice. The dysregulation of these cytokines may be critical in + autoreactivity and immune dysfunction." "Serum levels of both cytokines were significantly higher in old versus + young mice. However, in old mice subjected to long term CR the serum levels were comparable to those of young + mice. The potential involvement of normalization of TNF-alpha and IL-6 levels in the life extension effect of CR + are discussed." Cytokine 1999 May; 11(5):326-33. Induction of haem oxygenase contributes to the synthesis of + pro-inflammatory cytokines in re-oxygenated rat macrophages: role of cGMP. Tamion F, Richard V, Lyoumi S, Hiron + M, Bonmarchand G, Leroy J, Daveau M, Thuillez C, Lebreton JP. Clin Sci (Colch) 1994 Aug;87(2):173-8. Complex + modulation of cytokine induction by endotoxin and tumour necrosis factor from peritoneal macrophages of rats by + diets containing fats of different saturated, monounsaturated and polyunsaturated fatty acid composition. Tappia + PS, Grimble RF. Infect Immun 1996 Mar;64(3):769-74. Lipopolysaccharide-induced lethality and cytokine production + in aged mice. Tateda K, Matsumoto T, Miyazaki S, Yamaguchi K Hepatology 2000 Jan;31(1):117-23. Estrogen is + involved in early alcohol-induced liver injury in a rat enteral feeding model. Yin M, Ikejima K, Wheeler MD, + Bradford BU, Seabra V, Forman DT, Sato N, Thurman RG. "Blood endotoxin and hepatic levels of CD14 messenger RNA + (mRNA) and protein were increased by ethanol. This effect was blocked in ovariectomized rats and elevated by + estrogen replacement. Moreover, Kupffer cells isolated from ethanol-treated rats with estrogen replacement + produced more tumor necrosis factor alpha (TNF-alpha) than those from control and ovariectomized rats. It is + concluded, therefore, that the sensitivity of rat liver to alcohol-induced injury is directly related to + estrogen, which increases endotoxin in the blood and CD14 expression in the liver, leading to increased + TNF-alpha production." Shock 1998 Dec;10(6):436-41. Acetazolamide treatment prevents in vitro + endotoxin-stimulated tumor necrosis factor release in mouse macrophages. West MA, LeMieur TL, Hackam D, + Bellingham J, Claire L, Rodriguez JL. Hepatology 2000 Jan;31(1):117-23. Estrogen is involved in early + alcohol-induced liver injury in a rat enteral feeding model. Yin M, Ikejima K, Wheeler MD, Bradford BU, Seabra + V, Forman DT, Sato N, Thurman RG Anim Reprod Sci 1998 Feb 27;50(1-2):57-67. Elevation in tumour necrosis + factor-alpha (TNF-alpha) messenger RNA levels in the uterus of pregnant gilts after oestrogen treatment. Yu Z, + Gordon JR, Kendall J, Thacker PA Immunology 1995 Sep;86(1):18-24. In vivo modulation of murine serum tumour + necrosis factor and interleukin-6 levels during endotoxemia by oestrogen agonists and antagonists. Zuckerman SH, + Bryan-Poole N, Evans GF, Short L, Glasebrook AL. "Oestrogen treatment resulted in a significant increase in + serum TNF while serum IL-6 levels, relative to the placebo group, decreased in response to an endotoxin + challenge." Inflammation 1996 Dec;20(6):581-97. Estriol: a potent regulator of TNF and IL-6 expression in a + murine model of endotoxemia. Zuckerman SH, Ahmari SE, Bryan-Poole N, Evans GF, Short L, Glasebrook AL. Proc + Assoc Am Physicians 1996 Mar;108(2):155-64 Potential mechanism of estrogen-mediated decrease in bone formation: + estrogen increases production of inhibitory insulin-like growth factor-binding protein-4. Kassem M, Okazaki R, + De Leon D, Harris SA, Robinson JA, Spelsberg TC, Conover CA, Riggs BL. +

+ © Ray Peat Ph.D. 2006. All Rights Reserved. www.RayPeat.com +

+ + diff --git a/raypeat-articles/processed/estrogen-progesterone-cancer.html b/raypeat-articles/processed/estrogen-progesterone-cancer.html new file mode 100644 index 0000000..7bd2f0e --- /dev/null +++ b/raypeat-articles/processed/estrogen-progesterone-cancer.html @@ -0,0 +1,1342 @@ + + + Estrogen, progesterone, and cancer: Conflicts of interest in regulation and product promotion. + + +

+ Estrogen, progesterone, and cancer: Conflicts of interest in regulation and product promotion. +

+ + What is Cancer? (Johns Hopkins Univ.) +

+

+ "The + term cancer refers to a new growth which will invade surrounding tissues, metastasize (spread + to other organs) and may eventually lead to the patient's death if untreated. +

+

+ A tumor is not necessarily a cancer. The word tumor simply refers to a mass. For example, a collection of + pus is by definition a tumor. A cancer is a particularly threatening type of tumor. +

+

+ neoplasm- + + An abnormal new growth of tissue that grows more rapidly than normal cells and will continue to grow if not + treated. These growths will compete with normal cells for nutrients. This is a non-specific term that can + refer to benign or malignant growths. A synonym for tumor. +

+

+ tumor- + The more commonly used term for a neoplasm. The word tumor simply refers to a mass. This is a general term + that can refer to benign or malignant growths. +

+

+ benign tumor- A non-malignant/non-cancerous tumor. A benign tumor is usually localized, + rarely spreads to other parts of the body and responds well to treatment. However, if left untreated, benign + tumors can lead to serious disease. +

+

+ malignant tumor- Cancer. A malignant tumor is resistant to treatment, may spread to other + parts of the body and often recurs after removal. +

+ +

+ cancer- + A malignant tumor (a malignant neoplasm)." +

+

+ http://pathology2.jhu.edu/pancreas/pc_overview.cfm +

+ +

+ Issues that at first seem scientific too often turn out to be merely propagandistic. + + When a claim has no scientific value, it's necessary to directly attack that claim, but the propagandist + hopes to (and often does) control the discourse, by resorting to techniques such as censorship, public + relations, and financial-political power. The pharmaceutical industry uses all of those anti-scientific + powers just as effectively as the military-industrial lobby does. +

+

+ While Donald Rumsfeld answered the question, "where are the weapons of mass destruction?" by saying "We know + where they are. They're in the area around Tikrit and Baghdad and east, west, south and north somewhat," the + estrogen industry responds to the evidence that estrogen causes breast cancer, strokes, heart attacks, blood + clots and Alzheimer's disease by saying "it's progesterone that is responsible." +

+

+ To deal with the antiscientific fraudulent claims of the estrogen industry, it isn't necessary to search + every square meter of Iraq, as it was with Rumsfeld's claim; it's enough to show that there is no science + involved in their claims, by analyzing their experimental methods. But it's also important to examine some + of the methods they have used to further their goals, despite the absence of any factual basis. +

+ +

+ For more than 60 years, the estrogen industry has been using the techniques of public relations, including + the placement of pseudoscientific articles in medical journals, to promote their sales. Recently, Carla + Rothenberg documented a conspiracy of the estrogen industry in the 1940s to get medical and governmental + approval of their products by shifting attention away from the clear evidence of estrogen's toxicity. Her + paper competently reviews the subsequent history of "Hormone Replacement Therapy." + http://leda.law.harvard.edu/leda/data/711/Rothenberg05.pdf +

+ +

+ After 2002 when the Women's Health Initiative study announced some of the harmful effects of hormone + treatment, resulting in a disastrous decrease in estrogen sales, the industry has intensified and + diversified its public relations efforts, and has succeeded in recovering some of their lost market. + Historically, whenever some of the claimed benefits of estrogen have been disproved, the industry shifts its + emphasis to new, previously unmentioned "virtues" of the product. Hundreds of different benefits claimed for + estrogen in prestigious medical journals have been proven false, but until 2002, the industry's profits grew + steadily. Now, compensating for the annual loss of billions of dollars, they are highly motivated. +

+

+ Dozens of toxic effects of estrogen were demonstrated and never refuted, but a variety of techniques of + distraction and misdirection gradually emerged, to prevent the accumulated evidence of estrogen's toxicity + (and/or ineffectiveness) from interfering with the campaigns to market it for the widest possible variety of + conditions. +

+

+ Since the WHI study involved the use of Prempro (PREMPROTM--conjugated estrogens and + medroxyprogesterone acetate), the emphasis of the industry has been to divert attention from the toxic + effects of estrogen, by blaming everything on "progesterone." An intense campaign is underway to assign all + of estrogen's harmful effects to progesterone. +

+ +

+ The pharmaceutical industry has a long history of lying about natural progesterone (and many other natural + substances), to promote sales of their competing products. The price ratio of retail estrogen tablets to + bulk estrogen can be 1000 to 1, while the ratio for progesterone products is often less than 10 to 1. With + the increased use of progesterone (its sales in the US have increased more than 100-fold), the estrogen + industry has had to develop new kinds of attack. A small shift of the market away from estrogen costs the + drug industry hundreds of millions of dollars. The loss of estrogen sales following the 2002 WHI study, that + convincingly demonstrated its toxicity, was huge, with the decreased sales of Wyeth alone amounting to + billions of dollars. Wyeth has petitioned the FDA to prevent compounding pharmacies from selling the natural + hormones. +

+

+ People who have made a career of research that, according to them, reveals the "benefits" of estrogen have, + in recent years, expanded their work to argue that it is progesterone, rather than estrogen, that causes + diabetes, heart disease, dementia, and cancer. +

+

+ The EPA currently has a document draft on the internet which, in relation to the evaluation of a + carcinogenic herbicide, reviews the issue of the balance between estrogen and progesterone in the + development of cancer in rats, and includes the observation that progesterone is not carcinogenic to + rats, + and that it instead is protective against cancer, because of its antiestrogenic effects. +

+

+ Recently, stores in California have placed warnings near their progesterone-containing cosmetics, saying + that the State of California "knows" progesterone to be a carcinogen. +

+ +

+ Californians often talk about their state's having the world's sixth largest economy. The state accounts for + 14% of the GDP of the U.S. If the state regulates a product made in Michigan, Texas, or France, the producer + is very likely to change the product to suit California. +

+

+ If an industry wants to control its competitors or potential competitors, an investment in California's + regulatory system can pay huge rewards. +

+

+ California has listed progesterone as a carcinogen under the Safe Drinking Water and Toxic Enforcement Act, + called Proposition 65. The law doesn't prevent the sale of carcinogens, it simply requires a warning. + Warnings are posted in grocery stores and restaurants, on sports equipment, in beauty parlors, on apartments + and parking lots, but there is so little effort spent on realistic evaluation of risks that the effect of + the law is to allow the major polluters to go unnoticed among the ubiquitous warnings. But California has + other laws that encourage its lawyers to sue for "unfair business practices" when they believe Prop 65 has + been violated. That has resulted in a culture of vigilantism with bounty-hunting lawyers, some of whom try + to enforce Prop 65 even against companies that are clearly exempt. +

+

+ California's regulatory board that lists progesterone as a carcinogen cites two bodies that have evaluated + carcinogens, the US National Toxicology Program (NTP), and the UN's International Agency for Research on + Cancer (IARC), as authoritative sources. One of those, the US National Toxicology Program + (NTP) cites the other's, the + + IARC's, evaluation of progesterone as the basis for its own listing of progesterone, so the opinion of IARC + has been very influential. +

+

+ The IARC publications discussed the toxicity of several of the synthetic progestins, and concluded that some + of them are possible human carcinogens. The (1987) entry for medroxyprogesterone acetate, for example, has + three sections: "A. Evidence for carcinogenicity to humans (inadequate)," "B. Evidence for carcinogenicity + to animals (sufficient)," and C., that it can damage chromosomes. + Eight citations, besides two IARC monographs (1974 and 1979), are given as supporting evidence. +

+

+ The entry for progesterone, oddly, has only two sections, "A. Evidence for carcinogenicity + to animals (sufficient)," + + and B, that it doesn't damage chromosomes. There is no mention of human carcinogenicity at all. + Besides the IARC monographs, only one study is mentioned, a test in beagles (I'll comment on the + competency of that study below). At the end of the whole section, which included eleven synthetics and + progesterone, it concludes: "Overall evaluation" "Progestins are possibly carcinogenic to + humans (Group 2B)," oddly neglecting to distinguish progesterone from the synthetics. +

+

+ The corruption of the term "progestin" or "progestogen" by the industry and the drug regulators has been + terribly consequential. The synthetic chemicals classified as progestins often have anti-progesterone + actions, and shouldn't be called progestins at all, because they don't support gestation, contrary to what + the term falsely implies. It is exactly their anti-progesterone/antigestational action that led to their use + as contraceptives. +

+

+ Since the 1987 review by IARC, it seems that their only other review of progesterone's carcinogenicity was + of a single study in 1999, and that study clearly gave evidence that progesterone prevented cancer. +

+

+ But California's board of "qualified experts" in the Office of Environmental Health Hazard Assessment + (OEHHA) identify progesterone + + as known to cause cancer, and cites the group of studies listed by IARC in the medroxyprogesterone acetate + report as their evidence. Rather than trying to clarify the confusions that exist in the IARC documents, + this board has compounded the confusion. +

+

+ In the transcript of the meeting, at which they decided to list progesterone as a carcinogen, they received + testimony from only one outside expert, Richard Edgren, who answered the chairman's question, why don't you + want progesterone listed, by saying, because it isn't a carcinogen. He said that the inclusion of a large + number of non-carcinogenic materials "could vitiate the use of the list." +

+

+ But the chairman had, early in Edgren's review of the shortcomings of animal studies of carcinogenesis, + heard the word "metastasis," in connection with beagle dogs, and--although Edgren hadn't said that any + metastatic cancer had been found in the progesterone test (it hadn't)--the committee's decision to list + progesterone appears to have hinged on that word. +

+ +

+ Edgren, referring to "various + synthetic and semi-synthetic progestogens," said that administering them by injection + "leads to the development of mammary nodules, some of which have the characteristics of malignant tumors, + although these tumors rarely metastasize." A little later, Kilgore said "I mean, I heard you say that it was + rare that it metastasized. I would say any kind of metastasizing is important." Edgren isn't quoted in the + transcript as having attempted to explain that the malignant and metastatic cancers appeared only in beagles + treated with synthetic progestins. At best, the behavior of the chairman and the committee, as reflected in + that transcript, was erratic and confused, or more accurately, irrational. +

+

+ The only biologist on the committee who spoke during the meeting, Dr. Spangler, expressed confusion and + dissatisfaction with the evidence: +

+ +

+ ". . . in reviewing the information that was supplied to me regarding progesterone, I was confused and + concerned by what appears to be a variety of discrepancies in the way the compound has been reviewed." "In + one place, IARC says there is limited evidence; in another place, it says there is sufficient evidence. And + NTP says there is sufficient evidence. And they cite as their sufficient evidence a variety of very + convoluted experimental procedures, in which mouse mammary tumor virus positive mice were used in a study; + and, in addition to that, some other carcinogen, some other potent carcinogen, was applied at the same time + or after." "It was just very confusing. And I had a lot difficulty evaluating it." +

+

+ The State's rules explicitly state that all the relevant evidence + is to be presented to the committee for consideration, and that the evidence must show clearly, by + accepted scientific methods, that + a material causes cancer (i.e., malignant tumors) before it can be listed. What is clearly + shown by the few papers provided to the committee is that their procedures were not followed at all. + Providing publications that didn't even claim to have involved the development of cancer, and ignoring an + immense amount of more relevant evidence, the committee, in a parody of legal process, didn't even get a + randomly selected sampling of the relevant evidence. +

+

+ In my correspondence with OEHHA, when I pressed for information regarding the criteria for selecting + evidence, and the qualifications of the staff who had the responsibility of selecting "all relevant + evidence," their response was that they lacked the resources to answer the question. +

+

+ Edgren, who had argued that progesterone wasn't a carcinogen, didn't make a very good presentation of the + case against the few studies that had been mentioned by NTP and IARC. Even if he had been able to do that, + in the few minutes he had (six or seven different substances were on the agenda for consideration for + listing during that meeting), it doesn't seem likely that the committee would have been interested. +

+ +

+ In a letter he wrote to the committee before it met, Edgren said "Careful evaluation of data from a + properly conducted oral study is a prerequisite before the carcinogenicity of any chemical can be + adequately evaluated." + The reason for that statement is that it had become clear in the 1970s and 1980s that the invasive + introduction of anything into the body's tissues creates inflammation and a complex series of systemic + stress reactions that affect the immune system, and that can lead to the development or promotion of cancer, + no matter how inert and innocuous seeming the injected material might be. The people on the committee didn't + even discuss that issue. Worse, the studies mentioned by IARC included some that hadn't met basic scientific + standards of experimental design, failing to use proper experimental controls, including vehicle controls, + and failing to describe the actual composition of the vehicle or solvent used for administering + progesterone. +

+

+ Every good high school science teacher or science student knows that the experimental variables have to be + clearly defined. The United Nations' IARC, the US's NTP, and California's Panel of Qualified Experts chose + to draw conclusions on some studies that don't meet any standards for testing carcinogens, such as those + published by the US government. And while disregarding basic standards of experimental design, their review + of the literature had an even more serious flaw--it "cherry-picked" the published evidence that they + apparently preferred, ignoring the studies which, over a period of more than 20 years, showed that + progesterone prevents and/or cures tumors. And in an extremely unrepresentative selection of studies on the + subject of progesterone's carcinogenicity, the selected studies presented some clear evidence of some of + progesterone's anticarcinogenic effects, along with some results that can't be interpreted clearly. +

+

+ One of the early papers listed as evidence of progesterone's carcinogenicity in animals actually concluded + that their experiments completely failed "to produce any beneficial effect by the administration of + progesterone on the mammary cancer in mice," and cautioned that their results showed "the need for care in + attempting to generalize results even in different strains of the same species and emphasizes the difficulty + of attempting to carry over results obtained in experimental animals to human pathology." (Burrows and Hoch- + Ligeti, 1946). +

+

+ The work (demonstrations of the anti-tumor effect of progesterone) that they were not able to confirm had + included explicit observations that + intermittent injections of progesterone were not effective in preventing tumors or causing them + to regress, and emphasized the importance of continuous exposure. Knowing that, the Burrows and Hoch-Ligeti + publication appears to have been designed propagandistically to oppose the work that was demonstrating the + anti-tumor actions of progesterone, since they--without explanation--used the already discredited method of + giving periodic injections of progesterone dissolved in peanut oil. +

+

+ Without reading the article, people seeing it included on the agencies' list of studies supposedly providing + evidence of progesterone's carcinogenicity would assume that it provided such evidence. It didn't. If the + agencies cite this study, why didn't they mention any of the numerous studies showing that progesterone + prevents tumors or causes them to regress? The reason this study was done was to argue against the studies + that had demonstrated progesterone's protective effects, so anyone reading it had to know of those other + studies' existence, as well as knowing that this study itself provided no evidence at all of + carcinogenicity. +

+

+ Reproducibility is the essence of science, and the anti-tumor effects of progesterone were repeatedly + demonstrated by different investigators. The single study by Burrows and Hoch-Ligetti has never been + replicated, and the reason for its failure to show an anti-tumor effect was already explained by the other + workers. +

+ +

+ Since the 1920s, many studies had demonstrated that "spontaneous" cancers increase in proportion to the + quantity of polyunsaturated fat (especially linoleic acid) in the diet. By the end of the 1960s, the + carcinogenicity of vegetable oils, or at least their "co-carcinogenicity" or "tumor promoting" effects had + become widely known, and one of the World Health Organization publications observed that progesterone + carcinogenicity studies using vegetable oil as the vehicle couldn't be recognized as valid. +

+

+ More recently, ethanol has been found to antagonize progesterone's anticancer and anti-proliferative + actions. +

+ +

+ Studies using implanted pellets or plastic tubes containing a solution of progesterone sometimes neglected + to even mention the nature of the solvent used. Since implanted pieces of inert materials, such as disks of + plastic, could be carcinogenic, it was recognized that a proper control for a hormone-containing pellet or + tube would require the implantation of a pellet or tube without the hormone. Sometimes, instead of actually + implanting the object, sham surgery, similar to that involved in implantation of the pellet, would be used, + in recognition that the surgical trauma itself could have far reaching effects on the organism. +

+

+ Any tissue damage or irritation causes the release of cytokines and mediators of inflammation, which are + known to be involved in tissue growth and cancer. When injected, even plain water and other normally + harmless things are carcinogenic. +

+

+ The need for proper experimental controls when using implanted devices is shown by a study that analyzed the + fibrotic tumors that had grown around implanted plastic tubes. Crystals of talc were found in the tumor, + that were assumed to have originated from the surgical gloves used during the operation. Talc is now widely + recognized as a carcinogen, and is suspected of causing ovarian cancer. +

+

+ Overlooked variables are the reason for the essentiality of repeatability and confirmation in science. +

+

+ In the 1970s, a new method for suspending or dissolving oily chemicals in water was being explored. A cyclic + carbohydrate, cyclodextrin, makes it possible to wet substances that are insoluble in water, such as + progesterone, even if the substance remains in a solid crystalline form. Several companies were promoting + the use of these for the administration of hydrophobic drugs. +

+

+ In 1976, D.W. Frank reported that the cyclodextrins produced nephrosis in rats. In 1978, a study by Perrin, + et al., reported its toxicity to the kidneys. Twenty years later, Horsky and Pitha at NIH reported that the + cyclodextrins can synergize with carcinogens, and in 1982 a group in Japan reported that cyclodextrins can + increase the production of kidney cancers by another carcinogen (Hiasa, et al.). The intrinsic + carcinogenicity of a more water soluble cyclodextrin, that was considered "more toxicologically benign," was + found to cause pathological changes in lungs, liver, and kidney, and to increase the formation of tumors in + the pancreas and intestines of rats (Gould and Scott, 2005). +

+

+ In 1974, D. W. Frank and others at Upjohn had begun testing the effects of progesterone and + medroxyprogesterone acetate in beagle dogs, using an "aqueous suspension." Their 1979 publication describing + that four year study didn't mention the way in which the "aqueous solution" had been made, and didn't + mention cyclodextrins at all. Frank's published observation during the beagle study that cyclodextrins are + toxic to the kidneys suggests that someone at Upjohn had noticed a problem with the "wetting agent" that was + already in use in the beagle study. +

+ +

+ Another remarkable feature of the four year beagle study was that, of 140 dogs that began the intended 7 + year study, 28 had died by the time they published the report, and none died of cancer, but the causes of + death were not reported. The only experimental group in which there were no deaths by the end of four years + was the low dose progesterone group. The dogs in the high dose progesterone group received weekly + intramuscular injections of 1140 mg of progesterone suspended in 11.4 ml of "aqueous vehicle." 2345 ml of + the vehicle was received by each dog during the four years. Only four dogs in that group were still alive at + the time of publication, but the cause of death of the other 16 wasn't mentioned. Quarts of a toxic material + that had never before been used in this way, injected into their muscles, and the unexplained deaths of so + many animals, make this a unique experiment that is unlikely ever to be repeated. +

+

+ Their failure to mention injection-site muscle damage is just another indication of the study's low quality. +

+

+ At the time of the study, it had been known for many years that interference with the organism's detoxifying + systems, especially the liver and kidneys, can contribute to the development of cancer. Although the study + was planned to continue for 7 years to meet the FDA requirement, none of the eight authors ever + published again on a related topic, and most of them didn't publish again at all. + +

+ +

+ When I tried to contact one of the authors, he didn't respond. I assume they were embarrassed by the + shoddiness of their methods. Richard Edgren has commented, "I can't believe how fast and how completely they + shut down. They fired people and retrained the rest for other areas." +

+

+ But the regulatory agencies have tied their reputations to studies of that sort. +

+

+ No malignant cancers were reported in this four-year beagle study. Beagles normally have a high incidence of + cancer, especially mammary cancer. In a different study in which 172 beagles were treated with contraceptive + hormones, nine of them developed malignant cancers, and of those, five metastasized. (This might be why the + chairman of the committee was thinking about metastatic cancer, but if so, he was simply confused, because + the issue they were considering was the listing of natural progesterone, which wasn't reported to have + produced any malignant or metastatic tumors.) +

+

+ Two other studies cited by the IARC and other agencies, by Jones and Bern, 1977, and Rebout and Pageaut, + hardly seem appropriate studies to support the idea that progesterone is carcinogenic. +

+ +

+ Jones' and Bern's paper described the production, 12 months after neonatal treatment with progesterone, of + vaginal and cervical lesions, and mammary nodules, which are also referred to as tumors. "Progesterone alone + induced cervical lesions in only 1 of 32 mice...and induced vaginal lesions in only 2 or 32 mice. + Furthermore, progesterone given with either dose of estrogen to intact mice reduced the incidence of + hyperplastic lesions, compared with intact groups treated with estrogen alone." They commented (page 74) + that their results were "mammary tumor virus dependent," and that this might account for the production of + "hyperplastic alveolar nodules as opposed to" tumors of possible ductal origin, that had been seen in other + studies when the carcinogen DMBA was used. +

+

+ In another 1977 publication, Jones, Bern, and Wong described changes seen when the mice were 1.5 to 2 years + old. This later publication appears to clarify the meaning of nodules or tumors in the younger animals: + + "Although mammary tumors were observed neither in control nor in progesterone-treated intact mice, many + of the latter group possessed hyperplastic alveolar-like mammary nodules and other dysplasias." + Neither of these studies refers to the carcinogenicity of progesterone. +

+

+ The 1977 study (at the University of California, Berkeley) was explicitly motivated by Jones' and Bern's + concern with the risks of the medical practice of treating pregnant women with DES and a synthetic + progestin, and they used mammary tumor virus-bearing mice, and they didn't continue the study to observe the + incidence of actual cancers. (Their choice of infant rodents to study progesterone might be questioned, + because of earlier work showing that immature rat ovaries are able to convert progesterone to + estrogens, unlike the tissues of other animals or humans: Quattropani and Weisz, 1973; Weniger, + et al., 1984, later reported similar results.) +

+

+ Anyone working with mammary tumor virus-bearing mice in the 1970s should have been aware of the effects of + sex hormones on the expression of virus and development of cancer in the infected mice, as studied by + Strong, Figge, and others for about 40 years. Excess estrogen causes the virus to be expressed, progesterone + opposes its expression. +

+ +

+ Jones and Bern injected the newborn mice with 0.02 ml of sesame oil daily for five days, with or without + estrogen and progesterone. A newborn mouse weighs a little over a gram. On a weight and volume basis, this + would be like injecting an adult human with more than a quart of sesame oil daily for five days. The + proportionate weight of progesterone in an adult human would be several grams per day. +

+

+ This amount of progesterone is far more than the anesthetic dose. Since the authors didn't mention + anesthesia, very little of the progesterone could have been absorbed, meaning that deposits of crystals + would have remained in their tissues. +

+

+ Tissue irritation from foreign bodies and from vegetable oil, even in relatively small amounts, can produce + severe systemic reactions, because of the reactive production of nitric oxide, prostanoids, and a great + variety of pro-inflammatory and tumor-promoting cytokines. +

+

+ This study might have had the formal appearance of a scientific experiment, but the unfamiliarity of the men + with the material they were using, their use of mice carrying the mammary tumor virus, and, more + importantly, the extremely complex reactions produced when extraneous materials are injected into the + tissues, make this a useless experiment. The value of Richard Edgren's statement about the need to test + carcinogens orally, rather than by injection, is becoming clearer all the time, as the role of irritation in + cancer development is being better understood. +

+

+ In their second 1977 study, Jones, Bern and Wong reported that at the age of 1.5 to 2 years, nearly two + thirds of the progesterone treated mice had genital tract lesions. In another study published in 1977 + (Iguchi and Takasugi) neonatal mice were given the same daily amount of progesterone, but for ten days + rather than five, giving them twice the dose. These authors reported that there were no permanent + changes in the vaginal and uterine epithelium. This study wasn't mentioned by any of the agencies, but + it calls the results of the California study into question. +

+ +

+ In a 1973 study by Rebout and Pageaut, progesterone was administered in a pellet, the composition of + which was not mentioned, and there was no vehicle control at all. Each mouse received 45 mg of + progesterone. The average mouse weighs about 30 grams. Invasive squamous carcinomas were produced by the + carcinogen 20-methylcholanthrene, and these were more numerous in the progesterone treated mice. + Methylcholanthrene is an extremely hydrophobic, highly irritating hydrocarbon which has often been used to + create experimental cancers. The method of administering the carcinogen isn't clearly described: "Local + exposure of carcinogen ... in the cervical canal for 9 weeks ... induced one invasive carcinoma in the + vagina-exocervix and five in the endocervix." It was introduced into the cervical canal, but in what form + and how often isn't described. Methylcholanthrene has some estrogenic properties. +

+

+ Estrogen increases the production of mucus in the cervix and vagina, and increases its water content and + mobility. Abundant and fluid mucus has a cleaning action, eliminating bacteria and other material. + Progesterone makes the mucus more viscous and less hydrophilic, and when it dominates the reproductive + physiology, it effectively creates a plug in the cervix that prevents the entry of sperms. +

+

+ The choice of the cervix and vagina suggests that the authors were "engineering" the experimental outcome, + because the effect of progesterone on cervical mucus is very well known. To apply the irritant to an area + where it would normally be washed away by the mucus, but where it is kept in place by hormonally altering + the mucus, is really a way of manipulating how much exposure to the irritating chemical the tissue will + receive. It's analogous to studying the "toxicity" of an antihistamine, by applying a toxin to the nasal + membrane of a person with a cold, and then administering the antihistamine to stop the flow of mucus, + allowing the membrane to fully absorb the applied dose of toxin. +

+

+ A different chemical carcinogen, 7,12-dimethylbenz(a)anthracene was used in another 1973 study (Jabara, et + al.), in combination with progesterone. In this experiment, the carcinogen was administered to rats in one + dose by stomach tube, dissolved in corn oil. The progesterone was injected subcutaneously in 3 mg doses in + corn oil three times per week. Unfortunately, there was no control group in which the corn oil was injected + alone. +

+

+ The progesterone was supposedly dissolved in the corn oil, one tenth ml per dose. That amount of + progesterone (3% weight/volume) will dissolve in hot corn oil, but as the oil cools, the progesterone + crystallizes and precipitates. That creates doubt regarding what the animals were actually receiving. +

+

+ Corn oil is one of the most effective vegetable oil tumor promoters/carcinogens, and it's now considered + improper to use it as a solvent for testing even oral carcinogens, since some chemicals that are + carcinogenic in the oil are relatively harmless when administered without the corn oil. The animals got 2 ml + of corn oil in the stomach feeding with the carcinogen. One of the groups (group 5) received, in addition, + more than 6 ml of corn oil in the injections. The experiment lasted only 135 days, and in the group that + received only the carcinogen, the mortality was only 5%, and that death occurred shortly after the + carcinogen was administered. All of the groups receiving the corn oil and progesterone injections had higher + mortality, two with 25%, one with 37.5% mortality. Despite the unexplained general problem with + prematurely dying rats, + + the authors found that "The relative incidence rates indicated that pretreatment with progesterone + inhibited tumorigenesis, + except in the group (5) in which progesterone treatment was continued for the duration of the experiment." + Without progesterone, it is almost certain that the additional corn oil injected would have + increased tumorigenesis in all experimental groups. +

+

+ Without that vehicle control group, the experiment can just as well be described as a test of corn oil, + rather than of progesterone. If you claim to be testing the capacity of a substance to promote tumors, it + shouldn't be administered in a standard tumor promoter. +

+

+ A 1968 publication by Glucksmann and Cherry was included in the documents offered as evidence of + progesterone's carcinogenicity. Unfortunately, they neglected to identify the vehicle used for giving twice + weekly intramuscular injections of 1 mg of progesterone, and they didn't have a vehicle control for the + progesterone injections. At that time, the most common vehicle was a mixture of 9% benzyl alcohol and oil, + usually sesame or peanut oil. Benzyl alcohol by itself is quite toxic, and was responsible for the death or + brain damage of thousands of babies in hospitals, even in the small amounts that remained as residue in + tubing after they had been rinsed with "bacteriostatic water," which contains 0.9% benzyl alcohol, and which + is still used as the vehicle for many injections, such as penicillin and vitamin B12. The antitoxic (or + "catatoxic") action of progesterone greatly reduces the toxicity of benzyl alcohol. +

+ +

+ In discussing the effects of hormones on the induction of sarcomas, Glucksmann and Cherry comment that "The + rate of induction of sarcomas in intact rats was slowed down slightly by treatment with progesterone and not + significantly increased in spayed animals...." +

+

+ In their Discussion section, they mention several previous studies in relation to their own results, and + comment, regarding other studies, that "The effect of progesterone on the type of induced cervical cancer in + mice consists in increasing the columnar component of mixed carcinomas in castrates . . . + without materially affecting the induction period and tumour yield. Thus the experimental evidence in rats + and mice + is not as clearly antitumorigenic as that of Lipschutz (1950) for guinea pigs and the clinical + observations (Ulfelder, 1962; Jolles, 1962)." +

+

+ Comparing this study to that of Burrows and Hoch-Ligetti, the dose of 2 mg per week per rat is lower, on a + body-weight basis, than the earlier study's dose of 1 mg per week in mice, but the greater frequency came a + little closer to the continuous treatment that Lipschutz said was necessary. This could account for the fact + that some of their results were intermediate between those of the Lipschutz group and those of Burrows and + Hoch-Ligetti. +

+ +

+ In Glucksmann's and Cherry's results, progesterone retarded one type of tumor and appeared to promote + another (an epithelial tumor, which wasn't described as malignant or cancerous), but if the progesterone was + dissolved in a tumor promoting solvent, it's impossible to ascribe the effect to progesterone. Vegetable oil + applied to epithelium that has been exposed to a carcinogen such as the DMBA they used will typically + increase the growth of the tumors. Without information about the vehicle, it's impossible to interpret that + part of their results clearly, but anyway, they didn't describe any carcinogenic effect of progesterone; + they did, however, describe a clearly anticarcinogenic action. +

+

+ A 1962 study, by Capel-Edwards, et al., was intended to compare the effects of prolonged administration of + high doses of progesterone with the known toxic effects of synthetic progestagens. They didn't find any + malignant tumors, so the study can't be taken as evidence of the carcinogenicity of progesterone. The + vehicle used for dissolving the progesterone consisted of benzyl alcohol, ethanol, and ethyl oleate. Some of + the solutions contained more than 10% progesterone. When this sort of solution interacts with water in the + tissues, it causes the progesterone to crystallize out of solution. The authors reported that "subcutaneous + tissue reactions developed at injection sites," and that these "occurred in all animals, including controls, + and were apparent for several days after the injection." These injection-site lesions sometimes developed + into "sterile abscesses which eventually ulcerated and healed." The only dog that died during the study was + in the control group, and although there were "a number of pathologic findings," the exact nature of that + dog's sickness couldn't be determined. The injections were given daily, for a total of 518 + injections in each animal, + and each injection contained as much as 4 ml of the vehicle. Almost an ounce per week of this material, + combined with the massive irritation produced by crystallization at hundreds of injection sites, would be + the most likely explanation for the various inflammatory changes they saw, including osmotic fragility of + red blood cells, and as much as a 50% enlargement of liver and kidneys. +

+

+ Although some of the basic ideas about canine physiology that were held when the Capel-Edwards study was + designed have been found to be mistaken, and the toxicity of their vehicle can now be seen, and they didn't + conclude that progesterone was carcinogenic, their study wasn't the worst of those that have been presented + as evidence of progesterone's carcinogenicity. +

+

+ When an experimenter doesn't yet have a clear hypothesis, it's reasonable to do some exploratory tests, just + to get an orientation to the possibilities so that it's possible to form a well defined hypothesis, before + designing an experiment that will test the hypothesis. Sometimes an experimenter and journal editors will + allow a merely exploratory experiment to be published. If they don't draw inappropriate conclusions from the + ambiguous results, the publication can be justified, simply because it might stimulate others to investigate + the subject more thoroughly. +

+ +

+ But often editors allow the author to draw conclusions from the experiment that are not directly implied by + the data, especially when those conclusions support the editor's prejudices. A conclusion may be consistent + with, though not implied by, the results of the experiment. These publications may be effective propaganda, + but they aren't good science. +

+

+ But California's OEHHA identifies those eight publications as "the relevant evidence that clearly shows + through scientifically valid testing according to generally accepted principles that progesterone causes + cancer." +

+

+ In 2004, the agency was petitioned to remove progesterone from the list. In the document rejecting that + petition, they mentioned that IARC in 1999 had reviewed newer evidence confirming the carcinogenicity of + progesterone. After months of asking the man in charge of rejecting the petition to identify that very + important new data, I hadn't received an answer, so I wrote to IARC, and the man in charge there responded: +

+

+ "The IARC (1999) review is actually an IARC Monographs volume (Vol.72) . . . . This volume focuses on + contraception and post-menopausal therapy. Progesterone is not used for these indications and, hence, after + a quick search in the book I found only one reference that clearly reports an experiment with progesterone." + [Wednesday, October 04, 2006 12:44 AM] +

+ +

+ That article (Grubbs CJ, Peckham JC & McDonough KD (1983) Effect of ovarian hormones on the + induction of 1-methyl-1-nitrosourea-induced mammary cancer. Carcinogenesis 4(4):495-497) + reported that progesterone + + reduced the incidence of mammary cancers caused by a carcinogen administered in vegetable oil. +

+

+ I don't think it's possible that anyone could read articles like this, + that don't even claim to show that progesterone causes cancer, and conclude that they provide + evidence of progesterone's carcinogenicity. + The choice of "evidence" seems to have been a selection of titles of unread articles. + And even the title of the 1999 IARC volume would have suggested to most people that it wasn't a + review of progesterone. +

+

+ The lack of vehicle controls in some of the studies, the use of an unnamed vehicle in one beagle study, and + the use of tumor-promoting vehicles in most if not all of the studies, means that no scientifically + competent or valid studies have been cited by IARC, NTP, or the California state bureaucracy, OEHHA, to + support California's claim that they know progesterone is a carcinogen. +

+

+ In their 2004 document, OEHHA mentioned 17 articles that had been submitted regarding progesterone's + protective effects. Some of these were identified; + two were egregiously misrepresented in a single sentence: +

+ +

+ Plu-Bureau, et al., were said to have reported "no association between breast cancer risk and progesterone + topically applied for the treatment of mastalgia and benign breast disease..." What Plu-Bureau, et al., said + immediately following that was "Although the

there was no significant difference in + the risk of breast cancer in percutaneous progesterone users versus nonusers among oral progestogen users." + (RR means "relative risk," or "risk ratio," and 0.5 means a 50% reduction in risk.) +

+ +

+ Cowan, et al. (1981), according to the OEHHA document, reported "reduced premenopausal breast cancer in + women who had a history of progesterone deficiency." What they actually said was "These women were + categorized as to the cause of infertility into 2 groups, those with endogenous progesterone deficiency (PD) + and those with nonhormonal causes (NH). Women in the PD group had 5.4 times the risk of + premenopausal breast cancer as compared to women in the NH group. This excess risk could not be + explained by differences between the 2 groups in age at menarche or age at menopause, history of oral + contraceptive use, history of benign breast diseases, or age at 1st birth. Women in the PD group + also experienced a 10-fold increase in deaths from all malignant neoplasm compared to the NH + group." +

+

+ Ending the paragraph that mentioned those studies, the California document continues: "However, there is + also evidence that progesterone may have a mitogenic effect. For example, Soderqvist et al. (1997) found + that in breast cells of healthy women, cell proliferation was correlated with serum progesterone levels, + thereby suggesting a proliferative action of progesterone." +

+ +

+ Such a suggestion is not made by that "correlation." The authors said, "Our objective was to assess + proliferation in normal breast epithelial cells from healthy women during the follicular and luteal phases + of the menstrual cycle." At the beginning of the luteal phase, both estrogen and + progesterone normally rise several-fold, so the small increase in proliferative rate also correlates with + estrogen levels. A "defective luteal phase" is common, in which the ratio of estrogen to progesterone is + high, and in that case progesterone's well established antiproliferative, differentiative effect will be + overridden by estrogen's proliferative stimulation. +

+ +

+ The state's reviewers didn't comment on the studies which showed that progesterone, besides inhibiting + proliferation, also inhibits an "oncogene" which is associated with cancer, rather than just with + proliferation. Instead, they cited a meaningless "correlation" as if it were some kind of argument against + progesterone's anticancer effects. The authors of this document don't seem to know very much about the + biology of cancer, but maybe they know too much about the issue of the proliferation of breast epithelium. +

+

+ In a paragraph "rebutting" the petitioner's point that "This new research supports that exogenous + progesterone actually reduces + + the risk of breast cancer in humans," the authors don't mention that point at all, but instead refer to + cancer treatment and to the various claims relating to progesterone's carcinogenicity, ending with the + mention of "studies that suggest progesterone stimulates cell proliferation (e.g., Soderqvist et al., + 1997)." Apparently the authors had no answer to the petitioners' point, and preferred to talk about + proliferation of breast cells. +

+

+ Nearing the end of the document, the authors say "The NCI also reports on other studies of estrogens with + progestins, which would suggest that progesterone increases the risk of + human breast cancer," and then quotes comments on studies of estrogens with (synthetic) progestins. The + authors cite two more studies with synthetic progestins, and then say "As discussed above, the mammary gland + was a main target site in animal cancer bioassays providing the basis for the IARC and NTP identification of + progesterone as carcinogenic." (The preceding discussion had mentioned the 4 year beagle study--which ended + the careers of the researchers--and a 1993 publication by Kordon, et al., which had no control group for + reference, and instead compared progesterone with different doses of medroxyprogesterone acetate, finding + that the fewest tumors occurred in the progesterone group.*) +

+

+ The techniques of distortion, diversion and evasion in this document are so obvious that any college + composition teacher would have returned it to the student for revision. The document says much more about + its authors than about its subject. +

+

+ I think this bureaucratic behavior is understandable only if you know the composition of the group that is + responsible for the progesterone listing, because the proliferation of breast cells has become an important + issue for the group around USC professor Malcolm Pike. +

+

+ Around 1980, Malcolm Pike, a statistician from South Africa, working in epidemiology, began arguing that the + use of oral contraceptives prevented cancer. This epidemiologist, unfamiliar with steroid physiology except + as it filtered through the oral contraceptive industry, decided that progesterone was the primary cause of + breast cancer, by stimulating + cell division and increasing the tissue density of the breast. +

+ +

+ This line of reasoning gained adherents in the USC Keck School of Medicine, despite an overwhelming amount + of contrary evidence, accumulated over more than 50 years, that progesterone protects against breast cancer, + partly by inhibiting cell division, and that increased breast density is + significantly associated with breast mitogens, such as serum insulin-like growth factor-I (IGF), prolactin, + and estrogens, rather than with progesterone. +

+

+ Breast mitogens correspond to both breast density and the risk of breast cancer (Boyd), but progesterone + (antimitogen) corresponds to factors associated with low risk of breast cancer. + + Progesterone may reduce breast density by inhibiting some growth factors, including IGF, NO (nitric oxide), + VEGF (vascular endothelial growth factor), bcl-2 (a protein that inhibits apoptosis), polyamines, and + prostaglandins. +

+

+ Much of the research at USC's Keck School has been generously funded by pharmaceutical companies with huge + interest in estrogen-related products. The medical school website has articles by their faculty that give + the impression that they are often more concerned with the fate of the estrogen market than with the science + they claim to be doing. For example, commenting on the WHI evidence showing that estrogen helps to cause + Alzheimer's disease, professor B.E. Henderson said "I continue to believe that estrogen therapy may help + reduce a woman's risk of developing Alzheimer's disease . . . ." I noticed that there were + hundreds of other estrogen-related items on the USC website. +

+ +

+ The medical school, some of its professors, government agencies, and private companies are involved in some + very complex, overlapping activities that give the impression of what used to be called "conflicts of + interest." +

+

+ The Keck School (a private institution), and the company, Balance Pharmaceuticals, Inc., controlled by three + of their professors, participate in the business promotion organization operated by the State of California, + Larta Institute, which manages Project T2, which is part of a "commercialization" system, involving awards + of federal government money: + "The organization will provide the awardees with assistance in all aspects of commercialization, including + business development, funding and capital acquisition, government regulatory processes, + intellectual property protection, licensing strategies, and merger and acquisition opportunities. SBIR Phase + II is the research and development stage of the well-known program, with award sizes typically starting at + $750,000 each." "Working with one of the Federal government's largest and most important agencies to assist + SBIR awardees on the cusp of commercialization is a natural extension of everything we've done for the past + ten years," said Larta Institute CEO Rohit Shukla. +

+

+ Besides the issue of giving public money to private groups to commercialize ideas, many of which were + developed using government-funded research, adding assistance with "government regulatory processes" to the + help given to private corporations should arouse suspicions. The idea of "privatization" is given a new + dimension: It's all for the insiders, without the usual lip-service paid to "competition." +

+

+ On California's committee that chooses chemicals to put on their list of "known carcinogens" is Juliet + Singh, who is the chief executive of Trans Pharma Corporation, a company that is developing + transdermal drug delivery systems, for example for giving hormones by applying them to the skin. Under + California's law, chemicals on the carcinogen list may to sold as drugs without a warning. +

+

+ On the committee with Singh are Anna Wu and Thomas Mack, who co-authored several papers with Malcolm Pike, + who was the most visible promoter of the campaign against progesterone, and who with two other USC + professors controls Balance Pharmaceuticals, Inc., which is being promoted by Larta Institute, and that's + planning to market a contraceptive based on the idea of suppressing progesterone. Three USC professors are + on California's carcinogen committee, more than from any of the other universities in the + state. +

+

+ In a jury trial, I think this would look like a tainted jury. +

+ +

+ Comparing the California agency's parody of legitimate process in this instance with its reconsideration in + 2002 of its listing of saccharin as a carcinogen is illuminating. In that case, there was at least a + pretense that the staff had made an attempt to provide "all relevant scientific evidence" for the committee + to review, as specified by the agency's regulations. And in its decision, the State's Qualified Experts made + a point of declaring, according to the language of the law, that in the opinion of the state's qualified + experts it had not been "clearly shown through scientifically valid testing according to generally accepted + principles to cause cancer." The Committee found that, in this case, it had to use a "'weight of evidence' + approach to evaluate the body of information available...." +

+

+ Unfortunately, the committee allowed some bizarre speculations about calcium phosphate to outweigh the fact + that saccharin is a mild carcinogen, and in evaluating the rat experiments they were in such a hurry to + remove saccharin from the list that they neglected to notice that calcium phosphate precipitation isn't + unique to rat urine, but very commonly occurs in human urine. Their decision to remove it from the list + rested on that non-fact. +

+ +

+ Although the agency cited 150 studies, and went through the formality of describing some of them in their + document, anyone reading the document justifying the delisting of saccharin, and the document rejecting the + delisting of progesterone, will find it hard to see a principle of law that could justify removing a + carcinogen from the list, because of uncertainty regarding the mechanism by which it causes cancer, and + keeping progesterone on the list, despite overwhelming evidence that it protects against cancer, and a great + amount of evidence regarding the mechanisms through which the protection occurs. +

+

+ The committee of experts who "weighed" speculations about calcium phosphate in the 2002 saccharin document, + chose not to consider, either in 1987 or 2004, any of the hundreds of empirical studies showing + progesterone's protective anticancer effects. The committee "considered" approximately half of all research + publications on saccharin and cancer, and fewer than 1% of those relating to progesterone and cancer. + Something other than scientific objectivity must explain those differences. +

+

+ The agency in charge of those processes of evaluating evidence of carcinogenicity declines to identify the + people who made those possibly biased, certainly bizarre, selections of articles, or to list their + qualifications for being in the crucial position of deciding what evidence would be provided to the + Scientific Advisory Panel. And in the list of studies that the committee did receive, are two (Kwapien, et + al., and Yager and Yager) that are about completely different chemicals, that the agency still identifies as + evidence of progesterone's carcinogenicity. +

+ +

+ Many progesterone products have been taken off the market because of California's warning signs and labels, + and as a result many women are having to rely on their physicians for progesterone. Too many physicians know + only what the pharmaceutical companies want them to know about progesterone and other hormones that had been + available for decades in places such as health food stores. +

+

+ An article in JAMA (Marcia Stefanick, April 11, 2006) was summed up by Stefanick in a way that seems + designed to encourage physicians to return to prescribing estrogen: "In the estrogen and + progestin trial those women who got on the active pills, we saw an increase in breast cancer within five + years. In the case of estrogen only, we not only do not see an increase by 7 years, but there's actually a + suggestion of a decrease." That is a serious misrepresentation of the study. +

+

+ The recently reported (December 15, 2006) decline of breast cancer incidence, coinciding with the great + decrease in the use of menopausal estrogen treatments, also coincided with an increased use of natural + progesterone, but if the lawyers, bureaucrats, and agents of the estrogen industry succeed in convincing the + public that progesterone is carcinogenic, its use will decline, and breast cancer incidence could be + expected to increase again. +

+

+ The studies that show cancer prevention by progesterone have, over the years, failed to resonate in the + medical culture. The confusion created by classifying the antiprogestational, carcinogenic synthetics as + "progestins" is largely responsible for the failure to understand the protective nature of progesterone. +

+

+ If the evidence showing that progesterone prevents or cures cancer could be weighed against the evidence + purporting to show that it is carcinogenic, I think it would be clear that something like a + cultural-commercial misogyny has been at work. The novelty of the newer misogyny is that it is so often led, + or at least figureheaded by women. +

+ +

+ *Note: Compare the results of Kordon, et al., 1993, with the later results of Aldaz, et al.: +

+ +

+ Kordon, et al., reported 58% of the animals had tumors in the group receiving low dose MPA pellets, 98% in + the high dose MPA group. +

+

+ Aldaz, et al., 1996, wrote "The synthetic progestin medroxyprogesterone acetate (MPA) was postulated by some + authors to increase mammary tumor incidence in various rodent models. However, controversy exists regarding + the role of MPA in experimental and human carcinogenesis." "MPA by itself did not produce any + mammary tumors." +

+

+

REFERENCES from IARC and OEHHA

+

+

+ 1. National Toxicology Program, U.S. Department of Health and Human Services, + Fourth Annual Report on Carcinogens (Summary), pages 392-393, 1985. +

+

+ 2. International Agency for Research on Cancer, IARC Monographs on the Evaluation of the + Carcinogenic Risk of Chemicals to Humans, Volume 21, pages 491-515, 1979. +

+

+ 3. International Agency for Research on Cancer, IARC Monographs on the Evaluation of the + Carcinogenic Risk of Chemicals to Man, Volume 6, pages 135-146, 1974. +

+

+ 4. International Agency for Research on Cancer, IARC Monograph on the Evaluation of the Carcinogenic + Risk of Chemicals to Humans, Supplement 4, pages 202-203, 1982. +

+ +

+ 5. Burrows, H. and Hoch-Ligeti, C., Effects Of Progesterone On The Development Of Mammary Cancer In + C3H Mice. Cancer Research, 6:608-609, 1946. +

+

+ 6. Capel-Edwards, K., et al., Long-Term Administration Of Progesterone To The Female Beagle Dog. + Toxicology and Applied Pharmacology 24:474-488, 1973. +

+

+ 7. Frank, DW, et al., Mammary Tumors And Serum Hormones In The Bitch Treated With + Medroxyprogesterone Acetate Or Progesterone For Four Years. + Fertility and Sterility, 31(3):340-346,1979. +

+ +

+ 8. Glucksmann, A. and Cherry, CP. The effect of oestrogens, testosterone and progesterone on the + induction of cervico-vaginal tumours in intact and castrate rats. + British Journal of Cancer 22(3):545-562, 1968. +

+

+ 9. Jabara, AG, et al., Effects Of Time And Duration Of Progesterone Administration On Mammary + Tumours Induced By 7, 12-dimethylbenz(A)Anthracene In Sprague-Dawley Rats. British Journal of + Cancer, 27:63-71,1973. +

+

+ 10. Jones, LA and Bern, HA. Long-Term Effects Of Neonatal Treatment With + + Progesterone, Alone And In Combination With Estrogen, On The Mammary Gland And Reproductive Tract Of + Female BALB/Cfc3h Mice. Cancer Research, 37:67-75,1977, [6 pages]. +

+ +

+ 11. Jones, LA, et al., Cervicovaginal And Mammary Gland Abnormalities In Old BALB/cCRGL Mice Treated + Neonatally With Progesterone. Journal of Toxicology and Environmental Health, 3:360-361, 1977. +

+

+ 12. Kwapien, RP, et al., Malignant Mammary Tumors In Beagle Dogs Dosed With Investigational Oral + Contraceptive Steroids. Journal of the National Cancer Institute, 65(1):137-144,1980. +

+

+ 13. Reboud, S. and Pageaut, G., Co-Carcinogenic Effect Of Progesterone On 20-Methylcholanthrene + Induced Cervical Carcinoma In Mice. Nature, 241:398, 1973. +

+ +

+ 14. Yager, JD and Yager, R., Oral Contraceptive Steroids As Promoters Of Hepatocarcinogenesis In + Female Sprague-Dawley Rats. Cancer Research, 40:3680-3685, 1980. +

+

+ 15. Letter addressed to Dr. Wendell Kilgore from Helen P. Shu, Ph.D., Syntex (U.S.A.) Inc., dated December + 3, 1987. +

+

+

OTHER REFERENCES

+

+

+ J Gynecol Obstet Biol Reprod (Paris). 1990;19(3):269-74. [The in vivo effect of the local + administration of progesterone on the mitotic activity of human ductal breast tissue. Results of a pilot + study] Barrat J, de Lignieres B, Marpeau L, Larue L, Fournier S, Nahoul K, Linares G, Giorgi H, + Contesso G. "Mean mitotic activity was significantly lower in progesterone treated group + (0.04/1,000 cells) than in placebo (0.10/1,000 cells) or in estradiol (0.22/1,000 cells) treated groups. + High concentration of progesterone sustained in human breast tissue in vivo during 11 to 13 days does not + increase, but actually decreases mitotic activity in normal lobular epithelial cells." +

+ +

+ Br J Cancer. 2002 Oct 7;87(8):876-82. The association of breast mitogens with mammographic + densities. Boyd NF, Stone J, Martin LJ, Jong R, Fishell E, Yaffe M, Hammond G, Minkin S. +

+

+ Bull Cancer. 2006 Sep 1;93(9):847-55. [Breast density: a biomarker to better understand and prevent + breast cancer] Brisson J, Berube S, Diorio C. +

+

+ J Steroid Biochem Mol Biol. 2005 Jul;96(2):95-108. Progestins and progesterone in hormone + replacement therapy and the risk of breast cancer. Campagnoli C, Clavel-Chapelon F, Kaaks R, + Peris C, Berrino F. "Controlled studies and most observational studies published over the last 5 years + suggest that the addition of synthetic progestins to estrogen in hormone replacement therapy (HRT), + particularly in continuous-combined regimen, increases the breast cancer (BC) risk compared to estrogen + alone. By contrast, a recent study suggests that the addition of natural progesterone in cyclic + regimens does not affect BC risk. This finding is consistent with in vivo data suggesting that + progesterone does not have a detrimental effect on breast tissue. The increased BC risk found + with the addition of synthetic progestins to estrogen + + could be due to the regimen and/or the kind of progestin used." +

+

+ Climacteric. 2004 Jun;7(2):129-37. Human breast cell proliferation and its relationship to steroid + receptor expression. + Clarke RB. +

+

+ Am J Epidemiol. 1981 Aug;114(2):209-17. Breast cancer incidence in women with a history of + progesterone deficiency. Cowan LD, Gordis L, Tonascia JA, Jones GS. "Women in the PD + [progesterone deficiency] group had 5.4 times the risk of premenopausal breast cancer as compared to women + in the NH group." "Women in the PD group also experienced a 10-fold increase in deaths from all malignant + neoplasm compared to the NH group." +

+ +

+ Climacteric 2002 Sep;5(3):229-35. Effects of progestogens on the postmenopausal breast. de + Lignieres B. The potential for an increased risk of breast cancer linked to the use of synthetic progestins + combined with oral estrogens is one of the main putative reasons for discouraging postmenopausal women from + using any type of hormone replacement therapy (HRT) for more than a few years. Because no definitive proof + exists, the available epidemiological results can be interpreted according to what seems biologically + plausible to each investigator, including potential differences between various schedules of various + steroids in various species and in vitro models. More than 60 years after the discovery of progesterone, the + main effects of this endogenous steroid on the physiopathology of the breast during a normal luteal phase + are still controversial. The lack of consensus on such basic knowledge concerning one of the most + important targets of a natural ovarian hormone discovered in 1934 is amazing. In the most cited studies, + nothing has been done to measure progesterone in plasma and to correlate the extremely disparate + cytological results with extremely erratic steroid levels at the time of surgical stress. In a recent + study, with a better design, the physiological rise of endogenous progesterone during the luteal phase + coincided with a drop in proliferation of breast epithelial cells, which appears to be only slightly + delayed in comparison with what is described in the endometrium. + Differences in doses and schedules of treatments with various synthetic progestins have largely contributed + to the inconsistency in clinical recommendations. Based on the analysis of proliferation markers in surgical + biopsies from normal human postmenopausal breast tissue, it is plausible that mitogenic activity is not + identical during therapy with unopposed estrogens versus estrogens combined with progestogens, and + is higher during HRT that combines oral conjugated equine estrogens with medroxyprogesterone acetate + than during HRT that combines transdermal estradiol and progesterone. It is misleading to put all + progestogens in the same bag irrespective of their chemical structure, and, more important, + their effect may vary according to whether it is estrone or estradiol that is mainly accumulated in the + breast tissue. The hypothesis of progesterone decreasing the proliferative effect of estradiol in + the postmenopausal breast remains highly plausible. +

+

+ Eur J Cancer. 2000 Sep;36 Suppl 4:S90-1. Progesterone receptor activation. an alternative to SERMs + in breast cancer. Desreux J, Kebers F, Noel A, Francart D, Van Cauwenberge H, Heinen V, Thomas + JL, Bernard AM, Paris J, Delansorne R, Foidart JM. "In postmenopausal women, adding progesterone to + percutaneously administrated oestradiol significantly reduces the proliferation induced by + oestradiol." +

+ +

+ Int J Cancer. 1992 May 28;51(3):416-24. Capacity of adipose tissue to promote growth and metastasis + of a murine mammary carcinoma: effect of estrogen and progesterone. Elliott BE, Tam SP, Dexter + D, Chen ZQ. "Estrogen can stimulate growth of SPI in adipose tissue sites, whereas progesterone + inhibits growth." + + "Our results are consistent with the model that adipose tissue exerts an estrogen-dependent positive + regulatory effect on primary SPI tumor growth, and promotes the formation of metastases." +

+

+ Br J Cancer 1981 Aug;44(2):177-81. Morphological evaluation of cell turnover in relation to the + menstrual cycle in the "resting" human breast. Ferguson DJ, Anderson TJ. +

+ +

+ Fertil Steril. 1998 May;69(5):963-9. Estradiol and progesterone regulate the proliferation of human + breast epithelial cells. Foidart JM, Colin C, Denoo X, Desreux J, Beliard A, Fournier S, de + Lignieres B. +

+

+ Mol Cell Biochem 1999 Dec;202(1-2):53-61. Bcl-2, survivin and variant CD44 v7-v10 are downregulated + and p53 is upregulated in breast cancer cells by progesterone: inhibition of cell growth and induction + of apoptosis. + Formby B, Wiley TS. This study sought to elucidate the mechanism by which progesterone inhibits the + proliferation of breast cancer cells. Utilizing breast cancer cell lines with and without progesterone + receptors (T47-D and MDA-231, respectively) in vitro, the authors looked at apoptosis (programmed cell + death) in response to progesterone exposure as a possible mechanism. The genetic markers for apoptosis - + p53, bcl-2 and surviving, were utilized to determine whether or not the cells underwent apoptosis. The + results demonstrated that progesterone does produce a strong antiproliferative effect on breast cancer cell + lines containing progesterone receptors, and induced apoptosis. The relatively high levels of + progesterone utilized were similar to those seen during the third trimester of human pregnancy. +

+

+ Ann Clin Lab Sci 1998 Nov-Dec;28(6):360-9. Progesterone inhibits growth and induces apoptosis in + breast cancer cells: inverse effects on Bcl-2 and p53. Formby B, Wiley TS. +

+ +

+ Mol Cell Biol. 2006 Oct;26(20):7632-44. TReP-132 Is a Novel Progesterone Receptor Coactivator + Required for the Inhibition of Breast Cancer Cell Growth and Enhancement of Differentiation by + Progesterone. + + Gizard F, Robillard R, Gross B, Barbier O, Revillion F, Peyrat JP, Torpier G, Hum DW, Staels B. +

+

+ Int J Cancer. 1992 Nov 11;52(5):707-12. Breast cancer and timing of surgery during menstrual cycle. + A 5-year analysis of 385 pre-menopausal women. Gnant MF, Seifert M, Jakesz R, Adler A, + Mittlboeck M, Sevelda P. +

+

+ Am J Epidemiol. 2005 Nov 1;162(9):826-34. Epub 2005 Sep 21. The association of endogenous sex + steroids and sex steroid binding proteins with mammographic density: results from the Postmenopausal + Estrogen/Progestin Interventions Mammographic Density Study. + Greendale GA, Palla SL, Ursin G, Laughlin GA, Crandall C, Pike MC, Reboussin BA. +

+ +

+ Am J Physiol Regul Integr Comp Physiol. 2001 Jul;281(1):R365-72. + Moderate levels of ethanol induce expression of vascular endothelial growth factor and stimulate + angiogenesis. Gu JW, Elam J, Sartin A, Li W, Roach R, Adair TH. +

+

+ Cancer Research 1982 42:3232-39. Endogenous hormones as a major factor in human cancer. + Henderson, B.E., R.K. Ross, M.C. Pike, and J.T. Casagrande. +

+

+ Reprod Biol Endocrinol. 2003 Oct 7;1(1):73. Epub 2003 Oct 07. Estrogen, Progesterone and Epithelial + Ovarian Cancer. Ho SM. "New convincing data have indicated that estrogens favor neoplastic + transformation of the OSE while progesterone offers protection against OCa development. Specifically, + estrogens, particularly those present in ovulatory follicles, are both genotoxic and mitogenic to OSE cells. + In contrast, + pregnancy-equivalent levels progesterone are highly effective as apoptosis inducers for OSE and OCa + cells. In this regard, high-dose progestin may exert an + + exfoliation effect and rid an aged OSE of pre-malignant cells." +

+

+ Breast Cancer Res. 2004;6(4):R352-65. Epub 2004 May 7. Cytochrome P450 1A2 (CYP1A2) activity and + risk factors for breast cancer: a cross-sectional study. Hong CC, Tang BK, Hammond GL, + Tritchler D, Yaffe M, Boyd NF. +

+

+ Zhonghua Fu Chan Ke Za Zhi 2000 Jul;35(7):423-6. [The effect of progesterone on proliferation and + apoptosis in ovarian cancer cell] + Hu Z, Deng X. "It is suggested in the present + study that progesterone can inhibit the proliferation of epithelial ovarian cancer cells in vitro and + there is an accordant dose-response relationship. Its anticancer effect seems to be due to induction of + apoptosis which maybe a result of down-regulation of the anti-apoptotic protein bcl-2." +

+ +

+ Endocrinol Jpn. 1977 Aug;23(4):328-32. Occurrence of permanent changes in vaginal and uterine + epithelia in mice treated neonatally with progestin, estrogen and aromatizable or non-aromatizable + androgens. Iguchi T, Takasugi N. "Two other groups of female mice were given neonatal + injections with 20 microgram estradiol-17beta and 100 microgram progesterone for 10 days, + respectively." "Neonatal progesterone treatment failed to induce the permanent changes in the + vaginal and uterine epithelia." +

+

+ Gynecol Oncol 2001 Jul;82(1):116-21. Production of steroids by human ovarian surface epithelial + cells in culture: possible role of progesterone as growth inhibitor. Ivarsson K, Sundfeldt K, + Brannstrom M, Janson PO. +

+ +

+ J Natl Cancer Inst. 2005 May 18;97(10):755-65. Serum sex steroids in premenopausal women and breast + cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). + Kaaks R, & 40 co-authors, Nutrition and Hormones Group, International Agency for Research on Cancer + (IARC-WHO), Lyon, France. "The absolute risk of breast cancer for women younger than 40 + followed up for 10 years was estimated at 2.6% for those in the highest quartile of serum testosterone + versus 1.5% for those in the lowest quartile; for the + highest and lowest quartiles of progesterone, these estimates were 1.7% and 2.6%, respectively." +

+

+ Cancer Epidemiol Biomarkers Prev. 2002 Dec;11(12):1531-43. Obesity, endogenous hormones, and + endometrial cancer risk: a synthetic review. Kaaks R, Lukanova A, Kurzer MS. Hormones and + Cancer Group, International Agency for Research on Cancer, 69372 Lyon, France. kaaks@iarc.fr + + "These relationships can all be interpreted in the light of the 'unopposed estrogen' hypothesis, which + proposes that endometrial cancer may develop as a result of the mitogenic effects of estrogens, when + these are insufficiently counterbalanced by progesterone." + "After the menopause, when progesterone synthesis has ceased altogether, excess weight may continue + increasing risk through elevated plasma levels of androgen precursors, increasing estrogen levels + through the aromatization of the androgens in adipose tissue." +

+

+ J Steroid Biochem Mol Biol. 2000 Jun;73(3-4):171-81. + Progesterone effect on cell growth, ultrastructural aspect and estradiol receptors of normal human + breast epithelial (HBE) cells in culture. Malet C, Spritzer P, Guillaumin D, Kuttenn F. "Cells + exhibited a proliferative appearance after E2 treatment, and returned to a quiescent appearance when P was + added to E2. In both studies, P proved to be as efficient as the synthetic progestin R5020. Moreover, the + immunocytochemical study of E2 receptors indicated that E2 increases its own receptor level whereas P and + R5020 have the opposite effect, thus limiting the stimulatory effect of E2 on cell growth. In the HBE cell + culture system and in long-term treatment, P and R5020 appear predominantly to inhibit cell growth, + both in the presence and absence of E2." +

+ +

+ Ann Endocrinol (Paris). 1986;47(3):179-87. + [Estradiol-progesterone interaction in normal and pathological human breast cells] + Mauvais-Jarvis P, Kuttenn F, Gompel A, Malet C, Fournier S. "The antiestrogenic activity of P is + carried out through the decrease of ER resynthesis and stimulation of 17 beta-hydroxysteroid + dehydrogenase enzyme activity, which transforms E2 into its less active metabolite estrone (E1) in the + target cells. These biochemical events are well documented concerning the endometrium. They + have also been observed in normal mammary cells in primary cultures as well as in breast fibroadenomas with + high epithelial cellularity. Moreover, data from literature indicate that E2 could be both a direct and + indirect factor of cell multiplication in cancerous cell lines. P as well as progestins have the opposite + effect. Recent results from this laboratory indicate that E2 and P also have antagonistic effects on the + cell multiplication of normal human mammary cells in primary culture. Therefore, the hypothesis that a lack + of P during a long period of the female genital like could be a factor in the promotion of breast cancer + must be considered." +

+

+ Horm Res. 1987;28(2-4):212-8. Antiestrogen action of progesterone in breast tissue. + Mauvais-Jarvis P, Kuttenn F, Gompel A. +

+

+ Cancer Lett. 2005 Apr 18;221(1):49-53. Effects of progesterone on ovarian tumorigenesis in + xenografted mice. McDonnel AC, Van Kirk EA, Isaak DD, Murdoch WJ. "We report that the + tumorigenic capacity of human ovarian carcinoma (SKOV-3) cells inoculated into the peritoneal cavity of + athymic mice is suppressed by pretreatment with subcutaneous progesterone-releasing pellets." "Progesterone prevented tumors from forming on the liver. Life spans of progesterone-treated animals were + prolonged." "Our findings implicate a role for progesterone in ovarian cancer prophylaxis." +

+

+ J Natl Cancer Inst. 1986 Sep;77(3):617-20. Endogenous sex hormones, prolactin, and mammographic + features of breast tissue in premenopausal women. Meyer F, Brisson J, Morrison AS, Brown JB. +

+

+ Int J Cancer. 2004 Nov 1;112(2):312-8. Endogenous sex hormones and subsequent breast cancer in + premenopausal women. +

+ + Progesterone was inversely associated with adjusted RR for highest vs. lowest tertile of 0.40 +
+ where adjusted RR was 0.12 +
+

+ +

+ Endocrinology 2002 Sep;143(9):3671-80. Ovarian hyperstimulation by LH leads to mammary gland + hyperplasia and cancer predisposition in transgenic mice. + Milliken EL, Ameduri RK, Landis MD, Behrooz A, Abdul-Karim FW, Keri RA. +

+

+ J Steroid Biochem Mol Biol 2000 Nov 30;74(5):357-64. + Estrogens in the causation of breast, endometrial and ovarian cancers - evidence and hypotheses from + epidemiological findings. Persson I. "Estrogens cause endometrial cancer, an effect that + can be reduced, prevented or reversed by progesterone/progestin - if allowed to act for a sufficiently + long period of each cycle." + +

+ +

+ Endocrinology. 1973 Dec;93(6):1269-76. Conversion of progesterone to estrone and estradiol in vitro + by the ovary of the infantile rat in relation to the development of its interstitial tissue. + Quattropani SL, Weisz J. +

+

+ Ann Oncol. 1991 Apr;2(4):269-72. Timing of breast cancer surgery within the menstrual cycle: + influence on lymph-node involvement, receptor status, postoperative metastatic spread and local + recurrence. Rageth JC, Wyss P, Unger C, Hochuli E. +

+

+ Cancer Res. 1984 Feb;44(2):841-4. High testosterone and low progesterone circulating levels in + premenopausal patients with hyperplasia and cancer of the breast. Secreto G, Recchione C, + Fariselli G, Di Pietro S. +

+ +

+ Cancer Res. 1984 Feb;44(2):841-4. High testosterone and low progesterone circulating levels in + premenopausal patients with hyperplasia and cancer of the breast. Secreto G, Recchione C, + Fariselli G, Di Pietro S. +

+

+ J Natl Cancer Inst Monogr. 1994;(16):85-90. Menstrual timing of treatment for breast cancer. + + Senie RT, Kinne DW. +

+

+ Cancer Causes Control. 2004 Feb;15(1):45-53. Serum levels of sex hormones and breast cancer risk in + premenopausal women: a case-control study (USA). Sturgeon SR, Potischman N, Malone KE, Dorgan + JF, Daling J, Schairer C, Brinton LA. "For luteal progesterone, the RR for the highest versus lowest + tertile was 0.55 (0.2-1.4)." +

+ +

+ Biomed Pharmacother 1984;38(8):371-9. Breast cancer and oral contraceptives: critique of the + proposition that high potency progestogen products confer excess risk. Sturtevant FM A recent + report by Pike et al. from the U. S. A. concluded on the basis of epidemiologic evidence that an increased + risk of breast cancer was manifested by young women who had used combination oral contraceptives (OC) with a + high "potency" of progestogen over a prolonged period. This conclusion is criticized in the present article, + centering on three cardinal defects in the Pike study: (1) The assigned potencies of OC's are + fiction and were derived from out-dated delay-of-menses data; (2) Well-known risk factors for breast + cancer were ignored; (3) The method assumed no error of recall of OC brand, dose and duration of use + occurring many years before telephone interviews. Noting that others have not been able to confirm these + findings, it is concluded that there is no scientific basis for accepting the suggestion of Pike et + al. +

+

+ Pathol Oncol Res. 2006;12(2):69-72. Epub 2006 Jun 24. Leptin--from regulation of fat metabolism to + stimulation of breast cancer growth. Sulkowska M, Golaszewska J, Wincewicz A, Koda M, Baltaziak + M, Sulkowski S. +

+ +

+ Cancer Res. 2004 Nov 1;64(21):7886-92. Reduction of human metastatic breast cancer cell + aggressiveness on introduction of either form a or B of the progesterone receptor and then treatment + with progestins. Sumida T, Itahana Y, Hamakawa H, Desprez PY. +

+

+ Acta Pharmacol Toxicol (Copenh). 1983 Apr;52(4):298-304. Local muscle damage and oily vehicles: a + study on local reactions in rabbits after intramuscular injection of neuroleptic drugs in aqueous or + oily vehicles. + Svendsen O. +

+

+ Jpn J Cancer Res 1998 Dec;89(12):1334-42. Effects of sex steroids and growth factors on invasive + activity and 5'-deoxy-5-fluorouridine sensitivity in ovarian adenocarcinoma OMC-3 cells. + + + Ueda M, Fujii H, Yoshizawa K, Kumagai K, Ueki K, Terai Y, Yanagihara T, Ueki M. "The inhibitory + effect of Prog on tumor cell invasion may depend on its inhibitory action on the motility of tumor + cells." +

+

+ Endocrinology. 1965 Oct;77(4):735-44. Estrogen and androgen production in vitro from + 7-3-H-progesterone by normal and polycystic rat ovaries. Weisz J, Lloyd CW. +

+

+ J Steroid Biochem. 1984 Sep;21(3):347-9. Conversion of testosterone and progesterone to oestrone by + the ovary of the rat embryo in organ culture. Weniger JP, Chouraqui J, Zeis A. +

+

+ + © Ray Peat Ph.D. 2007. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/fatigue-aging-recuperation.html b/raypeat-articles/processed/fatigue-aging-recuperation.html new file mode 100644 index 0000000..3084a47 --- /dev/null +++ b/raypeat-articles/processed/fatigue-aging-recuperation.html @@ -0,0 +1,554 @@ + + + +

+ +

+ + Fatigue, aging, and recuperation + +
- Old people and sick people tire easily. Surprisingly, little is known to explain that common fact.- + Myths about lactic acid and oxygen debt have misdirected most fatigue research.- The cellular processes involved + in fatigue overlap with those of aging.- Knowledge about the mechanisms of fatigue should be useful in + preventing some tissue swelling disorders, organ failure, degenerative calcification, and other energy-related + problems. 
GLOSSARY:* Uncoupling--In cellular respiration, oxidation of "fuel" in the mitochondrion is + coupled to the phosphorylation of ADP, forming ATP. Uncouplers are chemicals that allow oxidation to proceed + without producing the usual amount of ATP.* DNP--Dinitrophenol, an uncoupler that was once popular as a + weight-loss drug.* NAD+ and NADH--Nicotinamide adenine dinucleotide, and its reduced form are coenzymes for many + oxidation and reduction reactions in cells.* Hyperammonemia--The presence of too much ammonia in the blood.* + Vicinal water--water near surfaces, especially hydrophobic surfaces, that is physically and chemically different + from ordinary water.* Hydrophobic--insoluble in water, a nonpolar oil-like molecule that repels water.
Unlike the somewhat technical medical concept of "stress," the idea of fatigue is something everyone + understands, to some extent. Hans Selye's studies of stress weren't widely accepted until about 40 years after + their publication, but some of the main investigators of the fatigue phenomenon are still practically unknown in + the universities, many years after they published their work. Several things have kept fatigue research + from advancing, including the common feeling that fatigue is already sufficiently understood, and that it is + somehow trivial, compared to problems such as growth, reproduction, and disease.Fatigue is usually described as + decreased responsiveness resulting from over-exertion: For example, a muscle's decreased strength or speed of + contraction, or a nerve's decreased speed of conduction, or a sense organ's decreased ability to detect or to + discriminate. Another meaning of fatigue, a decreased resistance or strength, can be applied to materials, as + well as to some biological functions, for example when fatigue leads to sickness or + infections. "Responsiveness" implies sensitivity, and decreased sensitivity to stimulation can be seen in + fatigued sense organs, nerves, muscles, and many other types of cell--immune cells, secretory cells, etc. Even + plant cells have very similar processes of excitability that can be depleted by repetition.In a series of + lectures to the Royal Society in England (1895-1901), the physicist Jagadis Chandra Bose described work that at + first excited, and then disturbed, many physicists and biologists. He had invented devices for both producing + and detecting electromagnetic waves, and he had been the first to produce millimeter length radio waves + (microwaves). In Marconi's first transatlantic radio transmission Bose's signal detecting device was used. This + device was based on the fact that two pieces of metal in superficial contact became electrically fused (cohered) + in the presence of an electrical or electromagnetic field. After they cohered, a mechanical shock would separate + them, breaking the electrical fusion.When Bose was experimenting with his "self-restoring coherer," a + semiconducting device that spontaneously broke the connection without being mechanically shaken, he observed + that it became insensitive after prolonged use, that is, it lost its self-restoring capacity, but that after a + rest, it recovered its sensitivity. He recognized the complex behavior of his instrument as being very similar + to the electrical physiology of living cells.He then began a series of experiments on plants, animals, and + minerals, that showed similar responses to all kinds of stimulation, including mechanical and thermal and + electromagnetic.The idea of metal fatigue wasn't new, but Bose was able to think far beyond the ideas of the + metallurgists. Biologists were thinking of electrical responsiveness as a defining feature of life, and Bose + demonstrated that plants had electrical responsiveness very similar to that of animals, but also that similar + reactions could be demonstrated in minerals.This was what disturbed the English scientists. Sensitivity, + irritability, fatigue, and memory were supposed to be special properties related to life, and maybe to + consciousness. For the Englishmen, there were religious implications in this Hindu's research.There were several + reasons that European and American scientists couldn't accept the universal nature of the electrical properties + that they were studying in animals. One of their motives was to see life as something immaterial, or of an + absolutely different nature than inorganic matter. Another problem had to do with the developing belief that the + special properties of life were enclosed in the hereditary substance of each cell, and that the electrical + functions of cells were produced entirely by the presence of a membrane, surrounding a drop of water containing + randomly moving dissolved chemicals.  For the membrane electricity theory, it was essential to believe in + the random behavior of things dissolved in the cell water.So they considered the electrical-mechanical reactions + and interactions of minerals to be so unlike the processes of life that it was inappropriate to see analogies + between them. Minerals were composed of atoms, and, according to the doctrine of the time, they could have no + "physiological" functions except on the atomic scale. It was more than 20 years before mainstream physicists + began thinking about "delocalized" forces and fields in minerals. Between 1915 and 1934, Michael Polanyi + made many observations that made it clear that the old kind of electrical atomism was completely unfounded. The + behavior of mineral crystals, and the interactions between different phases of material, such as gas or liquid + with a solid, could be understood only in terms of relatively long-range forces. Polanyi's experiments showed, + for example, that events on the surface of a crystal modified the strength and deformability of the + crystal. Many others between 1900 and 1940-- Lepeschkin, Nasonov, Bungenberg de Jong, and Solco Tromp, for + example--argued that the sensitivity of protoplasm had to be understood in terms of long range order, something + like a liquid crystalline state of matter that would require some of the kinds of knowledge of matter that were + being developed by physicists, metallurgists, and a variety of others investigating the condensed states of + matter.But the mainstream biologists preferred to describe cells in terms that would make impossible any of the + responsivities or sensitivities seen in the "simple" solid state of minerals. To defend their ideology of the + immateriality of life, they denied that the subtlest features of matter had anything to do with life, reducing + life to a debased set of special, merely theoretical, mechanisms. The now defunct physical theory of merely + localized atomic electrical forces became the paradigm for the new biology. The many demonstrations of coherent, + ordered physical behavior of the cytoplasm, for example Gurwitch's mitogenic radiation, were dismissed with + prejudice. During G. W. Crile's long career (1889-1941), understanding shock, biological energy, and + fatigue were his main concerns. He believed that shock was the result of brain exhaustion, and in one of his + last publications he showed that the brains from exhausted animals produced less bioluminescence than those from + rested animals. His importance was in demonstrating that fatigue and shock are systemic conditions of the + organism, rather than isolated events in muscles and nerves. Recent publications are showing the validity of + this view. Crile's approach to the prevention and treatment of shock was based on isolating the damaged area + with local anesthetics. Blocking the nerves from one injured part of the body, for example the sciatic nerve in + the leg, could preserve energy production (and normal cell functions) throughout the rest of the body.About 30 + years earlier (1901), Vvedensky had demonstrated that some types of fatigue appear to be a defensive blocking of + responsiveness, such that intense stimulation would produce no response, while weak stimulation could sometimes + produce a response. These changes affected cell functions in a variety of ways, that he called narcosis and + parabiosis.There have been two popular ways to "explain" fatigue, one by saying that the cell's energy (usually + thought of as ATP or glycogen) is used up, the other saying that the accumulation of a metabolic product + (usually lactic acid) prevents further functioning. The obvious problem with these explanations is that the + fatigue response is quite independent of those metabolic changes. Another problem is that those ideas don't + explain the real changes that occur in cells that are demonstrating fatigue.Fatigued cells take up water, and + become heavier. They also become more permeable, and leak. When more oxygen is made available, they are less + resistant to fatigue, and when the organism is made slightly hypoxic, as at high altitude, muscles have more + endurance, and are stronger, and nerves conduct more quickly. These facts don't fit with the standard model of + the cell, in which its sensitivity is strictly governed by the behavior of its "membrane." (For example, how can + a membrane leak large molecules at the same time that it is intact and causing the cell to swell osmotically?) + They are consistent with the model of the cell that treats protoplasm as a special phase of matter.Another + feature of fatigue (and often of aging, stress, and sickness) is that the relaxation of muscles is retarded and + impaired.Hypothyroidism causes muscle relaxation to be slowed, both in skeletal muscles and in the heart. F/Z. + Meerson showed that stress causes heart muscles to be exposed to increased calcium, followed by breakdown of + fats and proteins, and that these changes keep the injured heart in a continuous state of partial contraction, + making it stiff, and resistant to complete contractile shortening. When many cardiologists talk about the + heart's stiffness, they are thinking of muscular thickening and fibrosis, but those are late consequences of the + kind of contractile, unrelaxed stiffness that Meerson described.The hypothyroid heart does eventually become + fibrotic, but before that, it is just unable to relax properly, and unable to contract fully. This failure to + empty fully with each contraction is a kind of "heart failure," but it can be corrected very quickly by + supplementing thyroid. Even the fibrotic heart can recover under the influence of adequate thyroid.The analogy + of the "coherer" would suggest that the overstimulated muscle isn't able to decohere itself, until it has had a + rest. It responds to stimulation, lets the energy flow, but then can't turn it off, and the energy keeps + flowing, because of a change in physical state. Albert Szent-Gyorgyi was probably the first person to + seriously investigate the semiconducting properties of living material. Since he was aware of W.F. Koch's idea + of a free radical catalyst to support oxidative metabolism, his suggestion in 1941 that cellular proteins could + function as electrical conductors (or semiconductors) was very likely based on his research in cellular + respiration, as well as on his work with muscle proteins. He had observed that ATP lowers the viscosity of a + solution of the muscle protein myosin, and that it would cause a filament formed by precipitating myosin to + contract. The polymerization and contraction of proteins under the influence of free radicals was at the heart + of F.W. Koch's therapeutic ideas, but Koch's work was about 100 years too early, by medical + standards.Szent-Gyorgyi observed that, although ATP was involved in the contraction of muscles, its post-mortem + disappearance caused the contraction and hardening of muscles known as rigor mortis. When he put hardened dead + muscles into a solution of ATP, they relaxed and softened. The relaxed state is a state with adequate energy + reserves.After Szent-Gyorgyi moved to the U.S., in 1947, he demonstrated the effect of muscle cytoplasm on the + behavior of fluorescent substances, which was analogous to that of ice, until the muscle was stimulated. During + contraction, the fluorescent material behaved as it would in ordinary liquid water. This effect involved the + stabilization of the excited state of electrons. This single demonstration should have caused biologists to + abandon the membrane theory of cellular excitation, and to return to basic physics for their understanding of + cell behavior. The implications of Szent-Gyorgyi's work were enormous for biology and medicine, and even for the + understanding of semiconductors, but most of the world was hypnotized by a simple textbook model of cell + membranes.Szent-Gyorgyi also demonstrated that the combination of properly balanced electron donors and electron + acceptors (D-A pairs) would cause a muscle to contract. He compared this to "doping" an inorganic + superconductor, to regulate its electronic behavior. Although these experiments were done half a century after + Koch's application of free radical chemistry to medicine, they still didn't rouse the pharmaceutical industry + from its toxic slumber.I suspect that it was Szent-Gyorgyi's research with those interesting electronic + properties of cellular water and proteins that in 1960 gave Linus Pauling the idea to explain anesthesia, + specifically noble gas anesthesia, in terms of water clathrate formation, the restructuring of cellular water by + the hydrophobic atom or molecule of an anesthetic. His suggestion caused a reaction among biologists that + discouraged research into the subject for about 40 years.Gilbert Ling's view of cytoplasmic structure gives a + different emphasis to the function of electrons, which I think is an essential complement to Szent-Gyorgyi's + view. Ling's emphasis is on how the inductive effect of adsorbed substances (for example, ATP and progesterone + has powerful adsorptive effects) on proteins changes the charge concentration on ionizable groups. When the + charge concentration is in one configuration (more acidic), the preferred counterion is potassium, and in + another (less acidic) configuration, it is sodium. Gilbert Ling's biophysical calculations were useful to + physical chemists, and were soon put to practical use for understanding ion exchange resins, such as water + softeners. Many sorts of evidence showed their validity for cell physiology, but nearly all biologists rejected + them, preferring to talk about membranes, pumps, and channels, despite the evidence showing that the properties + ascribed to those are simply impossible. NMR imaging (MRI) was developed by Raymond Damadian specifically as an + application of Ling's description of cell physiology.Although metals are conductors, the function of the + coherers of Bose and others shows that the surface is a semiconductor, that requires the slight excitation of an + electromagnetic wave to become conductive, at which point the conduction band of electrons in the metal becomes + coherent and extends from one particle into the others. The surface of any phase of a substance has electronic + properties distinct from those of the bulk phase, and in a sense the interface constitutes a special phase of + matter.  When the electrons of the interface lose their special properties, the structure of the whole + system changes.When a muscle cell is stimulated enough to cause a contraction, the interruption of its resting + phase causes a shift in the charge concentration on the proteins, potassium ions are exchanged for sodium ions, + calcium ions enter, and phosphate ions separate from ATP, and are replaced by the transfer of phosphate to ADP + from creatine phosphate. Since the quantum physicist E. Schroedinger wrote his book, Time's Arrow, people + have often thought of life in terms of negentropy, going against the general tendency of entropy to increase, + except for aging and death, which are seen as obeying a law of increasing entropy. But A. Zotin investigated + organisms, rather than abstractions about electrons, and shows that aging involves a decrease in entropy, and a + slowing of metabolism. The decrease of entropy with aging, according to his view, would be analogous to + crystallization, a sort of progressive freezing.When a nerve is stimulated, it releases energy suddenly, and + much of this heat seems to be the result of a change of structure in the cytoplasm, since (in crustaceans' + nerves, which can function at low temperature) during the resting recovery of the nerve, its temperature goes + slightly below the ambient temperature, despite the release of some heat from the chemical changes of + metabolism, stimulated by the nerve's activity. When a physical change is endothermic, as the nerve's + recovery is, that can be interpreted as an increase in overall entropy, as when a rubber band spontaneously + contracts, and becomes cooler.Bose's rested coherer, which, with time, spontaneously recovered its + semiconductive (i.e., relatively insulating) property, wasn't being powered by metabolism. As the particles + returned to their relatively isolated state, there was a decrease of order, and the change was probably somewhat + like the spontaneous energy change in the stimulated crustacean nerve. I assume the change would result from the + absorption of environmental heat, possibly with infrared resonance with electron conduction bands.Seeing the + structure of the cytoplasm as something like a spring-driven mechanism, able to bounce between two states or + "phases," makes it easier to see cellular fatigue as something different from the various metabolic energy + sources, ATP, glycogen, and oxygen, which--contrary to conventional assumptions--aren't closely tied to the + functional losses occurring in fatigue.The role of metabolism, then, becomes analogous to the role of the + "tapper" in the early forms of the coherer.Water in its normal state is a dielectric. But when it is polarized + by an electrical charge, or by the presence of a phase boundary, its normal state is altered. This is the + special interfacial water, or vicinal water. With the movement of ions (mainly potassium, sodium, calcium, and + magnesium) during excitation, the state of the cellular water is necessarily changed by the presence of + different substances. In the excited state, cell water is less hydrophobic, more hydrophilic than in the relaxed + state. A network of "hydrophobic" interactions extends through the relaxed cell. One of the properties of a + dielectric is that it tends to move into the space between charges, with a force similar in principle to that + involved in dielectrophoresis. In the resting state, potassium is the main inorganic ion, and it is + associated with acidic groups, such as aspartic and glutamic acid. During excitation, potassium is partly + exchanged for sodium, which becomes the preferred counter-ion for the acid groups, and calcium enters the cell + along with the sodium. Potassium's interaction with water is very weak (its hydration has been called negative), + allowing water to form the structures that are stable in the presence of hydrophobic surfaces. Sodium and + especially calcium (smaller atoms, with higher surface charge concentration) powerfully interact with water + molecules, more strongly than water interacts with itself, disrupting the delicate somewhat hydrophobic + structures of the intracellular water.(Calcium, with its two charges, has important binding and stabilizing + functions in the resting cell. In the excited cell, these internal calcium ions are released, while + extracellular calcium ions enter the cell.)With the increased movement of charged particles during the + stimulation of a nerve or muscle, as one kind of counterion is exchanged for another, and the destruction of + some of the water's structure, there are more opportunities for bulk dielectric water to enter cells, + interfering with the arrangement of proteins, and tending to cause swelling and separation of the structural + elements of the cell. Electron micrographs of fatigued muscle show a remarkable separation of the actin and + myosin proteins.In the excited state, NMR studies show that cell water behaves more like bulk water, that is, + its molecular movements are relatively free, indicating the momentary loss of the interfacial state. In this + state, the uptake of water, and the fatigue-related swelling of nerves and muscles, would be driven at least + partly by the principle that a dielectric tends to be pulled into the spaces separating charges. The bulk water + that enters a cell during the breakdown of vicinal water functions as an extraneous material somewhat beyond the + cell's control.These bulk-like high dielectric properties of water in the excited cellular state can explain + many changes of enzyme activity. Previously nonpolar lipids would develop a negative surface charge (from + accumulating hydroxyl groups: Marinova, et al., 1996), which would tend to increase their oxidation and + degradation. With the loss of the interfacial water, the cell's high energy resting state is replaced by an + active mobilization of its resources, to maintain and restore the cell's structure. Metabolic energy begins to + flow into the processes of restoration, serving the function of the tapper in the earliest coherers.Looking at + fatigability, muscle contraction, and nerve conduction in a variety of situations, we can test some of the + traditional explanations, and see how well the newer "bioelectronic" explanations fits the facts. Osmotic + pressure, hydrostatic pressure, atmospheric pressure, and the degree of metabolic stimulation by thyroid hormone + affect fatigue in ways that aren't consistent with the membrane-electrical doctrine.The production of lactic + acid during intense muscle activity led some people to suggest that fatigue occurred when the muscle wasn't + getting enough oxygen, but experiments show that fatigue sets in while adequate oxygen is being delivered to the + muscle. Underwater divers sometimes get an excess of oxygen, and that often causes muscle fatigue and soreness. + At high altitudes, where there is relatively little oxygen, strength and endurance can increase.An excess of + oxygen can slow nerve conduction, while hypoxia can accelerate it. (Increasing the delivery of oxygen at higher + pressure doesn't increase the cellular use of oxygen or decrease lactic acid production in the exercising muscle + [Kohzuki, et al., 2000], but it will increase lipid peroxidation.)High hydrostatic pressure causes muscles to + contract, though for many years the membrane-doctrinaires couldn't accept that. Underwater divers experience + brain excitation under very high pressure. Since vicinal water has a larger volume than ordinary water + (analogous to the expansion when ice is formed, though the volume increase in cell water is slightly less, about + 4%, than in ice, which is 11% more voluminous than liquid water), compression under high pressure converts + vicinal cell water to the state that occurs in the excited cell, the way ice melts under pressure. The excited + state exists as long as water remains in that state.These changes of state under pressure are reminiscent of + Bose's use of pressure in some of his coherers, and of the fact that pressure alters the sensitivity of + electrons in a semiconductor, by altering their "band gap," the amount of energy needed to make them enter the + conductive zone.One of the early demonstrations that cell water undergoes a phase change during muscle + contraction involved simply measuring the volume of an isolated muscle. With stimulation and contraction, the + volume of the muscle decreases slightly. (The muscle was immersed in water in a sealed chamber, and the volume + decrease in the whole chamber was measured.)  This corresponds to the conversion of vicinal water to + bulk-like (dielectric) water.  (The threatening implications of those experiments with spontaneous volume + change were very annoying to many biologists of my professors' generation.)In the stimulated state, the cell's + uptake of water from its environment coincides closely with its electrical and thermal activity, and its + expulsion of water coincides with its recovery. In a small nerve fiber, or near the surface of a larger fiber, + these changes are very fast, and in a large muscle the uptake of water is faster than the flow of water from + capillaries can match, but it will become massive if stimulation is continued for several minutes. For example, + two minutes of stimulation can cause a muscle's overall weight to increase by 6%, but its extracellular + compartment loses 4%, so the muscle cells gain much more than 6% of their weight in that short time (Ward, et + al., 1996). The water that is taken up by cells is taken from the blood, which becomes relatively dehydrated and + thicker in the process.The belief in "semipermeable membranes" (which hasn't been a viable explanation of cell + physiology for a very long time) forces people to explain cell swelling osmotically, which means that they + simply assume that the number of solute particles inside the cell has drastically increased in a very short + time. In Tasaki's experiments (1980, 1981, 1982), the swelling in a nerve coincides with the electrical action + potential, which, according to the osmotic explanation, means that a very large increase in internal osmolarity + happened in essentially no time. The action potential comes and goes in about 2 milliseconds. The swelling also + coincides with heat production and shortening of the nerve fiber. The shrinkage of the nerve fiber after the end + of the action potential may be just as rapid, and the membrane theory offers no explanation for that, either. + (But the restoration of the unswollen state can be very prolonged, depending on conditions extrinsic to the + particular muscle or cell.) Troshin's survey of the theory of osmotic regulation of cell volume showed that the + idea of the cell as a membrane osmometer was false, but very few biologists read his book.Since the excited or + fatigued muscle or nerve swells and gains weight, it's interesting to see what happens to their sensitivity and + strength when they are exposed to hypotonic solutions that tend to promote swelling, or to hypertonic solutions, + that help to prevent swelling.In a hypotonic solution, cells are excited (Lang, et al., 1995: "Exposure of + aortic strips from guinea-pigs to hypotonic extracellular fluid is followed by marked vasoconstriction..."), but + the early excitation is followed by decreased responsiveness (Ohba, et al., 1984: "Exposure of muscle to + hypotonic solutions [70% of normal solution] produced initially a transient increase in twitch after which + twitch declined below the control level"). Hypertonic solutions tend to produce relaxation in normal muscles, + including the aorta (Tabrizchi, 1999), but when muscle function is impaired (especially in the circulatory + system, as in shock) they improve contractile function (Elgjo, et al., 1998: "The maximum contraction force + measured in isolated right papillary muscles ex vivo was significantly greater in HSD-treated than normal + saline-treated animals"). Athletes can lose 4% of their weight by dehydration without decreasing their muscular + strength.Hypothyroidism tends to cause loss of sodium from the blood, and the hyponatremia sometimes leads to a + generalized hypotonicity of the body fluids. The thyroid hormone itself functions as an antioxidant, but much of + its protective effect against cell damage is probably the result of preventing cell swelling and accelerating + the removal of calcium from the cell. (Swelling, like fatigue, causes intracellular calcium to increase.)The + electrical surface charging of lipids in bulk water probably accounts for the increased lipid peroxidation that + occurs in fatigue, edema, and hypothyroidism, when water loses its normal partial hydrophobicity. Increased + carbon dioxide is known to decrease lipid peroxidation, and its production requires adequate thyroid + function.Thyroid stimulation of oxygen consumption tends to prevent lactic acid production, because it keeps the + cytoplasm in a state of relative oxidation, i.e., it keeps the concentration of NAD+ hundreds of times higher + than that of NADH. NADH is required for the conversion of pyruvate to lactate. It is also the source of reducing + potential in many kinds of toxic redox cycling, that generate lipid peroxides, and it maintains the sulfhydryl + system, involving the balance of reduced glutathione with the sulfhydryl-disulfide system of protein bonds, + which governs the cell's electronic state and affects its balance of hydrophobicity and hydrophilicity.The + harmful lipid oxidation interferes with energy production and regulatory processes, and is responsible for some + of the prolonged effects of fatigue, swelling, and hypothyroidism. These lingering effects of lipid oxidation + are undoubtedly amplified by the presence of larger amounts of unstable polyunsaturated fats, as the energy + demands of the fatigued state mobilize free fatty acids from the tissues. One of the oldest tests for + hypothyroidism was the Achilles tendon reflex test, in which the rate of relaxation of the calf muscle + corresponded to thyroid function--the relaxation is slow in hypothyroid people. Water, sodium and calcium are + more slowly expelled by the hypothyroid muscle. Exactly the same slow relaxation occurs in the hypothyroid heart + muscle, contributing to congestive heart failure, because the semi-contracted heart can't receive as much blood + as the normally relaxed heart. The hypothyroid blood vessels are unable to relax properly, contributing to + hypertension. Hypothyroid nerves don't easily return to their energized relaxed state, leading to insomnia, + paresthesias, movement disorders, and nerves that are swollen and very susceptible to pressure damage. With + aging, hypothyroidism, stress, and fatigue, the amount of estrogen in the body typically rises. Estrogen is + catabolic for muscle, and causes systemic edema, and nerve excitation. It weakens muscle contraction in the + bladder, although it lowers the threshold for stimulation of sensation and contraction (Dambros, et al., 2004). + This is the pattern that causes people to wake up frequently, to pass a small amount of urine. (Progesterone has + the opposite effect in the urinary bladder, raising the threshold of response, but strengthening contraction, as + it does in the gallbladder.) Estrogen lowers stimulation threshold in the gallbladder, as it does in the brain. + Part of its excitatory action might be the result of increased hypotonic tissue water, but its effects on nerve + thresholds are practically instantaneous. In 1971 and '72, I gave some of the reasons for thinking that + estrogen's biological effects result from its direct effects on cell water, causing it to become more like bulk + (high dielectric) water. For example, NMR (spin echo) of estrogen treated uterus and of the uterus from an old + animal were closer to bulk water than that of a young animal. Estrogen, like fatigue or excessive oxygen, slows + nerve conduction.Lactic acid production increases with fatigue, aging, hypothyroidism, estrogen excess, and + other inefficient biological states. Its presence, when oxygen is available, indicates that something is + interfering with efficient oxidative energy metabolism. Ammonia, free fatty acids, and various inflammatory + cytokines are also likely to increase in those stress states.A dangerously high level of ammonia in the blood + (hyperammonemia) can be produced by exhaustive exercise, but also by hyperbaric oxygen (or a high concentration + of oxygen), by high estrogen, and by hypothyroidism. It tends to be associated with an excess of lactic acid, + probably because ammonia stimulates glycolysis. Excess oxygen, like hypothyroidism, is equivalent to + "hyperventilation," in producing an abnormally low level of carbon dioxide in the blood. The Krebs cycle, during + stress, is limited by the unavailability of carbon dioxide. These factors result in the waste of glucose, + turning it into lactic acid, rather than carbon dioxide and energy. In these ways, the metabolism of fatigued + muscle (or any cell under stress) is similar to tumor metabolism.Hyperammonemia disturbs excitatory processes, + and can cause seizures, as well as stupor, and is probably involved in mania and depression. Lithium happens to + complex electronically with ammonia, and I think that accounts for some of its therapeutic effects, but carbon + dioxide is the main physiological factor in the elimination of ammonia, since it combines with it to form urea. + The changes in cell water in the excited/fatigued state represent an increase in the water's "structural + temperature," and that would imply that less carbon dioxide could remain dissolved during excitation.Eating + sugar and using caffeine, which increases the oxidation of sugar (Yeo, et al., 2005), can reduce fatigue, both + subjectively and objectively. Metabolically, they increase the production of carbon dioxide. Increasing sugar + decreases the liberation and use of fatty acids, and by a variety of mechanisms, helps to lower the production + of ammonia, lactate, and inflammatory cytokines. (Lactic acid, in combination with acidosis and free + phospholipids, can interfere with efficient cell functions [Pacini and Kane, 1991; Boachie-Ansah, et al., + 1992].) Free fatty acids release tryptophan from albumin, contributing to the formation of serotonin, which + increases the sense of fatigue.Aspirin and niacin help to prevent fatigue symptoms, and to prevent many of the + harmful systemic oxidative after-effects. (Both are antilipolytic; aspirin uncouples mitochondria.)Uncoupling of + mitochondrial oxidative metabolism from ATP production helps to consume the sugar which otherwise would be + diverted into lactic acid, and converts it into carbon dioxide instead. Mild hypoxia, as at high altitude, + suppresses lactic acid production ("the lactate paradox"), and increases the amount of carbon dioxide in + tissues. Aspirin and thyroid (T3) increase uncoupling. A drug that used to be used for weight reduction, + DNP, also uncouples mitochondrial metabolism, and, surprisingly, it has some of the beneficial effects of + thyroid and aspirin. It stimulates the consumption of lactic acid and the formation of carbon dioxide.The + squirrel monkey, which on average weighs about 2 or 3 pounds as an adult, lives much longer than other mammals + of its size, usually about 20 years, as long as 27. It has an extremely high rate of oxygen consumption. This is + probably the result of natural uncoupling of the mitochondria, similar to that seen in long-lived mice. Mice + with 17% higher resting oxygen consumption lived 36% longer than slow respiring mice of a related strain + (Speakman, et al., 2004).Living at a high altitude, people tend to eat more and stay leaner than when they live + near sea level. Apparently, their mitochondria are relatively uncoupled, and they have more mitochondria, which + would partly account for their lower production of lactic acid during muscular exertion. Increased thyroid + activity, too, tends to increase mitochondrial mass, as well as their uncoupling.Most of the things that we + think of as fatigue result from disturbances of the hydration of cells, whose sensitivity, composition, and + structure change according to the extent of the disturbance. The hydration is governed by the cells' + "electrical" properties, which are regulated by internal metabolic processes and by systemic processes. When + cellular fatigue reaches a certain point, only the interactions of all the organs can restore stable cellular + structure and functions. The liver eliminates lactic acid and ammonia, the adrenals and gonads provide + stabilizing steroids, and the brain alters activity and behavior, in ways that can reverse most of the effects + of fatigue.But, when the tissues contain large amounts of polyunsaturated fats, every episode of fatigue and + prolonged excitation leaves a residue of oxidative damage, and the adaptive mechanisms become progressively less + effective. When the most powerful adaptive mechanisms, such as the timely synthesis of progesterone, + pregnenolone, DHEA, T3, and the inhibitory transmitters, GABA and glycine, fail, then some of the primitive + defense mechanisms will become chronically activated, and even sleep may fail to restore normal cellular water + and metabolism. Hyperventilation often becomes a problem, making capillary leakiness worse.Water in the body + occupies three major compartments--blood vessels, extracellular matrix, and the moist cell substance itself--and + its condition in each compartment is a little different, and subject to variation. There are no textbooks in use + in the U.S. that treat intracellular water scientifically, and the result is that physicians are confused when + they see patients with edema or with disturbances in blood volume. It rarely occurs to physicians to consider + disturbances of water distribution in problems such as chronic fatigue, fibromyalgia, sleep disturbances, + frequent urination, slow bladder emptying, anxiety, paresthesia, movement disorders, the tunnel syndromes, or + even slowed thinking, but "intracellular fatigue" leading to over-hydration is probably the central problem in + these, and many other degenerative and inflammatory problems. The improvements in cell functions and water + distribution that are inversely related to oxygen pressure, and directly related to carbon dioxide, won't be + discussed in medical textbooks until they have given up the idea of membrane-regulated cells. The + "treatment" for intracellular fatigue consists of normalizing thyroid and steroid metabolism, and eating a diet + including fruit juice, milk, some eggs or liver, and gelatin, assuring adequate calcium, potassium sodium, and + magnesium, and using supplements of niacin-amide, aspirin, and carbon dioxide when necessary. Simply increasing + carbon dioxide decreases lactic acid and ammonia, increases GABA (the sleep improving nerve inhibitor), and + regulates mineral and water disposition.One of the outcomes of the study of the physiology of fatigue is that it + leads to a better understanding of cells in general, and offers some new insights into aging, inflammation, and + a variety of stress-related diseases.

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Hyopthyroidism should be considered in the differential diagnosis of encephalopathy in patients with + liver disease.J Trauma. 1992 Jun;32(6):704-12; discussion 712-3. Effects of hypertonic saline dextran + resuscitation on oxygen delivery, oxygen consumption, and lipid peroxidation after burn injury. Tokyay R, + Zeigler ST, Kramer GC, Rogers CS, Heggers JP, Traber DL, Herndon DN.Eur J Pharmacol. 1999 Oct 15;382(3):177-85. + Influence of increase in osmotic pressure with sucrose on relaxation and cyclonucleotides levels in isolated rat + aorta. Tabrizchi R. J. Chem. Phys. 117 (2002) 5101-5104. Predicting water's phase diagram and liquid-state + anomalies, Truskett TM and K. A. Dill KA.J Appl Physiol. 1978 Mar;44(3):333-9. Selected brain amino acids and + ammonium during chronic hypercapnia in conscious rats. Weyne J, Van Leuven F, Kazemi H, Leusen I. "Hypercapnia + increased glutamine and GABA and decreased glutamic and aspartic acids. Changes occurred within 1 h and were + maintained during the observation period of 3 wk." "The changes observed may have a role in metabolic pH + homeostasis of brain tissue and may also be relevant to the modified brain excitability in hypercapnia."J Appl + Physiol. 2005 Apr 14; Caffeine increases exogenous carbohydrate oxidation during exercise. Yeo SE, Jentjens RL, + Wallis GA, Jeukendrup AE. +

 

+ + © Ray Peat Ph.D. 2013. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/lactate.html b/raypeat-articles/processed/lactate.html new file mode 100644 index 0000000..7aff0a3 --- /dev/null +++ b/raypeat-articles/processed/lactate.html @@ -0,0 +1,732 @@ + + Lactate vs. CO2 in wounds, sickness, and aging; the other approach to cancer + +

+ Lactate vs. CO2 in wounds, sickness, and aging; the other approach to cancer +

+ +

+

+
+
+

+ +

+ + GLOSSARY +

+

+ Aerobic glycolysis, the conversion of glucose to lactic acid even in the presence of + oxygen. The presence of oxygen normally restrains glycolysis so that glucose is converted to carbon dioxide + instead of lactic acid. +

+

+ Anaerobic glycolysis, the increased conversion of glucose to lactic acid when the supply of + oxygen isn't sufficient, which is a normal event during intense muscle action. +

+ +

+ "Warburg Effect" refers to Otto Warburg's observation that cancer cells produce lactic acid + even in the presence of adequate oxygen. Cancer cells don't "live on glucose," since they are highly adapted + to survive on protein and fats. +

+

+ Pasteur Effect, the normal response of cells to restrain glycolysis in the presence of + adequate oxygen. +

+ +

+ Crabtree Effect, observed originally in yeast, refers to the inhibition of respiration in + the presence of glucose. This occurs in cancers (e.g., Miralpeix, et al., 1990) and in rapidly proliferating + normal cells (e.g., Guppy, et al., 1993). +

+

+ "Cancer metabolism" or stress metabolism typically involves an excess of the adaptive + hormones, resulting from an imbalance of the demands made on the organism and the resources available to the + organism. Excessive stimulation depletes glucose and produces lactic acid, and causes cortisol to increase, + causing a shift to the consumption of fat and protein rather than glucose. Increased cortisol activates the + Randle effect (the inhibition of glucose oxidation by free fatty acids), accelerates the breakdown of + protein into amino acids, and activates the enzyme fatty acid synthase, which produces fatty acids from + amino acids and pyruvate, to be oxidized in a "futile cycle," producing heat, and increasing the liberation + of ammonia from the amino acids. Ammonia suppresses respiratory, and stimulates glycolytic, activity. +

+

+

+
+
+

+

+ The presence of lactic acid in our tissues is very meaningful, but it is normally treated as only an + indicator, rather than as a cause, of biological problems. Its presence in rosacea, arthritis, heart + disease, diabetes, neurological diseases and cancer has been recognized, and recently it is being recognized + that suppressing it can be curative, after fifty years of denial. +

+

+ The influence of politics on science is so profound that neither historians nor scientists often care to + consider it honestly and in depth. +

+

+ From the 19th century until the second quarter of the 20th century, cancer was investigated mainly as a + metabolic problem. This work, understanding the basic chemistry of metabolism, was culminating in the 1920s + in the work of Otto Warburg and Albert Szent-Gyorgyi on respiration. Warburg demonstrated as early as 1920 + that a respiratory defect, causing aerobic glycolysis, i.e., the production of lactic acid even in the + presence of oxygen, was an essential feature of cancer. (The formation of lactic acid is normal and adaptive + when the supply of oxygen isn't adequate to meet energy demands, for example when running.) +

+

+ Many people recognized that this was likely to be the key to the "cancer problem." But in the US, several + factors came together to block this line of investigation. +

+ +

+ The world wars contributed to the isolation of German scientists, and Warburg, of the famous Jewish banking + family, continued his work in Germany with the support of the government, despite his open opposition to + Nazism. In the years after the war, nothing positive could be said in the US about his work on cancer. +

+

+ The metabolic interpretation of disease that had been making progress for several decades was suddenly + submerged when government research financing began concentrating on genetic and viral interpretations of + disease. +

+

+ If an apparently non-infectious disease couldn't be explained on the basis of an inherited + tendency---insanity, epilepsy, diabetes, toxemia of pregnancy, and cancer, for example---then genetic + changes occurring in the individual, as a result of chance or a virus, were invoked. Nutrition and other + conditions of life were until fairly recently said to have no influence on health if the person consumed + sufficient calories and a minimum amount of the essential vitamins, minerals, and protein. The cult of + genetic determinism was so powerful that it wasn't affected by the facts. +

+

+ In 1932, a pediatrician, Alexis Hartmann (with M. Senn) in St. Louis, injected intravenously a solution of + sodium lactate into patients with metabolic acidosis, and several of them survived---despite the fact that + some of them were already suffering from an excess of lactate. The subsequent widespread use of lactate + solutions in hospitals has contributed to the general denial of its toxicity. +

+

+ Hartmann and Senn used racemic lactate, that is, a mixture of D-lactate and L-lactate. Our own tissues + produce mostly L-lactate, but they can produce small amounts of D-lactate; larger amounts are produced by + diabetics. Intestinal bacteria can produce large amounts of it, and it has many toxic effects. Methylglyoxal + can be formed from either form of lactate, and it is an important factor in the glycation of proteins. It + can also be formed from MDA, a product of lipid peroxidation. Protein glycation is an important factor in + diabetes and aging, but glucose, rather than lactate and polyunsaturated fats, is commonly said to be the + cause. +

+ +

+ About 50 years ago, lactate was known to induce the formation of new blood vessels, and for a much longer + time it has been known to cause vasodilation and edema. In 1968, it was shown to stimulate collagen + synthesis. +

+

+ Normally, collagen synthesis and neovascularization are caused by lack of oxygen, but lactate can cause them + to occur even in the presence of oxygen. Maintenance of a normal extracellular matrix is essential for + normal functioning and cellular differentiation. Abnormally stimulated collagen synthesis probably + accelerates tumor growth (Rajkumar, et al., 2006). +

+

+ Nervous and hormonal factors can cause lactate to accumulate, even without prior damage to the mitochondria + (e.g., B. Levy, et al., 2003). Psychological, as well as physical, stress and overactivation of glutamate + receptors can cause harmful accumulation of lactate in the brain (Uehara, et al., 2005). Rather than just + being "associated with" tissue damage, lactate directly contributes to the damage, for example in the brain, + causing nerve cell loss by increasing the release of excitotoxic glutamate (Xiang, et al, 2004). When a + panic reaction is produced by sodium lactate, the reduction of protective neurosteroids appears to + contribute to the excitatory state (Eser, et al. 2006); this would make the brain more susceptible to + damage. +

+

+ Lactate increases blood viscosity, mimics stress, causes inflammation, and contributes to shock. Lactated + Ringer's solution contributes to the tissue damage caused by shock, when it's used to resuscitate shock + victims (Deree, et al., 2007, 2008): it contributes to the inflammatory processes associated with shock, + unlike the use of hypertonic saline and other solutions. Lactate contributes to diabetes, inhibiting the + ability to oxidize glucose. It promotes endothelial cell migration and leakiness, with increased vascular + permeability factor (VPF or vascular endothelial growth factor, VEGF) (Nagy, et al. 1985): this can lead to + breakdown of the "blood-brain barrier." +

+ +

+ In the brain, lactate can cause nerve damage, increasing intracellular fat accumulation, chromatin clumping, + and mitochondrial swelling (Norenberg, et al., 1987). +

+

+ The lactate in peritoneal dialysis solution impairs differentiation and maturation of (immune, monocyte + derived) dendritic cells; according to the authors of the study, "These findings have important implications + for the initiation of immune responses under high lactate conditions, such as those occurring within tumor + tissues or after macrophage activation" + (Puig-Kr"ger, et al., 2003). +

+

+ Lactate also causes macrophages and synovial fibroblasts to release PGE2, which can contribute to + inflammation and bone resorption (Dawes and Rushton, 1994). This is the prostaglandin known to activate the + formation of estrogen (Haffty, et al., 2008). +

+

+ Hartmann's lactated solution has been widely used in hospitals for resuscitation and for patients after + heart surgery and other stressful procedures, but until recently only a few people have objected to its use, + and most of the objection has been to the use of racemic lactate, rather than to lactate itself. In recent + years several studies have compared hypertonic saline (lacking the minerals considered essential since + Sydney Ringer formulated his solution around 1885), and have found it in some cases superior to the + "balanced" lactate solution. Even hypertonic glucose, without minerals, has produced good results in some + studies. +

+ +

+ A solution containing a large amount of lactate has been used for peritoneal dialysis when there is kidney + failure, but several studies have compared solutions using bicarbonate instead of lactate, and found that + they don't cause the severe damage that always happened with the traditional solution. +

+

+ While Warburg was investigating the roles of glycolysis and respiration in cancer, a + physician with a background in chemistry, W.F. Koch, in Detroit, was showing that the ability to use oxygen + made the difference between health and sickness, and that the cancer metabolism could be corrected by + restoring the efficient use of oxygen. He argued that a respiratory defect was responsible for + immunodeficiency, allergy, and defective function of muscles, nerves, and secretory cells, as well as + cancer. Koch's idea of cancer's metabolic cause and its curability directly challenged the doctrine of the + genetic irreversibility of cancer that was central to governmental and commercial medical commitments. +

+

+ Albert Szent-Gyorgyi respected Koch's work, and spent years investigating the involvement of the lactate + metabolites, methylgyoxal and glyoxal, in cell physiology, but since the government's campaign against Koch + was still active when Szent-Gyorgyi came to the U.S., he worked out many of the implications of Koch's work + relating to cellular oxidation without mentioning his name. +

+ +

+ Lactate formation from glucose is increased when anything interferes with respiratory energy production, but + lactate, through a variety of mechanisms, can itself suppress cellular respiration. (This has been called + the Crabtree effect.) Lactate can also inhibit its own formation, slowing glycolysis. In the healthy cell, + the mitochondrion keeps glycolysis working by consuming pyruvate and electrons (or "hydrogens") from NADH, + keeping the cell highly oxidized, with a ratio of NAD+/NADH of about 200. When the mitochondrion's ability + to consume pyruvate and NADH is limited, the pyruvate itself accepts the hydrogen from NADH, forming lactic + acid and NAD+ in the process. As long as lactate leaves the cell as fast as it forms, glycolysis will + provide ATP to allow the cell to survive. Oxygen and pyruvate are normally "electron sinks," regenerating + the NAD+ needed to produce energy from glucose. +

+

+ But if too much lactate is present, slowing glycolytic production of ATP, the cell with defective + respiration will die unless an alternative electron sink is available. The synthesis of fatty acids is such + a sink, if electrons (hydrogens) can be transferred from NADH to NADP+, forming NADPH, which is the reducing + substance required for turning carbohydrates and pyruvate and amino acids into fats. +

+

+ This transfer can be activated by the transhydrogenase enzymes in the mitochondria, and also by interactions + of some dehydrogenase enzymes. +

+

+ The enzyme, fatty acid synthase (FAS), normally active in the liver and fat cells and in the + estrogen-stimulated uterus, is highly active in cancers, and its activity is an inverse indicator of + prognosis. Inhibiting it can cause cancer cells to die, so the pharmaceutical industry is looking for drugs + that can safely inhibit it. This enzyme is closely associated with the rate of cell proliferation, and its + activity is increased by both cortisol and estrogen. +

+ +

+ The first biochemical event when a cell responds to estrogen is the synthesis of fat. Estrogen can activate + transhydrogenases, and early studies of estrogen's biological effects provided considerable evidence that + its actions were the result of the steroid molecule's direct participation in hydrogen transfers, oxidations + and reductions. E.V. Jensen's claim that estrogen acts only through a "receptor protein" which activated + gene transcription was based on his experimental evidence indicating that estrogen doesn't participate in + oxidation and reduction processes in the uterus, but subsequently his claim has turned out to be false. +

+

+ Glycolysis is very inefficient for producing usable energy compared to the respiratory metabolism of the + mitochondria, and when lactate is carried to the liver, its conversion to glucose adds to the energy drain + on the organism. +

+

+ The hypoglycemia and related events resulting from accelerated glycolysis provide a stimulus for increased + activity of the adaptive hormones, including cortisol. Cortisol helps to maintain blood sugar by increasing + the conversion of protein to amino acids, and mobilizing free fatty acids from fat stores. The free fatty + acids inhibit the use of glucose, so the stress metabolism relies largely on the consumption of amino acids. + This increases the formation of ammonia, yet the combination of glycolysis and fat oxidation provides less + carbon dioxide, which is needed for the conversion of ammonia to urea. Ammonia stimulates the formation of + lactate, while carbon dioxide inhibits it. +

+

+ Starving an animal with a tumor increases the stress hormones, providing free fatty acids and amino acids, + and accelerates the tumor's growth (Sauer and Dauchy, 1987); it's impossible to "starve a tumor," by the + methods often used. Preventing the excessive breakdown of protein and reducing the release of fatty acids + from fat cells would probably cause many cancer cells to die, despite the availability of glucose, because + of lactate's toxic effects, combined with the energy deficit caused by the respiratory defect that causes + their aerobic glycolysis. Recently, the intrinsically high rate of cell death in tumors has been recognized. + The tumor is maintained and enlarged by the recruitment of "stem cells." These cells normally would repair + or regenerate the tissue, but under the existing metabolic conditions, they fail to differentiate properly. +

+ +

+ The extracellular matrix in the tumor is abnormal, as well as the metabolites and signal substances being + produced there, and the new cells fail to receive the instructions needed to restore the normal functions to + the damaged tissue. These abnormal conditions can cause abnormal differentiation, and this cellular state is + likely to involve chemical modification of proteins, including remodeling of the chromosomes through + acetylation of the histones (Alam, et al., 2008; Suuronen, et al., 2006). The protein-protective effects of + carbon dioxide are replaced by the protein-damaging effects of lactate and its metabolites. +

+

+ The ability of lactic acid to displace carbon dioxide is probably involved in its effects on the blood + clotting system. It contributes to disseminated intravascular coagulation and consumption coagulopathy, and + increases the tendency of red cells to aggregate, forming "blood sludge," and makes red cells more rigid, + increasing the viscosity of blood and impairing circulation in the small vessels. (Schmid-Sch"nbein, 1981; + Kobayashi, et al., 2001; Martin, et al., 2002; Yamazaki, et al., 2006.) +

+

+ The features of the stress metabolism include increases of stress hormones, lactate, ammonia, free fatty + acids, and fat synthesis, and a decrease in carbon dioxide. Factors that lower the stress hormones, increase + carbon dioxide, and help to lower the circulating free fatty acids, lactate, and ammonia, include vitamin B1 + (to increase CO2 and reduce lactate), niacinamide (to reduce free fatty acids), sugar (to reduce cortisol, + adrenaline, and free fatty acids), salt (to lower adrenaline), thyroid hormone (to increase CO2). Vitamins + D, K, B6 and biotin are also closely involved with carbon dioxide metabolism. Biotin deficiency can cause + aerobic glycolysis with increased fat synthesis (Marshall, et al., 1976). +

+

+ A protein deficiency, possibly by increasing cortisol, is likely to contribute to increased FAS and fat + synthesis (Bannister, et al., 1983), but the dietary protein shouldn't provide an excess of tryptophan, + because of tryptophan's role as serotonin precursor--serotonin increases inflammation and glycolysis + (Koren-Schwartzer, et al., 1994). +

+ +

+ Incidental stresses, such as strenuous exercise combined with fasting (e.g., running or working before + eating breakfast) not only directly trigger the production of lactate and ammonia, they also are likely to + increase the absorption of bacterial endotoxin from the intestine. Endotoxin is a ubiquitous and chronic + stressor. It increases lactate and nitric oxide, poisoning mitochondrial respiration, precipitating the + secretion of the adaptive stress hormones, which don't always fully repair the cellular damage. +

+

+ Aspirin protects cells in many ways, interrupting excitotoxic processes by blocking nitric oxide and + prostaglandins, and consequently it inhibits cell proliferation, and in some cases inhibits glycolysis, but + the fact that it can inhibit FAS (Beynen, et al., 1982) is very important in understanding its role in + cancer. +

+

+ There are several specific signals produced by lactate that can promote growth and other features of cancer, + and it happens that aspirin antagonizes those: HIF, NF-kappaB, the kinase cascades, cyclin D1, and heme + oxygenase. +

+

+ Lactate and inflammation promote each other in a vicious cycle (Kawauchi, et al., 2008). +

+

+ The toxic mechanism of bacterial endotoxin (lipopolysaccharide) involves inappropriate stimulation (Wang and + White, 1999) of cells, followed by inflammation and mitochondrial inhibition. The stimulation seems to be a + direct "biophysical" action on cells, causing them to take up water (Minutoli, et al., 2008), which is + especially interesting, since estrogen's immediate excitatory effect causes cells to take up water. +

+ +

+ Hypoosmolarity itself is excitatory and anabolic. It stimulates lipolysis and fat oxidation (Keller, et al. + 2003), and osmotic swelling stimulates glycolysis and inhibits mitochondrial respiration (Levko, et al., + 2000). Endotoxin causes hyponatremia (Tyler, et al., 1994), and a hypertonic salt solution is protective, + lactate solutions are harmful. Other stresses and inflammations also cause hyponatremia. +

+

+ One of the effects of endotoxin that leads to prolonged cellular excitation is its inhibition of the + glucuronidation system (B"nhegyi, et al., 1995), since this inhibition allows excitatory estrogen to + accumulate. +

+

+ In women and rats, antibiotics were found to cause blood levels of estrogen and cortisol to decrease, while + progesterone increased. This effect apparently resulted from the liver's increased ability to inactivate + estrogen and to maintain blood sugar when the endotoxin stress was decreased. +

+

+ Now that hog farmers' use of antibiotics to stimulate growth has been discouraged, they have sought + vegetables that have a natural antibiotic effect, reducing the formation and absorption of the intestinal + toxins. The human diet can be similarly adjusted, to minimize the production and absorption of the bacterial + toxins. +

+

+ In 2007, two Canadian researchers announced that they were investigating the drug dichloroacetate, which + blocks glycolysis, stopping the production of lactic acid, as a cancer treatment, with success. The drug + (dichloroacetate) has toxic side effects, but it is useful in several other conditions involving + over-production of lactic acid. Other drugs that inhibit glycolysis have also shown anticancer effects in + animals, but are in themselves very toxic. On the theoretical level, it would be better to inhibit only + aerobic glycolysis, rather than inhibiting enzymes that are essential for all glycolysis. +

+ +

+ Since endotoxemia can produce aerobic glycolysis in an otherwise healthy person (Bundgaard, et al., 2003), a + minimally "Warburgian" approach--i.e,, a merely reasonable approach--would involve minimizing the absorption + of endotoxin. Inhibiting bacterial growth, while optimizing intestinal resistance, would have no harmful + side effects. Preventing excessive sympathetic nervous activity and maintaining the intestine's energy + production can be achieved by optimizing hormones and nutrition. Something as simple as a grated carrot with + salt and vinegar can produce major changes in bowel health, reducing endotoxin absorption, and restoring + constructive hormonal functions. +

+

+ Medical tradition and inertia make it unlikely that the connection between cancer and bowel toxins will be + recognized by the mainstream of medicine and governemt. In another article I will describe some of the + recent history relating to this issue. +

+

+ It's nice that some cancer researchers are now remembering Warburg, but unfortunately they are usually just + fitting the fact of cancer's aerobic glycolysis into the genetic mutant cell paradigm, thinking of the + respiratory defect as just another opportunity for killing the evil deviant cancer cell, rather than looking + for the causes of the respiratory defect. Warburg, Koch, and Szent-Gyorgyi had a comprehensive view of + biology, in which the aerobic production of lactate, resulting from a respiratory defect, itself was + functonally related to the nature of cancer. +

+

+ A focus on correcting the respiratory defect would be relevant for all of the diseases and conditions + (including heart disease, diabetes, dementia) involving inflammation and inappropriate excitation, not just + for cancer. +

+

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+ +

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+

+ Cancer Res. 2007 Oct 1;67(19):9013-7. Loss of the mitochondrial bioenergetic capacity underlies the + glucose avidity of carcinomas. L"pez-R"os F, S"nchez-Arag" M, Garc"a-Garc"a E, Ortega AD, + Berrendero JR, Pozo-Rodr"guez F, L"pez-Encuentra A, Ballest"n C, Cuezva JM +

+

+ J Biol Chem. 2002 Jun 28;277(26):23111-5. Epub 2002 Apr 9. Hypoxia-inducible factor 1 activation by + aerobic glycolysis implicates the Warburg effect in carcinogenesis. Lu H, Forbes RA, Verma A. +

+ +

+ Nutr Metab. 1976;20(1):41-61. + Biotin status and lipid metabolism in adult obese hypercholesterolemic inbred rats. Marshall + MW, Haubrich M, Washington VA, Chang MW, Young CW, Wheeler MA. +

+

+ J Cardiothorac Vasc Anesth. 2002 Aug;16(4):441-6. A prospective, randomized comparison of + thromboelastographic coagulation profile in patients receiving lactated Ringer's solution, 6% hetastarch + in a balanced-saline vehicle, or 6% hetastarch in saline during major surgery. Martin G, + Bennett-Guerrero E, Wakeling H, Mythen MG, el-Moalem H, Robertson K, Kucmeroski D, Gan TJ. +

+

+ J Biol Chem. 2008 Jun 9. [Epub ahead of print] Pyruvate dehydrogenase complex activity controls + metabolic and malignant phenotype in cancer cells. McFate T, Mohyeldin A, Lu H, Thakar J, + Henriques J, Halim ND, Wu H, Schell MJ, Tsang TM, Teahan O, Zhou S, Califano JA, Jeoung NH, Harris RA, Verma + A. +

+ +

+ Invest Ophthalmol Vis Sci. 2007 Apr;48(4):1615-21. Lactate treatment causes NF-kappaB activation and + CD44 shedding in cultured trabecular meshwork cells. Miller AM, Nolan MJ, Choi J, Koga T, Shen + X, Yue BY, Knepper PA. "To challenge human trabecular meshwork (TM) cells using lactate to mimic cell stress + and observe the effects on cell viability, NF-kappaB, and membrane type 1 matrix metalloproteinase (MT1-MMP) + expression and the ectodomain shedding of soluble (s)CD44." "Lactate treatment resulted in dose- and + time-dependent effects on human TM cell viability, translocation of NF-kappaB, and activation of MT1-MMP. + + Increased shedding of sCD44 occurred with the l mM dose of lactate." +

+

+ Eur J Pharmacol. 2008 Apr 12. [Epub ahead of print] + Trehalose: A biophysics approach to modulate the inflammatory response during endotoxic shock. + Minutoli L, Altavilla D, Bitto A, Polito F, Bellocco E, Lagan" G, Fiumara T, Magaz" S, Migliardo F, Venuti + FS, Squadrito F. +

+ +

+ Acta Neuropathol. 1985;68(2):160-3. + Blood-brain barrier impairment by low pH buffer perfusion via the internal carotid artery in + rat. + Nagy Z, Szab" M, H"ttner I. +

+

+ Am J Physiol Endocrinol Metab. 2005 Oct;289(4):E534-42. Sodium lactate increases LPS-stimulated MMP + and cytokine expression in U937 histiocytes by enhancing AP-1 and NF-kappaB transcriptional + activities. Nareika A, He L, Game BA, Slate EH, Sanders JJ, London SD, Lopes-Virella MF, Huang + Y. +

+

+ Eukaryot Cell. 2003 Feb;2(1):143-9. + Glucose regulation of Saccharomyces cerevisiae cell cycle genes. Newcomb LL, Diderich JA, + Slattery MG, Heideman W. "These results indicate a link between the rate of glycolysis and the + expression of genes that are critical for passage through G(1)." +

+ +

+ J Neuropathol Exp Neurol. 1987 Mar;46(2):154-66. + Effects of lactic acid on astrocytes in primary culture. Norenberg MD, Mozes LW, Gregorios JB, + Norenberg LO. +

+

+ Int J Gynecol Pathol. 1997 Jan;16(1):45-51. Expression of fatty acid synthase is closely linked to + proliferation and stromal decidualization in cycling endometrium. Pizer ES, Kurman RJ, + Pasternack GR, Kuhajda FP. +

+

+ J Leukoc Biol. 2003 Apr;73(4):482-92. Peritoneal dialysis solutions + inhibit the differentiation and maturation of human monocyte-derived dendritic cells: effect of lactate + and glucose-degradation products. + + Puig-Kr"ger A, Pello OM, Selgas R, Criado G, Bajo MA, S"nchez-Tomero JA, Alvarez V, del Peso G, + S"nchez-Mateos P, Holmes C, Faict D, L"pez-Cabrera M, Madrenas J, Corb" AL. +

+

+ Cell Biol Int. 2006 Feb;30(2):164-8. Epub 2006 Jan 4. Influence of estradiol on mammary tumor + collagen solubility in DMBA-induced rat mammary tumors. + Rajkumar L, Balasubramanian K, Arunakaran J, Govindarajulu P, Srinivasan N. +

+

+ Mol Cell Biol. 2006 Jul;26(14):5449-69. + Cyclin D1 determines mitochondrial function in vivo. Sakamaki T, Casimiro MC, Ju X, Quong AA, + Katiyar S, Liu M, Jiao X, Li A, Zhang X, Lu Y, Wang C, Byers S, Nicholson R, Link T, Shemluck M, Yang J, + Fricke ST, Novikoff PM, Papanikolaou A, Arnold A, Albanese C, Pestell R. +

+

+ Cancer Res. 1987 Feb 15;47(4):1065-8. + Blood nutrient concentrations and tumor growth in vivo in rats: relationships during the onset of an + acute fast. Sauer LA, Dauchy RT. +

+ +

+ Ric Clin Lab. 1981;11 Suppl 1:13-33. + Blood rheology and physiology of microcirculation. Schmid-Sch"nbein H. +

+

+ Neurochem Int. 2006 Nov;49(6):610-8. Epub 2006 Jun 22. Characterization of the pro-inflammatory + signaling induced by protein acetylation in microglia. + Suuronen T, Huuskonen J, Nuutinen T, Salminen A. +

+

+ Am J Vet Res. 1994 Feb;55(2):278-87. + Clinical and clinicopathologic changes in cows with endotoxin-induced mastitis treated with small + volumes of isotonic or hypertonic sodium chloride administered intravenously. + + Tyler JW, Welles EG, Erskine RJ, Lin HC, Williams MA, Spano JS, Gaslin JT, McClure KA. +

+

+ Brain Res. 2005 Dec 14;1065(1-2):86-91. Epub 2005 Nov 23. Enhancement of lactate metabolism in the + basolateral amygdala by physical and psychological stress: role of benzodiazepine receptors. + + Uehara T, Sumiyoshi T, Matsuoka T, Tanaka K, Tsunoda M, Itoh H, Kurachi M. +

+

+ Pharmacol Biochem Behav. 2008 Aug;90(2):273-81. Lactate production and neurotransmitters; evidence + from microdialysis studies. Uehara T, Sumiyoshi T, Itoh H, Kurata K. +

+

+ J Natl Cancer Inst. 1968 Aug;41(2):267-86. Factors affecting anaerobic glycolysis in mouse and rat + liver and in Morris rat hepatomas. Woods M, Burk D, Hunter J. +

+ +

+ Exp Neurol. 2004 Mar;186(1):70-7. + Lactate induced excitotoxicity in hippocampal slice cultures. Xiang Z, Yuan M, Hassen GW, + Gampel M, Bergold PJ. +

+

+ Masui. 2006 Jun;55(6):699-703. [Blood lactate concentrations as predictors of outcome in serious + hemorrhagic shock patients] [Article in Japanese] + + Yamazaki Y, Saito A, Hasegawa K, Takahashi H. +

+

+ Cytokine. 1993 Sep;5(5):436-47. Cachectin/TNF-mediated lactate production in cultured myocytes is + linked to activation of a futile substrate cycle. + + Zentella A, Manogue K, Cerami A. +

+

+ Chin Med J (Engl). 2002 Jul;115(7):1035-8.Effect of emodin on proliferation and differentiation of + 3T3-L1 preadipocyte and FAS activity. + + Zhang C, Teng L, Shi Y, Jin J, Xue Y, Shang K, Gu J. +

+ + © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/leakiness.html b/raypeat-articles/processed/leakiness.html new file mode 100644 index 0000000..2ab9784 --- /dev/null +++ b/raypeat-articles/processed/leakiness.html @@ -0,0 +1,270 @@ + + Leakiness, aging, and cancer + +

+ Leakiness, aging, and cancer +

+ + A thin layer of fibrin lining blood vessels provides a filtering barrier that helps to strengthen the wall and + prevent other proteins from leaking out of the vessels, and it participates in repair processes when the blood + vessel is broken.

+ Cellular energy metabolism is the basis for maintaining the barrier functions. Energy depletion causes the + endothelial cells lining blood vessels to become excessively permeable. +

+

+ When the organism's resistance is low, proteins and fats that normally remain inside the bloodstream can + escape into the extracellular matrix and enter cells, contributing to their stress and disorganization, and + other materials can escape from cells and enter the bloodstream. +

+

+ One of the simplest demonstrations of fibrin leakage is to shine a beam of light into the eye; the presence + of fibrin and other inappropriate molecules diffuses the light, causing a "flare" in the aqueous + compartment. Albumin, a small protein from the blood, is often seen in the urine during stress. The effects + of that sort of leakage vary with each organ. +

+

+ Fibrin is an essential structural and functional part of the organism, but when it escapes from the + bloodstream it participates in the degenerative processes of inflammation, fibrosis, and tumor formation. + (Its fragments stimulate secretion of inflammatory mediators: Hamaguchi et al., 1991.) +

+

+ In the hormonal environment dominated by estrogen, mild stresses such as exertion, or even restless sleep, + allow toxins (and sometimes bacteria) from the intestine to enter the bloodstream, triggering a complex + chain of events that create a systemic inflammatory state. Although these processes have been observed in + many simple experiments, their implications are almost always neglected or denied or explained away. + Incorporation of certain polyunsaturated fats into the tissues increases the leakiness of blood vessels, and + amplifies the reactions to stresses and inflammatory stimuli. +

+

+ Antioxidants, thyroid hormone, progesterone, and antiinflammatory agents, including glycine or gelatin, + niacin, and saturated fats, can prevent, and in many cases reverse, these degenerative inflammatory + processes. +

+

+ Even a single celled organism has to keep its parts separate, and highly differentiated multicelled + organisms have many special systems that serve to keep their parts separate, so the different tissues and + organs can maintain their distinct functions. +

+

+ The movement of substances from blood to cell, and from cell to cell, is normally very tightly controlled, + and when the systems that control those movements of water and its solutes are damaged, the tissues' + structures and functions are altered. The prevention of inappropriate leakiness can protect against the + degenerative processes, and against aging itself, which is, among other things, a state of generalized + leakiness. +

+

+ When cells' energy is depleted, water and various dissolved molecules are allowed to move into the cells, + out of the cells, and through or around cells inappropriately. The weakened cells can even permit whole + bacteria and similar particles to pass into and out of the blood stream more easily. +

+

+ One of the earliest investigators of the effects of stress and fatigue on nerves and other cells was A.P. + Nasonov, in the first half of the 20th century. A.S. Troshin (1956) has reviewed his work in detail. He + showed that in cells as different as algae and nerve cells, fatigue caused them to take up dyes, and that + the dyes were extruded, if the cells were able to recover their energy. When nerve cells are excited for a + fraction of a second, they take up sodium and calcium, but quickly eliminate them. Prolonged excitation, + leading to fatigue, can gradually shift the balance, allowing more substances to enter, and to stay longer. +

+

+ When nerves or other cells are quickly killed with heavy metals such as osmium, the metals are visible in a + layer at the surface, which is sometimes taken as evidence of a "cytoplasmic membrane," but if the cells + have suffered oxygen deprivation or have been injured by X-rays, the metal will be visible as a grey color + evenly distributed through the cell. The deposition of the metal occurs when it reacts with electrons. In + the relatively vital cell, the heavy metal stops at the surface, and is mostly reduced there, but the + devitalized cell presents no structural or chemical barrier to the entry of the metal, and the reactive + electrons appear to be evenly distributed through the cell. Oxygen deprivation, X-irradiation, and other + stresses cause the cell to be unable to use electrons to produce energy, and instead the electrons are + available to react destructively with whatever may be available. While Nasonov showed that dyes and even + particles enter energetically depleted cells, newer techniques are able to show that the leaky cells are + structurally disrupted by the excessive reduction of their proteins, by excited electrons and free radicals. +

+

+ In the 1970s, experimenters found that muscles from vitamin E deficient animals released their enzymes when + washed in a saline solution, more easily than did the muscles from vitamin E replete animals. Other + experiments around the same time showed that reducing the ATP of muscles caused a similar loss of their + ability to retain their proteins. +

+

+ Over the years, many experiments have established, both in vitro and in vivo, that fatigue, stress, aging, + and inflammation cause cells to lose their normal constituents, but also to allow foreign materials to enter + more easily. +

+

+ When I was working on my thesis, around 1970, investigating the effects of aging on the metabolism of the + uterus, I found that the changes occuring during aging were (in all the ways I tested) the same as those + produced by X-irradiation, excess estrogen, oxygen deprivation, excess polyunsaturated fats, and vitamin E + deficiency. +

+

+ Although everyone working in the lab was familiar with the appearance of the uterus from old hamsters (they + are typically large, stiff, and bluish), everyone was surprised when I suggested that the aged uteri seemed + to function as if they were under the influence of a considerable amount of estrogen. Everyone was familiar + with the medical textbook doctrine that "menopause is caused by estrogen deficiency." In humans, + gynecologists know about "Chadwick's sign," the fact that the uterine cervix turns blue or purple during + pregnancy, and everyone knows that blood is blue when it's deprived of oxygen, so it's surprising that + estrogen's effect on tissue oxygenation isn't widely recognized. +

+

+ When estrogen is given to an animal, it almost instantly causes capillaries to become leaky, allowing water + to move out of the blood stream, and at the same time, estrogen causes cells to take up water. Both of these + processes are the same as the early effects of oxygen deprivation. In the normal reproductive cycle, the + surge of estrogen lasts only a few hours, and normal permeability is quickly restored by increasing + progesterone. During those intermittent short exposures to estrogen, there isn't a massive leakage of serum + proteins into the tissues. During the time of estrogenic influence, all kinds of cells are influenced, with + the excitatory equilibrium of nerve cells, glandular cells, and immune system cells being shifted, lowering + the threshold of excitation, or prolonging the excited state. +

+

+ Anything that causes inflammation causes a similar loss of water from the blood, as it is taken up by + swelling cells. If inflammation is generalized, it causes circulatory shock, because the volume of the blood + has become insufficient to serve the organism's needs. One of Hans Selye's earliest observations of the + effect of an overdose of estrogen was that it causes shock. +

+

+ Although water loss causes the blood to become more viscous under the influence of estrogen, the plasma + becomes hypotonic, meaning that it contains fewer osmotically active solutes than normal; some of the sodium + that helps to maintain the blood's osmotic balance is lost through the kidneys, and some is taken up by the + red blood cells and other cells. The osmotic imbalance of the blood causes tissue cells to take up more + water, contributing to their increased excitability. In many cases, the vascular leakage of inflammation and + shock can be corrected by using osmotically active substances, such as starch solutions, gelatin, or + concentrated sodium chloride. +

+

+ The tissue water retention caused by estrogen, hypoxia, and stress is analogous to the swelling of gels and + colloids, that is, it's governed by the state of the electrons and counterions in the system. Excitation, + fatigue, or injury can cause a shift of pH toward alkalinity, causing water uptake and swelling. +

+

+ The blue color of the pregnant cervix, or of the uterus in an animal given an overdose of estrogen, + indicates that the tissue isn't sufficiently oxygenated to maintain its normal red color, even though the + flow of blood is increased. Some experimenters have noticed that newborn animals sometimes have the postural + reflex (lordosis) that indicates an estrogenic state, and that suffocation can produce the same reflex. + Irradiating animals with x-rays will also produce the whole range of estrogenic effects. +

+

+ One of the features of the aged uterus that I studied was the age pigment, lipofuscin, a brown waxy material + that accumulates in old or stressed tissues. Prolonged dosage with estrogen accelerates the formation of + this pigment, which is largely derived from oxidized polyunsaturated fatty acids. Increased amounts of those + fats in the diet, or a deficiency of vitamin E, or exposure to ionizing radiation, or oxygen deprivation, + can also accelerate the formation of the age pigment. The presence of the pigment intensifies the effect of + estrogen, since the pigment wastes oxygen by functioning as an oxidase enzyme. +

+

+ Other tests that I did on aged, or estrogenized, uterine tissue indicated that several oxidative systems + were activated; for example, the tissues showed an extremely high activity of the enzyme peroxidase, and a + very intense reduction of a chemical dye (tetrazolium/formazan) that indicates the presence of reductive and + oxidative activity, of the sorts caused by radiation and oxygen deprivation. These reductive and oxidative + processes include the production of some free radicals that are capable of reacting randomly with + polyunsaturated fatty acids. +

+

+ The interactions between estrogen and the polyunsaturated fats are now coming to be more widely recognized + as important factors in the inflammatory/hyperpermeable conditions that contribute to the development of + heart and blood vessel disease, hypertension, cancer, autoimmune diseases, dementia, and other less common + degenerative conditions. +

+

+ Estrogen increases lipid peroxidation, and maintains a chronically high circulating level of free fatty + acids, mainly PUFA, activates the phospholipases that release arachidonic acid from cells leading to + formation of prostaglandins and isoprostanes, and increases the enzymes that form the inflammation-promoting + platelet activating factor (PAF) while suppressing the enzymes that destroy it, and increases a broad range + of other inflammatory mediators, interleukins, and NF-kappa B. +

+

+ The leakage of enzymes out of cells and into the blood stream is recognized medically as evidence of damage + to the organ that is losing them. Different combinations of enzymes are commonly considered to be evidence + of a heart attack, or skeletal muscle damage, or liver disease, pancreatitis, prostate cancer, etc. But + often the reason for the leakage isn't understood. Hypothyroidism, for example, causes leakage of enzymes, + possibly mainly from the liver, but also from other organs. Excess estrogen, intense exercise, starvation, + anything that increases lipid peroxidation and free radical production, such as drinking alcohol when the + tissues contain polyunsaturated fats, can cause organs such as heart and liver to leak their components. +

+

+ The loss of enzymes increases the energy needed to stay alive, but it doesn't necessarily change the basic + functions of the cell. (Though when mitochondrial enzymes leak out into the cytoplasm, the cell's energy + metabolism is impaired, at least temporarily.) But the entry of catalytic materials from other tissues + changes the organization of a cell, giving it conflicting instructions. In many situations, as L.V. + Polezhaev and V. Filatov demonstrated, the substances released during stress and degeneration serve to + stimulate healing and regeneration. But when the resources aren't available for full repair or regeneration, + only a scar, or atrophic fibrosis, or a tumor will be formed. +

+

+ In severe stress, intracellular fibrin deposits have been found in the heart and other organs, including the + prostate gland. Deficiency of testosterone causes vascular leakage into the prostate. Fibrin promotes tumor + growth, partly by serving as a matrix, partly by releasing stimulatory peptides. +

+

+ Kidney disease, diabetes, pregnancy toxemia and retinal degeneration are probably the best known problems + involving vascular leakage, but increasingly, cancer and heart disease are being recognized as consequences + of prolonged permeability defects. Congestive heart failure and pulmonary hypertension commonly cause + leakage of fluid into the lungs, and shock of any sort causes the lung to get "wet," a waterlogged condition + called "shock lung." Simply hyperventilating for a couple of minutes will increase leakage from the blood + into the lungs; hyperventilation decreases carbon dioxide, and increases serotonin and histamine. Hyperoxia + itself contributes to lung injury, and exacerbates emphysema, though it is common to see patients breathing + a high concentration of oxygen. Emphysema (which can be caused by hypothyroidism or hyper-estrogenism, and + often can be cured by thyroid or progesterone) and many other respiratory problems are associated with + capillary leakage. Cells of the lung and intestine are able to synthesize their own fibrin, apparently + because of their special problems in preventing leakage. Prolonged systemic inflammation can lead to lung + fibrosis, and fibrosis increases the likelihood of lung cancer. +

+

+ The inflammatory state that causes exaggerated cellular permeability is very closely related to + "hyperventilation," the loss of too much carbon dioxide. The release of serotonin during hyperventilation + isn't the only cause of vascular leakage; the carbon dioxide itself is an essential factor in regulating the + state of cellular electrons and in maintaining cellular integrity. Hyperventilation, like the shift from + oxidative to glycolytic energy production that typifies estrogenized or stressed cells or cancer, raises + intracellular pH. In the case of mast cells, increasing alkalinity causes them to release histamine + (Alfonso, et al., 2005), but similar "alkaline-induced exocytosis" seems to occur in all stressed tissues. +

+

+ The blood platelets that become incontinent and leak serotonin in the absence of carbon dioxide are + undergoing the same structural stresses experience by endothelial cells, smooth muscle cells, mast cells and + all other cells when carbon dioxide is depleted. Although it has been about 70 years since Yandell Henderson + made it clear that supplemental oxygen should be combined with carbon dioxide, mechanical ventilation in + hospitals is still causing lung injury resulting from hyperventilation, i.e., the absence of carbon dioxide. + A similar misunderstanding of biology was involved in the use of dialysis to treat kidney disease. Until + recently, commercial dialysis fluids contained acetate and/or racemic lactate instead of bicarbonate, + because of the difficulty of preparing bicarbonate solutions, and the result was that very prolonged + dialysis would damage the brain and other organs. (Veech and Gitomer, 1988, Veech and Fowler, 1987.) + Dialysis has been seen to increase lung permeability Bell, et al., 1988). +

+

+ Amyloidosis produced by chronic dialysis affects all organs, but its effects are best known in the brain, + heart, kidneys, and lungs. Serum amyloid-A is one of the acute phase proteins, like C-reactive protein + (CRP), that are produced by inflammation. Estrogen, radiation and other stresses increase those + pro-inflammatory acute phase proteins, and decrease protective albumin, which is called a "negative acute + phase protein," since it decreases when the other acute phase proteins increase. The liver is the major + source of the acute phase proteins, and it is constantly burdened by toxins absorbed from the bowel; + disinfection of the bowel is known to accelerate recovery from stress. +

+

+ Seen from the perspective of the stress-leakage syndrome, any serious injury or sickness damages all organs. + The exhaled breath is being used to diagnose inflammatory lung disease, since so many of the mediators of + inflammation are volatile, but systemic diseases such as cancer and arthritis, and relatively minor stress + can be detected by changes in the chemicals found in the breath. Polyunsaturated fats and their breakdown + products--aldehydes, prostaglandins, isoprostanes, hydrocarbons, and free radicals--and carbon monoxide, + nitric oxide, nitrite, and hydrogen peroxide are increased in the breath by most stresses. Both proline and + glycine (which are major amino acids in gelatin) are very protective for the liver, increasing albumin, and + stopping oxidative damage. +

+

+ Saturated fats are protective against free radical damage and can reverse liver fibrosis. Thyroid hormone + protects against excess estrogen, and can prevent or reverse fibrosis of the heart. Antiestrogens are widely + effective against vascular leakage. Thyroid, progesterone, and testosterone are among the most effective + natural antiestrogens, and they are curative in many conditions that involve vascular leakage. Progesterone + and pregnenolone have been called the antifibromatic steroids, and it has been used to treat many + inflammatory and fibrotic diseases, including cancer. +

+

+ The antiserotonin drugs are being increasingly used to treat fibrotic diseases, and other problems related + to vascular leakage. +

+

+ Antiinflammatory and anticoagulant things, especially aspirin and vitamin E, protect against the accelerated + turnover of fibrinogen/fibrin caused by estrogen and the various inflammatory states. +

+

+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com +

+ + diff --git a/raypeat-articles/processed/multiple-sclerosis-hormone-related-brain-syndromes.html b/raypeat-articles/processed/multiple-sclerosis-hormone-related-brain-syndromes.html new file mode 100644 index 0000000..3926d4f --- /dev/null +++ b/raypeat-articles/processed/multiple-sclerosis-hormone-related-brain-syndromes.html @@ -0,0 +1,318 @@ + + + +

+ +

+
+ MULTIPLE SCLEROSIS AND OTHER HORMONE-RELATED BRAIN SYNDROMES (1993) + + Since I am trying to discuss a complex matter in a single article, I have separately outlined the essential + technical points of the argument in a section at the beginning, then I explain how my ideas on the subject + developed, and finally there is a glossary.  If you start with "Short-day brain stress," "Estrogen's + effects," and "Symptoms and therapies," you will have the general picture, and can use the other sections to + fill in the technical details. +   + THE ARGUMENT:    1) The hormones pregnenolone, thyroid, and estrogen are + involved in several ways with the changes that occur in multiple sclerosis, but no one talks about them. 2) + The process of myelination is known to depend on the thyroid hormone.  The myelinating cells are the + oligodendroglia (oligodendrocytes) which appear to stop functioning in MS (and  sometimes to a milder + degree in Alzheimer's disease, and other  conditions).  The cells' absorption of thyroid hormone + is influenced by dietary factors. 3) The oligodendrocytes are steroid-producing cells (1),  and + steroidogenesis is dependent on thyroid hormone, and on  thyroid-dependent respiratory enzymes and on + the heme-enzyme P-450scc, which are all sensitive (2) to poisoning by carbon monoxide and cyanide.  The + steroid produced by the oligodendrocytes is pregnenolone, which is known to have a profound  + anti-stress action (3), and which appears to be the main  brain-protective steroid. 4) Lesions + resembling those of MS can be produced experimentally by carbon monoxide or cyanide poisoning.(4)  The + lesions  tend to be associated with individual small blood vessels, which   are likely to contain + clots.  (Since all animals have enzymes to  detoxify cyanide, this poison is apparently a + universal problem,  and can originate in the bowel. "Detoxified" cyanide is still toxic to the + thyroid.)  5) Pregnenolone and progesterone protect against nerve damage (5) by the excitotoxic amino + acids (glutamic acid, aspartic acid, monosodium glutamate, aspartame, etc.), while estrogen (6) and cortisol + (7) are nerve-destroying, acting through the excitotoxic amino acids.  Excitotoxins destroy certain + types of nerve, especially the dopaminergic and cholinergic types, leaving the noradrenergic types (8), + paralleling the changes that occur in aging.  The clustering of oligodendrocytes around deteriorating + nerve cells could represent an adaptive attempt to provide pregnenolone to injured nerve cells. 6) The + involvement of hormones and environmental factors probably accounts for the intermittent progress of + multiple sclerosis. To the extent that the environmental factors can be  corrected, the disease can + probably be controlled. + +  SHORT-DAY BRAIN STRESS + Shortly after I moved from Mexico to Montana, one of my students, a 32 year old woman, began having the same + sensory symptoms her older sister had experienced at the same age, at the onset of multiple sclerosis.  + Vertigo and visual distortions of some sort made her consider withdrawing from the university. I'm not sure + why she tried eating a whole can of tuna for lunch a couple of days after the onset of symptoms, but it + seemed to alleviate the symptoms, and she stayed on a high protein diet and never had a recurrence.  + She told me some of the lore of MS: That it mostly affects young adults between the ages of 20 and 40, that + it is common in high latitudes and essentially unknown in the tropics, and that it is sometimes exacerbated + by pregnancy and stress.  (Later, I learned that systemic lupus erythematosis and other "auto-immune" + diseases also tend to occur mainly during the reproductive years.  I discussed some of the implications + of this in "Bean Syndrome.") Having enjoyed the mild climate of Mexico, I became very conscious of the harm + done to us by northern winters, and began developing the idea of "winter sickness."  In 1966-67, + allergies, PMS, weight gain, colitis, and arthritis came to my attention as winter-related problems, and I + assumed that the high-latitude incidence of MS related to what I was seeing and experiencing.  Studies + in Leningrad began revealing that mitochondria are injured during darkness, and repaired during + daylight.  I observed that hamsters' thymus glands shrank in the winter and regenerated in the summer; + shrinkage of the thymus gland is a classical feature of stress, and usually reflects the dominance of + cortisone, though estrogen and testosterone also cause it to shrink.  Winter's darkness is stressful in + a very fundamental way, and like any stress it tends to suppress thyroid function.  In the hypothyroid + state, any estrogen which is produced tends to accumulate in the body, because of liver sluggishness. I + began to see that PMS could be controlled by certain things--extra light, supplements of sodium and + magnesium, high quality protein, and correction of deficiencies of thyroid and progesterone.  In + working on my dissertation, I saw that tissue hypoxia (lower than optimal concentrations of oxygen in the + blood) may result from estrogen excess, vitamin E deficiency, or aging.  There is a close biological + parallel between estrogen-dominance and the other hypoxic states, such as stress/shock, and aging.   + ESTROGEN'S EFFECTS + As a portrait painter, I had been very conscious of the blue aspect that can often be seen in the skin of + young women. In pale areas, the color may actually be blue, and in areas with a rich supply of blood, such + as the lips, the color is lavender during times of high estrogen influence--around ovulation and puberty, + for example.  During these times of estrogen dominance, the blood is not only poorly oxygenated, but it + has other special properties, such as an increased tendency to clot.  The Shutes' work in the 1930s + began with the use of vitamin E to antagonize estrogen's clot-promoting tendency, and led them to the + discovery that vitamin E can be very therapeutic in heart disease.  More recently, it has been found + that men with heart disease have abnormally high estrogen (9), that women using oral contraceptives have + higher mortality from heart attacks (10), and that estrogen tends to  promote spasm of blood vessels + (11).  (These reactions are probably  related to the physiology of menstruation, in which + progesterone withdrawal causes spasms in the spiral arteries of the uterus,  producing endometrial + anoxia and cell death.) In toxemia of late pregnancy, or eclampsia, the exaggerated clotting tendency caused + by excess estrogen (or by inadequately opposed estrogen, i.e., progesterone deficiency), can cause + convulsions and strokes.  Vascular spasms could be involved here, too.  The stasis caused by the + vasospasm would facilitate clotting. (Vascular spasm has been observed in epilepsy, too.  Epilepsy can + be brought on by the premenstrual excess of estrogen, and in that situation there is no evidence that + clotting is involved.  Leakage of hemoglobin out of red cells can cause vasospasm, so bleeding, + clotting, strokes, and seizures can interact complexly.)  The brains of women who have + died following eclampsia show massive clotting in the blood vessels, and their livers are + characteristically injured, with clots (12). Tom Brewer and others have shown very clearly that + malnutrition, especially protein deficiency, is the cause of toxemia of late pregnancy.  (In Nutrition + for Women, I discussed the importance of protein in allowing the liver to eliminate estrogen.) Various + researchers have demonstrated that the plaques of MS usually occur in the area served by a single blood + vessel (13, 14), and some have suggested that clotting is the cause.  MS patients have been found to + have an abnormal clotting time, and it has been suggested that an altered diet might be able to correct the + clotting tendency. Studies in animals have shown clearly that a protein deficiency increases the fibrinogen + content of blood. (Field and Dam, 1946.)  Other factors that increase blood clotting are elevated + adrenalin and cortisone.  Protein deficiency causes an adaptive decrease in thyroid function, which + leads to a compensatory increase in adrenaline and cortisone.  The combination of high estrogen with + high adrenaline increases the tendency for both clots and spasms of the blood vessels (11). In experimental + poisoning of animals with carbon monoxide or cyanide, the brain lesions resembling MS include blood + clots.  The patchy distribution of these spots in the brain suggests that the clotting is secondary to + metabolic damage in the brain.  Presumably, the same would be true in ordinary MS, with clots and + spasms being induced in certain areas by metabolic abnormalities in brain cells.  The injured cells + that are responsible for myelination of nerve fibers are steroid-forming cells.  A failure to secrete + their protective pregnenolone could cause a local spasm of a blood vessel.  The circulatory problem + would exacerbate the respiratory problem. Steroid production is dependent on NADH and NADPH, and so requires + adequate energy supplies and energy metabolism.  The phenomenon of blood-sludging, studied by M. + Knisely at the University of Chicago in the l930s and l940s, is apparently a general result of decreased + energy metabolism, and is likely to be a factor in energy-and-circulatory vicious circles. +   + SYMPTOMS AND THERAPIES          + Around 1976 I met a woman in her mid-thirties who heard about my work with progesterone in animals.  + She had been disabled by a brain disease that resembled MS or Devic's disease, inflammation of the optic + nerves.  It would sometimes cause blindness and paralysis that persisted for weeks at a time.  + During remissions, sometimes using a wheelchair, she would go to the medical school library to try to + understand her condition.  She came across Katherina Dalton's work with progesterone, and convinced a + physician to give her a trial injection.  Although she had trouble finding people who were willing to + give her progesterone, her recovery was so complete that she was able to climb stairs and drive her car, and + she came  to my endocrinology class and gave a very good (and long) lecture on progesterone + therapy.  Although her sensory and motor functions became normal, she remained very fat, and + chronically suffered from sore areas on her arms and legs that seemed to be abnormal blood vessels, possibly + with phlebitis.  She appeared to need thyroid hormone as well as larger amounts of progesterone, but + never found a physician who would cooperate, as far as I know. In the late 1970s I was seeing a lot of + people who had puzzling health problems.  In a period of two or three years, there were five people who + had been diagnosed by neurologists as having multiple sclerosis.  In talking to them, it seemed clear + that they had multiple symptoms of hypothyroidism.   They weren't severely disabled.  Since they + weren't fat or lethargic, their physicians hadn't thought they could be hypothyroid.  When they tried + taking a thyroid supplement, all of their symptoms disappeared, including those that had led to their MS + diagnosis.  One of the women went to her doctor to tell him that she felt perfectly healthy since + taking thyroid, and he told her to stop taking it, because people who have MS need a lot of rest, and she + wouldn't get enough rest if she was living in a normally active way. The assumption seemed to be that the + diagnosis was more important than the person. (When I refer to a "thyroid supplement" I mean one that + contains some T3.  Many people experience "neurological symptoms" when they take thyroxine by + itself.  Experimentally, it has been found to suppress brain respiration, probably by diluting the T3 + that was already present in the brain tissue.)   +   + METABOLISM OF THE OLIGODENDROCYTES + The rate-regulating step in steroid synthesis involves the entry of cholesterol into the mitochondria, where + the heme-enzyme P-450scc then removes the side-chain of cholesterol  (by introducing oxygen atoms), to + produce pregnenolone.  This enzyme can be poisoned by carbon monoxide or cyanide, and light can + eliminate the poison (15); this could be one aspect of the winter-sickness problem.   Peripheral nerves + are myelinated by essentially the same sort of cell that is called an oligodendrocyte in the brain, but + outside the brain it is called a Schwann cell.  It is easier to study the myelin sheath in peripheral + nerves, and the electrical activity of a nerve is the most easily studied aspect of its physiology.  + Certain experiments seemed to indicate a "jumping" (saltatory) kind of conduction along the nerve between + Schwann cells, and it was argued that the insulating function of the myelin sheath made this kind of + conduction possible.  This idea has become a standard item in physiology textbooks, and its familiarity + leads many people to assume that the presence of myelin sheaths in the brain serves the same "insulating" + function. For a long time it has been known that heat production during nerve conduction reveals a more + continuous mode of  conduction, that doesn't conform to the idea of an electrical  current jumping + around an insulator.  Even if the myelin functioned primarily to produce "saltatory conduction" in + peripheral nerves, it isn't clear how this process could function in the brain.  I think of the issue + of "saltatory conduction at the nodes of Ranvier" as another of the fetish ideas that have served to + obstruct progress in biology in the United States.  A more realistic approach to nerve function can be + found in Gilbert Ling's work.  Ling has demonstrated in many ways that the ruling dogma of "cell + membrane" function isn't coherently based on fact.  He found that hormones such as progesterone + regulate the energetic and structural stability of cells.  Many people, unaware of his work, have felt + that it was necessary to argue against the idea that there are anesthetic steroids with generalized + protective functions, because of their commitment to a textbook dogma of "cell membrane" physiology. I think + the myelinating cells do have relevance to nerve conduction, but I don't think they serve primarily as + electrical insulators.  If the adrenal cortex were inside the heart, it would be obvious to ask whether + its hormones aren't important for the heart's function.  Since the oligodendrocytes are + steroid-synthesizers, it seems obvious to ask whether their production of pregnenolone in response to stress + or fatigue isn't relevant to the conduction processes of the nerves they surround.      +                         +   + OLD AGE + A biologist friend of mine who was about 85 became very senile.  His wife started giving him thyroid, + progesterone, DHEA and pregnenolone, and within a few days his mental clarity had returned.  He + continued to be mentally active until he was 89, when his wife interfered with his access to the hormones. + In old age the brain steroids fall to about 5% of their level in youth.  Pregnenolone and DHEA improve + memory in old rats, and improve mood stability and mental clarity of old people.  Pregnenolone's action + in improving the sense of being able to cope with challenges probably reflects a quieting and coordinating + of the "sequencing" apparatus of the forebrain, which is the area most sensitive to energy + deprivation.  This is the area that malfunctions in hyperactive and "dyslexic" children.  + Weakening of the sequencing and sorting processes probably explains the common old-age inability to extract + important sounds from environmental noise, creating a kind of "confusion deafness."  Insomnia, worry + and "restless legs" at bedtime are problems for many old people, and I think they are variations of the + basic energy-depletion problem. The oligodendrocytes were reported (Hiroisi and Lee, 1936) to be the source + of the senile plaques or amyloid deposits of Alzheimer's disease.(16)  Hiroisi and Lee showed the cells + in different stages of degeneration, ending with translucent "mucoid" spots that stained the same as + amyloid, the material in the senile plaques.  This type of cell also appears to form a halo or crown + around degenerating nerve cells--possibly in a protective reaction to provide the nerve cell  with any + pregnenolone the oligodendrocytes are able to make.  The  oligodendrocytes, the source of the + brain steroids (that people previously believed came from the adrenals and gonads, and were just stored in + the brain), myelinate nerve fibers under the  influence of thyroid hormone (17).  Thyroid is + responsible for both myelination and hormone formation.  In old age, glial cells become more numerous, + and nerve cells become structurally  and functionally abnormal, but usually there is no problem  + with the formation of myelin.  In MS, the problem is just with  myelination, and there are no + senile plaques or defects in the  nerve cells themselves.        These differences + suggest the possibility that Alzheimer's  disease involves a specific premature loss of brain + pregnen-  olone production, but not of thyroid.  Recent work suggests a central role for + pregnenolone and progesterone in the regulation of consciousness (18), and possibly in the brain's + detoxifying system.  Elsewhere, I have suggested that vitamin A deficiency might cause the excessive + production of the "amyloid" protein.  A vitamin A deficiency severely inhibits steroid synthesis.  + (It is used so massively in steroid synthesis that a progesterone supplement can prevent the symptoms of + vitamin A deficiency.)  I suspect that vitamin A is necessary for the side-chain cleavage that converts + cholesterol to pregnenolone.  Iron-stimulated lipid peroxidation is known to block steroid formation, + and vitamin A is very susceptible to destruction  by iron and oxidation.  Iron tends to + accumulated in tissues  with aging.  Gajdusek has demonstrated that brain deterioration  is + associated with the retention of whatever metal happens to be abundant in the person's environment, not just + with aluminum.  (One type of glial cell is known for its metal-binding function, causing them to be + called "metallophils.").  According to Gajdusek, "calcium and other di- and trivalent elements" are + "deposited as hydroxyapatites in brain cells" in brain degeneration of the Alzheimer's type.(19) Even early + forms of Alzheimer's disease begin at an age  when the youth-associated steroids have begun to decline. + If  MS involves a deficiency of thyroid (or of T3 within the oligodendrocytes, where T3 normally can be + made from thyroxine; many things, including protein deficiency, can block the conversion of T4 to T3), those + cells would necessarily be deficient in their ability to produce pregenolone, but in  young people the + brain would still be receiving a little pregnenolone, progesterone, and DHEA from the adrenals and + gonads.  This relatively abundant youthful supply of hormones would keep most of the body's organs in + good condition,  and could keep the bodies of the major brain cells from deteriorating. But if proper + functioning of the nerve fibers requires that they be fed a relatively high concentration of pregnenolone + from their immediately adjacent neighbors (with the amount increasing during stress and fatigue), then their + function would be impaired when they had to depend on the hormones that arrived from the blood stream. For + many years it has been recognized that the brain atrophy of "Alzheimer's disease" resembles the changes seen + in the brain in many other situations:  The traumatic dementia of boxers; toxic dementia; the + slow-virus diseases; exposure of the brain to x-rays (20); ordinary old age; + and in people with Down's syndrome who die around the age of thirty.          +   In menopause, certain nerve cells have lost their ability to regulate the ovaries, because of + prolonged exposure to estrogen (6).  The cells that fail as a result of prolonged estrogen exposure + aren't the same cells that fail from prolonged exposure to the glucocorticoids (7), but they have in common + the factor of excitatory injury. Since people who experience premature menopause are known to be more likely + than average to die prematurely, it is reasonable to view menopause as a model of the aging process. It is + now well established that progesterone fails to be produced at the onset of menopause (the first missed + period, increased loss of calcium, symptoms such as hot flashes, etc.), and that estrogen continues to be + produced at monthly intervals for about four years.  The essential question for aging, in the present + context, is why the anesthetic steroids are no longer produced at a rate that allows them to protect + tissues, including brain cells, from the excitotoxins.  Using menopause as a model for aging, we can + make the question more answerable by asking why progesterone stops being produced. During stress, we are + designed not to get pregnant, and the simplest aspect of this is that ACTH, besides stimulating the adrenals + to produce stress-related hormones, inhibits the production of progesterone by the ovary.  Other + stress-induced factors, such as increased prolactin and decreased thyroid, also inhibit progesterone + production.  Stress eventually makes us more susceptible to stress.  Menopause and other landmarks + of aging simply represent upward inflections in the rate-of-aging curve.  Individual variations in type + of stress, hormonal response and diet, etc., probably govern the nature of the aging process in an + individual. The amphetamine-like action of estrogen, which undoubtedly  contributes to the general + level of stress and excitotoxic  abuse of nerve cells, is probably the only "useful" facet of  + estrogen treatment, but a little cocaine might achieve the  same effect with no more harm, possibly + less.  The toxicity of catecholamines has been known for over thirty years, and estrogen's stimulating + effects are partly the result of its conversion to catechol-estrogens which increase the activity of brain + catecholamines.  Estrogen's powerful ability to nullify learning seems never to be mentioned by the + people who promote its use.  The importance of a good balance of brain steroids for mood, attention, + memory, and reasoning is starting to be recognized, but powerful economic forces militate against its + general acceptance. Since the brain is the organ that can allow us to adapt without undergoing stress in the + hormonal sense, it is very important to protect its flexibility and to keep its energy level high, so it can + work in a relaxed way.  It is the low energy cellular state that leads to the retention of calcium and + iron, and to the production of age pigment, and other changes that constitute the vicious circle of + aging.  And mental activity that challenges obsession and rigidity might be the most important brain + energizer.  Pseudo-optimism, humor-as-therapy, has a certain value, but a deeper optimism involves a + willingness to assimilate new information and to change plans accordingly. +   + SUPPLEMENTS + Nutritional supplements that might help to prevent or correct these brain syndromes include: Vitamin E + and  coconut oil; vitamin A; magnesium, sodium; thyroid which  includes T3; large amounts of + animal protein, especially  eggs; sulfur, such as magnesium sulfate or flowers of  sulfur, but not + to take continuously, because of sulfur's interference with copper absorption; pregnenolone; progesterone if + needed.  Bright light, weak in the blue end of the spectrum and with protection against ultraviolet, + activates respiratory metabolism and quenches free radicals.  Raw carrot fiber and/or laxatives if + needed; charcoal occasionally for gas or bowel  irritation.  Coconut oil serves several + purposes.  Its butyric acid is known to increase T3 uptake by glial cells.  It has a general + pro-thyroid action, for example by diluting and displacing antithyroid unsaturated oils, its short- and + medium-chain fatty acids sustain blood sugar and have antiallergic actions, and it protects mitochondria + against stressinjury.  P.S.:  In 1979, a woman whose husband was suffering from advanced + Amyotrophic Lateral Sclerosis (ALS) asked me if I had any ideas for slowing his decline.  I described + my suspicion that ALS involved defective metabolism or regulation of testosterone.  In some tissues, + testosterone is selectively concentrated to prevent atrophy, and ALS is a disease of middle-age, when + hormone regulation often becomes a special problem.  In the late 1970s, there was discussion of a + higher incidence of ALS in males, and especially in athletes.  I told her about progesterone's general + protective effects, its antagonism to testosterone, and its prevention of atrophy in various tissues.  + She decided to ask her doctor to try progesterone for her husband.  Later, I learned that her husband + had gone into a very rapid decline immediately after the injection, and died within a week; the physician + had given him testosterone, since, he said, "testosterone and progesterone are both male hormones."  + Besides making me more aware of the problems patients have in communicating with physicians, this tended to + reinforce my feeling that a hormone imbalance is involved in ALS.  Although I haven't written much + about testosterone's toxicity, Marian Diamond's work showed that prenatal testosterone is similar to + prenatal estrogen, in causing decreased thickness of the cortex of the brain; both of those hormones oppose + progesterone's brain-protecting and brain-promoting actions. + +

REFERENCES

 + 1)  Z. Y. Hu, et al., P.N.A.S. (USA) 84, 8215-9, 1987. 2)  P. F. Hall, Vitamins and Hormones 42, + 315-370, 1985. 3)  J. J. Lambert, et al., Trends in Pharmac. Sci. 8, 224-7, 1987. 4)  W. A. D. A. + Anderson, Pathology (second edition), C. V. Mosby, St. Louis, 1953. 5)  S. S. Smith, et al., Brain Res. + 422, 52-62, 1987. 6)  P. M. Wise, Menopause, 1984; S. S. Smith, et al., Brain Res. 422, 40-51, 1987. + 7)  R. M. Sapolsky, et al., J. Neuroscience 5, 1222-1227, 1985; R. M. Sapolsky and W. Pulsinelli, + Science 229, 1397-9, 1985. 8)  C. B. Nemeroff, (Excitotoxins)  290-305, 1984. 9)  G. B. + Phillips, Lancet 2, 14-18, 1976; G. B. Phillips, et al., Am. J. Med. 74, 863-9, 1983; M. H. Luria, et al., + Arch Intern Med 142, 42-44, 1982; E. L. Klaiber, et al., Am J Med 73, 872-881, 1982. 10)  J. I. Mann, + et al., Br Med J 2, 241-5, 1975. 11)  V. Gisclard and P. M. Vanhoutte, Physiologist 28, 324(48.1). + 12)  W. A. D. A. Anderson, Pathology, 1953; H. H. Reese, et al.,  editors, 1936 Yearbook of + Neurology, Psychiatry, and Endocrinology,  Yearbook Publishers, Chicago, 1937.    13)  + T. J. Putnam, Ann Int Med 9, 854-63, 1936; JAMA 108, 1477, 1937. 14)  R. S. Dow and G. Berglund, Arch + Neurol and Psychiatry 47, 1, 1992. 15)  R. W. Estabrook, et al., Biochem Z. 338, 741-55, 1963. + 16)  S. Hiroisi and C. C. Lee, Arch Neurol and Psychiat 35, 827-38, 1936. 17)  J. M. Matthieu, et + al., Ann Endoc. 1974. 18)  K. Iwaharhi, et al., J Ster Biochem and Mol Biol 44(2), 163-4, 1993. + 19)  D. C. Gajdusek, Chapter 63, page 1519 in Virology (B. N. Fields, et al., editors), Raven Press, + N.Y., 1985. 20)  K. Lowenberg-Scharenberg and R. C. Bassett, J Neuropath and Exper Neurol 9, 93, 1950. + GLOSSARY   1.  Amyloid is the old term for the "starchy" appearing (including the way it + stains) proteins seen in various diseases, and in the brain in Alzheimer's disease. 2.  Cytochrome + P450scc.  The cytochromes are "pigments," in the same sense that they contain the colored "heme" group + that gives hemoglobin its color.  P450 means "protein that absorbs light at a wavelength of 450.  + The scc means "side-chain cleaving," which refers to the removal of the 6 carbon atoms that distinguish + cholesterol from pregnenolone. Other Cyt P450 enzymes are important for their detoxifying oxidizing action, + and some of these are involved in brain metabolism. 3.  Glial means "glue-like," and glial cells are + mostly spidery-shaped cells that used to be thought of as just connective, supportive cells in the brain. + 4.  Mitochondria (the "thread-like bodies") are the structures in cells which produce most of our + metabolic energy by respiration, in response to the thyroid hormones. 5.  Mucoid--refers to a + mucoprotein, a protein which contains some carbohydrate.  A glycoprotein; usually not intended as a + precise term. 6.  Myelination.  Myelin is a multilayered enclosure of the axons (the long + processes) of nerve cells, composed of proteins and complex lipids, including cholesterol.  The layered + material is a flat, thin extension of the cytoplasm of the oligodendroglial cells. 7.  Oligodendrocytes + are one of the kinds of glial (or neuroglial) cells, and structurally they are unusual in having sheet-like, + rather than just thread-like processes; they have a sensitivity ("receptors") to stress and valium, and + produce pregnenolone when activated.  Under the influence of thyroid hormone, they wrap themselves in + thin layers around the conductive parts of nerve cells, leaving a multilayered "myelin" coating.  Their + absorption of thyroid hormone is promoted by butyrate, an anti-stress substance found in butter and coconut + oil. 8.  Steroidogenesis is the creation of steroids, usually referring to the conversion of + cholesterol to hormones. +
+ + © Ray Peat Ph.D. 2013. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/multiple-sclerosis.html b/raypeat-articles/processed/multiple-sclerosis.html new file mode 100644 index 0000000..a9df6ce --- /dev/null +++ b/raypeat-articles/processed/multiple-sclerosis.html @@ -0,0 +1,626 @@ + + + +

+ +

+
+ MULTIPLE SCLEROSIS AND OTHER HORMONE-RELATED BRAIN SYNDROMES (1993) +
+
+
+ Since I am trying to discuss a complex matter in a single article, I have separately outlined the + essential technical points of the argument in a section at the beginning, then I explain how my + ideas on the subject developed, and finally there is a glossary.  If you start with + "Short-day brain stress," "Estrogen's effects," and "Symptoms and therapies," you will have the + general picture, and can use the other sections to fill in the technical details. +
+
+
+ THE ARGUMENT: +
+
+ 1) The hormones pregnenolone, thyroid, and estrogen are involved in several ways with the changes + that occur in multiple sclerosis, but no one talks about them. +
+
+ 2) The process of myelination is known to depend on the thyroid hormone.  The myelinating + cells are the oligodendroglia (oligodendrocytes) which appear to stop functioning in MS + (and  sometimes to a milder degree in Alzheimer's disease, and other  + conditions).  The cells' absorption of thyroid hormone is influenced by dietary + factors. +
+
+ 3) The oligodendrocytes are steroid-producing cells (1),  and steroidogenesis is dependent on + thyroid hormone, and on  thyroid-dependent respiratory enzymes and on the heme-enzyme + P-450scc, which are all sensitive (2) to poisoning by carbon monoxide and cyanide.  The + steroid produced by the oligodendrocytes is pregnenolone, which is known to have a + profound  anti-stress action (3), and which appears to be the main  brain-protective + steroid. +
+
+ 4) Lesions resembling those of MS can be produced experimentally by carbon monoxide or cyanide + poisoning.(4)  The lesions  tend to be associated with individual small blood vessels, + which   are likely to contain clots.  (Since all animals have enzymes to  + detoxify cyanide, this poison is apparently a universal problem,  and can originate in the + bowel. "Detoxified" cyanide is still toxic to the thyroid.)  +
+
+ 5) Pregnenolone and progesterone protect against nerve damage (5) by the excitotoxic amino acids + (glutamic acid, aspartic acid, monosodium glutamate, aspartame, etc.), while estrogen (6) and + cortisol (7) are nerve-destroying, acting through the excitotoxic amino acids.  + Excitotoxins destroy certain types of nerve, especially the dopaminergic and cholinergic types, + leaving the noradrenergic types (8), paralleling the changes that occur in aging.  The + clustering of oligodendrocytes around deteriorating nerve cells could represent an adaptive + attempt to provide pregnenolone to injured nerve cells. +
+
+ 6) The involvement of hormones and environmental factors probably accounts for the intermittent + progress of multiple sclerosis. To the extent that the environmental factors can be  + corrected, the disease can probably be controlled. +
+
+
+ SHORT-DAY BRAIN STRESS +
+
+ Shortly after I moved from Mexico to Montana, one of my students, a 32 year old woman, began having + the same sensory symptoms her older sister had experienced at the same age, at the onset of + multiple sclerosis.  Vertigo and visual distortions of some sort made her consider + withdrawing from the university. I'm not sure why she tried eating a whole can of tuna for lunch + a couple of days after the onset of symptoms, but it seemed to alleviate the symptoms, and she + stayed on a high protein diet and never had a recurrence.  She told me some of the lore of + MS: That it mostly affects young adults between the ages of 20 and 40, that it is common in high + latitudes and essentially unknown in the tropics, and that it is sometimes exacerbated by + pregnancy and stress.  (Later, I learned that systemic lupus erythematosis and other + "auto-immune" diseases also tend to occur mainly during the reproductive years.  I + discussed some of the implications of this in "Bean Syndrome.") +
+
+ Having enjoyed the mild climate of Mexico, I became very conscious of the harm done to us by + northern winters, and began developing the idea of "winter sickness."  In 1966-67, + allergies, PMS, weight gain, colitis, and arthritis came to my attention as winter-related + problems, and I assumed that the high-latitude incidence of MS related to what I was seeing and + experiencing.  Studies in Leningrad began revealing that mitochondria are injured during + darkness, and repaired during daylight.  I observed that hamsters' thymus glands shrank in + the winter and regenerated in the summer; shrinkage of the thymus gland is a classical feature + of stress, and usually reflects the dominance of cortisone, though estrogen and testosterone + also cause it to shrink.  Winter's darkness is stressful in a very fundamental way, and + like any stress it tends to suppress thyroid function.  In the hypothyroid state, any + estrogen which is produced tends to accumulate in the body, because of liver sluggishness. +
+
+ I began to see that PMS could be controlled by certain things--extra light, supplements of sodium + and magnesium, high quality protein, and correction of deficiencies of thyroid and + progesterone.  In working on my dissertation, I saw that tissue hypoxia (lower than optimal + concentrations of oxygen in the blood) may result from estrogen excess, vitamin E deficiency, or + aging.  There is a close biological parallel between estrogen-dominance and the other + hypoxic states, such as stress/shock, and aging. +
+
+
+ ESTROGEN'S EFFECTS +
+
+ As a portrait painter, I had been very conscious of the blue aspect that can often be seen in the + skin of young women. In pale areas, the color may actually be blue, and in areas with a rich + supply of blood, such as the lips, the color is lavender during times of high estrogen + influence--around ovulation and puberty, for example.  During these times of estrogen + dominance, the blood is not only poorly oxygenated, but it has other special properties, such as + an increased tendency to clot.  The Shutes' work in the 1930s began with the use of vitamin + E to antagonize estrogen's clot-promoting tendency, and led them to the discovery that vitamin E + can be very therapeutic in heart disease.  More recently, it has been found that men with + heart disease have abnormally high estrogen (9), that women using oral contraceptives have + higher mortality from heart attacks (10), and that estrogen tends to  promote spasm of + blood vessels (11).  (These reactions are probably  related to the physiology of + menstruation, in which progesterone withdrawal causes spasms in the spiral arteries of the + uterus,  producing endometrial anoxia and cell death.) +
+
+ In toxemia of late pregnancy, or eclampsia, the exaggerated clotting tendency caused by excess + estrogen (or by inadequately opposed estrogen, i.e., progesterone deficiency), can cause + convulsions and strokes.  Vascular spasms could be involved here, too.  The stasis + caused by the vasospasm would facilitate clotting. (Vascular spasm has been observed in + epilepsy, too.  Epilepsy can be brought on by the premenstrual excess of estrogen, and in + that situation there is no evidence that clotting is involved.  Leakage of hemoglobin out + of red cells can cause vasospasm, so bleeding, clotting, strokes, and seizures can interact + complexly.)  The brains of women who have died following eclampsia show massive + clotting in the blood vessels, and their livers are characteristically injured, with clots + (12). +
+
+ Tom Brewer and others have shown very clearly that malnutrition, especially protein deficiency, is + the cause of toxemia of late pregnancy.  (In Nutrition for Women, I discussed the + importance of protein in allowing the liver to eliminate estrogen.) +
+
+ Various researchers have demonstrated that the plaques of MS usually occur in the area served by a + single blood vessel (13, 14), and some have suggested that clotting is the cause.  MS + patients have been found to have an abnormal clotting time, and it has been suggested that an + altered diet might be able to correct the clotting tendency. +
+
+ Studies in animals have shown clearly that a protein deficiency increases the fibrinogen content of + blood. (Field and Dam, 1946.)  Other factors that increase blood clotting are elevated + adrenalin and cortisone.  Protein deficiency causes an adaptive decrease in thyroid + function, which leads to a compensatory increase in adrenaline and cortisone.  The + combination of high estrogen with high adrenaline increases the tendency for both clots and + spasms of the blood vessels (11). +
+
+ In experimental poisoning of animals with carbon monoxide or cyanide, the brain lesions resembling + MS include blood clots.  The patchy distribution of these spots in the brain suggests that + the clotting is secondary to metabolic damage in the brain.  Presumably, the same would be + true in ordinary MS, with clots and spasms being induced in certain areas by metabolic + abnormalities in brain cells.  The injured cells that are responsible for myelination of + nerve fibers are steroid-forming cells.  A failure to secrete their protective pregnenolone + could cause a local spasm of a blood vessel.  The circulatory problem would exacerbate the + respiratory problem. Steroid production is dependent on NADH and NADPH, and so requires adequate + energy supplies and energy metabolism.  The phenomenon of blood-sludging, studied by M. + Knisely at the University of Chicago in the l930s and l940s, is apparently a general result of + decreased energy metabolism, and is likely to be a factor in energy-and-circulatory vicious + circles. +
+
+
+ SYMPTOMS AND THERAPIES +
+
+ Around 1976 I met a woman in her mid-thirties who heard about my work with progesterone in + animals.  She had been disabled by a brain disease that resembled MS or Devic's disease, + inflammation of the optic nerves.  It would sometimes cause blindness and paralysis that + persisted for weeks at a time.  During remissions, sometimes using a wheelchair, she would + go to the medical school library to try to understand her condition.  She came across + Katherina Dalton's work with progesterone, and convinced a physician to give her a trial + injection.  Although she had trouble finding people who were willing to give her + progesterone, her recovery was so complete that she was able to climb stairs and drive her car, + and she came  to my endocrinology class and gave a very good (and long) lecture on + progesterone therapy.  Although her sensory and motor functions became normal, she remained + very fat, and chronically suffered from sore areas on her arms and legs that seemed to be + abnormal blood vessels, possibly with phlebitis.  She appeared to need thyroid hormone as + well as larger amounts of progesterone, but never found a physician who would cooperate, as far + as I know. +
+
+ In the late 1970s I was seeing a lot of people who had puzzling health problems.  In a period + of two or three years, there were five people who had been diagnosed by neurologists as having + multiple sclerosis.  In talking to them, it seemed clear that they had multiple symptoms of + hypothyroidism.   They weren't severely disabled.  Since they weren't fat or + lethargic, their physicians hadn't thought they could be hypothyroid.  When they tried + taking a thyroid supplement, all of their symptoms disappeared, including those that had led to + their MS diagnosis.  One of the women went to her doctor to tell him that she felt + perfectly healthy since taking thyroid, and he told her to stop taking it, because people who + have MS need a lot of rest, and she wouldn't get enough rest if she was living in a normally + active way. The assumption seemed to be that the diagnosis was more important than the person. + (When I refer to a "thyroid supplement" I mean one that contains some T3.  Many people + experience "neurological symptoms" when they take thyroxine by itself.  Experimentally, it + has been found to suppress brain respiration, probably by diluting the T3 that was already + present in the brain tissue.)   +
+
+
+ METABOLISM OF THE OLIGODENDROCYTES +
+
+ The rate-regulating step in steroid synthesis involves the entry of cholesterol into the + mitochondria, where the heme-enzyme P-450scc then removes the side-chain of cholesterol  + (by introducing oxygen atoms), to produce pregnenolone.  This enzyme can be poisoned by + carbon monoxide or cyanide, and light can eliminate the poison (15); this could be one aspect of + the winter-sickness problem.   +
+
+
+ Peripheral nerves are myelinated by essentially the same sort of cell that is called an + oligodendrocyte in the brain, but outside the brain it is called a Schwann cell.  It is + easier to study the myelin sheath in peripheral nerves, and the electrical activity of a nerve + is the most easily studied aspect of its physiology.  Certain experiments seemed to + indicate a "jumping" (saltatory) kind of conduction along the nerve between Schwann cells, and + it was argued that the insulating function of the myelin sheath made this kind of conduction + possible.  This idea has become a standard item in physiology textbooks, and its + familiarity leads many people to assume that the presence of myelin sheaths in the brain serves + the same "insulating" function. +
+
+ For a long time it has been known that heat production during nerve conduction reveals a more + continuous mode of  conduction, that doesn't conform to the idea of an electrical  + current jumping around an insulator.  Even if the myelin functioned primarily to produce + "saltatory conduction" in peripheral nerves, it isn't clear how this process could function in + the brain.  I think of the issue of "saltatory conduction at the nodes of Ranvier" as + another of the fetish ideas that have served to obstruct progress in biology in the United + States.  A more realistic approach to nerve function can be found in Gilbert Ling's + work.  Ling has demonstrated in many ways that the ruling dogma of "cell membrane" function + isn't coherently based on fact.  He found that hormones such as progesterone regulate the + energetic and structural stability of cells.  Many people, unaware of his work, have felt + that it was necessary to argue against the idea that there are anesthetic steroids with + generalized protective functions, because of their commitment to a textbook dogma of "cell + membrane" physiology. +
+
+ I think the myelinating cells do have relevance to nerve conduction, but I don't think they serve + primarily as electrical insulators.  If the adrenal cortex were inside the heart, it would + be obvious to ask whether its hormones aren't important for the heart's function.  Since + the oligodendrocytes are steroid-synthesizers, it seems obvious to ask whether their production + of pregnenolone in response to stress or fatigue isn't relevant to the conduction processes of + the nerves they surround. +
+
+
+ OLD AGE +
+
+ A biologist friend of mine who was about 85 became very senile.  His wife started giving him + thyroid, progesterone, DHEA and pregnenolone, and within a few days his mental clarity had + returned.  He continued to be mentally active until he was 89, when his wife interfered + with his access to the hormones. +
+
+ In old age the brain steroids fall to about 5% of their level in youth.  Pregnenolone and DHEA + improve memory in old rats, and improve mood stability and mental clarity of old people.  + Pregnenolone's action in improving the sense of being able to cope with challenges probably + reflects a quieting and coordinating of the "sequencing" apparatus of the forebrain, which is + the area most sensitive to energy deprivation.  This is the area that malfunctions in + hyperactive and "dyslexic" children.  Weakening of the sequencing and sorting processes + probably explains the common old-age inability to extract important sounds from environmental + noise, creating a kind of "confusion deafness."  Insomnia, worry and "restless legs" at + bedtime are problems for many old people, and I think they are variations of the basic + energy-depletion problem. +
+
+ The oligodendrocytes were reported (Hiroisi and Lee, 1936) to be the source of the senile plaques + or amyloid deposits of Alzheimer's disease.(16)  Hiroisi and Lee showed the cells in + different stages of degeneration, ending with translucent "mucoid" spots that stained the same + as amyloid, the material in the senile plaques.  This type of cell also appears to form a + halo or crown around degenerating nerve cells--possibly in a protective reaction to provide the + nerve cell  with any pregnenolone the oligodendrocytes are able to make.  The  + oligodendrocytes, the source of the brain steroids (that people previously believed came from + the adrenals and gonads, and were just stored in the brain), myelinate nerve fibers under + the  influence of thyroid hormone (17).  Thyroid is responsible for both myelination + and hormone formation.  In old age, glial cells become more numerous, and nerve cells + become structurally  and functionally abnormal, but usually there is no problem  with + the formation of myelin.  In MS, the problem is just with  myelination, and there are + no senile plaques or defects in the  nerve cells themselves.   +
+
+      These differences suggest the possibility that Alzheimer's  disease involves a + specific premature loss of brain pregnen-  olone production, but not of + thyroid.  Recent work suggests a central role for pregnenolone and progesterone in + the regulation of consciousness (18), and possibly in the brain's detoxifying + system.  Elsewhere, I have suggested that vitamin A deficiency might cause the + excessive production of the "amyloid" protein.  A vitamin A deficiency severely + inhibits steroid synthesis.  (It is used so massively in steroid synthesis that a + progesterone supplement can prevent the symptoms of vitamin A deficiency.)  I + suspect that vitamin A is necessary for the side-chain cleavage that converts + cholesterol to pregnenolone.  Iron-stimulated lipid peroxidation is known to block + steroid formation, and vitamin A is very susceptible to destruction  by iron and + oxidation.  Iron tends to accumulated in tissues  with aging.  Gajdusek + has demonstrated that brain deterioration  is associated with the retention of + whatever metal happens to be abundant in the person's environment, not just with + aluminum.  (One type of glial cell is known for its metal-binding function, causing + them to be called "metallophils.").  According to Gajdusek, "calcium and other di- + and trivalent elements" are "deposited as hydroxyapatites in brain cells" in brain + degeneration of the Alzheimer's type.(19) +
+
+ Even early forms of Alzheimer's disease begin at an age  when the youth-associated steroids + have begun to decline. If  MS involves a deficiency of thyroid (or of T3 within the + oligodendrocytes, where T3 normally can be made from thyroxine; many things, including protein + deficiency, can block the conversion of T4 to T3), those cells would necessarily be deficient in + their ability to produce pregenolone, but in  young people the brain would still be + receiving a little pregnenolone, progesterone, and DHEA from the adrenals and gonads.  This + relatively abundant youthful supply of hormones would keep most of the body's organs in good + condition,  and could keep the bodies of the major brain cells from deteriorating. But if + proper functioning of the nerve fibers requires that they be fed a relatively high concentration + of pregnenolone from their immediately adjacent neighbors (with the amount increasing during + stress and fatigue), then their function would be impaired when they had to depend on the + hormones that arrived from the blood stream. +
+
+
+ For many years it has been recognized that the brain atrophy of "Alzheimer's disease" resembles the + changes seen in the brain in many other situations:  The traumatic dementia of boxers; + toxic dementia; the slow-virus diseases; exposure of the brain to x-rays (20); ordinary old age; + and in people with Down's syndrome who die around the age of thirty.        +     +
+
+ In menopause, certain nerve cells have lost their ability to regulate the ovaries, because of + prolonged exposure to estrogen (6).  The cells that fail as a result of prolonged estrogen + exposure aren't the same cells that fail from prolonged exposure to the glucocorticoids (7), but + they have in common the factor of excitatory injury. +
+
+ Since people who experience premature menopause are known to be more likely than average to die + prematurely, it is reasonable to view menopause as a model of the aging process. It is now well + established that progesterone fails to be produced at the onset of menopause (the first missed + period, increased loss of calcium, symptoms such as hot flashes, etc.), and that estrogen + continues to be produced at monthly intervals for about four years.  The essential question + for aging, in the present context, is why the anesthetic steroids are no longer produced at a + rate that allows them to protect tissues, including brain cells, from the excitotoxins.  + Using menopause as a model for aging, we can make the question more answerable by asking why + progesterone stops being produced. +
+
+ During stress, we are designed not to get pregnant, and the simplest aspect of this is that ACTH, + besides stimulating the adrenals to produce stress-related hormones, inhibits the production of + progesterone by the ovary.  Other stress-induced factors, such as increased prolactin and + decreased thyroid, also inhibit progesterone production.  Stress eventually makes us more + susceptible to stress.  Menopause and other landmarks of aging simply represent upward + inflections in the rate-of-aging curve.  Individual variations in type of stress, hormonal + response and diet, etc., probably govern the nature of the aging process in an individual. +
+
+
+ The amphetamine-like action of estrogen, which undoubtedly  contributes to the general level + of stress and excitotoxic  abuse of nerve cells, is probably the only "useful" facet + of  estrogen treatment, but a little cocaine might achieve the  same effect with no + more harm, possibly less.  The toxicity of catecholamines has been known for over thirty + years, and estrogen's stimulating effects are partly the result of its conversion to + catechol-estrogens which increase the activity of brain catecholamines.  Estrogen's + powerful ability to nullify learning seems never to be mentioned by the people who promote its + use.  The importance of a good balance of brain steroids for mood, attention, memory, and + reasoning is starting to be recognized, but powerful economic forces militate against its + general acceptance. +
+
+ Since the brain is the organ that can allow us to adapt without undergoing stress in the hormonal + sense, it is very important to protect its flexibility and to keep its energy level high, so it + can work in a relaxed way.  It is the low energy cellular state that leads to the retention + of calcium and iron, and to the production of age pigment, and other changes that constitute the + vicious circle of aging.  And mental activity that challenges obsession and rigidity might + be the most important brain energizer.  Pseudo-optimism, humor-as-therapy, has a certain + value, but a deeper optimism involves a willingness to assimilate new information and to change + plans accordingly. +
+
+
+ SUPPLEMENTS +
+
+ Nutritional supplements that might help to prevent or correct these brain syndromes include: + Vitamin E and  coconut oil; vitamin A; magnesium, sodium; thyroid which  includes T3; + large amounts of animal protein, especially  eggs; sulfur, such as magnesium sulfate or + flowers of  sulfur, but not to take continuously, because of sulfur's interference with + copper absorption; pregnenolone; progesterone if needed.  Bright light, weak in the blue + end of the spectrum and with protection against ultraviolet, activates respiratory metabolism + and quenches free radicals.  Raw carrot fiber and/or laxatives if needed; charcoal + occasionally for gas or bowel  irritation.  Coconut oil serves several purposes.  + Its butyric acid is known to increase T3 uptake by glial cells.  It has a general + pro-thyroid action, for example by diluting and displacing antithyroid unsaturated oils, its + short- and medium-chain fatty acids sustain blood sugar and have antiallergic actions, and it + protects mitochondria against stressinjury.  +
+
+ P.S.:  In 1979, a woman whose husband was suffering from advanced Amyotrophic Lateral + Sclerosis (ALS) asked me if I had any ideas for slowing his decline.  I described my + suspicion that ALS involved defective metabolism or regulation of testosterone.  In some + tissues, testosterone is selectively concentrated to prevent atrophy, and ALS is a disease of + middle-age, when hormone regulation often becomes a special problem.  In the late 1970s, + there was discussion of a higher incidence of ALS in males, and especially in athletes.  I + told her about progesterone's general protective effects, its antagonism to testosterone, and + its prevention of atrophy in various tissues.  She decided to ask her doctor to try + progesterone for her husband.  Later, I learned that her husband had gone into a very rapid + decline immediately after the injection, and died within a week; the physician had given him + testosterone, since, he said, "testosterone and progesterone are both male hormones."  + Besides making me more aware of the problems patients have in communicating with physicians, + this tended to reinforce my feeling that a hormone imbalance is involved in ALS.  Although + I haven't written much about testosterone's toxicity, Marian Diamond's work showed that prenatal + testosterone is similar to prenatal estrogen, in causing decreased thickness of the cortex of + the brain; both of those hormones oppose progesterone's brain-protecting and brain-promoting + actions. +
+
+
+

REFERENCES

 +
+
+ 1)  Z. Y. Hu, et al., P.N.A.S. (USA) 84, 8215-9, 1987. +
+
+ 2)  P. F. Hall, Vitamins and Hormones 42, 315-370, 1985. +
+
+ 3)  J. J. Lambert, et al., Trends in Pharmac. Sci. 8, 224-7, 1987. +
+
+ 4)  W. A. D. A. Anderson, Pathology (second edition), C. V. Mosby, St. Louis, 1953. +
+
+ 5)  S. S. Smith, et al., Brain Res. 422, 52-62, 1987. +
+
+ 6)  P. M. Wise, Menopause, 1984; S. S. Smith, et al., Brain Res. 422, 40-51, 1987. +
+
+ 7)  R. M. Sapolsky, et al., J. Neuroscience 5, 1222-1227, 1985; R. M. Sapolsky and W. + Pulsinelli, Science 229, 1397-9, 1985. +
+
+ 8)  C. B. Nemeroff, (Excitotoxins)  290-305, 1984. +
+
+ 9)  G. B. Phillips, Lancet 2, 14-18, 1976; G. B. Phillips, et al., Am. J. Med. 74, 863-9, + 1983; M. H. Luria, et al., Arch Intern Med 142, 42-44, 1982; E. L. Klaiber, et al., Am J Med 73, + 872-881, 1982. +
+
+ 10)  J. I. Mann, et al., Br Med J 2, 241-5, 1975. +
+
+ 11)  V. Gisclard and P. M. Vanhoutte, Physiologist 28, 324(48.1). +
+
+ 12)  W. A. D. A. Anderson, Pathology, 1953; H. H. Reese, et al.,  editors, 1936 Yearbook + of Neurology, Psychiatry, and Endocrinology,  Yearbook Publishers, Chicago, 1937.  +   +
+
+ 13)  T. J. Putnam, Ann Int Med 9, 854-63, 1936; JAMA 108, 1477, 1937. +
+
+ 14)  R. S. Dow and G. Berglund, Arch Neurol and Psychiatry 47, 1, 1992. +
+
+ 15)  R. W. Estabrook, et al., Biochem Z. 338, 741-55, 1963. +
+
+ 16)  S. Hiroisi and C. C. Lee, Arch Neurol and Psychiat 35, 827-38, 1936. +
+
+ 17)  J. M. Matthieu, et al., Ann Endoc. 1974. +
+
+ 18)  K. Iwaharhi, et al., J Ster Biochem and Mol Biol 44(2), 163-4, 1993. +
+
+ 19)  D. C. Gajdusek, Chapter 63, page 1519 in Virology (B. N. Fields, et al., editors), Raven + Press, N.Y., 1985. +
+
+ 20)  K. Lowenberg-Scharenberg and R. C. Bassett, J Neuropath and Exper Neurol 9, 93, + 1950. +
+
+
+ GLOSSARY   +
+
+ 1.  Amyloid is the old term for the "starchy" appearing (including the way it stains) proteins + seen in various diseases, and in the brain in Alzheimer's disease. +
+
+ 2.  Cytochrome P450scc.  The cytochromes are "pigments," in the same sense that they + contain the colored "heme" group that gives hemoglobin its color.  P450 means "protein that + absorbs light at a wavelength of 450.  The scc means "side-chain cleaving," which refers to + the removal of the 6 carbon atoms that distinguish cholesterol from pregnenolone. Other Cyt P450 + enzymes are important for their detoxifying oxidizing action, and some of these are involved in + brain metabolism. +
+
+ 3.  Glial means "glue-like," and glial cells are mostly spidery-shaped cells that used to be + thought of as just connective, supportive cells in the brain. +
+
+ 4.  Mitochondria (the "thread-like bodies") are the structures in cells which produce most of + our metabolic energy by respiration, in response to the thyroid hormones. +
+
+ 5.  Mucoid--refers to a mucoprotein, a protein which contains some carbohydrate.  A + glycoprotein; usually not intended as a precise term. +
+
+ 6.  Myelination.  Myelin is a multilayered enclosure of the axons (the long processes) of + nerve cells, composed of proteins and complex lipids, including cholesterol.  The layered + material is a flat, thin extension of the cytoplasm of the oligodendroglial cells. +
+
+ 7.  Oligodendrocytes are one of the kinds of glial (or neuroglial) cells, and structurally + they are unusual in having sheet-like, rather than just thread-like processes; they have a + sensitivity ("receptors") to stress and valium, and produce pregnenolone when activated.  + Under the influence of thyroid hormone, they wrap themselves in thin layers around the + conductive parts of nerve cells, leaving a multilayered "myelin" coating.  Their absorption + of thyroid hormone is promoted by butyrate, an anti-stress substance found in butter and coconut + oil. +
+
+ 8.  Steroidogenesis is the creation of steroids, usually referring to the conversion of + cholesterol to hormones. +
+

 

+ + © Ray Peat Ph.D. 2013. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/natural-estrogens.html b/raypeat-articles/processed/natural-estrogens.html new file mode 100644 index 0000000..856d33d --- /dev/null +++ b/raypeat-articles/processed/natural-estrogens.html @@ -0,0 +1,863 @@ + + Natural Estrogens + +

+ Natural Estrogens +

+ +

+ The fact that an extremely large number of naturally occurring compounds, and an unlimited number of + synthetic compounds, have an estrogen-like activity has been exploited by the drug companies to produce + patented proprietary drugs, especially the contraceptives. +

+

+ The promotion of "natural estrogens" is a new marketing strategy that capitalizes on the immense promotional + investment of the drug companies in the concept of estrogen replacement as "therapy." +

+

+

+

+

+ "Whether weak or strong, the estrogenic response of a chemical, if not overcome, will add extra + estrogenic burden to the system. At elevated doses, natural estrogens and environmental estrogen-like + chemicals are known to produce adverse effects. The source of extra or elevated concentration of + estrogen could be either endogenous or exogenous. The potential of exposure for humans and + animals to environmental estrogen-like chemicals is high." +

+ +

D. Roy, et al., 1997

+

+

+
+

+

+ Estrogen marketing has entered a new phase, based on the idea of "specific estrogen-receptor modulators," + the idea that a molecule can be designed which has estrogen's "good qualities without its bad qualities." + This specific molecule will be "good for the bones, the heart, and the brain," without causing cancer of the + breast and uterus, according to the estrogen industry. Meanwhile, soybeans are said to contain estrogens + that meet that goal, and it is often said that "natural estrogens" are better than "synthetic estrogens" + because they are "balanced." +

+

+ Estrogen's effects on cells are immediate and profound, independent of the "estrogen receptors." +

+ +

+ Japanese women's relative freedom from breast cancer is independent of soy products: + traditional soy foods aren't the same as those so widely used in the US, for example, soy sauce doesn't + contain the so-called soy estrogens, and tea is used much more commonly in Japan than in the US, and + contains health protective ingredients. The "estrogenic" and "antioxidant" polyphenolic compounds of tea are + not the protective agents (they raise the level of estrogen), but tea's caffeine is a very powerful + and general anti-cancer protectant. The influential article in + Lancet (D. Ingram, Lancet 1997;350:990-994. "Phytoestrogens and their role in + breast cancer," + Breast NEWS: Newsletter of the NHMRC National Breast Cancer Centre, Vol. 3, No. 2, Winter 1997) + used a method known to produce false results, namely, comparing the phytoestrogens (found in large amounts + in soybeans) in the urine of women with or without breast cancer. For over fifty years, it has been known + that the liver excretes estrogens and other toxins from the body, and that when (because of liver inertia) + estrogen isn't excreted by the liver and kidneys, it is retained in the body. This process was observed in + both animals and humans decades ago, and it is also well established that estrogen itself suppresses the + detoxifying systems, causing fewer carcinogens to be excreted in the urine. Ingram's evidence + logically would suggest that the women who have cancer are failing to eliminate estrogens, including + phytoestrogens, at a normal rate, and so are retaining a higher percentage of the chemicals consumed in + their diets. Flavonoids and polyphenols, like our own estrogens, suppress the detoxifying systems of the + body. +

+ +

+ Our bodies produce estrogen in a great variety of tissues, not just in the ovaries. Fat cells are a major + source of it. The tendency to gain weight after puberty is one of the reasons that women's estrogen levels + rise with aging throughout the reproductive years, though this isn't the basic reason for estrogen's + lifelong growing influence, even in men. +

+

+ Our diets provide very significant, if not always dangerous, amounts of estrogen. "Weak estrogens" generally + have the full range of harmful estrogenic effects, and often have additional toxic effects. American women + who eat soy products undergo changes that appear to predispose them to cancer, making their tissues even + more unlike those of the relatively breast-cancer resistant Japanese than they were before eating the soy + foods. +

+

+ People under stress, or who have a thyroid deficiency, or who don't eat enough protein, typically have + elevated estrogen levels. The accumulation of the "essential fatty acids," the polyunsaturated oils, in the + tissues promotes the action of estrogen in a variety of ways, and this effect of diet tends to be + cumulative, and to be self-accelerating. +

+ +

+ Science is a method that helps us to avoid believing things that are wrong, but there is a distinct herd + instinct among people who "work in science," which makes it easy to believe whatever sounds plausible, if a + lot of other people are saying it is true. This is just as evident in physics as it is in medicine. + Sometimes powerful economic interests help people to change their beliefs, for example as the insurance + industry helped to convince the public of the dangers of smoking. Two of the biggest industries in the + world, the estrogen industry and the soy bean industry, spend vast amounts of money helping people to + believe certain plausible-sounding things that help them sell their products. Sometimes they can achieve + great things just by naming the substance. +

+

+ Estrogenicity can be defined most simply as "acting the way estrogen does," (originally, the term "estrogen" + meant "producing estrus," the female readiness to mate) and since our natural estrogen does many things, the + definition is often, for practicality, based on the rapid changes produced in certain female organs by + estradiol, specifically, the enlargement of the uterus by first taking up a large amount of water, and + secondarily by the multiplication of cells and the production of specific proteins. A similar process + occurring in the breast is also recognized as an important feature of the estrogen reaction, but as we try + to define just what "estrogenicity" is, we see that there is something deeply wrong with this method of + defining a hormone, because we are constantly learning more about the actions of estrogen, or of a specific + form of the molecule. Calling it "the female hormone" distracted attention from its many functions in the + male, and led to great confusion about its antifertility actions and its other toxicities. Many biologists + called it "folliculin," because of the ovarian follicle's significant role in its production, but the + pharmaceutical industry succeeded in naming it in relation to + one of its functions, and then in extending that idea of it as "the producer of female + receptivity" to the even more misleading idea that it is "the female hormone." But when people speak about + the "estrogenicity" of a substance, they mean that it has properties that parallel those of "folliculin," + the particular group of ovarian hormones that includes estradiol, estrone, and estriol. +

+

+ Over the last 100 years, thousands of publications about estrogen's toxicity have created a slight + resistance to the consumption of the major estrogen products. One ploy to overcoming this resistance is to + call certain products "natural estrogen," as distinguished from "synthetic estrogens." The three + main estrogens in our bodies are estradiol, estrone, and estriol, though there are many other minor + variants on the basic molecule. These three estrogens, singly or in combinations, are being + sold as natural estrogens, with their virtues explained in various ways. Implicit in many of these + explanations, is the idea that these are safer than synthetics. They are sometimes contrasted to the "horse + estrogen" in Premarin, as if they are better because they are like the estrogens that people produce. But it + was exactly the normal human estrogens, produced by the ovaries, that led to the basic discoveries about the + toxicity of estrogen, its ability to produce cancer in any organ, to cause seizures, blood clots, birth + defects, accelerated aging, etc. +

+ +

+ Although I would suppose that a hormone from a horse might be "more natural" for a person's body than a + hormone from a plant, the word "natural" as used in the phrases "natural food store," or "natural medicine," + has come to be associated strongly with things derived from plants. The health food industry, now largely + taken over by giant corporations to sell products that weren't producing as much revenue when sold in + supermarkets and drugstores, has helped to create a culture in which botanical products are thought to be + especially good and safe. Naturally grown free-range chickens used to be favored, because they could eat + anything they wanted, but now eggs laid by factory chickens, eating an industrial corn-and-soy diet, are + from "vegetarian chickens," because the marketers know the public will favor eggs that have the vegetarian + mystique. +

+

+ Biologically active molecules have both general and specific properties. Estrogenicity is a general + property, but all molecules which have that property also have some other specific properties. Estriol is a + little more water soluble than estrone, so it interacts with every body system in a slightly different way, + entering oily environments with slightly less ease, etc. +

+

+ The estrogen which occurs in yeasts, estradiol, is identical to the major human estrogen, and it is thought + to have a reproductive function in yeasts, though this isn't really understood. A feature of this molecule, + and of all other molecules that "act like estrogen," is the phenolic function, an oxygen and hydrogen group + attached to a resonant benzene ring. Phenol itself is estrogenic, and the phenolic group is so extremely + common in nature that the number of existing estrogenic substances is great, and the number of potential + molecules with estrogen-function is practically infinite. +

+

+ The phenolic group has many biological functions. For example, it commonly functions as an "antioxidant," + though something which functions as an antioxidant in one situation is often a pro-oxidant in another + situation. The molecule can have catalytic, germicidal, aromatic, neurotropic, and other functions. But it + also always has, to some degree, the "estrogenic" function. This overlap of functions probably accounts for + why so many plants have significant estrogenic activity. (Natural estrogens, like other phenolics, including + the flavonoids, are also mutagenic.) +

+ +

+ The estrogenic properties of legumes were studied when sheep farmers found that their sheep miscarried when + they ate clover. (I think it's interesting how this terribly toxic effect has been neglected in recent + decades.) All legumes have this property, and all parts of the plant seem to contain some of the active + chemicals. In beans, several substances have been found to contribute to the effect. The estrogenic effects + of the seed oils and the isoflavones have been studied the most, but the well-known antithyroid actions + (again, involving the oils, the isoflavones, and other molecules found in legumes) have an indirect + estrogen-promoting action, since hypothyroidism leads to hyperestrogenism. (Estrogens are known to be + thyroid suppressors, so the problem tends to be self-accelerating.) +

+

+ The various specific actions of the many estrogenic substances in beans and other legumes haven't been + throughly studied, but there is evidence that they are also--like estrogen itself--both mutagenic and + carcinogenic. +

+

+ The estrogen-promoting actions of soy oil apply to all of the commonly used polyunsaturated fatty + acids. The same fatty acids that suppress thyroid function, have estrogenic effects. +

+ +

+ The isoflavones (many of which are now being promoted as "antioxidants" and "cancer preventives") are toxic + to many organs, but they have clear estrogenic effects, and are active not only immediately in the mature + individual, but when they are present prenatally, they cause feminization of the male genitalia and + behavior, and early maturation of the female offspring, with the tissue changes that are known to be + associated with increased incidence of cancer. +

+

+ There are interesting associations between vegetable "fiber" and estrogens. Because of my own experience in + finding that eating a raw carrot daily prevented my migraines, I began to suspect that the carrot fiber was + having both a bowel-protective and an antiestrogen effect. Several women who suffered from premenstrual + symptoms, including migraine, had their serum estrogen measured before and after the "carrot diet," and they + found that the carrot lowered their estrogen within a few days, as it relieved their symptoms. +

+

+ Undigestible fiber, if it isn't broken down by bowel bacteria, increases fecal bulk, and tends to speed the + transit of material through the intestine, just as laxatives do. But some of these "fiber" materials, e.g., + lignin, are themselves estrogenic, and other fibers, by promoting bacterial growth, can promote the + conversion of harmless substances into toxins and carcinogens. When there is a clear "antiestrogen" effect + from dietary fiber, it seems to be the result of accelerated transit through the intestine, speeding + elimination and preventing reabsorption of the estrogen which has been excreted in the bile. Laxatives have + this same effect on the excretion of estradiol. +

+

+ Some of the isoflavones, lignins, and other phytoestrogens are said to prevent bowel cancer, but some of + them, e.g., lignin, appear to sometimes increase its likelihood. +

+ +

+ The phytoestrogens appear to pose a risk to organs besides the breast and uterus, for example the liver, + colon, and pancreas, which isn't surprising, since estrogen is known to be carcinogenic for every tissue. + And carcinogenesis, like precancerous changes, mutations, and reduced repair of DNA, is probably just an + incidental process in the more general toxic effect of acceleration of aging. +

+

REFERENCES & ABSTRACTS

+

+ "Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal + women," Petrakis NL; Barnes S; King EB; Lowenstein J; Wiencke J; Lee MM; Miike R; Kirk M; + Coward L Department of Epidemiology and Biostatistics, University of California, San Francisco 94143-0560, + USA. Cancer Epidemiol Biomarkers Prev, 1996 Oct, 5:10, 785-94 "Soy foods have been reported to have + protective effects against premenopausal breast cancer in Asian women. No studies have been reported on + potential physiological effects of dietary soy consumption on breast gland function. We evaluated the + influence of the long-term ingestion of a commercial soy protein isolate on breast secretory activity. We + hypothesized that the features of nipple aspirate fluid (NAF) of non-Asian women would be altered so as to + resemble those previously found in Asian women. At monthly intervals for 1 year, 24 normal pre- and + postmenopausal white women, ages 30 to 58, underwent nipple aspiration of breast fluid and gave blood and + 24-h urine samples for biochemical studies. No soy was administered in months 1-3 and 10-12. Between months + 4-9 the women ingested daily 38 g of soy protein isolate containing 38 mg of genistein. NAF volume, gross cystic disease fluid protein (GCDFP-15) concentration, and NAF cytology were used as + biomarkers of possible effects of soy protein isolate on the breast. In addition, plasma concentrations of + estradiol, progesterone, sex hormone binding globulin, prolactin, cholesterol, high density + lipoprotein-cholesterol, and triglycerides were measured. Compliance was assessed by measurements of + genistein and daidzein and their metabolites in 24-h urine samples. Excellent compliance with the study + protocol was obtained. Compared with NAF volumes obtained in months 1-3, a 2-6-fold increase in NAF + volume ensued during months 4-9 in all premenopausal women. A minimal increase or no response + was found in postmenopausal women. No changes were found in plasma prolactin, sex hormone binding globulin, + cholesterol, high density lipoprotein cholesterol, and triglyceride concentrations. Compared with + concentrations found in months 1-3 (no soy), plasma estradiol concentrations were elevated + erratically throughout + + + a "composite" menstrual cycle during the months of soy consumption. No significant changes were seen in + plasma progesterone concentrations. No significant changes were found in plasma estrogen levels in + postmenopausal women. A moderate decrease occurred in the mean concentration of GCDFP-15 in NAF in + premenopausal women during the months of soy ingestion. + Of potential concern was the cytological detection of epithelial hyperplasia in 7 of 24 women + (29.2%) during the months they were consuming soy protein isolate. The findings did not support our + a priori hypothesis. Instead, this pilot study indicates that prolonged consumption of soy protein + isolate has a stimulatory effect on the premenopausal female breast, characterized by increased + secretion of breast fluid, the appearance of hyperplastic epithelial cells, and elevated levels + of plasma estradiol. + These findings are suggestive of an estrogenic stimulus from the isoflavones genistein and daidzein + contained in soy protein isolate. +

+

+ J Clin Endocrinol Metab 1995 May;80(5):1685-1690 Dietary intervention study to assess estrogenicity + of dietary soy among postmenopausal women. Baird DD, Umbach DM, Lansdell L, Hughes CL, Setchell + KD, Weinberg CR, Haney AF, Wilcox AJ, Mclachlan JA. National Institute of Environmental Health Sciences, + Research Triangle Park, North Carolina 27709, USA. We tested the hypothesis that postmenopausal women on a + soy-supplemented diet show estrogenic responses. Ninety-seven postmenopausal women were randomized to either + a group that was provided with soy foods for 4 weeks or a control group that was instructed to eat + as usual. Changes in urinary isoflavone concentrations served as a measure of compliance and + phytoestrogen dose. Changes in serum FSH, LH, sex hormone binding globulin, and vaginal cytology were + measured to assess estrogenic response. The percentage of vaginal superficial cells (indicative of + estrogenicity) increased for 19% of those eating the diet compared with 8% of controls +

+

+ +

+ Oncol Rep 1998 May-Jun;5(3):609-16 + "Maternal genistein exposure mimics the effects of estrogen on mammary gland development in female mouse + offspring." Hilakivi-Clarke L, Cho E, Clarke R Lombardi Cancer Center, Research Bldg., Room + W405, Georgetown University, 3970 Reservoir Road, NW, Washington, DC, 20007-2197, USA. Human and + animal data indicate that a high maternal estrogen exposure during pregnancy increases breast cancer + risk among daughters. This may reflect an increase in the epithelial structures that are the + sites for malignant transformation, i.e., terminal end buds (TEBs), and a reduction in epithelial + differentiation in the mammary gland. Some phytoestrogens, such as genistein which is a major + component in soy-based foods, and zearalenone, a mycotoxin found in agricultural products, have + estrogenic effects on the reproductive system, breast and brain. + The present study examined whether in utero exposure to genistein or zearalenone influences mammary + gland development. Pregnant mice were injected daily with i) 20 ng estradiol (E2); ii) 20 microg genistein; + iii) 2 microg zearalenone; iv) 2 microg tamoxifen (TAM), a partial estrogen receptor agonist; or v) + oil-vehicle between days 15 and 20 of gestation. E2, genistein, zearalenone, and tamoxifen all + increased the density of TEBs in the mammary glands. Genistein reduced, and zearalenone increased, + epithelial differentiation. Zearalenone also increased epithelial density, when compared with + the vehicle-controls. None of the treatments had permanent effects on circulating E2 levels. + Maternal exposure to E2 accelerated body weight gain, physical maturation (eyelid opening), and puberty + onset (vaginal opening) in the female offspring. Genistein and tamoxifen had similar effects on puberty + onset than E2. Zearalenone caused persistent cornification of the estrus smears. These findings + indicate that maternal exposure to physiological doses of genistein mimics the effects of E2 on the + mammary gland and reproductive systems in the offspring. Thus, our results suggest that genistein acts + as an estrogen in utero, and may increase the incidence of mammary tumors if given through a pregnant + mother. + + + The estrogenic effects of zearalenone on the mammary gland, in contrast, are probably counteracted by the + permanent changes in estrus cycling. +

+

+ [The effects on the thyroid gland of soybeans administered experimentally in healthy + subjects] + Ishizuki Y; Hirooka Y; Murata Y; Togashi K Nippon Naibunpi Gakkai Zasshi, 1991 May 20, 67:5, 622-9 To + elucidate whether soybeans would suppress the thyroid function in healthy adults, we selected 37 subjects + who had never had goiters or serum antithyroid antibodies. They were given 30g of soybeans everyday and were + divided into 3 groups subject to age and duration of soybean administration. In group 1, 20 subjects were + given soybeans for 1 month. Groups 2 and 3 were composed of 7 younger subjects (mean 29 y.o.) and 10 elder + subjects (mean 61 y.o.) respectively, and the subjects belonging to these groups received soybeans for 3 + months. The Wilcoxon-test and t-test were used in the statistical analyses. In all groups, the various + parameters of serum thyroid hormones remained unchanged by taking soybeans, however TSH levels rose + significantly although they stayed within normal ranges. The TSH response after TRH stimulation in group 3 + revealed a more significant increase than that in group 2, although inorganic iodide levels were lowered + during the administration of the soybeans. We have not obtained any significant correlation between serum + inorganic iodide and TSH. Hypometabolic symptoms (malaise, constipation, sleepiness) and goiters appeared in + half the subjects in groups 2 and 3 after taking soybeans for 3 months, but they disappeared 1 month after + the cessation of soybean ingestion. These findings suggested that excessive soybean ingestion for a certain + duration might suppress thyroid function and cause goiters in healthy people, especially elderly subjects. +

+

+ Exp Clin Endocrinol Diabetes 1996;104 Suppl 4:41-5 Iodolactones and iodoaldehydes--mediators of + iodine in thyroid autoregulation. Dugrillon A Central Clinical Laboratory, University of + Heidelberg, Germany. "Within the last decades multiple iodolipid-classes have been identified in thyroid + tissue. For a long time they have been supposed to be involved in thyroid autoregulation, but for the time + being no specific compounds could be isolated. A new approach was stimulated by the finding that thyroid cells were able to iodinate polyunsaturated fatty acids to form iodolactones and by the + identification of alpha-iodohexadecanal (alpha-IHDA) as the major compound of an iodolipid fraction." +

+ +

+ Plasma free fatty acids, inhibitor of extrathyroidal conversion of T4 to T3 and thyroid hormone + binding inhibitor in patients with various nonthyroidal illnesses. + Suzuki Y; Nanno M; Gemma R; Yoshimi T Endocrinol Jpn, 1992 Oct, 39:5, 445-53. +

+

+ [Endemic goiter in Austria. Is iodine deficiency the primary cause of goiter?] + Grubeck-Loebenstein B; Kletter K; Kiss A; Vierhapper H; Waldh"usl W Schweiz Med Wochenschr, 1982 Oct 30, + 112:44, 1526-30 + In spite of government-regulated iodide admixture to table salt, the incidence of goiter is still high + in Austria. + Iodine excretion and thyroid function were therefore investigated in 80 patients suffering from ordinary + goiter in whom thyroid size and resulting symptoms had increased lately. 25 euthyroid non-goitrous subjects + served as controls. 48% of the goitrous patients investigated presented with iodine excretion of less than + 70 micrograms/24 h, suggesting an insufficient iodine supply. Thyroid I131 uptake, basal and TRH-stimulated + plasma TSH concentrations, and serum T3 levels were higher, whereas serum T4 levels were lower in these + patients than in goitrous patients with higher iodine excretion and non-goitrous controls. Iodine deficiency + thus appears to be of pathogenetic relevance in about half of the goitrous Austrian population. Other factors enhancing goiter development seem to assume particular importance in goitrous patients with a + sufficient iodine supply. +

+

+ Biochemical and molecular changes at the cellular level in response to exposure to environmental + estrogen-like chemicals. Roy D; Palangat M; Chen CW; Thomas RD; Colerangle J; Atkinson A; Yan + ZJ Environmental Toxicology Program, University of Alabama, Birmingham 35294, USA. J Toxicol Environ Health, + 1997 Jan, 50:1, 1-29. Estrogen-like chemicals are unique compared to nonestrogenic xenobiotics, because in + addition to their chemical properties, the estrogenic property of these compounds allows them to act like + sex hormones. + Whether weak or strong, the estrogenic response of a chemical, if not overcome, will add extra + estrogenic burden to the system. At elevated doses, natural estrogens and environmental estrogen-like + chemicals are known to produce adverse effects. The source of extra or elevated concentration of + estrogen could be either endogenous or exogenous. The potential of exposure for humans and + animals to environmental estrogen-like chemicals is high. Only a limited number of estrogen-like compounds, + such as diethylstilbestrol (DES), bisphenol A, nonylphenol, polychlorinated biphenyls (PCBs), and + dichlorodiphenyltrichloroethane (DDT), have been used to assess the biochemical and molecular changes at the + cellular level. Among them, DES is the most extensively studied estrogen-like chemical, and therefore this + article is focused mainly on DES-related observations. In addition to estrogenic effects, environmental + estrogen-like chemicals produce multiple and multitype genetic and/or nongenetic hits. + Exposure of Syrian hamsters to stilbene estrogen (DES) produces several changes in the nuclei of target + organ for carcinogenesis (kidney): (1) Products of nuclear redox reactions of DES modify transcription + regulating proteins and DNA; (2) transcription is inhibited; (3) tyrosine phosphorylation of nuclear + proteins, including RNA polymerase II, p53, and nuclear insulin-like growth factor-1 receptor, is altered; + and (4) DNA repair gene DNA polymerase beta transcripts are decreased and mutated. Exposure + of Noble rats to DES also produces several changes in the mammary gland: proliferative activity is + drastically altered; the cell cycle of mammary epithelial cells is perturbed; telomeric length is + attenuated; etc. It appears that some other estrogenic compounds, such as bisphenol A and nonylphenol, may + also follow a similar pattern of effects to DES, because we have recently shown that these compounds alter cell cycle kinetics, produce telomeric associations, and produce chromosomal aberrations. + + + Like DES, bisphenol A after metabolic activation is capable of binding to DNA. However, it should be noted + that a particular or multitype hit(s) will depend upon the nature of the environmental estrogen-like + chemical. The role of individual attack leading to a particular change is not clear at this stage. + Consequences of these multitypes of attack on the nuclei of cells could be (1) nuclear toxicity/cell death; + (2) repair of all the hits and then acting as normal cells; or (3) sustaining most of the hits and acting as + unstable cells. Proliferation of the last type of cell is expected to result in transformed cells. +

+

+ Potential adverse effects of phytoestrogens. Whitten PL; Lewis C; Russell E; Naftolin F + Department of Anthropology, Emory University, Atlanta, GA 30322. J Nutr, 1995 Mar, 125:3 Suppl, 771S-776S + Evaluation of the potential benefits and risks offered by naturally occurring plant estrogens requires + investigation of their potency and sites of action when consumed at natural dietary concentrations. Our + investigations have examined the effects of a range of natural dietary concentrations of the most potent + plant isoflavonoid, coumestrol, using a rat model and a variety of estrogen-dependent tissues and endpoints. + Treatments of immature + females demonstrated agonistic action in the reproductive tract, brain, and pituitary at natural dietary + concentrations. Experiments designed to test for estrogen antagonism demonstrated that coumestrol did + not conform to the picture of a classic antiestrogen. + + However, coumestrol did suppress estrous cycles in adult females. Developmental actions were examined by + neonatal exposure of pups through milk of rat dams fed a coumestrol, control, or commercial soy-based diet + during the critical period of the first 10 postnatal days or throughout the 21 days of lactation. The 10-day + treatment did not significantly alter adult estrous cyclicity, but the 21-day treatment produced in a + persistent estrus state in coumestrol-treated females by 132 days of age. In contrast, the + 10-day coumestrol treatments produced significant deficits in the sexual behavior of male + offspring. These findings illustrate the broad range of actions of these natural estrogens and + the variability in potency across endpoints. This variability argues for the importance of fully + characterizing each phytoestrogen in terms of its sites of action, balance of agonistic and antagonistic + properties, natural potency, and short-term and long-term effects. +

+ +

+ Am J Obstet Gynecol 1987 Aug;157(2):312-317 + Age-related changes in the female hormonal environment during reproductive life. Musey VC, + Collins DC, Musey PI, Martino-Saltzman D, Preedy JR. Previous studies have indicated that serum levels of + follicle-stimulating hormone rise with age during the female reproductive life, but the effect on other + hormones is not clear. We studied the effects of age, independent of pregnancy, by comparing serum hormone + levels in two groups of nulliparous, + premenopausal women aged 18 to 23 and 29 to 40 years. We found that increased age during reproductive + life is accompanied by a significant rise in both basal and stimulated serum follicle-stimulating + hormone levels. This was accompanied by an increase in the serum level of estradiol-17 beta and the + urine levels of estradiol-17 beta and 17 beta-estradiol-17-glucosiduronate. The serum level of + estrone sulfate decreased with age. Serum and urine levels of other estrogens were unchanged. The basal and + stimulated levels of luteinizing hormone were also unchanged. There was a significant decrease in basal and + stimulated serum prolactin levels. Serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate + decreased with age, but serum testosterone was unchanged. It is concluded that significant age-related + changes in the female hormonal environment occur during the reproductive years. +

+

+ Rodriguez, P; Fernandez-Galaz, C; Tejero, A. Controlled neonatal exposure to estrogens: A suitable + tool for reproductive aging studies in the female rat. + Biology of Reproduction, v.49, n.2, (1993): 387-392. The present study was designed to determine whether the + modification of exposure time to large doses of estrogens provided a reliable model for early changes in + reproductive aging. Silastic implants containing estradiol benzoate (EB) in solution were placed into + 5-day-old female Wistar rats and removed 1 day (Ei1 group) or 5 days (Ei5) later. In addition, 100 mu-g EB + dissolved in 100 mu-l corn oil was administered s.c. to another group (EI). Control rats received either + vehicle implants or 100 mu-l corn oil. Premature occurrence of vaginal opening was observed in all three + estrogenized groups independently of EB exposure. However, females bearing implants for 24 h had first + estrus at the same age as their controls and cycled regularly, and neither histological nor gonadal + alterations could be observed at 75 days.. Interestingly, they failed to cycle regularly at 5 mo whereas + controls continued to cycle. On the other hand, the increase of EB exposure (Ei5, EI) resulted in a gradual + and significant delay in the onset of first estrus and in a high number of estrous phases, as frequently + observed during reproductive decline. At 75 days, the ovaries of these last two groups showed a reduced + number of corpora lutea and an increased number of large follicles. According to this histological pattern, + ovarian weight and progesterone (P) content gradually decreased whereas both groups showed higher + estradiol (E-2) content than controls. This resulted in a higher E-2:P ratio, + comparable to that observed in normal aging rats. The results allow us to conclude that the + exposure time to large doses of estrogens is critical to the gradual enhancement of reproductive decline. + Furthermore, exposures as brief as 24 h led to a potential early model for aging studies that will be useful + to verify whether neuroendocrine changes precede gonadal impairment. +

+ +

+ Cancer Lett 1992 Oct 30;67(1):55-59 + Evidence of hypothalamic involvement in the mechanism of transplacental carcinogenesis by + diethylstilbestrol. Smith DA, Walker BE Anatomy Department, Michigan State University, East + Lansing 48824-1316. Disruption of hypothalamic sex differentiation in the fetus is one hypothesis to explain + female reproductive system anomalies and cancer arising from prenatal exposure to diethylstilbestrol (DES). + To further test this hypothesis, breeding performance and behavior were monitored in a colony of mice + exposed prenatally to DES, using a schedule previously shown to produce anomalies and cancer of the female + reproductive system. + Fertility decreased with age more rapidly in DES-exposed females than in control females. + DES-exposed females were less accepting of the male than control females. These observations support the + hypothesis of abnormal hypothalamic sex differentiation as a basic mechanism in DES transplacental + carcinogenesis. +

+

+ Int J Cancer 1980 Aug;26(2):241-6 + The influence of the lipid composition of the feed given to mice on the immunocompetence and tumour + resistance of the progeny. + Boeryd B, Hallgren B. In inbred CBA mice, the immunocompetence of adult progeny from breeding pairs fed + three different diets was compared. + Substitution of soy oil for animal fat in the feed of the mice during gestation or lactation + significantly decreased the PFC response to SRBC in the adult offspring. Addition of + 2-methoxy-substituted glycerol ethers to the feed of mothers deprived of animal fat during lactation partly + restored the PFC response of the male offspring. In the adult mice fed differently pre- and perinatally the + resistance to a transplanted syngeneic sarcoma was similar. The growth of offspring from mice fed the three + diets was similar. In mice deprived of animal fat at weaning and for the following 21 days the immune + reactivity to SRBC, tested about 3 months after stopping the diet, was not influenced. However, the + resistance to a transplanted tumour in similarly fed mice was increased and this resistance was brought + approximately to the control level by methoxy-substituted glycerol ethers. +

+ +

+ Cancer Res 1987 Mar 1;47(5):1333-8. + Effects of dietary fats and soybean protein on azaserine-induced pancreatic carcinogenesis and plasma + cholecystokinin in the rat. Roebuck BD, Kaplita PV, Edwards BR, Praissman M + Both dietary unsaturated fat and raw soybean products are known to enhance pancreatic carcinogenesis + when fed during the postinitiation phase. A comparison of these two dietary components was made + to evaluate the relative potency of each ingredient for enhancing pancreatic carcinogenesis and + to determine if this enhancement was correlated with an increase in plasma cholecystokinin (CCK) levels. + Male Wistar rats were initiated with a single dose of azaserine (30 mg/kg body weight) at 14 days of age. + The rats were weaned to test diets formulated from purified ingredients. Dietary protein at 20% by weight + was either casein or soy protein isolate (heat treated or raw).. Corn oil was the unsaturated fat of major + interest and it was fed at either 5 or 20% by weight. Pancreases were quantitatively evaluated for + carcinogen-induced lesions at 2- and 4-month postinitiation. In a second experiment designed to closely + mimic the above experiment, rats were implanted with cannulae which allowed plasma to be repetitively + sampled over a 2.5-week period during which the test diets were fed. Plasma was collected both prior to + introduction of the test diets and afterwards. Plasma CCK was measured by a specific radioimmunoassay. Both + the 20% corn oil diet and the raw soy protein isolate diet enhanced pancreatic carcinogenesis. The effects + of the raw soy protein isolate on the growth of the carcinogen-induced lesions were significantly greater + than the effects of the 20% corn oil diet. Plasma CCK values were not elevated in the rats fed the 20% corn + oil diet, but they were significantly elevated in the rats fed the raw soy protein isolate. Heat-treated soy + protein isolate neither enhanced carcinogenesis nor elevated the plasma CCK level. This + study demonstrates that certain plant proteins enhance the growth of carcinogen-induced pancreatic foci + and that this effect is considerably greater than the enhancement by high levels of dietary unsaturated + fat. Furthermore, the enhancement by the raw soy protein isolate may be mediated by CCK; but this does + not appear to be the mechanism by which the unsaturated fat, corn oil, enhances pancreatic + carcinogenesis. +

+

+ J Biol Chem 1988 Mar 15;263(8):3639-3645 + Dynamic pattern of estradiol binding to uterine receptors of the rat. + + Inhibition and stimulation by unsaturated fatty acids. Vallette G, Christeff N, Bogard C, + Benassayag C, Nunez E +

+

+ J Biol Chem 1986 Feb 25;261(6):2954-2959 + Modifications of the properties of human sex steroid-binding protein by nonesterified fatty + acids. Martin ME, Vranckx R, Benassayag C, Nunez EA The effect of unsaturated and saturated + nonesterified fatty acids (NEFAs) on the electrophoretic, immunological, and steroid-binding properties of + human sex hormone-binding protein (SBP) were investigated. Tests were carried out on whole serum from + pregnant women and on purified SBP using polyacrylamide gel electrophoresis, crossed immunoelectrophoresis + with autoradiography, and equilibrium dialysis. All three methods showed that NEFAs influence the binding of + sex steroids to SBP both in whole serum and with the purified protein. Saturated NEFAs caused a 1.5-2-fold + increase in binding of + dehydrotestosterone, testosterone, and estradiol to SBP, while unsaturated NEFAs, such as oleic (18:1) + and docosahexaenoic (22:6) acids inhibited the binding of these steroids to SBP. Thus, unsaturated + NEFAs in the concentration range 1-100 microM are more inhibitory for estradiol binding than + for testosterone or dehydrotestosterone binding. In addition to these binding changes, polyacrylamide gel + electrophoresis and immunoelectrophoretic studies revealed a shift in SBP from the slow-moving active native + form to a fast-moving inactive one. There was also a reduction in the apparent SBP concentration by Laurell + immunoelectrophoresis in the presence of unsaturated NEFA (5.5 nmol of NEFA/pmol of protein). These studies + indicate that unsaturated NEFAs induce conformational changes in human SBP which are reflected in its + electrophoretic, immunological, and steroid-binding properties. They suggest that the fatty acid content of + the SBP environment may result in lower steroid hormone binding and thus increased free hormone levels. +

+

+ J Biol Chem 1986 Feb 25;261(6):2954-2959 + Modifications of the properties of human sex steroid-binding protein by nonesterified fatty + acids. Martin ME, Vranckx R, Benassayag C, Nunez EA The effect of unsaturated and saturated + nonesterified fatty acids (NEFAs) on the electrophoretic, immunological, and steroid-binding properties of + human sex hormone-binding protein (SBP) were investigated. Tests were carried out on whole serum from + pregnant women and on purified SBP using polyacrylamide gel electrophoresis, crossed immunoelectrophoresis + with autoradiography, and equilibrium dialysis. All three methods showed that NEFAs influence the binding of + sex steroids to SBP both in whole serum and with the purified protein. Saturated NEFAs caused a 1.5-2-fold + increase in binding of + dehydrotestosterone, testosterone, and estradiol to SBP, while unsaturated NEFAs, such as oleic (18:1) + and docosahexaenoic (22:6) acids inhibited the binding of these steroids to SBP. + + + Thus, unsaturated NEFAs in the concentration range 1-100 microM are more inhibitory for estradiol binding + than for testosterone or dehydrotestosterone binding. In addition to these binding changes, polyacrylamide + gel electrophoresis and immunoelectrophoretic studies revealed a shift in SBP from the slow-moving active + native form to a fast-moving inactive one. There was also a reduction in the apparent SBP concentration by + Laurell immunoelectrophoresis in the presence of unsaturated NEFA (5.5 nmol of NEFA/pmol of protein). These + studies indicate that unsaturated NEFAs induce conformational changes in human SBP which are reflected in + its electrophoretic, immunological, and steroid-binding properties. They suggest that the fatty acid content + of the SBP environment may result in lower steroid hormone binding and + thus increased free hormone levels. + +

+

+ J Steroid Biochem 1986 Feb;24(2):657-659 + Free fatty acids: a possible regulator of the available oestradiol fractions in plasma. Reed + MJ, Beranek PA, Cheng RW, James VH Consumption of dietary fats has been linked to the high incidence of + breast cancer found in Western women. In vitro studies we have carried out show that + unsaturated free fatty acids can increase the biologically available oestradiol fractions in + plasma. It is possible therefore that the increased risk for breast cancer associated with a + diet high in fats may be related to an elevation in the biologically available oestradiol fractions in + plasma. +

+

+ Endocrinology 1986 Jan;118(1):1-7 + Potentiation of estradiol binding to human tissue proteins by unsaturated nonesterified fatty + acids. Benassayag C, Vallette G, Hassid J, Raymond JP, Nunez EA Nonesterified fatty acids + (NEFAs) have been recently shown in the rat to be involved in steroid hormone expression, having effects on + plasma transport and intracellular activity. + + This study examines the influence of saturated and unsaturated NEFAs on estradiol (E2) binding to cytosol + from human uterus, breast, and melanoma. Binding was analyzed after separation with dextran-coated charcoal + or hydroxylapatite and by sucrose density gradient centrifugation. + Unsaturated NEFAs induced a 2- to 10-fold increase (P less than 0.001) in E2 binding to cytosol + from normal, fibromatous, and neoplastic uteri, while saturated NEFAs + had a slight inhibitory effect (P less than 0.05). Similar effects were seen with cytosol from + metastatic melanoma lymph nodes and neoplastic breast tissues. By contrast, unsaturated NEFAs did not + increase E2 binding to serum from these patients. Density gradient centrifugation indicated that the + increased binding was associated with the proteins present in the 2- to 4 S region. Analysis of E2 + metabolites in the presence of unsaturated NEFAs showed the formation of water-soluble derivatives. Seventy + percent of these E2 derivatives were trichloracetic acid precipitable, suggesting a covalent link between + the steroid and a protein. The existence of such water-soluble metabolites could be erroneously interpreted + as a true binding to soluble cytoplasmic receptors. +

+

+ Ann N Y Acad Sci 1988;538:257-264 + Possible relevance of steroid availability and breast cancer. Bruning PF, Bonfrer JM + Netherlands Cancer Institute (Antoni van Leeuwenhoekhuis), Amsterdam. "The as yet circumstantial evidence + for a central role of estrogens in the promotion of human breast cancer is supported by many data. However, + it has not been possible to identify breast cancer patients or women at risk by abnormally elevated estrogen + levels in plasma. The concept of available, i.e., non-SHBG bound sex steroid seems to offer a better + understanding than total serum steroid levels do. We demonstrated that sex steroid protein binding is + decreased by free fatty acids." +

+

+ J Surg Oncol 1993 Feb;52(2):77-82. + The effect of the fiber components cellulose and lignin on experimental colon neoplasia. Sloan + DA, Fleiszer DM, Richards GK, Murray D, Brown RA Department of Surgery, University of Kentucky College of + Medicine, Lexington. Sixty Sprague-Dawley rats were pair-fed one of three nutritionally identical diets. One + diet contained "low-fiber" (3.8% crude fiber); the others contained "high fiber" (28.7% crude fiber) + composed of either cellulose or lignin. Although both "high fiber" diets had similar stool bulking effects, + only the cellulose diet + was associated with a reduction in 1,2-dimethylhydrazine (DMH)-induced colon neoplasms. The cellulose diet + was also associated with distinct changes in the gut bacterial profile and with a lowered serum cholesterol. +

+ +

+ Nutr Cancer 1984;6(2):77-85 + Enhancement of 1,2-dimethylhydrazine-induced large bowel tumorigenesis in Balb/c mice by corn, soybean, + and wheat brans. Clapp NK, Henke MA, London JF, Shock TL This study was designed to determine + the effects of four well-characterized dietary brans on large bowel tumorigenesis induced in mice with + 1,2-dimethylhydrazine (DMH). Eight-week-old barrier-derived male Balb/c mice were fed a semisynthetic diet + with 20% bran added (either corn, soybean, soft winter wheat, or hard spring wheat) or a no-fiber-added + control diet. Half of each group was given DMH (20 mg/kg body weight/week, subcutaneously for 10 weeks) + beginning at 11 weeks of age. Surviving mice were killed 40 weeks after the first DMH injection. Tumors were + not found in mice not subjected to DMH. In DMH-treated mice, tumors were found almost exclusively in the + distal colon. Tumor incidences were as follows: controls, 11%; soybean group, 44%; soft winter wheat + group, 48%; hard spring wheat group, 58%; and corn group, 72%. + + Tumors per tumor-bearing mouse ranged from 1.4 to 1.6, except in the corn group, which had 2.1. A + positive correlation was found between percentage of neutral detergent fiber in the brans and tumor + incidences + but not between the individual components of cellulose, hemicellulose, or lignin. The enhancement of + DMH-induced large bowel tumorigenesis by all four bran types may reflect a species and/or mouse strain + effect that is bran-source related. These data emphasize the importance of using well-defined bran in + all "fiber" studies. + +

+

+ Prev Med 1987 Jul;16(4):540-4 + Fiber, stool bulk, and bile acid output: implications for colon cancer risk. McPherson-Kay R + Dietary fiber has direct effects on stool bulk and bile acid output that may be of relevance in the etiology + of colon cancer. Most types of fiber increase the total volume of stool and reduce the concentration of + specific substances, including bile acids, that are in contact with the bowel wall. However, fibers differ + in their effect on stool bulk, with wheat fiber being a more effective stool bulking agent than fruit and + vegetable fibers. In addition, the extent to which a specific fiber reduces bile acid concentration will be + modified by its concomitant effects on total fecal sterol excretion. Whereas wheat bran reduces fecal bile + acid concentration, pectin, lignin, and oat bran do not. These three fibers significantly increase + total bile acid output. Bile acids act as promoters of colonic tumors in mutagenesis assay systems and + in various animal models. Human epidemiological studies show a relationship between various + dietary variables, including fat and fiber intake, fecal concentration of bile acids, and colon cancer risk. +

+

+ Eur J Gastroenterol Hepatol 1998 Jan;10(1):33-9 Intestinal absorption of oestrogen: the effect of + altering transit-time. Lewis SJ, Oakey RE, Heaton KW University Department of Medicine, Bristol + Royal Infirmary, UK. OBJECTIVE: The mechanism by which a high fibre diet may reduce serum oestrogens is + unknown. We hypothesized that time is a rate-limiting factor in oestrogen absorption from the colon so that + changes in colonic transit-rate affect the proportion of oestrogen that is deconjugated and/or absorbed. + AIM: To determine if alteration of intestinal transit rate would influence the absorption of an oral dose of + oestradiol glucuronide. PARTICIPANTS: Twenty healthy postmenopausal women recruited by advertisement. + SETTING: Department of Medicine, Bristol Royal Infirmary. METHODS: Volunteers consumed, in turn, wheat bran, + senna, loperamide and bran shaped plastic flakes, each for 10 days with a minimum 2 week washout period + between study periods, dietary intake being unchanged. Before and in the last 4 days of each intervention + whole-gut transit-time, defecation frequency, stool form, stool beta-glucuronidase activity, stool pH and + the absorption of a 1.5 mg dose of oestradiol glucuronide were measured. RESULTS: Wheat bran, senna and + plastic flakes led to the intended reduction in whole-gut transit-time, increase in defecatory frequency and + increase in stool form score. Loperamide caused the opposite effect. The length of time the absorbed + oestrogen was detectable in the serum fell with wheat bran and senna, although this was only significant + for oestradiol. + Oestrone, but not oestradiol, was detectable for a longer time with loperamide. Plastic flakes had no effect + on either oestrogen. Areas under the curve did not change significantly but tended to fall with the three + transit-accelerating agents and to rise with loperamide. CONCLUSION: Our data indicate there is likely to be + an effect of intestinal transit on the absorption of oestrogens but more refined techniques are needed to + characterize this properly. +

+

+ Br J Cancer 1997;76(3):395-400. + Lower serum oestrogen concentrations associated with faster intestinal transit. Lewis SJ, + Heaton KW, Oakey RE, McGarrigle HH University Department of Medicine, Bristol Royal Infirmary, UK. Increased + fibre intake has been shown to reduce serum oestrogen concentrations. We hypothesized that fibre exerts this + effect by decreasing the time available for reabsorption of oestrogens in the colon. We tested this in + volunteers by measuring changes in serum oestrogen levels in response to manipulation of intestinal transit + times with senna and loperamide, then comparing the results with changes caused by wheat bran. Forty healthy + premenopausal volunteers were placed at random into one of three groups. The first group took senna for two + menstrual cycles then, after a washout period, took wheat bran, again for two menstrual cycles. The second + group did the reverse. The third group took loperamide for two menstrual cycles. At the beginning and end of + each intervention a 4-day dietary record was kept and whole-gut transit time was measured; stools were taken + for measurement of pH and beta-glucuronidase activity and blood for measurement of oestrone and oestradiol + and their non-protein-bound fractions and of oestrone sulphate. + Senna and loperamide caused the intended alterations in intestinal transit, whereas on wheat bran + supplements there was a trend towards faster transit. Serum oestrone sulphate fell with wheat bran (mean + intake 19.8 g day(-1)) and with senna; total- and non-protein-bound oestrone fell with senna. + No significant changes in serum oestrogens were seen with loperamide. No significant changes were seen in + faecal beta-glucuronidase activity. Stool pH changed only with senna, in which case it fell. In conclusion, + speeding up intestinal transit can lower serum oestrogen concentrations. +

+

+ J Steroid Biochem Mol Biol 1991 Aug;39(2):193-202 Influence of wheat bran on NMU-induced mammary + tumor development, plasma estrogen levels and estrogen excretion in female rats. Arts CJ, de + Bie AT, van den Berg H, van 't Veer P, Bunnik GS, Thijssen JH TNO Toxicology and Nutrition Institute, The + Netherlands. In our animal experiments the hypothesis was tested that a high-fiber (HF) diet reduces tumor + promotion + by interruption of the enterohepatic circulation resulting in lowered estrogen exposure of the + estrogen-sensitive tissue. + + + In the first experiment the development of N-nitrosomethylurea (NMU) induced mammary tumors was + investigated. One group of rats (HF) was fed a HF diet (11% fiber, based on wheat bran), the other group + (LF) fed a low-fiber diet (0.5% fiber, based on white wheat flour). Tumor incidence (90 and 80%, + respectively) and latency (121 and 128 days, respectively) were similar in the HF and LF groups. Compared to + the LF group, HF rats had lower tumor weights (0.16 vs 0.55 g; P less than 0.01) and a slightly lower tumor + multiplicity (1.8 vs 2.8 tumors per tumor-bearing rat). These differences were reduced after adjustment for + body weight. In a second experiment rats, not treated with the carcinogen, were kept on the same HF and LF + diets. From these rats 24-h urine and feces and orbital blood samples were + collected for analysis of (un)conjugated estrogens. The excretion of both free and conjugated estrogens + in fecal samples was about 3-fold higher in HF rats than in LF rats. During the basal period of the + cycle urinary excretion of estrone was lower in HF rats (mean 9.7 ng/day) than in LF rats (mean 13.0 + ng/day; P less than 0.05). It is concluded that wheat bran interrupts the enterohepatic circulation of + estrogens, but plasma levels are not affected. Whether the development of mammary tumors is reduced by + the introduction of specific components of wheat bran, or by a reduced body weight due to a lower + (effective) energy intake remains to be determined. + +

+

+ Nutr Cancer 1998;31(1):24-30 + Dietary lignin, and insoluble fiber, enhance uterine cancer but did not influence mammary cancer induced + by N-methyl-N-nitrosourea in rats. + Birt DF, Markin RS, Blackwood D, Harvell DM, Shull JD, Pennington KL Eppley Institute for Research in Cancer + and Allied Disease, University of Nebraska Medical Center, Omaha 69198, USA. Previous investigations + suggested potential breast cancer-preventive properties of dietary fiber from cabbage. The purpose of the + present investigation was to determine whether lignin, a component of cabbage fiber, would protect against + mammary carcinogenesis by N-methyl-N-nitrosourea (MNU) in Sprague-Dawley rats. A six-week study was + conducted using diets containing 0.5-5% dietary wood lignin (a readily available, purified source). These + diets were well tolerated by the rats, and a carcinogenesis study using 5 mg MNU/100 g body wt i.v. at 50 + days of age was conducted, with the 2.5% lignin diet fed from 6 through 8 weeks of age followed by 5% lignin + diet until 20 weeks after MNU. Dietary lignin and MNU treatment increased food consumption (p < 0.05), + and body weight was slightly reduced at 10 and 20 weeks after MNU in the MNU-5% lignin diet group (p < + 0.05). Serum estradiol was not altered by dietary lignin or MNU treatment, but uterine weights were highest + in the MNU-control diet group 4 and 12 weeks after MNU. Expression of creatine kinase B, an + estrogen-responsive gene, was lower in the uteri of the MNU-lignin diet group than in other groups at 20 + weeks. Mammary carcinogenesis was not altered by dietary lignin. + However, uterine endometrial adenocarcinoma was observed only in the MNU-lignin diet group (4 + carcinomas/40 effective rats) (p < 0.05). + +

+ +

+ Ginecol Obstet Mex 1998 Mar;66:111-8 + [Estrogens of vegetable origin]. [Article in Spanish] Rubio Lotvin B Reproduccion y de + Ginecologia y Obstetricia Facultad de Medicina, UNAM Depto. de Ginecologia y Obstetricia Hospital Americano, + Britanico Cowdray. Mexico, D.F. In recent years, estrogens of vegetable origin have acquired some importance + that justify the presentation of the available data. The compounds that have estrogenic effect when ingested + as food through + vegetables include isoflavones, lignines and lactones. The review comprises their chemical + structure, metabolism and excretion as well as their effect on plasmatic levels of estrogens + FSH, LH and SHBG as well as their activity over lipoproteins and, naturally, their action on menopause + symptoms and breast cancer. +

+

+ Proc Soc Exp Biol Med 1995 Jan;208(1):6-12 Chemical studies of phytoestrogens and related compounds + in dietary supplements: flax and chaparral. Obermeyer WR, Musser SM, Betz JM, Casey RE, Pohland + AE, Page SW Division of Natural Products, Food and Drug Administration, Washington, District of Columbia + 20204. High-performance liquid chromatographic (HPLC) and mass spectrometric (MS) procedures were developed + to determine lignans in flaxseed (Linum usitatissimum) and chaparral (Larrea tridentata). + Flaxseed contains high levels of phytoestrogens. Chaparral has been associated with acute nonviral toxic + hepatitis and contains lignans that are structurally similar to known estrogenic compounds. + + + Both flaxseed and chaparral products have been marketed as dietary supplements. A mild enzyme hydrolysis + procedure to prevent the formation of artifacts in the isolation step was used in the determination of + secoisolariciresinol in flaxseed products. HPLC with ultraviolet spectral (UV) or MS detection was used as + the determinative steps. HPLC procedures with UV detection and mass spectrometry were developed to + characterize the phenolic components, including lignans and flavonoids, of chaparral and to + direct fractionation studies for the bioassays. +

+

+ Brain Res 1994 Jul 25;652(1):161-3 + The 21-aminosteroid antioxidant, U74389F, prevents estradiol-induced depletion of hypothalamic + beta-endorphin in adult female rats. + Schipper HM, Desjardins GC, Beaudet A, Brawer JR Department of Anatomy and Cell Biology, Bloomfield Centre + for Research in Aging, Jewish General Hospital, McGill University, Montreal, Que., Canada. + A single intramuscular injection of 2 mg estradiol valerate (EV) results in neuronal degeneration + and beta-endorphin depletion in the hypothalamic arcuate nucleus of adult female rats. We have + hypothesized that peroxidase-positive astrocytes in this brain region oxidize estrogens and + catecholestrogens to semiquinone radicals which mediate oxidative neuronal injury. In the present study, + dietary administration of the potent antioxidant 21-aminosteroid, U-74389F, completely blocked EV-induced + beta-endorphin depletion in the hypothalami of adult female rats. Neither EV nor 21-aminosteroid treatment + had any effect on hypothalamic concentrations of neuropeptide Y and Met-enkephalin, confirming that + the estradiol lesion is fairly selective for the beta-endorphin cell population. + + The present findings support the hypothesis that the toxic effect of estradiol on hypothalamic + beta-endorphin neurons is mediated by free radicals. +

+

+ J Steroid Biochem Mol Biol 1998 Feb;64(3-4):207-15, "Effects of tea polyphenols and flavonoids on + liver microsomal glucuronidation of estradiol and estrone." + Zhu BT, Taneja N, Loder DP, Balentine DA, Conney AH "Administration of 0.5 or 1% lyophilized green tea (5 or + 10 mg tea solids per ml, respectively) as the sole source of drinking fluid to female Long-Evans rats for 18 + days stimulated liver microsomal glucuronidation of estrone, estradiol and 4-nitrophenol by 30-37%, 15-27% + and 26-60%, respectively. Oral administration of 0.5% lyophilized green tea to female CD-1 mice for 18 days + stimulated liver microsomal glucuronidation of estrone, estradiol and 4-nitrophenol by 33-37%, 12-22% and + 172-191%, respectively. The in vitro addition of a green tea polyphenol mixture, a black tea polyphenol + mixture or (-)-epigallocatechin gallate inhibited rat liver microsomal glucuronidation of estrone and + estradiol in a concentration-dependent manner and their IC50 values for inhibition of estrogen metabolism + were approximately 12.5, 50 and 10 microg/ml, respectively. Enzyme kinetic analysis indicates that the + inhibition of estrone glucuronidation by 10 microM (-)-epigallocatechin gallate was competitive while + inhibition by 50 microM (-)-epigallocatechin gallate was noncompetitive. Similarly, several flavonoids + (naringenin, hesperetin, kaempferol, quercetin, rutin, flavone, alpha-naphthoflavone and + beta-naphthoflavone) also inhibited rat liver microsomal glucuronidation of estrone and estradiol to varying + degrees. Naringenin and hesperetin displayed the strongest inhibitory effects (IC50 value of approximately + 25 microM). These two hydroxylated flavonoids had a competitive mechanism of enzyme inhibition for estrone + glucuronidation at a 10 microM inhibitor concentration and a predominantly noncompetitive mechanism of + inhibition at a 50 microM inhibitor concentration." +

+ +

+ Toxicology 1997 Sep 26;122(1-2):61-72, + "Effects of co-administration of butylated hydroxytoluene, butylated hydroxyanisole and flavonoids on + the activation of mutagens and drug-metabolizing enzymes in mice." Sun B, Fukuhara M Effects of + co-administration of food additives and naturally occurring food components were studied on the activation + of mutagens. Male mice (ddY) were given diets containing butylated hydroxytoluene (BHT) or butylated + hydroxyanisole (BHA) and flavone or flavanone (2,3-dihydroflavone) for two weeks and the ability of hepatic + microsomes to activate aflatoxin B1, benzo[a]pyrene and N-nitrosodimethylamine was determined by the + mutagenicity test. Co-administration of an antioxidant (0.1% BHT or 0.2% BHA in diet) and a flavonoid (0.1% + flavone or 0.1% flavanone) resulted in additive effects on the activation of aflatoxin B1 and + benzo[a]pyrene, while the activation of N-nitrosodimethylamine was not elevated significantly + by the co-administration. To understand the mechanism for the additive effects, induction of specific + isozymes of cytochrome P450 involved in the activation of the mutagens was studied. Co-administration of BHT + (0.1%) and flavone (0.1%) increased markedly the levels of proteins and the activities of the enzymes + related to the isozymes of CYP2A and CYP2B, while co-administration of BHA (0.2%) and flavanone (0.1%) + elevated those related to CYP1A. Further, the activation of aflatoxin B1 and benzo[a]pyrene in hepatic + microsomes was inhibited by the antibodies against these isozymes, which suggested that the enhanced + activation of the mutagens by the co-administration might be mediated by the induction of these isozymes. +

+

+ Biochem Soc Trans 1977;5(5):1489-92. Frameshift mutagenicity of certain naturally occurring phenolic + compounds in the 'Salmonella/microsome' test: activation of anthraquinone and flavonol glycosides by gut + bacterial enzymes. Brown JP, Dietrich PS, Brown RJ +

+ +

+ Mutagenesis 1997 Sep;12(5):383-90 + "Involvement of rat cytochrome 1A1 in the biotransformation of kaempferol to quercetin: relevance to the + genotoxicity of kaempferol." Silva ID, Rodrigues AS, Gaspar J, Maia R, Laires A, Rueff J. + "Kaempferol is a flavonoid widely distributed in edible plants and has been shown to be genotoxic to V79 + cells in the absence of external metabolizing systems. The presence of an external metabolizing system, such + as rat liver homogenates (S9 mix), leads to an increase in its genotoxicity, which is attributed to its + biotransformation to the more genotoxic flavonoid quercetin, via the cytochrome P450 (CYP) + mono-oxygenase system." +

+

+ Environ Health Perspect 1997 Apr;105 Suppl 3:633-6 Dietary estrogens stimulate human breast cells to + enter the cell cycle. Dees C, Foster JS, Ahamed S, Wimalasena J. + "Our findings are consistent with a conclusion that dietary estrogens at low concentrations do not act + as antiestrogens, but act like DDT and estradiol to stimulate human breast cancer cells to enter the + cell cycle." +

+ +

+ © Ray Peat 2008. All Rights Reserved. www.RayPeat.com +

+ + diff --git a/raypeat-articles/processed/oils-in-context.html b/raypeat-articles/processed/oils-in-context.html new file mode 100644 index 0000000..d08f46d --- /dev/null +++ b/raypeat-articles/processed/oils-in-context.html @@ -0,0 +1,856 @@ + + Oils in Context + +

+ Oils in Context +

+ +

+ An oil researcher[0] + + spent 100 days eating what he considered to be the "Eskimo diet," seal blubber and mackerel paste. He + observed that his blood lipid peroxides (measured as malondialdehyde, MDA) reached a level 50 times higher + than normal, and although MDA is teratogenic, he said he wasn't worried about fathering deformed children, + because his sperm count had gone to zero. Evidently, he didn't have a very thorough understanding of the + Eskimo way of life. In most traditional cultures, the whole animal is used for food, including the brain and + the endocrine glands. Since unsaturated fats inhibit thyroid function, and since Eskimos usually have a high + caloric intake but are not typically obese, it seems that` their metabolic rate is being promoted by + something in their diet, which might also be responsible for protecting them from the effects experienced by + the oil researcher. (According to G. W. Crile, the basal metabolic rate of Eskimos was 125% of that of + people in the United States.) +

+

+ People who eat fish heads (or other animal heads) generally consume the thyroid gland, as well as the brain. + The brain is the body's richest source of cholesterol, which, with adequate thyroid hormone and vitamin A, + is converted into the steroid hormones pregnenolone, progesterone, and DHEA, in proportion to the quantity + circulating in blood in low-density lipoproteins. The brain is also the richest source of these very + water-insoluble (hydrophobic) steroid hormones; it has a concentration about 20 times higher than the serum, + for example. The active thyroid hormone is also concentrated many-fold in the brain. +

+

+ DHEA (dehydroepiandrosterone) is known to be low in people who are susceptible to heart disease [1] or cancer, and all three of these steroids have a broad spectrum of protective actions. Thyroid + hormone, vitamin A, and cholesterol, which are used to produce the protective steroids, have been found to + have a similarly broad range of protective effects, even when used singly. For example, according to + MacCallum, +

+

+ It has been shown that certain lipoid substances, especially cholesterine, can act as inhibiting or + neutralizing agents toward such haemolytic poisons as saponin, cobra poison, etc., through forming with them + an innocuous compound. Hanes showed that the relative immunity of puppies from chloroform poisoning is due + to the large amount of cholesterin esters in their tissues. When artificially introduced into the tissues of + adult animals a similar protection is conferred.[2] +

+

+ A high level of serum cholesterol is practically diagnostic of hypothyroidism, and can be seen as an + adaptive attempt to maintain adequate production of the protective steroids. Broda Barnes' work clearly + showed that hypothyroid populations are susceptible to infections, heart disease, and cancer. [3] +

+

+ In the 1940s, some of the toxic effects of fish oil (such as testicular degeneration, softening of the + brain, muscle damage, and spontaneous cancer) were found to result from an induced vitamin E deficiency. + Unfortunately, there isn't much reason to think that just supplementing vitamin E will provide general + protection against the unsaturated fats. The half-life of fats in human adipose tissue is about 600 days, + meaning that significant amounts of previously consumed oils will still be present up to four years after + they have been removed from the diet. [4] + According to Draper, et al., [5] +

+

+ , , , + enrichment of the tissues with highly unsaturated fatty acids results in an increase in lipid peroxidation + in vivo even in the presence of normal concentrations of vitamin E. Fasting for more than 24 hours also + results in an increase in MDA excretion, implying that lipolysis is associated with peroxidation of the + fatty acids released. +

+ +

+ According to Lemeshko, et al., it seems that this effect increases with the age of the animal. [6] +

+

+ Commercial advertising (including medical conferences sponsored by pharmaceutical companies) and + commercially sponsored research are creating some false impressions about the role of unsaturated oils in + the diet. Like the man who poisoned himself with the "Eskimo diet," many people focus so intently on + avoiding one problem that they create other problems. Since I have discussed the association of unsaturated + fats with aging, lipofuscin, and estrogen elsewhere, I will outline some of the other problems associated + with the oils, especially as they relate to hormones. +

+

+ Mechanisms and Essentiality: + When something is unavoidable, in ordinary life, talking about "essentiality," or the minimum + amount required for life or for optimal health, is more important as an exploration into the nature of our + life than as a practical health issue. For example, how much oxygen, how many germs (of what kinds), how + many cosmic rays (of what kinds), would produce the nicest human beings? The fact that we have adapted to + something---oxygen at sea level, microbes, or vegetable fats, for example--doesn't mean that we are normally + exposed to it in ideal amounts. +

+ +

+ Animals contain desaturase enzymes, and are able to produce specific unsaturated fats (from oleic and + palmitoleic acids) when deprived of the ordinary "essential fatty acids," [7] so it can be + assumed that these enzymes have a vital purpose. The high concentration of unsaturated fats in + mitochondria--the respiratory organelles where it seems that these lipids present a special danger of + destructive oxidation--suggests that they are required for mitochondrial structure, or function, or + regulation, or reproduction. Unsaturated fats have special properties of adsorption, [8] and are + more soluble in water than are saturated fats. The movement and modulation of proteins and nucleic acids + might require these special properties. As the main site of ATP production, I suspect that their + water-retaining property might be crucial. When a protein solution (even egg-white) is poured into a high + concentration of ATP, it contracts or "superprecipitates." This condensing, water-expelling property of ATP + in protein solutions is similar to the effect of certain concentrations of salts on any polymer. It would + seem appropriate to have a substance to oppose this condensing effect, to stimulate swelling [9, + 10] and the uptake of precursor substances. Something that has an intrinsic structure-loosening or + water-retaining effect would be needed. The ideas of "chaotropic agents" and "structural antioxidants" have + been proposed by Vladimirov [11] to bring generality into our understanding of the mitochondria. + Lipid peroxides are among the chaotropic agents, and thyroxin is among the structural antioxidants. The + known oxygen-sparing effects of progesterone [12, 13] would make it appropriate to include it + among the structural antioxidants. The incorporation of the wrong unsaturated fats into mitochondria would + be expected to damage the vital respiratory functions. +

+ +

+ Some insects that have been studied have been found not to require the essential fatty acids. [14]* According to reviewers, hogs and humans have not been shown to require the "essential" fatty acids. [15] In vitro studies indicate that they are not required for human diploid cells to continue + dividing in culture. + [16] + According to Guarnieri, [17] EFA-deficient animals don't die from their deficiency. The + early studies showing "essentiality" of unsaturated fats, by producing skin problems and an increased + metabolic rate, have been criticized [18] in the light of better nutritional information, e.g., + pointing out that the diets might have been deficient in vitamin B6 and/or biotin. The similar skin + condition produced by vitamin B6 deficiency was found to be improved by adding unsaturated fats to the diet. + A fat-free liver extract cured the "EFA deficiency." I think it would be reasonable to investigate the + question of the increased metabolic rate produced by a diet lacking unsaturated fats (which inhibit both + thyroid function and protein metabolism) in relation to the biological changes that have been observed. + Since diets rich in protein are known to increase the requirement for vitamin B6 [19] (which is a + co-factor of transaminases, for example), the increased rate of energy production and improved digestibility + of dietary protein on a diet lacking unsaturated fats would certainly make it reasonable to provide the + experimental animals with increased amount of other nutrients. With increasing knowledge, the old + experiments indicating the "essentiality" of certain oils have lost their ability to convince, and they + haven't been replaced by new and meaningful demonstrations. In the present state of knowledge, I don't think + it would be unreasonable to suggest that the optional dietary level of the "essential fatty acids" might be + close to zero, if other dietary factors were also optimized. The practical question, though, has to do with + the dietary choices that can be made at the present time. +

+
+

+ *If we followed Linus Pauling's reasoning in determining optimal vitamin C intake, this study of the + linoleic acid content of the tissues of an animal which can synthesize it would suggest that we are eating + about 100 times more "EFA" than we should. +

+

+ In evaluating dietary fat, it is too often forgotten that the animals' diet (and other factors, including + temperature) affect the degree of saturation of fats in its tissues, or its milk, or eggs. The fat of wild + rabbits or summer-grazing horses, for example, can contain 40% linolenic acid, about the same as linseed + oil. Hogs fed soybeans can have fat containing over 30% linoleic acid. [20] + Considering that most of our food animals are fed large amounts of grains and soybeans, it isn't accurate to + speak of their fats as "animal fats." And, considering the vegetable oil contained in our milk, eggs, and + meat, it would seem logical to select other foods that are not rich in unsaturated oils. +

+

+ Temperature and Fat: The fact that saturated fats are dominant in tropical plants and in + warm-blooded animals relates to the stability of these oils at high temperatures. Coconut oil which had been + stored at room temperature for a year was found to have no measurable rancidity. Since growing coconuts + often experience temperatures around 100 degrees Fahrenheit, ordinary room temperature isn't an oxidative + challenge. Fish oil or safflower oil, though, can't be stored long at room temperature, and at 98 degrees F, + the spontaneous oxidation is very fast. +

+ +

+ Bacteria vary the kind of fat they synthesize, according to temperature, forming more saturated fats at + higher temperatures.[21] The same thing has been observed in seed oil plants. [22] + Although sheep have highly saturated fat, the superficial fat near their skin is relatively unsaturated; it + would obviously be inconvenient for the sheep if their surface fat hardened in cool weather, when their skin + temperature drops considerably. Pigs wearing sweaters were found to have more saturated fat than other + pigs.[23] + Fish, which often live in water which is only a few degrees above freezing, couldn't function with hardened + fat. At temperatures which are normal for fish, and for seeds which germinate in the cold northern + springtime, rancidity of fats isn't a problem, but rigidity would be. +

+

+ Unsaturated Fats Are Essentially Involved In Heart Damage: + + The toxicity of unsaturated oils for the heart is well established, + [24, 25, 26] though not well known by the public. +

+ +

+ In 1962, it was found that unsaturated fatty acids are directly toxic to mitochondria. [27] Since + stress increases the amount of free fatty acids circulating in the blood (as well as lipid peroxides), and + since lack of oxygen increases the intracellular concentration of free fatty acids, stored unsaturated fats + would seem to represent a special danger to the stressed organism. Meerson and his colleagues + [18] have demonstrated that stress liberates even local tissue fats in the heart during stress, + and that systematic drug treatment, including antioxidants, can stop the enlargement of stress-induced + infarctions. Recently, it was found that the cardiac necrosis caused by unsaturated fats (linolenic acid, in + particular) could be prevented by a cocoa butter supplement. [29] The author suggests that this + is evidence for the "essentiality" of saturated fats, but points out that animals normally can produce + enough saturated fat from dietary carbohydrate or protein, to prevent cardiac necrosis, unless the diet + provides too much unsaturated fat. A certain proportion of saturated fat appears to be necessary for + stability of the mitochondria. Several other recent studies show that the "essential" fatty acids decrease + the P/O ratio, or the phosphorylation efficiency, [30] the amount of usable energy produced by + cellular respiration. +

+ +

+ There has been some publicity about a certain unsaturated fat, eicosapentaenoic acid, or EPA, which can have + some apparently protective and anti-inflammatory effects. A study in which butter was added to the animals' + diet found that serum EPA was elevated by the butter. The investigator pointed out that other studies had + been able to show increased serum EPA from an EPA supplement only when the animals had previously been fed + butter. [31] +

+

+ Intense lobbying by the soybean oil industry has created the widespread belief that "tropical oils" cause + heart disease. In a comparison of many kinds of oil, including linseed oil, olive oil, whale oil, etc., palm + oil appeared to be the most protective. The same researcher + [32] more recently studied palm oil's antithrombotic effect, in relation to platelet aggregation. + It was found that platelet aggregation was enhanced by sunflowerseed oil, but that palm oil tended to + decrease it. +

+

+ Much current research has concentrated on the factors involved in arterial clotting. Since the blood moves + quickly through the arteries, rapid processes are of most interest to those workers, though some people do + remember to think in terms of an equilibrium between formation and removal of clot material. For about 25 + years there was interest in the ability of vitamin E to facilitate clot removal, apparently by activating + proteolytic enzymes.[33] Unsaturated fats' ability to inhibit proteolytic enzymes in the blood + has occasionally been discussed, but seldom in the U.S. The equilibrium between clotting and clot + dissolution is especially important in the veins, where blood moves more slowly, and spends more time. +

+

+ . . . + the slower blood flows the greater its predisposition to clotting. However, this intrinsic process, leading + to fibrin production, is slow, taking up to a minute or more to occur. Thrombosis as a result of stasis, + therefore, occurs in the venous circulation; typically in the legs where"venous return is slowest. In fact, + many thousands of small thrombi are formed each day in the lower body. These pass via the vena cava into the + lungs where thrombolysis occurs, this being a normal metabolic function of the organ. [34] +

+

+ In the Shutes' research in the 1930s and 1040s, vitamin E and estrogen acted in opposite directions on the + clot-removing enzymes.[33] + Since estrogen increases blood lipids, and increases the incidence of strokes and heart attacks, it would be + interesting to expand the Shutes' work by considering the degree of saturation of blood lipids in relation + to the effects of vitamin E and estrogen on clot removal. Estrogen's effect on clotting is very complex, + since it increases the ratio of unsaturated to saturated fatty acids in the body, and increases the tendency + of blood to pool in the large veins, in addition to its direct effects on the clotting factors. +

+

+ Immunodeficiency and Unsaturated Fats: + Intravenous feeding with unsaturated fats is powerfully immunosuppressive [35] (though + it often was used to give more calories to cancer patients) and is now advocated as a way to prevent graft + rejection. The deadly effect of the long-chain unsaturated fats on the immune system has led to the + development of new products containing short and medium-chain saturated fats for intravenous feeding. [36] It was recently reported that the anti-inflammatory effect of n-3 fatty acids (fish oil) might + be related to the observed suppression of interleukin-1 and tumor necrosis factor by those fats. [37] The suppression of these anti-tumor immune factors persists after the fish oil treatment is + stopped. +

+ +

+ As mentioned above, stress and hypoxia can cause cells to take up large amounts of fatty acids. Cortisol's + ability to kill white blood cells (which can be inhibited by extra glucose) is undoubtedly an important part + of its immunosuppressive effect, and this killing is mediated by causing the cells to take up unsaturated + fats. [38] +

+

+ Several aspects of the immune system are improved by short-chain saturated fats. Their anti-histamine action + [39] is probably important, because of histamine's immunosuppressive effects.[40] + Unsaturated fats have been found to cause degranulation of mast cells.[41] + The short-chain fatty acids normally produced by bacteria in the bowel apparently have a local + anti-inflammatory action.[42] +

+

+ A recent discussion of "tissue destruction by neutrophils" mentions "a fascinating series of experiments + performed between 1888 and 1906," in which "German and American scientists established the importance of + neutrophil proteinases and plasma antiproteinases in the evolution of tissue damage in vivo." [43] + MacCallum's Pathology described some related work: +

+

+ . . . + Jobling has shown that the decomposition products of some fats--unsaturated fatty acids and their + soaps--have the most decisive inhibiting action upon proteolytic ferments, their power being in a sense + proportional to the degree of unsaturation of the fatty acid. So universally is it true that such + unsaturated fatty acids can impede the action of proteolytic ferments that many pathological conditions + (such as the persistence of caseous tuberculous material in its solid form) can be shown to be due to their + presence. If they are rendered impotent by saturation of their unsaturated group with iodine, the + proteolysis goes on rapidly and the caseous tubercle or gumma rapidly softens.[44] +

+

+ Another comment by MacCallum suggests one way in which unsaturated fats could block the action of cytotoxic + cells: +

+

+ This function of the wandering cells is, of course, of immediate importance in connection with their task of + cleaning up the injured area to prepare it for repair. While the proteases thus produced are active in the + solution of undesirable material, their unbridled action might be detrimental. As a matter of fact, it is + shown by Jobling and Petersen that the anti-ferment known to be present in the serum and to restrict the + action of the ferment is a recognizable chemical substance, usually a soap or other combination of an + unsaturated fatty acid. It is possible to remove or decompose this substance or to saturate the fatty acid + with iodine and thus release the ferment to its full activity. [45] +

+

+ Unsaturated Fats Are Essential For Cancer: + + The inhibition of proteolytic enzymes by unsaturated fats will act at many sites: digestion of protein, + "digestion" of clots, "digestion" of the colloid in the thyroid gland which releases the hormones, the + activity of white cells mentioned above, and the normal "digestion" of cytoplasmic proteins involved in + maintaining a steady state as new proteins are formed and added to the cytoplasm. It has been suggested that + inhibition of the destruction of intracellular proteins would shift the balance toward growth.[46] + Cancer cells are known to have a high level of unsaturated fats,[47] + + yet they have a low level of lipid peroxidation;[48] lipid peroxidation inhibits growth, and is + often mentioned as a normal growth restraining factor.[49] +

+

+ In 1927, it was observed that a diet lacking fats prevented the development of spontaneous tumors.[50] Many + subsequent investigators have observed that the unsaturated fats are essential for the development of + tumors. [51, 52, 53] Tumors secrete a factor which mobilizes fats from storage, [54] + presumably guaranteeing their supply in abundance until the adipose tissues are depleted. Saturated + fats--coconut oil and butter, for example--do not promote tumor growth.[55] Olive oil is not a + strong tumor promoter, but in some experiments it does have a slightly permissive effect on tumor growth. + [56, 57] In some experiments, the carcinogenic action of unsaturated fats could be offset by + added thyroid, [57] + + an observation which might suggest that at least part of the effect of the oil is to inhibit thyroid. Adding + cystine to the diet (cysteine, the reduced form of cystine, is a thyroid antagonist) also increases the + tumor incidence.[58] In a hyperthyroid state, the ability to quickly oxidize larger amounts of + the toxic oils would very likely have a protective effect, preventing storage and subsequent peroxidation, + and reducing the oils' ability to synergize with estrogen. +

+

+ Consumption of unsaturated fat has been associated with both skin aging and with the sensitivity of the skin + to ultraviolet damage, Ultraviolet light-induced skin cancer seems to be mediated by unsaturated fats and + lipid peroxidation.[59] +

+

+ In a detailed study of the carcinogenicity of different quantities of unsaturated fat, Ip, et al., tested + levels ranging from 0.5% to 10%, and found that the cancer incidence varied with the amount of "essential + oils" in the diet. Some of their graphs make the point very clearly: + [52} +

+ +

+ This suggests that the optimal EFA intake might be 0.5% or less. +

+

+ Butter and coconut oil contain significant amounts of the short and medium-chain saturated fatty acids, + which are very easily metabolized,[60] + inhibit the release of histamine,[39] promote differentiation of cancer cells,[61] + tend to counteract the stress-induced proteins,[62] decrease the expression of prolactin + receptors, and promote the expression of the T3 (thyroid) receptor. [63] + + (A defect of the thyroid receptor molecule has been identified as an "oncogene," responsible for some + cancers, as has a defect in the progesterone receptor.) +

+

+ Besides inhibiting the thyroid gland, the unsaturated fats impair intercellular communication,[64] suppress + several immune functions that relate to cancer, and are present at high concentrations in cancer cells, + where their antiproteolytic action would be expected to interfere with the proteolytic enzymes and to shift + the equilibrium toward growth. In the free fatty acid form, the unsaturated fats are toxic to the + mitochondria, but cancer cells are famous for their compensatory glycolysis. +

+

+ By using lethargic connective tissue cells known to have a very low propensity to take up unsaturated fats + [65] as controls in comparison with, e.g., breast cancer cells, with a high affinity for fats, it + is possible to show a "selective" toxicity of oils for cancer cells. However, an in vivo test of an + alph-linolenic acid ester showed it to have a stimulating effect on breast cancer.[66] + Given a choice, skin fibroblasts demonstrate a very specific preference for oleic acid, over a + polyunsaturated fat.[67] +

+ +

+ Even if unsaturated fats were (contrary to the best evidence) selectively toxic for cancer cells, their use + in cancer chemotherapy would have to deal with the issues of their tendency to cause pulmonary + embolism,their suppression of immunity including factors specifically involved in cancer resistance, and + their carcinogenicity. +

+

+ Brain Damage And Lipid Peroxidation: + + When pregnant mice were fed either coconut oil or unsaturated seed oil, the mice that got coconut oil had + babies with normal brains and intelligence, but the mice exposed to the unsaturated oil had smaller brains, + and had inferior intelligence. In another experiment, radioactively labeled soy oil was given to nursing + rats, and it was shown to be massively incorporated into brain cells, and to cause visible structural + changes in the cells. In 1980, shortly after this study was published in Europe, the U.S. Department of + Agriculture issued a recommendation against the use of soy oil in infant formulas. More recently, [68] pregnant rats and their offspring were given soy lecithin with their food, and the exposed + offspring developed sensorimotor defects. +

+

+ Many other studies have demonstrated that excessive unsaturated dietary fats interfere with learning and + behavior, [70, 71] and the fact that some of the effects can be reduced with antioxidants + suggests that lipid peroxidation causes some of the damage. Other studies are investigating the involvement + of lipid peroxidation in seizures.[72] +

+ +

+ The past use of soy oil in artificial milk (and in maternal diets) has probably caused some brain damage. + The high incidence of neurological defects (e.g., 90%) that has been found among violent criminals suggests + that it might be worthwhile to look for unusual patterns of brain lipids in violent people. +

+

+ There have been a series of claims that babies' brains or eyes develop better when their diets are + supplemented with certain unsaturated oils, based on the idea that diets may be deficient in certain types + of oil, Some experimenters claim that the supplements have improved the mental development of babies, but + other researchers find that the supplemented babies have poorer mental development. But the oils that are + added to the babies' diets are derived from fish or algae, and contain a great variety of substances (such + as vitamins) other than the unsaturated fatty acids, and the researchers consistently fail to control for + the effects of such substances. +

+

+ It has shown that it is probably impossible to experience a detectable deficiency of linoleic acid outside + of the laboratory setting,[69] but the real issue is probably whether the amount in the normal + diet is harmful to development. Until the research with animals has produced a better understanding of the + effects of unsaturated oils, experimenting on human babies seems hard to justify. +

+

+ Marion Diamond, who has studied the improved brain growth in rats given a stimulating environment (which, + like prenatal progesterone, produced improved intelligence and larger brains), observed that in old age the + "enriched" rats' brains contained less lipofuscin (age pigment).[73] + It is generally agreed that the unsaturated oils promote the formation of age pigment. The discovery that + stress or additional cortisone (which, by blocking the use of glucose, forces cells to take up more fat) + causes accelerated aging of the brain[74] should provide new motivation to investigate the + antistress properties of substances such as the protective steroids mentioned above, and the short-chain + saturated fats. +

+ +

+ Essential for Liver Damage: Both experimental and epidemiological studies have shown that + dietary linoleic acid is required for the development of alcoholic liver damage.[75] + Animals fed tallow and ethanol had no liver injury, but even 0.7% or 2.5% linoleic acid with ethanol caused + fatty liver, necrosis, and inflammation. Dietary cholesterol at a level of 2% was found to cause no + harm,[76] + but omitting it entirely from the diet caused leakage of amino-transferase enzymes. This effect of the + absence of cholesterol was very similar to the effects of the presence of linoleic acid with ethanol. +

+

+ Obesity: + For many years studies have been demonstrating that dietary coconut oil causes decreased fat synthesis and + storage, when compared with diets containing unsaturated fats. More recently, this effect has been discussed + as a possible treatment for obesity.[77] + The short-chain fats in coconut oil probably improve tissue response to the thyroid hormone (T3), and its + low content of unsaturated fats might allow a more nearly optimal function of the thyroid gland and of + mitochondria. A survey of other tropical fruits' content of short and medium chain fatty acids might be + useful, to find lower calorie foods which contain significant amounts of the shorter-chain fats. +

+ +

+ Other Problem Areas: + The presence of palmitate in the lung surfactant phospholipids[78] suggests that + maternal overload with unsaturated fats might interfere with the formation of these important substances, + causing breathing problems in the newborn. The bone-calcium mobilizing effect of prostaglandins suggests + that dietary fats might affect osteoporosis; the absence of osteoporosis in some tropical populations might + relate to their consumption of coconut oil and other saturated tropical oils. The steroids which occur in + association with some seed oils might be nutritionally significant, in the way animal hormones in foods + undoubtedly are. For example, soy steroids can be converted by bowel bacteria into estrogens. R. Marker, et + al., found diosgenin (the material in the Mexican yam from which progesterone, etc., are derived) in a palm + kernel, Balanites aegyptica (Wall).[79] + Another palm fruit also contains sterols with anti-androgenic and anti-edematous actions.[80, 81] + +

+

+ If the amount of ingested unsaturated fats (inhibitors of protein digestion) were lower, protein + requirements might be lower. +

+ +

+ The similar effects of estrogen and of polyunsaturated fats (PUFA) are numerous. They include antagonism to + vitamin E and thyroid, to respiration and proteolysis; promotion of lipofuscin formation and of clot + formation, promotion of seizure activity, impairment of brain development and learning; and involvement in + positive or negative regulation of cell division, depending on cell type. +

+

+ These parallels suggest that the role of PUFA in reproduction might be similar to that of estrogen, namely, + the promotion of uterine and breast cell proliferation, water uptake, etc. Such parallels should be a + caution in generalizing from the conditions which are essential for reproduction to the conditions which are + compatible with full development and full functional capacity. If a certain small amount of dietary PUFA is + essential for reproduction, but for no other life function, then it is analogous to the brief "estrogen + surge," which must quickly be balanced by opposing hormones. The present approach to contraception through + estrogen-induced miscarriage might give way to fertility regulation by diet. A self-actualizing + pro-longevity diet, low in PUFA, might prolong our characteristically human condition of delayed + reproductive maturity, and, if PUFA are really essential for reproduction, unsaturated vegetable oils could + temporarily be added to the diet when reproduction is desired. +

+

+ Conclusions: + Polyunsaturated fats are nearly ubiquitous, but if they are "essential nutrients," in the way vitamin A, or + lysine, is essential, that has not been demonstrated. It seems clear that they are + + essential for cancer, and that they have other properties which cause them to be toxic at certain levels. It + might be time to direct research toward determining whether there is a threshold of toxicity, or whether + they are, like ionizing radiation, toxic at any level. +

+ +

Note:

+

+ A possible mitochondrial site for toxicity: + + In 1971 I was trying to combine some of the ideas of Albert Szent-Gyorgyi, Otto Warburg, W. F. Koch, and L. + C. Strong. I was interested in the role of ubiquinone in mitochondrial respiration. In one experiment, I was + using paper chromatography to compare oils that I had extracted from liver with vitamin E and with + commercially purified ubiquinone. Besides using the pure substances, I decided to combine vitamin E with + ubiquinone for another test spot. As soon as I combined the two oils, their amber and orange colors turned + to an inky, greenish black color. I tested both bacterial and mammalian ubiquinone, and benzoquinone, and + they all produced similar colors with vitamin E. When I ran the solvent up the paper, the vitamin E and the + ubiquinone traveled at slightly different speeds. The black spot, containing the mixture, also moved, but + each substance moved at its own speed, and as the materials separated, their original lighter colors + reappeared. Charge-transfer bonds, which characteristically produce dark colors, are very weak bonds. I + think this must have been that kind of bond. Years later, I tried to repeat the experiment, using + "ubiquinone" from various capsules that were sold for medical use. Instead of the waxy yellow-orange + material I had used before, these capsules contained a liquid oil with a somewhat yellow color. Very likely, + the ubiquinone was dissolved in vegetable oil. At the time, I was puzzled that the color reaction didn't + occur, but later I realized that a solvent containing double bonds (e.g., soy oil or other oil containing + PUFA) would very likely prevent the close association between vitamin E and ubiquinone which is necessary + for charge-transfer to occur. Since I think Koch and Szent-Gyorgyi were right in believing that electronic + activation is the most important feature of the living state, I think the very specific electronic + interaction between vitamin E and ubiquinone must play an important role in the respiratory function of + ubiquinone. Ubiquinone is known to be a part of the electron transport chain which can leak electrons, so + this might be one of the ways in which vitamin E can prevent the formation of toxic free-radicals. If it can + prevent the "leakage" of electrons, then this in itself would improve respiratory efficiency. If unsaturated + oils interfere with this very specific but delicate bond, then this could explain, at least partly, their + toxicity for mitochondria. ["Electron leak" reference: B. Halliwell, in Age Pigments (R. S. Sohal, + ed.), pp. 1-62, Elsevier, Amsterdam, 1981.] +

+
+

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+ +

© Ray Peat 2006. All Rights Reserved. www.RayPeat.com

+ + diff --git a/raypeat-articles/processed/osteoporosis-aging.html b/raypeat-articles/processed/osteoporosis-aging.html new file mode 100644 index 0000000..babfc97 --- /dev/null +++ b/raypeat-articles/processed/osteoporosis-aging.html @@ -0,0 +1,495 @@ + + + +

+ +

+ Osteoporosis, aging, tissue renewal, and product science +

+

+ The incidence of osteoporosis, like obesity, has been increasing in recent decades. The number of hip + fractures in many countries has doubled in the last 30 or 40 years (Bergstrom, et al., 2009). An exception + to that trend was Australia in the period between 2001 and 2006, where the annual incidence of hip fractures + in women over 60 years old decreased by 28.3%. During those years, the number of prescriptions for "hormone + replacement therapy" decreased by 54.6%, and the number of prescriptions for bisphosphonate increased by + 245%. The publication of the Women's Health Initiative results in 2002 (showing that the Prem-Pro treatment + caused breast cancer, heart attacks, and dementia), led to a great decrease in the use of estrogen + treatments everywhere. After the FDA approved estrogen's use in 1972 for the prevention of osteoporosis the + number of women using it increased greatly, and by 1994, 44% of women in the US had used it. After the WHI + results were published, the number of prescriptions for "HRT" fell by more than half, and following that + decrease in estrogen sales, the incidence of breast cancer decreased by 9% in women between the ages of 50 + and 54.With the incidence of hip fractures increasing while the percentage of women using estrogen was + increasing, it seems likely that there is something wrong with the theory that osteoporosis is caused by an + estrogen deficiency. That theory was derived from the theory that menopause was the consequence of ovarian + failure, resulting from the failure to ovulate and produce estrogen when the supply of eggs was depleted. + The theory was never more than an ideological preference, but the estrogen industry saw it as an opportunity + to create a huge market.There are many studies that seem to imply that the greater incidence of osteoporotic + fractures among women is the result of their exposure to estrogen during their reproductive years. This + would be analogous to the understanding that it is the cumulative exposure to estrogen that ages the nerves + in the hypothalamus that control the cyclic release of the gonadotropic hormones, causing the + menopause.. . . the nature of science itself changed around the middle of the last century, becoming + product and disease oriented, so that now relatively few people are continuing to study bones + objectively.Animal studies show that estrogen stunts growth, including bone growth. The high + estrogen levels in girls' teen years and early twenties accounts for the fact that women's bones are lighter + than men's. In rat studies, treatment with estrogen was found to enlarge the space between the jawbone and + the teeth, which is a factor in periodontal disease (Elzay, 1964). Teeth are very similar to bones, so it's + interesting that treating male or female rats with estrogen increases their incidence of tooth decay, and + removing their gonads was found to decrease the incidence (Muhler and Shafer, 1952). Supplementing them with + thyroid hormone decreased the incidence of cavities in both males and females (Bixler, et al., 1957).One of + the "estrogen receptors" appears to actively contribute to bone loss (Windahl, et al., 1999, 2001). Studies + in dogs following the removal of their ovaries found that there was an increase of bone remodeling and bone + formation rate in the first month, followed by a few months of slowed bone formation, but that by 10 months + after the surgery the bones had returned to their normal remodeling rate, and that "at no time was a + significant reduction in bone volume detected" (Boyce, et al., 1990). With the removal of the ovaries, the + production of progesterone as well as estrogen is affected, but the adrenal glands and other tissues can + produce those hormones.Until the influence of the estrogen industry overwhelmed it, ordinary science was + studying bone development in comprehensive ways, understanding its biological roles and the influences of + the environment on it. But the nature of science itself changed around the middle of the last century, + becoming product and disease oriented, so that now relatively few people are continuing to study bones + objectively.The outstanding physical-chemical property of bone is that it is a reservoir-buffer of carbon + dioxide, able to bind huge amounts of the gas into its structure.When carbon dioxide increases in the + bloodstream it is at first absorbed rapidly by the bones, and if the blood level of CO2 is kept high day + after day, the rate of absorption gradually slows down, but in experiments that have continued for several + weeks the bones were still slowly absorbing more carbon dioxide; the absorption curve seems to be + asymptotic. When people move to or from high altitudes, their bones appear to continue adapting to the + different gas pressures for years. A reduction of atmospheric pressure (which allows the tissues to retain + more carbon dioxide) helps to reduce the calcium loss caused by immobility (Litovka and Berezovs'ka, 2003; + Berezovs'kyi, et al., 2000), and promotes the healing of damaged bone (Bouletreau, et al., 2002). Ultrasound + treatment, which accelerates bone healing, stimulates processes similar to reduced oxygen supply (Tang, et + al., 2007). The mineral in newly formed bone is calcium carbonate, and this is gradually changed to include + a large amount of calcium phosphate. Besides forming part of the mineral, carbon dioxide is also + incorporated into a protein (in a process requiring vitamin K), in a process that causes this protein, + osteocalcin, to bind calcium. The osteocalcin protein is firmly bonded to a collagen molecule. Collagen + forms about 30% of the mass of bone; several percent of the bone consists of other organic molecules, + including osteocalcin, and the rest of the mass of the bone consists of mineral.Thyroid hormone is essential + for forming carbon dioxide. In the early 1940s, experimental rabbits were fed their standard diet, with the + addition of 1% desiccated thyroid gland, which would be equivalent to about 150 grains of Armour thyroid for + a person. They became extremely hypermetabolic, and couldn't eat enough to meet their nutritional needs for + growth and tissue maintenance. When they died, all of their tissues weighed much less than those of animals + that hadn't received the toxic dose of thyroid, except for their bones, which were larger than normal. + Experiments with the thin skull bones of mice have shown that the active thyroid hormone, T3, increases the + formation of bone. To increase cellular respiration and carbon dioxide production, T3 increases the activity + of the enzyme cytochrome oxidase, which uses copper as a co-factor. Increased thyroid activity increases the + absorption of copper from foods.There is an inherited condition in humans, called osteopetrosis or marble + bone disease, caused by lack of a carbonic anhydrase enzyme, which causes them to retain a very high level + of carbon dioxide in their tissues. Using a chemical that inhibits carbonic anhydrase, such as the diuretic + acetazolamide, a similar condition can be produced in animals. Acetazolamide inhibits the bone resorbing + actions of parathyroid hormone, including lactic acid formation and the release of the lysosomal enzyme, + beta-glucuronidase (Hall and Kenny, 1987). While lactic acidosis causes bone loss, acidosis caused by + increased carbonic acid doesn't; low bicarbonate in the body fluids seems to remove carbonate from the bone + (Bushinsky, et al., 1993), and also mineral phosphates (Bushinsky, et al., 2003). The parathyroid hormone, + which removes calcium from bone, causes lactic acid to be formed by bone cells (Nijweide, et al., 1981; + Lafeber, et al., 1986). Lactic acid produced by intense exercise causes calcium loss from bone (Ashizawa, et + al., 1997), and sodium bicarbonate increases calcium retention by bone. Vitamin K2 (Yamaguchi, et al., 2003) + blocks the removal of calcium from bone caused by parathyroid hormone and prostaglandin E2, by completely + blocking their stimulation of lactic acid production by bone tissues. Aspirin, which, like vitamin K, + supports cell respiration and inhibits lactic acid formation, also favors bone calcification. Vitamin K2 + stimulates the formation of two important bone proteins, osteocalcin and osteonectin (Bunyaratavej, et al., + 2009), and reduces the activity of estrogen by oxidizing estradiol (Otsuka, et al, 2005).The formation of + eggshell, which is mostly calcium carbonate, is analogous to the early stage of bone formation. In hot + weather, when chickens pant and lower their carbon dioxide, they form thin shells. A sodium bicarbonate + supplement improves the quality of the eggshell (Balnave and Muheereza, 1997; Makled and Charles, 1987). + Chickens that habitually lay eggs with thinner shells have lower blood bicarbonate than those that lay thick + shelled eggs (Wideman and Buss, 1985). One of the arguments for stopping the sale of DDT in the US was that + it was threatening to cause extinction of various species of bird because it caused them to lay eggs with + very weak shells. Several other synthetic estrogenic substances, ethynylestradiol, lindane, PCBs, cause + eggshell thinning, partly by altering carbonic anhydrase activity (Holm, et al, 2006). Estrogen and + serotonin activate carbonic anhydrase in some tissues, progesterone tends to inhibit it. DDE, a metabolite + of DDT, reduces medullary bone formation in birds (Oestricher, et al., 1971) and bone mineral density in men + (Glynn, et al., 2000). Among its estrogenic effects, DDE increases prolactin (Watson, et al., 2007); one + form of DDT inhibits progesterone synthesis and increases estrogen (Wojtowics, et al., 2007)In youth, the + mineralization of the collagen framework is slightly lower than in maturity, and the bones are more + flexible. With aging, the mineralization increases progressively, and the proportion of collagen decreases + slightly, and the bones become increasingly brittle. (Rogers, et al., 1952; Mbuyi-Muamba, et al., 1987). + Collagen is a major part of the extracellular substance everywhere in the body, and its concentration + increases with aging in the non-calcified tissues. There is considerable renewal and modification of + collagen, as new molecules are formed and old molecules broken down, but its average structure changes with + aging, becomes less soluble and more rigid, as the result of chemical cross-links formed between molecules. + These cross-links are involved in regulating the differentiation of bone cells (Turecek, et al., 2008). + Recently (August 2, 2011), Deasey et al., have published evidence showing that cross-linking is required for + bone mineralization (2011).The outstanding physical-chemical property of bone is that it is a + reservoir-buffer of carbon dioxide, able to bind huge amounts of the gas into its structure.Around 1950, Fritz Verzar began studying the changes of collagen that occur with aging, and his work led to + the "collagen theory of aging." He showed that older, stiffer, less elastic tendons have a higher "melting" + or contracting temperature than young tendons. (This effect is responsible for the curling of a piece of + meat when it is frying.) Verzar and his colleagues investigated the effects of hormonal treatments on the + aging of rat collagen, especially in their tail tendons. They found that estrogen treatment increased the + stiffness and the melting temperature of collagenous tissues. While estrogen increased the cross-linking + with aging, removing the pituitary gland was found to retard the aging. Later, the cross-linking enzymes + transglutaminase and lysyl oxidase, which are induced by estrogen, were found to be a major factor in the + cross-linking of collagen and other molecules.When estrogen was found to age the connective tissues, it was + assumed that continual breeding during an animal's life-time, greatly increasing the total exposure of the + tissues to estrogen, would increase the aged rigidity of the connective tissues, but these animals were + found to have less rigid tissues. During pregnancy other hormones, especially progesterone, were also + increased, and it was suggested that this reversed the effects of aging and estrogen. Since most people had + believed that frequent pregnancies would cause a woman to age more rapidly, a large survey of records was + done, to compare the longevity of women with the number of pregnancies. It was found, in the very extensive + Hungarian records, that life-span was increased in proportion to the number of pregnancies.Despite these + very interesting results in the 1950s and 1960s, the growing influence of the estrogen industry changed the + direction of aging research, favoring the belief that decreasing estrogen accelerated the deterioration of + tissues in aging, and the popularity of Denham Harman's "free radical theory of aging" led many people to + assume that random reactions produced by lipid peroxidation were responsible for most of the cross-linking, + and that theory was gradually replaced by the "glycation" theory of aging, in which sugar molecules break + down and form the cross-links, by random, non-enzymic processes. Estrogen's role in aging was completely + by-passed.The meat industry is interested in reducing the toughness of meat, by influencing the nature of + the collagen in muscle. Castrated animals were found to produce meat that was tenderer than that of intact + males. When castrated animals were treated with testosterone, the amount of collagen was increased, making + the meat tougher. But when dihydrotestoserone, which can't be converted to estrogen was used, the meat + didn't become tough. Treatment with estrogen produced the same increase of collagen as treatment with + testosterone, showing that testosterone's effect was mainly the result of its conversion to estrogen + (Miller, et al., 1990).In the 1960s and '70s the estrogen industry was looking for ways to build on the + knowledge that in puberty estrogen is responsible for accelerating the calcification of the growth plate at + the ends of the long bones, and to find a rationale for selling estrogen to all women concerned with the + problems of aging. As bone metabolism was investigated, two kinds of cell were found to be active in + constantly remodeling the bone structure: Osteoclasts (breaking it down), and osteoblasts (building new + bone). Estrogen was found to slow the actions of the osteoclasts, so the idea that it would delay + osteoporosis became the basis for a huge new marketing campaign. Slowing bone metabolism became the focus. + Although estrogen was known to increase prolactin, and prolactin was known to accelerate bone loss, nearly + all publications began to focus on substances in the blood or urine that corresponded to the rate of bone + turnover, with the implication that increasing bone turnover would correspond to a net loss of bone.This was + the context in which, during the 1980s, articles about thyroxine's role in causing osteoporosis began to + appear. The thyroid hormone supports bone renewal, and increases indicators of bone breakdown in the blood + and urine. If estrogen's use was to be justified by slowing bone turnover, then the effects of thyroid, + accelerating bone turnover, should be interpreted as evidence of bone destruction.A basic problem with many + of the publications on thyroid and bone loss was that they were talking about an unphysiological medical + practice (prescribing the pre-hormone, thyroxine), which frequently failed to improve thyroid function, and + could even make it worse, by lowering the amount of T3 in the tissues.Later, it was noticed that high TSH + was associated with the signs of lower bone turnover. TSH rises when there is less thyroid hormone, but + (after the recombinant TSH became available for medical use) a few publications argued that it was the TSH + itself, rather than the absence of thyroid hormone, that was "protecting" the bones (lowering the evidence + of bone turnover). The doctrine that had been developed to support estrogen therapy was now used to oppose + thyroid therapy. Keeping the TSH high would slow bone turnover. Working in this cultural context, genetic + engineers at Amgen identified a protein that inhibited the formation of osteoclast cells, and slowed bone + metabolism. It was suggested that it was responsible for estrogen's suppression of the osteoclasts, and many + publications appeared showing that it was increased by estrogen. It was named "osteoprotegerin," meaning + "the bone protecting protein." Prolactin increases osteoprotegerin (OPG), reducing bone resorption just as + estrogen does. Serotonin also increases OPG, and it turns out that OPG is elevated in all of the + pathological conditions associated with high serotonin, including cancer, pulmonary artery hypertension, + vascular calcification, and even bone loss.While Arthur Everitt, Verzar, and others were studying the + effects of the rat's pituitary (and other glands) on collagen, W. D. Denckla investigated the effects of + reproductive hormones and pituitary removal in a wide variety of animals, including fish and mollusks. He + had noticed that reproduction in various species (e.g., salmon) was quickly followed by rapid aging and + death. Removing the pituitary gland (or its equivalent) and providing thyroid hormone, he found that animals + lacking the pituitary lived much longer than intact animals, and maintained a high metabolic rate. Making + extracts of pituitary glands, he found a fraction (closely related to prolactin and growth hormone) that + suppressed tissue oxygen consumption, and accelerated the degenerative changes of aging.Aging, estrogen, + cortisol, and a variety of stresses, including radiation and lipid peroxidation, chemically alter collagen, + producing cross-links that increase its rigidity, and affect the way it binds minerals. The cross-linking + enzymes induced by estrogen are involved in the normal maturation of bone collagen, and at puberty when + estrogen increases, bone growth is slowed, as the cross-linking and mineralization are accelerated. With + aging and the accumulation of heavy metals and polyunsaturated fats, random oxidative processes increase the + cross-linking. In bones, the relatively large masses of cartilage absorb oxygen and nutrients slowly, so + internally the amount of oxygen is very limited, about 1/5 as much as at the surface, and this low oxygen + tension is an important factor in regulating growth, differentiation, cross-linking, and calcification, + maintaining bone integrity. But in blood vessels the connective tissues are abundantly supplied with oxygen + and nutrients; this is normally a factor regulating the production of collagen and its cross-linking, and + preventing calcification. When the factors promoting collagen synthesis and maturation are increased + systemically, with aging and stress, the excess cross-linking slows the biological renewal process in bones, + but in blood vessels the same processes creating excess cross-linking initiate a calcification process, + involving the various factors that in youth are responsible for normal maturation of bone.Prolactin, like + estrogen, interferes with thyroid function and oxygen consumption (Wade, et al., 1986; Strizhkov, 1991; + Spatling, et al., 1982). Many years ago, repeated lactation was considered to cause osteoporosis and loss of + teeth, and prolactin, which mobilizes calcium from bones for the production of milk, was recognized as an + important factor in bone loss. Drugs that increase prolactin were found to cause osteoporosis. In the 40 + years since the drug industry began its intense promotion of estrogen to prevent and treat osteoporosis, + there has been very little attention to the fact that estrogen increases prolactin, which contributes to + osteoporosis, but some people (e.g., Horner, 2009) have noticed that oral contraceptives and menopausal + hormone treatments have damaged the bones of the inner ear, causing otosclerosis and impaired hearing, and + have suggested that prolactin mediates the effect.A few years ago, the "serotonin reuptake inhibitor" + antidepressants, already known to increase prolactin by increasing the effects of serotonin, were found to + be causing osteoporosis after prolonged use. Estrogen increases serotonin, which besides promoting the + secretion of prolactin, also stimulates the production of parathyroid hormone and cortisol, both of which + remove calcium from bone, and contribute to the calcification of blood vessels. The association between + weakened bones and hardened arteries is now widely recognized, but researchers are being careful to avoid + investigating any mechanisms that could affect sales of important drug products, especially estrogen and + antidepressants.Following the recognition that the SSRI drugs were causing osteoporosis, it was discovered + that the serotonin produced in the intestine causes bone loss, and that inhibiting intestinal serotonin + synthesis would stop bone loss and produce a bone building anabolic effect (Inose, et al., 2011). One group + that had been concentrating on the interactions of genes commented that, recognizing the effects of + intestinal serotonin, they had suddenly become aware of "whole organism physiology" (Karsenty and Gershon, + 2011).In previous newsletters I have talked about the ability of intestinal irritation and the associated + increase of serotonin to cause headaches, asthma, coughing, heart and blood vessel disease, muscular + dystrophy, flu-like symptoms, arthritis, inflammation of muscles and nerves, depression, and inflammatory + brain diseases. With the new recognition that serotonin is a basic cause of osteoporosis, intestinal health + becomes a major issue in aging research.The protein that inhibits intestinal formation of serotonin is the + low density lipoprotein receptor-related protein. This seems likely to have something to do with the fact + that "low" HDL is associated with better bones. A low level of LDL is associated with increased vertebral + fractures (Kaji, et al., 2010).Cartilage synthesis and turnover are highest at night. It is inhibited by + metabolic acidosis (increased lactic acid), but not by respiratory acidosis (CO2) (Bushinsky, 1995). Since + most calcium is lost from bone during the night (Eastell, et al., 1992; even in children: DeSanto, et al., + 1988) in association with the nocturnal rise of the catabolic substances, such as free fatty acids, + cortisol, prolactin, PTH, and adrenalin, things which minimize the nocturnal stress can decrease the bone + turnover. These include calcium (Blumsohn, et al., 1994) and sugar. Catabolic substances and processes + increase with aging, especially at night. Babies grow most during the night when bone turnover is high, and + even a daytime nap accelerates collagen turnover (Lutchman, et al., 1998). Discussions about whether a + certain person's osteoporosis is "menopausal osteoporosis" or "senile osteoporosis" have neglected the + possibility that osteoporosis doesn't begin in either menopause or old age, but that it is the result of + life-long developmental processes that interact with all the factors that are involved in aging. The fact + that the collagen content of old bone is lower than in young bone (as a percentage of bone weight) shows + that the problem in osteoporosis isn't a lack of calcification, it's a deficiency of tissue renewal, + parallel to sarcopenia, the decrease of muscle mass with aging. Systemically decreased tissue renewal would + account for the association of bone loss with other processes such as male baldness (Morton, et al., 2007) + and Alzheimer's disease (Zhou, et al., 2011, Duthie, et al., 2011).A high level of respiratory energy + production that characterizes young life is needed for tissue renewal. The accumulation of factors that + impair mitochondrial respiration leads to increasing production of stress factors, that are needed for + survival when the organism isn't able to simply produce energetic new tissue as needed. Continually + resorting to these substances progressively reshapes the organism, but the investment in short-term + survival, without eliminating the problematic factors, tends to exacerbate the basic energy problem. This + seems to be the reason that Denckla's animals, deprived of their pituitary glands, but provided with thyroid + hormone, lived so long: they weren't able to mobilize the multiple defenses that reduce the mitochondria's + respiratory energy production. Several things that the geneticists would never be able to fit into their + schemes of "bone regulatory molecules" such as OPG, growth hormone, parathyroid hormone, and estrogen, fit + neatly with the idea that bone health is maintained by respiratory energy and tissue renewal, under the + influence of thyroid hormone. For example, adrenaline, which is increased by stress, aging, and + hypothyroidism (and in many cases by estrogen), causes bone loss. Even the bone loss caused by immobility + can be blocked by an adrenaline blocker such as propranolol. (The stress of immobility also famously + increases serotonin.) Adrenaline tends to decrease carbon dioxide and increase lactic acid, and it strongly + increases parathyroid hormone (Ljunhgall S, et al., 1984). Calcium activates mitochondrial respiration, and + lowers adrenaline (Luft, et al., 1988), parathyroid hormone (Ohgitani, et al., 1997), and prolactin (Kruse + and Kracht, 1981). Copper, which is the co-factor for the cytochrome C oxidase enzyme, activated by thyroid, + is essential for bone formation and maintenance, and is consistently deficient in osteoporosis. Thyroid + hormone increases the body's ability to assimilate copper. Aspirin, which stimulates bone formation, has + other thyroid-like actions, including activation of mitochondrial respiration and energy production, with an + increase of cytochrome C oxidase (Cai, et al., 1996), and it lowers serotonin (Shen, et al., 2011). It also + apparently protects against calcification of the soft tissues, (Vasudev, et al., 2000), though there has + been surprisingly little investigation of that. "Aspirin can promote trabecular bone remodeling, improve + three-dimensional structure of trabecular bone and increase bone density of cancellous in osteoporotic rats + by stimulating bone formation. It may become a new drug for the treatment of osteoporosis" (Chen, et al., + 2011).A wide range of inflammatory mediators that accelerate inflammation and bone loss also inhibit thyroid + function. People who ate more polyunsaturated fat, which inhibits thyroid and oxidative metabolism, were + several times more likely to have osteoporotic fractures (that is, essentially spontaneous fractures) than + people who ate the least (Martinez-Ramirez, et al., 2007). Arachidonic acid stimulates prolactin secretion, + and prolactin acts on the thyroid gland to decrease its activity, and on other tissues to increase their + glycolysis (with lactate production), while decreasing oxidative metabolism (Spatling, et al., 1982; + Strizhkov, 1991). Living at high altitude, which strengthens bones, increases thyroid activity and decreases + prolactin (Richalet, et al., 2010) and parathyroid hormone (Khan, et al., 1996). It lowers free fatty acids, + which lower bone mass by reducing bone formation and increasing bone resorption (Chen, et al., 2010). In + menopausal women, polyunsaturated fatty acids and even monounsaturated fats are associated with bone loss, + fruit and vegetable consumption protects against bone loss (Macdonald, et al., 2004).While it's very + interesting that the drug propranol which blocks adrenaline, and drugs that block serotonin formation, have + bone protective and restorative effects, they also have undesirable side effects. Food choices that optimize + oxidative metabolism are the safest, as well as the most economical, way to approach the problem of + osteoporosis and other degenerative changes. A person can easily perceive changes in appetite, quality of + sleep, changes in skin, hair, and mood, etc., but blood tests could be used to confirm that the right + choices were being made. Tests for vitamin D, parathyroid hormone, free fatty acids, and CO2/bicarbonate, as + well as the hormones, can be helpful, if a person isn't sure whether their diet, sunlight exposure, and + thyroid supplementation is adequate. The popular medical understanding of the organism is based on a + mechanistic view of causality, in which genes have a central role, causing things to develop and function in + certain ways, and that hormones and drugs can cause genes to increase or decrease their activity. Genes that + build bones can be activated by one substance, and genes that tear down bones can be inhibited by another + substance. The "osteoprotegerin" story illustrates the problem with that kind of thinking. Vernadsky's + description of an organism as a "whirlwind of atoms" is probably a better way to think of how "causality" + works. The moving air in a whirlwind forms a self-intensifying system, with the motion reducing the + pressure, causing more air to be drawn into the system. The atoms moving in coordination aren't acting as + separate things, but as parts in a larger thing. The way in which increased metabolism in the bones acts + favorably on the metabolism of kidneys, blood vessels, lungs, liver, digestive system, etc., which in turn + favors the bones' renewal, is analogous to the tendency of a whirlwind to intensify as long as there is a + source of energy. The intensity of oxidative metabolism is the basic factor that permits continuing + coordination of activity, and the harmonious renewal of all the components of the organism. +

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Kruse K, Kracht U.Endocrinology. 1986 Nov;119(5):2249-55. Parathyroid + hormone-like effects of rainbow trout Stannius products on bone resorption of embryonic mouse calvaria + in vitro. Lafeber FP, Schaefer HI, Herrmann-Erlee MP, Wendelaar Bonga SE.Fiziol Zh. + 2003;49(2):58-65. [Oxygen deprivation as the initiator of osteogenesis in hypokinesia]. + Litovka IH, Berezovs'ka OP. Exp Clin Endocrinol. 1984 Dec;84(3):313-8. Effects of epinephrine and + norepinephrine on serum parathyroid hormone and calcium in normal subjects. Ljunhgall S, + Akerstrom G, Benson L, Hetta J, Rudberg C, Wide L.Ann Nutr Aliment. 1975;29(4):313-9. [Comparative + study of the effect of free and combined glucose and fructose on the absorption and retention of + calcium]. Lorinet A. 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Macdonald HM, New SA, Golden MH, Campbell MK, Reid + DM.Poult Sci. 1987 Apr;66(4):705-12. + Eggshell quality as influenced by sodium bicarbonate, calcium source, and photoperiod. Makled + MN, Charles OW.Eur J Clin Nutr. 2007 Sep;61(9):1114-20. Dietary fat intake and the risk of + osteoporotic fractures in the elderly. + Martinez-Ramirez MJ, Palma S, Martinez-Gonzalez MA, Delgado-Martinez AD, de la Fuente C, + Delgado-Rodriguez M.Clin Biochem. 1987 Jun;20(3):221-4. Studies on EDTA extracts and collagenase + digests from osteoporotic cancellous bone of the femoral head. Mbuyi-Muamba JM, Gevers G, + Dequeker J.J Anim Sci 1990, 68:1044-1048, Intramuscular collagen and serum hydroxyproline as related + to implanted testosterone, dihydrotestosterone and estradiol-17 beta in growing wethers, Miller + LF, Judge MD, Schanbacker BD.J Aging Health. 2007 Apr;19(2):275-85. Premature graying, balding, and + low bone mineral density in older women and men: the Rancho Bernardo study. 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Ohgitani S, Fujii Y, Fujita T.Life Sci. 2005 Apr 8;76(21):2473-82. + Vitamin K2 binds 17beta-hydroxysteroid dehydrogenase 4 and modulates estrogen metabolism. + Otsuka M, Kato N, Ichimura T, Abe S, Tanaka Y, Taniguchi H, Hoshida Y, Moriyama M, Wang Y, Shao RX, Narayan + D, Muroyama R, Kanai F, Kawabe T, Isobe T, Omata M.Osteoporos Int. 1995;5(6):472-7. Circadian rhythm + in type I collagen formation in postmenopausal women with and without osteopenia. Pedersen BJ, + Schlemmer A, Rosenquist C, Hassager C, Christiansen C.Acta Physiol Scand. 1997 Oct;161(2):161-9. Serotonin inhibition of 1-methylxanthine metabolism parallels its vasoconstrictor activity and inhibition + of oxygen uptake in perfused rat hindlimb. + Rattigan S, Appleby GJ, Miller KA, Steen JT, Dora KA, Colquhoun EQ, Clark MG.Am J Physiol Regul + Integr Comp Physiol. 2010 Dec;299(6):R1685-92. Effects of high-altitude hypoxia on the hormonal + response to hypothalamic factors. 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Response of biochemical markers of bone turnover to oral glucose load in diseases that affect bone + metabolism. + Yavropoulou MP, Tomos K, Tsekmekidou X, Anastasiou O, Zebekakis P, Karamouzis M, + Gotzamani-Psarrakou A, Chassapopoulou E, Chalkia P, Yovos JG.Exp Clin Endocrinol. 1984 Dec;84(3):294-8. + Hypercalcaemia and calcitonin inhibit prolactin secretion. Zofkova I, Nedvidkova J.J + Alzheimers Dis. 2011;24(1):101-8. Association between bone mineral density and the risk of + Alzheimer's disease. Zhou R, Deng J, Zhang M, Zhou HD, Wang YJ. +

+

+ © Ray Peat Ph.D. 2012. All Rights Reserved. www.RayPeat.com +

+ + diff --git a/raypeat-articles/processed/osteoporosis.html b/raypeat-articles/processed/osteoporosis.html new file mode 100644 index 0000000..1510322 --- /dev/null +++ b/raypeat-articles/processed/osteoporosis.html @@ -0,0 +1,536 @@ + + Osteoporosis, harmful calcification, and nerve/muscle malfunctions + +

+ Osteoporosis, harmful calcification, and nerve/muscle malfunctions +

+ +

+ During pregnancy, a woman's ability to retain dietary calcium and iron increases, and the baby seems to be + susceptible to overloading. A normal baby doesn't need dietary iron for several months, as it uses the iron + stored in its tissue, and recently it has been reported that normal fetuses and babies may have calcified + pituitary glands. Pituitary cell death is sometimes seen with the concretions. (Groisman, et al.) + Presumably, the calcification is resorbed as the baby grows. This is reminiscent of the "age pigment" that + can be found in newborns, representing fetal stress from hypoxia, since that too disappears shortly after + birth. Iron overload, age pigment, and calcification of soft tissues are so commonly associated with old + age, that it is important to recognize that the same cluster occurs at the other extreme of (young) age, and + that respiratory limitations characterize both of these periods of life. +

+

+ Calcium is probably the most popular element in physiological research, since it functions as a regulatory + trigger in many cell processes, including cell stimulation and cell death. Its tendency to be deposited with + iron in damaged tissue has often been mentioned. In hot weather, chickens pant to cool themselves, and this + can lead to the production of thin egg shells. Carbonated water provides enough carbon dioxide to replace + that lost in panting, and allows normal calcification of the shells. [Science 82, May, 1982] The deposition + of calcium is the last phase of the "tertiary coat" of the egg, to which the oviduct glands successively add + albumin, "egg membrane," and the shell, containing matrix proteins (including some albumin; Hincke, 1995) + and calcium crystals. Albumin is the best understood of these layers, but it is still complex and + mysterious; its unusual affinity for metal ions has invited comparisons with proteins of the immune system. + It is known to be able to bind iron strongly, and this is considered to have an "immunological" function, + preventing the invasion of organisms that depend on iron. Maria de Sousa ("Iron and the lymphomyeloid + system: A growing knowledge," Iron in Immunity, Cancer and Inflammation, ed. by M. de Sousa and J. H. Brock, + Wiley & Sons, 1989) has argued that the oxygen delivery system and the immune system evolved together, + recycling iron in a tightly controlled system. +

+

+ The role of macrophages in the massive turnover of hemoglobin, and as osteoclasts, gives us a perspective in + which iron and calcium are handled in analogous ways. Mechnikov's view of the immune system, growing from + his observations of the "phagocytes," similarly gave it a central role in the organism as a form-giving/ + nutrition-related process. In a family with "marble-bone disease," or osteopetrosis, it was found that their + red blood cells lacked one form of the carbonic anhydrase enzyme, and that as a result, their body fluids + retained abnormally high concentrations of carbon dioxide. Until these people were studied, it had been + assumed that an excess of carbon dioxide would have the opposite effect, dissolving bones and causing + osteoporosis or osteopenia, instead of osteopetrosis. The thyroid hormone is responsible for the carbon + dioxide produced in respiration. Chronic hypothyroidism causes osteopenia, and in this connection, it is + significant that women (as a result of estrogen's effects on the thyroid) are much more likely than men to + be hypothyroid, and that, relative to men, women in general are "osteopenic," that is, they have more + delicate skeletons than men do. +

+ +

+ In an experiment, rats were given a standard diet, to which had been added 1% Armour thyroid, that is, they + were made extremely hyperthyroid. Since their diet was inadequate (later experiments showed that this amount + of thyroid didn't cause growth retardation when liver was added to the diet) for their high metabolic rate, + they died prematurely, in an apparently undernourished state, weighing much less than normal rats. Their + bones, however, were larger and heavier than the bones of normal rats. A few incompetent medical "studies" + have made people fear that "taking thyroid can cause osteoporosis." Recognizing that hypothyroid women are + likely to have small bones and excessive cortisol production, the inadequate treatment of hypothyroidism + with thyroxin (the thyroid-suppressive precursor material), is likely to be associated with relative + osteoporosis, simply because it doesn't correct hypothyroidism. Similar misinterpretations have led people + to see an association between "thyroid use" (generally thyroxin) and breast cancer--hypothyroid women are + likely to have cancer, osteoporosis, obesity, etc., and are also likely to have been inadequately treated + for hypothyroidism. T3, the active form of thyroid hormone, does contribute to bone formation. (For example, + M. Alini, et al.) +

+

+ Around the same time (early 1940s) that the effects of thyroid on bone development were being demonstrated, + progesterone was found to prevent age-related changes in bones, and "excessive" seeming doses of thyroid + were found to prevent age-related joint diseases in rats. +

+

+ A logical course of events, building on these and subsequent discoveries, would have been to observe that + the glucocorticoids cause a negative calcium balance, leading to osteoporosis, and that thyroid and + progesterone oppose those hormones, protecting against osteoporosis. But the drug industry had discovered + the profits in estrogen ("the female hormone") and the cortisone-class of drugs. Estrogen was promoted to + prevent miscarriages, to stop girls (and boys) from growing too tall, to cure prostate and breast cancer, to + remedy baldness, and 200 other absurdities. As all of those frauds gradually became untenable, even in the + commercial medical culture, the estrogen industry began to concentrate on osteoporosis and femininity. Heart + disease and Alzheimer's disease back those up. +

+

+ "If estrogen causes arthritis, prescribe prednisone for the inflammation. If prednisone causes osteoporosis, + increase the dose of estrogen to retard the bone-loss. People are tough, and physiological therapies aren't + very profitable." +

+

+ Fifteen years ago I noted in a newsletter that hip fractures most often occur in frail, underweight old + women, and that heavier, more robust women seem to be able to bear more weight with less risk of fracture. + Although I hadn't read it at the time, a 1980 article (Weiss, et al.) compared patients with a broken hip or + arm with a control group made up of hospitalized orthopedic patients with problems other than hip or arm + fractures. The fracture cases' weight averaged 19 pounds lighter than that of the other patients. They were + more than 3.6 times as likely to be alcoholic or epileptic. It would be fair to describe them as a less + robust group. +

+

+ Since the use of estrogen has become so common in the U.S., it is reasonable to ask whether the incidence of + hip fractures in women over 70 has declined in recent decades. If estrogen protects against hip fractures, + then we should see a large decrease in their incidence in the relevant population. +

+

+ Hip fractures, like cancer, strokes, and heart disease, are strongly associated with old age. Because of the + baby-boom, 1945 to 1960, our population has a bulge, a disproportion in people between the ages of 35 and + 50, and those older. Increasingly, we will be exposed to publicity about the declining incidence of disease, + fraudulently derived from the actually declining proportion of old people. For example, analyzing claims + based on the pretense that the population bulge doesn't exist, I have seen great publicity given to studies + that would imply that our life-expectancy is now 100 years, or more. +

+

+ Comparing the number of hip fractures, per 1000 75 year old women, in 1996, with the rate in 1950, we would + have a basis for judging whether estrogen is having the effect claimed for it. +

+

+ The x-ray data seem to convince many people estrogen is improving bone health, by comparing measurements in + the same person before and after treatment. Does estrogen cause water retention? Yes. Does tissue water + content increase measured bone density? Yes. Are patients informed that their "bone scans" don't have a + scientific basis? No. The calcification of soft tissues under the influence of estrogen must also be taken + into account in interpreting x-ray evidence. (Hoshino, 1996) Granted that woman who are overweight have + fewer hip fractures (and more cancer and diabetes), what factors are involved? Insulin is the main factor + promoting fat storage, and it is anabolic for bone. (Rude and Singer, "Hormonal modifiers of mineral + metabolism.") The greatest decrease in bone mass resulting from insulin deficiency was seen in white + females, and after five years of insulin treatment, there was a lower incidence of decreased bone mass + (Rosenbloom, et al., 1977). McNair, et al. (1978 and 1979) found that the loss of bone mass coincided with + the onset of clinical diabetes. Since excess cortisol can cause both high blood sugar and bone loss, when + diabetes is defined on the basis of high blood sugar, it will often involve high blood sugar caused by + excess cortisol, and there will be calcium loss. Elsewhere, I have pointed out some of the similarities + between menopause and Cushing's syndrome; a deficiency of thyroid and progesterone can account for many of + these changes. Nencioni and Polvani have observed the onset of progesterone deficiency coinciding with bone + loss, and have emphasized the importance of progesterone's antagonism to cortisol. +

+ +

+ Johnston (1979) found that progesterone (but not estrone, estradiol, testosterone, or androstenedione) was + significantly lower in those losing bone mass most rapidly. +

+

+ Around the age of 50, when bone loss is increasing, progesterone and thyroid are likely to be deficient, and + cortisol and prolactin are likely to be increased. Prolactin contributes directly to bone loss, and is + likely to be one of the factors that contributes to decreased progesterone production. +

+

+ Estrogen tends to cause increased secretion of prolactin and the glucocorticoids, which cause bone loss, but + it also promotes insulin secretion, which tends to prevent bone loss. All of these factors are associated + with increased cancer risk. +

+

+ Thyroid and progesterone, unlike estrogen, stimulate bone-building, and are associated with a decreased risk + of cancer. It seems sensible to use thyroid and progesterone for their general anti-degenerative effects, + protecting the bones, joints, brain, immune system, heart, blood vessels, breasts, etc. +

+

+ But the issue of calcification/decalcification is so general, we mustn't lose interest just because the + practical problem of osteoporosis is approaching solution. +

+ +

+ For example, healthy high energy metabolism requires the exclusion of most calcium from cells, and when + calcium enters the stimulated or deenergized cell, it is likely to trigger a series of reactions that lower + energy production, interfering with oxidative metabolism. During aging, both calcium and iron tend to + accumulate and they both seem to have an affinity for similar locations, and they both tend to displace + copper. (Compare K. Sato, et al., on the calcification of copper-containing paints.) Elastin is a protein, + the units of which are probably bound together by copper atoms. In old age, elastin is one of the first + substances to calcify, for example in the elastic layers of arteries, causing them to lose elasticity, and + to harden into almost bone-like tubes. In the heart and kidneys, the mitochondria (rich in copper-enzymes) + are often the location showing the earliest calcification, for example when magnesium is deficient. +

+

+ Obviously, certain proteins have higher than average affinity for copper, iron, and calcium. For example, + egg-white's unusual behavior with copper can be seen if you make a meringue in a copper pan--the froth is + unusually firm. My guess is that copper atoms bind the protein molecules into relatively elastic systems. In + many systems, calcium forms the link between adhesive proteins. +

+

+ In brain degeneration, the regions that sometimes accumulate aluminum, will accumulate other metals instead, + if they predominate in the environment; calcium is found in this part of the brain in some of the Pacific + regions studied by Gajdusek. Certain cells in the brain used to be called "metalophils," because they could + be stained intensely with silver and other metals; I suppose these are part of the immune system, handling + iron as described by Maria de Sousa. Macrophages have been proposed as an important factor in producing + atherosclerotic plaques (Carpenter, et al.). There is evidence that they (and not smooth muscle cells) are + the characteristic foam cells, and their conversion of polyunsaturated oils into age pigment accounts for + the depletion of those fats in the plaques. The same evidence could be interpreted as a defensive reaction, + binding iron and destroying unsaturated fatty acids, and by this detoxifying action, possibly protecting + against calcification and destruction of elastin. (This isn't the first suggestion that atherosclerosis + might represent a protective process; see S. M. Plotnikov, et al., 1994.) +

+

+ Since carbon dioxide and bicarbonate are formed in the mitochondria, it is reasonable to suppose that the + steady outward flow of the bicarbonate anion would facilitate the elimination of calcium from the + mitochondria. Since damaged mitochondria are known to start the process of pathological calcification in the + heart and kidneys, it probably occurs in other tissues that are respiratorily stressed. And if healthy + respiration, producing carbon dioxide, is needed to keep calcium outside the cell, an efficient defense + system could also facilitate the deposition of calcium in suitable places--depending on specific protein + binding. The over-grown bones in the hyperthyroid rats and the women with osteopetrosis suggest that an + abundance of carbon dioxide facilitates bone formation. Since no ordinary inorganic process of + precipitation/crystallization has been identified that could account for this, we should consider the + possibility that the protein matrix is regulated in a way that promotes (or resists) calcification. The + affinity of carbon dioxide for the amine groups on proteins (as in the formation of carbamino hemoglobin, + which changes the shape of the protein) could change the affinity of collagen or other proteins for calcium. + Normally, ATP is considered to be the most important substance governing such changes of protein + conformation or binding properties, but ordinarily, ATP and CO2 are closely associated, because both are + produced in respiration. Gilbert Ling has suggested that hormones such as progesterone also act as cardinal + adsorbants, regulating the affinity of proteins for salts and other molecules. +

+

+ Cells have many proteins with variable affinity for calcium; for example in muscle, a system called the + endoplasmic reticulum, releases and then sequesters calcium to control contraction and relaxation. (This + calcium-binding system is backed up by--and is spatially in close association with--that of the + mitochondrion.) Ion-exchange resins can be chemically modified to change their affinity for specific ions, + and molecules capable of reacting strongly with proteins can change the affinities of the proteins for + minerals. What evidence is there that carbon dioxide could influence calcium binding? The earliest + deposition of crystals on implanted material is calcium carbonate. (J. Vuola, et al, 1996.) In newly formed + bone, the phosphate content is low, and increases with maturity. While mature bone has an apatite-like ratio + of calcium and phosphate, newly calcified bone is very deficient in phosphate (according to Dallemagne, the + initial calcium to phosphorus ratio is 1.29, and it increases to 2.20.) (G. Bourne, 1972; Dallemagne.) +

+

+ The carbonate content of bone is often ignored, but in newly formed bone, it is probably the pioneer. + Normally, "nucleation" of crystals is thought of as a physical event in a supersaturated solution, but the + chemical interaction between carbon dioxide and amino groups (amino acids, protein, or ammonia, for example) + removes the carbon dioxide from solution, and the carbamino acid formed becomes a bound anion with which + calcium can form a salt. With normal physiological buffering, the divalent calcium (Ca2+) should form a link + between the monovalent carbamino acid and another anion. Linking with carbonate (CO32-), one valence would + be free to continue the salt-chain. This sort of chemistry is compatible with the known conditions of bone + formation. +

+

+ Klein, et al. (1996), think of uncoupled oxidative phosphorylation in terms of "subtle thermogenesis," which + isn't demonstrated in their experiment, but their experiment actually suggests that stimulated production of + carbon dioxide is the factor that stimulates calcification. Their experiment seems to be the in vitro + equivalent of the various observations mentioned above. DHEA, which powerfully stimulates bone formation, is + (like thyroid and progesterone) thermogenic, but in these cases, the relevant event is probably the + stimulation of respiration, not the heat production. In pigs (Landrace strain) susceptible to malignant + hyperthermia, there is slow removal of calcium from the contractile apparatus of their muscles. Recent + evidence shows that an extramitochondrial NADH-oxidase is functioning. This indicates that carbon dioxide + production is limited. I think this is responsible for the cells' sluggishness in expelling calcium. +

+ +

+ Stress-susceptible pigs show abnormalities of muscle metabolism (e.g., high lactate formation) that are + consistent with hypothyroidism. (T. E. Nelson, et al., "Porcine malignant hyperthermia: Observations on the + occurrence of pale, soft, exudative musculature among susceptible pigs," Am. J. Vet. Res. 35, 347-350, 1974; + M. D. Judge, et al., "Adrenal and thyroid function in stress-susceptible pigs (Sus domesticus)," Am. J. + Physiol. 214(1), 146-151, 1968.) +

+

+ Malignant hyperthermia during surgery is usually blamed on genetic susceptibility and sensitivity to + anesthetics. (R. D. Wilson, et al., "Malignant hyperpyrexia with anesthesia," JAMA 202, 183-186, 1967; B.A + Britt and W. Kalow, "Malignant hyperthermia: aetiology unknown," Canad. Anaesth. Soc. J. 17, 316-330, 1970.) + Hypertonicity of muscles, various degrees of myopathy and rigidity, and uncoupling of oxidative + phosphorylation occur in these people, as in pigs. Lactic acidosis suggests that mitochondrial respiration + is defective in the people, as in the pigs. Besides the sensitivity to anesthetics, the muscles of these + people are abnormally sensitive to caffeine and elevated extracellular potassium. During surgery, artificial + ventilation, combined with stress, toxic anesthetics, and any extramitochondrial oxidation that might be + occurring (such as NADH-oxidase, which produces no CO2), make relative hyperventilation a plausible + explanation for the development of hyperthermia. Hyperventilation can cause muscle contraction. Panting + causes a tendency for fingers and toes to cramp. Free intracellular calcium is the trigger for muscle + contraction (and magnesium is an important factor in relaxation.) Capillary tone, similarly, is increased by + hyperventilation, and relaxed by carbon dioxide. The muscle-relaxing effect of carbon dioxide shows that the + binding of intracellular calcium is promoted by carbon dioxide, as well as by ATP. The binding of calcium in + a way that makes it unable to interfere with cellular metabolism is, in a sense, a variant of simple + extrusion of calcium, and the binding of calcium to extracellular materials. A relaxed muscle and a strong + bone are characterized by bound calcium. +

+

+ Activation of the sympathetic nervous system promotes hyperventilation. This means that hypothyroidism, with + high adrenalin (resulting from a tendency toward hypoglycemia because of inefficient use of glucose and + oxygen), predisposes to hyperventilation. +

+

+ Muscle stiffness, muscle soreness and weakness, and osteoporosis all seem to be consequences of inadequate + respiration, allowing lactic acid to be produced instead of carbon dioxide. Insomnia, hyperactivity, + anxiety, and many chronic brain conditions also show evidence of defective respiration, for example, either + slow consumption of glucose or the formation of lactic acid, both of which are common consequences of low + thyroid function. Several studies (e.g., Jacono and Robertson, 1987) suggest that abnormal calcium + regulation is involved in epilepsy. The combination of supplements of thyroid (emphasizing T3), magnesium, + progesterone and pregnenolone can usually restore normal respiration, and it seems clear that this should + normalize calcium metabolism, decreasing the calcification of soft tissues, increasing the calcification of + bones, and improving the efficiency of muscles and nerves. (Magnesium, like carbonate, is a component of + newly formed bone.) The avoidance of polyunsaturated vegetable oils is important for protecting respiration; + some of the prostaglandins they produce have been implicated in osteoporosis, but more generally, they + antagonize thyroid function and they can interfere with calcium control. The presence of the "Mead acid" + (the omega-9 unsaturated fat our enzymes synthesize) in cartilage suggests a new line of investigation + regarding the bone-toxicity of the polyunsaturated dietary oils. +

+

REFERENCES

+

+ G. R. Sauer, et al., "A facilitating role for carbonic anhydrase activity in matrix vesicle mineralization," + Bone and Mineral 26(1), 69-79, 1994. T. R. Anellet, "Effects of medium acidification by alteration of carbon + dioxide or bicarbonate concentration on the resorptive action of rat osteoclasts," J. Bone and Mineral Res. + 9(3), 375-379, 1994. (...resorption was almost abolished in the presence of 2.5% CO2 at pH 7.61 but + increased in a stepwise manner up to 1.3 pits per osteoclast when dentin slices were cultured with 10% CO2 + at pH 6.97.") +

+ +

+ D. A. Bushinsky, et al., "Acidosis and bone," Min. & Electrolyte Metab. 20(1-2), 40-52, 1994. ("During + acute respiratory acidosis there is no measurable influx of protons in bone and during chronic studies there + is no measurable calcium efflux.") +

+

+ D. A. Bushinsky, et al., "Decreased bone carbonate content in response to metabolic but not respiratory + acidosis," Amer. J. Physiol. 265(4, part 2), F530-F536, 1993. ("...elevated pCO2 doesn't allow bone + carbonate dissolution despite reduced pH.") +

+

+ J. Vuola, et al., "Bone marrow induced osteogenesis in hydroxyapatite and calcium carbonate implants," + Biomaterials 17(18), 1761-1766, 1996. A. H. Knell, I. J. Fairchild, and K. Swett, Palaios 8, 512-525, 1993. + (Late proterozoic ocean was supersaturated with calcium carbonate.) F. Marin, et al., "Sudden appearance of + calcified skeletons at precambrian-cambrian transition," Proc. Nat. Acad. Sci. U.S. 93(4), 1554-1559, 1996. +

+

+ M. J. Dallemagne, Acta Physiother. Rheumatol. Belg.3, 77, 1947; Nature (London) 161, 115, 1948; Annu. Rev. + Physiol. 12, 101, 1950; J. Physiol. (Paris) 43, 425, 1951. +

+

+ G. H. Bourne, ed., The Biochemistry and Physiology of Bone; Physiology and Pathology, Academic Press, 1972. +

+

+ J. A. Schlechte, et al., "Bone density in amenorrheic women with and without hyperprolactinemia," J. Clin. + Endocrinol. & Metabolism 56, 1120, 1983. (Evidence for a direct effect of prolactin on bone.) P. S. + Dannies, "Control of prolactin production by estrogen," chapter 9, p. 289, in Biochemical Actions of + Hormones XII, Academic Press, 1985. J.-J. Body, et al., "Calcitonin deficiency in primary hypothyroidism," + J. Clin. Endocrinology and Metabolism 62(4), 700, 1986. ("We conclude that the process that causes + hypothyroidism in patients with autoimmune thyroid disease can also cause marked CT deficiency.") T. + Nencioni and F. Polvani, "Rationale for the use of calcitonin in the prevention of post-menopausal + osteoporosis," in Calcitonin, A. Pecile, editor, Elsevier Science Publ., 1985. +

+

+ C. C. Johnston, et al., "Age-related bone loss," pages 91-100 in U. S. Barrel, editor, Osteoporosis II, + Grune and Stratton, N. Y., 1979. E. I. Barengolts, et al., "Progesterone antagonist RU 486 has bone-sparing + effects in ovariectomized rats," Bone 17(1), 21-25, 1995. "...progesterone prevents ovariectomy-induced bone + loss." M. Kasra and M. D. Grynpas, "The effects of androgens on the mechanical properties of primnate bone," + Bone 17(3), 265-270, 1995. D. J. Rickard, et al., "Importance of 1,25-dihydroxyvitamin D-3 and the + nonadherent cells of marrow for osteoblast differentiation from rat marrow stromal cells," Bone 16(6), + 671-678, 1995. ("...growth could be stimulated by...1,25-dihydroxyvitamin D-3, but not dexamethasone, 17 + beta-estradiol, or retinoic acid...." D-3 and glucocorticoids "may regulate osteogenesis from the bone + marrow but a similar role for estrogen is not supported.") P. W. Stacpoole, "Lactic acidosis and other + mitochondrial disorders," Metabolism 46(3), 306-321, 1997. +

+

+ L. M. Banks, et al., "Effect of degenerative spinal and aortic calcification on bone density measurements in + post-menopausal women: Links betwwen osteoporosis and cardiovascular disease?" Eur. J. of Clin. + Investigation 24(12), 813-817, 1994. ("Women with spinal degenerative calcification had higher spine bone + density when measured by dual photon absorptionmetry compared to those without calcification." "Women with + aortic calcification had significantly lower quantitative computer tomography and proximal femur bone + density compared to those without calcification." +

+

+ S. E. Wendelaar Bonga and G. Flik, "Prolactin and calcium metabolism in a teleost fish, Sarotherodon + mossambicus," Gen. Compar. Endocrinol. 46, 21-26, 1982. +

+ +

+ U.S. Barzel, "The skeleton as an ion exchange system: Implications for the role of acid-base imbalance in + the genesis of osteoporosis," J. of Bone and Mineral Res. 10(10), 1431-1436, 1995. +

+

+ P. Schneider and C. Reiners, Letter, JAMA 277(1), 23, Jan. 1, 1997. Dual-energy x-ray absorptiometry for + bone density can lead to false conclusions about bone mineral content, because of alterations in tissue fat + or water content. "The influence of fat distribution on bone mass measurements with DEXA can be of + considerable magnitude and ranges up to 10% error per 2 cm of fat." +

+

+ J. Pearson, et al, Osteoporosis 5, 174-184, 1995 J. Dequeker, et al, "Dual X-ray + absorptiometry--cross-calibration and normative reference ranges for the spine," Bone 17(3), 247-254, 1995 + ("...there is no uniformity in reporting results and in presenting reference data." "It is...crucially + important to select appropriate reference data in clinical and epidemiological studies.") T.M. Hangartner + and C. C. Johnston, "Influence of fat on bone measurements with dual-energy absorptionmetry," Bone Miner 9, + 71-81, 1990. R. Valkema, et al., "Limited precision of lumbar spine dual photon absorptiometry by variations + in the soft-tissue background," J. Nucl. Med. 31, 1774-1781, 1990. +

+ +

+ M. Silberberg and R. Silberberg, Arch. Path. 31(1), 85-92, 1941. (Progesterone counteracts aging of bone in + guinea pig.) M. Silberberg and R. Silberberg, Growth 4(3), 1305-14, 1940. (Decreased severity and incidence + of old-age changes in the joints of normal mice.) G. Coryn, "Recherche experimentale sur l'influence des + glands endocrines sur l'histologie du cartilage de conjugaison," Annales d'anatomie pathol. 16, 27, 1939. +

+

+ O. Rahn, "Protozoa need carbon dioxide for growth," Growth 5, 197-199, 1941. "On page 113 of this volume, + the statement of Valley and Rettger that all bacteria need carbon dioxide for growth had been shown to apply + to young as well as old cells." "...it is possible...to remove it as rapidly as it is produced, and under + these circumstances, bacteria cannot multiply." K. L. H. Carpenter, et al., "Production of ceroid and + oxidised lipids by macrophages in vitro," Lipofuscin--1987: State of the Art, I. Zs.-Nagy, editor, pp. + 245-268, 1988. +

+ +

+ A. Schlemmer, et al., "Posture, age, menopause, and osteopenia do not influence the circadian variation in + the urinary excretion of pyridinium crosslinks," J. Bone Miner. Res. 9(12), 1883-1888, 1994. N. S. Weiss, et + al., "Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen,:" N. + Engl. J. Med. 303, 1195-1198, 1980. +

+

+ S. M. Plotnikov, et al., "Anxiety, atherogenesis, and antioxidant protection: Clinico-pathogenetic + relationships," Bull. Exp. Biol. & Medicine 117(2), 221, 1994. +

+

+ G. M. Groisman, et al., "Calcified concretions in the anterior pituitary gland of the fetus and the newborn: + A light and electron microscopic study," Human Pathology 27(11), 1139-1143, 1996. (...calcified concretions + represent a normal finding in the anterior pituitary gland of fetuses and young infants.") +

+ +

+ K. S. G. Jie. "Vitamin K status and bone mass in women with and without aortic atherosclerosis: A + population-based study," Calc. Tiss. Intern. 59(5), 352-356, 1996. ("The finding that in atherosclerotic + women vitamin K status is associated with bone mass supports our hypothesis that vitamin K status affects + the mineralization processes in both bone and in atherosclerotic plaques." +

+

+ B. Y. Klein, et al., "Cell-mediated mineralization in culture at low temperature associated with subtle + thermogenic response," J. of Cellular Biochemistry 63(2), 229-238, 1996. "...cell-mediated mineralization is + preceded by characteristics of anaerobic and low efficiency energy metabolism." "Modulation of mitochondrial + membrane potential and energy metabolism could be linked to regulation of mineralization by the uncoupling + of oxidative phosphorylation. This uncoupling should be associated with thermogenesis in cells that induce + mineralization." C. R. Heath, B.S.C. Leadbeater, and M. E. Callow, "The control of calcification of + antifouling paints in hard waters using a phosphonate inhibitor," Biofouling 9(4), 317-325, 1996. ("All + paints contained cuprous oxide....) +

+ +

+ C. D. Yee, et al., "The relationship of nutritional copper to the development of postmenopausal osteoporosis + in rats," Biol. Trace Element Res. 48(1), 1-11, 1995. +

+

+ H Hoshino, et al., "The influence of aortic calcification on spinal bone mineral density in vitro," Calc. + Tiss. Intern 59(1), 21-23, 1996. ("...changes over time in a patient could falsely elevate values.") E. + Toussirot, et , "Giant calcification in soft tissue after shoulder corticosteroid injection, J. of + Rheumatology 23(1), 181-182, 1996, "Such periarticular calcifications are rarely observed and generally + after triamcinolone hexacetonide injection." +

+

+ M. Alini, et al., "In serum-free culture thyroid hormones can induce full expression of chondrocyte + hypertrophy leading to matrix calcification," J. of Bone and Mineral Res. 11(1), 105-113, 1996. ("...we + compared the capacity of T3 with T4 to stimulate expression of the hypertrophic phenotype and matrix + calcification in three . . . prehypertrophic chondrocyte subpopulations." "...T3 was at least 50-fold more + potent than T4. The effects of T3 were most pronounced with the most immature cells." "...matrix + calcification, measured by the incorporation of Ca45(2+) into the cell layer, always occurred earlier in + cells cultured with T3 compared with T4." +

+ +

+ M. T. Hincke, "Ovalbumin is a component of the chicken eggshell matrix," Connective Tissue Research 31(3), + 227-233, 1995. (Immunochemically demonstrated in the mammillary bodies of decalcified shell. "These results + indicate that ovalbumin is present during the initial phase of shell formation and becomes incorporated into + the protein matrix of the mammillary bodies.") +

+

+ A. L. Boskey, et al., "Persistence of complexed acidic phospholipids in rapidly mineralizing tissues is due + to affinity for mineral and resistance to hydrolytic attack: In vitro data," Calc. Tiss. Intern. 58(1), + 45-51, 1996. (Complexed acidic phospholipids may persist in the growth plate and facilitate initial mineral + deposition.) +

+

+ A.L. Boskey, et al., "Viable cells are a requirement for in vitro cartilage calcification," Calc. Tiss. + Intern. 58(3), 177-185, 1996. (Challenges dogma that chondrocyte death must precede calcification in the + growth plate.) K. Sekino, et , role of coccoliths in the utilization of inorganic carbon by a marine + unicellular coccolithophorid, Plant and Cell Physiol 37(2), 123-127, 1996. +

+ +

+ Y. Seyama, et al., "Effect of vitamin K2 on experimental calcinosis induced by vitamin D2 in rat soft + tissue," Intern. J. for Vitamin and Nutr. Res. 66(1), 36-38, 1996. +

+

+ R. Danielsen, et, "Predominance of aortic calcification as an atherosclerotic manifestation in women: The + Reykjavik study," J. of Clin. Epidemiology 49(3), 383-387, 1996. (...a potential relation to pulse pressure; + associated with blood sugar, use of antidiabetic drugs, serum cholesterol, smoking; much more frequent in + women.) F. Etcharry, et al., Fahr's disease and mitochondrial myopathy," Revue Neurologique 151(12), + 731-733, 1995. (Calcification of the basal ganglia, Fahr's disease, associated with mitochondrial myopathy.) + J. J. Jacono and J. M. Robertson, "The effects of estrogen, progesterone, and ionized calcium on seizures + during the menstrual cycle of epileptic women," Epilepsia 28(5), 571-577, 1987. +

+

+ J. E. Sojka and C. M. Weaver, "Magnesium supplementation and osteoporosis," Nutrition Reviews 53(3), 71-74, + 1995. ("...magnesium therapy appears to have prevented fractures and resulted in a significant increase in + bone density.") +

+ +

+ R. Eastell, "Management of corticosteroid-induced osteoporosis," J. Internal Medicine 237(5), 439-447, 1995. + "Corticosteroid therapy results in osteoporosis." "The most important mechanism for the bone loss is a + decrease in osteoblastic activity." +

+

+ J. P. Bonjour and R. Rizzoli, "Inadequate protein intake and osteoporosis: Possible involvement of the IGF + system,:" Nutritional Aspects of Osteoporosis '84, Challenges of Mod. Med. 7, 399-406, 1995. H. Pedersen, et + al, "Skin thickness in patients with osteoporosis..." Skin Pharmacology 8(4), 207-210, 1995. +

+

+ K. E. Schaefer, et al., "Phasic changes in bone CO2 fractions, calcium, and phosphorus during chronic + hypercapnia," J. Applied Physiol. 48(5), 802-811, 1980. +

+ +

+ F. C. Driessens, "Probable phase composition of the mineral in bone," Z. Naturforsch (C) 35(5-6), 357-362, + 1980. +

+

+ G. R. Sauer, et al., "A facilitative role for carbonic anhydrase activity in matrix vesicle mineralization," + Bone Miner. 26(1), 69-71, 1994, E. Reichart, et al., "CO2 storage in various organs during chronic + experimental hypercapnia," Bull. Eur. Physiopathol. Respir. 12(1), 19-32, 1976. ("During a four week + hypercapnia, this CO2 increase is very inmportant in bone and brain compared with that of other organs.... + ...the bone CO2 content is still increasing after four weeks.") H. Nitta, et al., "Effects of hot + environments and carbonated drinking water on bone characteristics of eight-week-old broiler chicks," Poult. + Sci. 65(3), 469-473, 1986. +

+ +

+ W. G. Bottje and P. C. Harrison, "Effect of carbonated water on growth performance of cockerels subjected to + constant and cyclic heat stress termperatures," Poult. Sci. 64(7), 1285-92, 1985. P. Quint, et al., + "Characteristic molar ratios of magnesium, carbon dioxide, calcium and phosphorus in the mineralizing + fracture callus and predentine," Calcif. Tissue Int.32(3), 257-261, 1980. ("It was found that the Mg and + CO2-contents are high in relation to Ca and P values during the prestages and early stages of + mineralization.") M. F. Gulyi, "Role of carbonic acid and ammonium nitrogen in regulation of metabolism and + physiological function in heterotrophic organisms," Ukr. Biokhim. Zh. 52(2), 141-145, 1980. +

+

+ K. E. Schaefer, et al., "Effect of intermittent exposure to 3% CO2 on respiration, acid-base balance, and + calcium-phosphorus metabolism," Undersea Biomed. Res. 6 Suppl, S115-34, 1979. ("The known renal response to + hypercapnia, consisting of an increased excretion of titratable acidity, ammonia, and hydrogen ion + excretion, occurred but was interrupted after the first day....") +

+ +

+ U. F. Rasmussen, et al., "Characterization of mitochondria from pig muscle: +

+

+ Higher activity of exo-NADH-oxidase in animals suffering from malignant hyperthermia," Biochem. J. 315(Pt. + 2), 659-663, 1996. R. K. Rude and F. R. Singer, "Hormone modifiers of mineral metabolism," in Disorders of + Mineral Metabolism, vol. II: Calcium Physiology, Ed. by F. Bronner and J. W. Coburn, Academic Press, 1982. +

+ +

+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com +

+ + diff --git a/raypeat-articles/processed/pathological-science-general-electric.html b/raypeat-articles/processed/pathological-science-general-electric.html new file mode 100644 index 0000000..ff168a6 --- /dev/null +++ b/raypeat-articles/processed/pathological-science-general-electric.html @@ -0,0 +1,383 @@ + + + +

+ +

+ Pathological Science & General Electric:Threatening the paradigm +

+

+ Everything in biology depends on the internal order of cells, and on the interactions of each cell with its + surroundings. All of these orderly interactions involve contacts between biological molecules and water. The + forces regulating interactions on that scale must be understood before life can be understood, but the + nature of the forces at these interfaces has been controversial for 100 years. In 1953, physicist Irving + Langmuir gave a talk at the General Electric laboratory about what he called "pathological science." That + talk is still resonating in the scientific culture, and it is used to reinforce attitudes similar to those + held by Langmuir, i.e., the dominant scientific paradigm of the 20th century, and to justify certain + institutions that regulate innovation. For Langmuir, there was a clearly defined "scientific method," and he + said some people were led away from the proper method by wishful thinking to interpret ambiguous results as + confirmations of their hypothesis. He listed 6 symptoms of pathological science: 1) An effect produced by a + barely detectable cause, and 2) the effect is barely detectable, or many measurements are needed because of + the very low statistical significance of the results, 3) claims of great accuracy, 4) they involve fantastic + theories contrary to experience, 5) criticisms are met by ad hoc excuses, and 6) the ratio of + supporters to critics approaches 50%, then fades toward zero. He failed to mention these features in any + research that supported his view of things, and called an idea pathological when people continued to work on + it despite disapproval by the recognized experts. He didn't mention the Nobel prizes that were given for the + worm theory of cancer or for treating psychological problems with lobotomies, and he didn't mention that + there were organized campaigns against the publication of disapproved ideas.The dominant view in biology, + which is analogous to Langmuir's view in physics, is that all decisive cellular processes involve the direct + mechanical contact of one molecule with another, the activation of a lock (an enzyme or receptor) by a key + that has the right shape, or the adhesion of a molecule to another substance according to its chemical + composition. An alternative view, now clearly supported by the evidence, is that there are forces that + aren't merely between molecular surfaces, but rather that the local conditions at the surfaces of proteins + and other molecules, and the properties of the solvent water, are modified by the surrounding conditions. It + is this alternative view that is now making progress in understanding disease and health, regeneration and + degeneration. But to judge the new work, it's important to know the nature of the opposition.Thomas Edison, + who was adept at publicizing himself as the inventor of ideas he had bought or stolen, founded General + Electric. Attempting to eliminate Nikola Tesla's system of alternating current, since Edison was invested in + direct current systems, Edison's GE tried to convince the public that direct current was safer, by using + alternating current to electrocute an elephant, and by promoting its use in the electric chair. GE + eventually gave up the direct current technology for electrifying cities, and they refined the electric + light bulb and were fairly successful in controlling, practically monopolizing, that market, and in + shortening the life of incandescent bulbs. Carbon filament bulbs made around 1900 often lasted decades; I + had one that kept working until it was broken during a move in 1960. Light bulbs made in England 65 years + ago, and in the Soviet Union, and bulbs currently made in China, had a life expectancy five times as long as + the bulbs made in the US since GE learned how to carefully control the rate at which the tungsten filament + deteriorates. Irving Langmuir was their leading light bulb scientist. In his 1932 Nobel lecture, he + tediously argued that molecules of gas can form only one layer on a surface such as a filament. About 17 + years earlier, Michael Polanyi had demonstrated that molecules can be adsorbed in multilayers, but his + evidence was dismissed because, according to the understanding of industrial experts such as Langmuir, and + the leading scientific authorities, Einstein, Nernst, and Haber, it was impossible. They were committed to + an explanatory system that didn't allow events such as those Polanyi described.Although Polanyi knew that + his adsorption isotherm was more realistic than Langmuir's (he had demonstrated many cases that Langmuir's + didn't describe correctly), and also easier to understand, he taught Langmuir's isotherm to his students, + because he knew that they would be required to know it to pass their examinations. He knew he had risked his + career by his earlier exposition of his ideas, and he was unwilling to endanger his students' careers by + involving them in the controversy.From 1920 to 1926, before the advent in 1927 of "quantum physics" (with + its still-argued features of delocalized electrons, molecular orbitals, resonance, non-locality, + incommensurability, indeterminism), Polanyi had turned his attention from the physics of adsorption to + chemical structure, and his group was the first to show that cellulose was made up of long molecules, + polymers, rather than of just associated clusters. That idea didn't catch on, so he turned to the behavior + of crystals and metals. He found that crystals were much weaker than they should be, according to the + strength of the bonds between their atoms, and showed that this was because of defects, and that during + repeated stresses, they became weaker, as energy migrated through relatively long distances in the + substance, to concentrate the defects. The idea of lattice defects was acceptable at that time, but + long-range mobility of bond energy was no more acceptable then than it had been when J.C. Bose described + metal fatigue, decades earlier. Polanyi also showed that the strength and rigidity of a crystal were altered + when the crystal was immersed in water. Again, such an influence of a surface on the over-all physical + properties of a solid substance had no noticeable effect on the scientific culture, although his results + were published in the major journals. To adjust one's interpretive system at that time to rationalize + Polanyi's results would have required discarding the basic assumptions that were behind Einstein's + explanation of the photoelectric effect, and maybe even his theory of Brownian motion. However, by 2011, + fewer people have invested their personal development in those ideas of short-range electrical binding + forces that prevailed early in the 20th century, and now, for example, the evidence of "delocalized holes in + DNA" can be discussed more openly. Eventually, science textbooks may be rewritten to show a steady + progression of understanding from Bose, though Polanyi, Perutz, Szent-Gyorgyi, Ling, and Damadian (inventor + of the MRI, holder of the patents infringed by GE, non-winner of the Nobel prize). In 1933 J.D. Bernal had + proposed a structural model of water that contained a considerable amount of order (Bernal and Fowler, 1933) + but by the 1950s the idea of spontaneous ordering in water was out of style, and he worked out a more random + structure. Max Perutz, continuing the study of hemoglobin he had begun with Bernal, became concerned with + long range forces acting through water: "The nature of the forces which keep particles parallel and + equidistant across such great thicknesses of water is not yet clear." Normal wet crystals of methemoglobin + contain regular layers of water 15 Angstroms thick. He suggested that a laminated structure of the water + could plausibly explain his measurements. Comparing the protein crystal to montmorillonite particles, which + incorporate several layers of water, each 3 Angstroms thick, each layer of water in the protein crystal + would be 4 Angstroms thick, since swelling proceeds in discrete steps of that thickness. 52.4% of the volume + of Perutz's normal, stable, wet protein crystals consisted of liquid. Part of the water is a fixed + monolayer, but the rest is apparently in the form of mobile, interactive, multilayers. By 1952, Perutz had + decided that long range forces weren't involved in hemoglobin crystallization, but he didn't comment on the + long range ordering of clays, tobacco mosaic viruses, and other particles and gels. In 2005, an interlaminar + distance of 17.9 Angstroms, or six layers of water, still seems to be stable in hydrated montmorillonite + (Odriozola & Aguilar, 2005). Clay continues to be studied in relation to nuclear waste disposal, so the + effects of surfaces on water's properties haven't been entirely excluded from science. The interfacial water + in clay has special catalytic properties that make it interesting to many researchers (Anderson, + 1970)Bernal's and Perutz' conformity in the 1950s rejection of long range forces and an ordered structure of + water represented the dominant ideas in physics and physical chemistry, but many people (with very little + financial or institutional support) were continuing to study the structure of water, both in the bulk phase + and near surfaces, as in cells. Philippa Wiggins, Albert Szent-Gyorgyi, Carlton Hazlewood, Freeman Cope, and + Ray Damadian were among the most active proponents of the importance of structured water in living cells. + Walter Drost-Hansen showed that water near surfaces (vicinal water) is several percent less dense, and has a + greater heat capacity, than bulk water, and that bulk water undergoes transitions at certain temperatures + that alter its effects on enzyme reactions.The question regarding the nature of the forces at surfaces or + interfaces affects how we think about everything, from life to nuclear energy. The political and economic + implications of "non-local energy" (which is most obvious at surfaces) have at times led to organized + campaigns to discourage research in those areas. When Alexandre Rothen found (beginning in 1946) that + enzymes and antibodies had non-local effects, several prestigious publications claimed to show how he must + have been mistaken: The films he used must have been + porous, despite his demonstrations of their continuity. The methods he developed at Rockefeller Institute + quickly became standard for accurately measuring very thin films. In the early 1970s, a GE employee, Ivar + Giaever, visited Rothen's lab to learn his methods. Shortly after his visit, he demonstrated his "new + method" to the press. I saw an article about it in Science News, and wrote them a short letter, pointing out + that the method had been developed and used by Rothen much earlier; they printed my note, + which could be seen as a criticism of the author of the news article. About a week later, I got a letter + from Rothen, thanking me for writing to the magazine; he said they had refused to publish his own letter + explaining the situation, including his interactions with Giaever during the visit. I assume that the + magazine felt some kind of pressure to protect Giaever and GE from an authoritative accusation of scientific + dishonesty.In 1968 when I began studying biology at the University of Oregon, the professor of microscopy, + Andrew Bajer, posted a display of dozens of micrographs, with explanatory captions, along the halls near the + entrance of one of the science buildings. The one that interested me most showed orderly rows of regularly + formed objects on a smooth surface. The caption described it as clusters of sodium atoms, deposited from + vapor, on a film of a polymer (formvar, I think), under which was a quartz crystal. The caption noted that + the sodium atoms had condensed in a pattern representing the crystal structure of the underlying quartz. + Although Rothen's work involved proteins deposited from solution, rather than sodium atoms deposited from + vapor, Bajer's image illustrated visually the projection of the forces of crystal structure through an + amorphous film. This seemed to be a graphic representation of Polanyi's adsorption potential, a force acting + on atoms in the space near a surface, as opposed to Langmuir's local atomic force that didn't reach beyond + the first layer of atoms. The long range order in this case arranged atoms geometrically, while Rothen's + preparations showed a "projected" specificity, but of a more complex sort. Just a few months later, someone + who knew of Stephen Carter's demonstration that fibroblasts will migrate on a glass slide coated with a gold + film, toward areas of greater thickness of the metal, did a similar experiment, but with a formvar film + between the gold and the cells. The cells still migrated up the gradient, toward the area of thicker gold + under the film. The reaction to that publication was the same as the reaction to Rothen's work 20 years + before, the formvar films contained holes, and the cells were reaching through the film to touch the metal + surface, sort of like kids peeking around a blindfold when they aren't supposed to be watching. I didn't + understand how the holes would explain anything, even if there were holes and if the cells had put out many + long filopodia to reach through the film, but in fact making a formvar film is a very standardized + technique. They can be made "holey," or like a very open net, or they can be made solid, just by choosing + the concentration of the polymer used. The difference is very clear, under an electron microscope, but the + professors needed an excuse for dismissing something they didn't want to understand. Further work was + discouraged by their ridicule.In Russia, GE had very little influence on the acceptability of ideas in + science, and Boris Deryagin continued (from the 1930s until 1990) to study the properties of water near + surfaces. In 1987 his group demonstrated that cells can clear particles from a space around themselves, + extending more than a cell's diameter away. This distance is similar to the cell free zone in flowing blood + adjacent to the walls of arterioles, which is probably the result of multiple interacting forces. At + present, processes such as cell adhesion of leukocytes and stem cells (and tumor cells) to the blood vessel + wall and movement through the blood vessel into the tissues (diapedesis) is explained in terms of adhesion + molecules, disregarding the plausible effects of long range attractive or repulsive forces. Clumping or + sludging of red blood cells occurs when the organism is failing to adapt to stress, and could be reasonably + explained by a failure of protective repulsive fields. These fields are developed and maintained by + metabolism, primarily oxidative energy metabolism, and are modified by endogenous regulatory substances and + external conditions, including electromagnetic and electrical fields. 100 years ago, Albert Einstein was a + major influence in popularizing the "only local" dogma of atomic interactions. (His work led directly to + "quantum physics," but he never accepted its irrational implications.(1) I don't + think he ever considered that the assumptions in his [atomic-quantized] theory of the photoelectric effect + were the problem.) One charged atom is completely neutralized by its association with an oppositely charged + atom, and the force is described by the inverse square law, that the force decreases with the square of the + distance between point charges, meaning that the force is very strong at very small distances. However, a + physicalsurface, a plane where one substance ends and another begins, follows + different rules. Different substances have different electron affinities, creating a phase boundary + potential, a charged layer at the interface. (Electrical double layers at interfaces are important in + semiconductors and electrodes, but biologists have carefully avoided discussing them, except in the very + narrow context of electrodes.) The electrically active surface of a substance, even though it's made of + atoms and electrons, projects its electrical field in proportion to its area. This principle is as old as + Coulomb's law, but the habit of thinking of electrical charge on the atomic scale seems to make people + forget it. It's exactly the sort of space-filling field that Polanyi's adsorption isotherm describes. It's + also involved in crystal strength and elasticity as studied by Polanyi, in piezoelectricity, and in + generation of semiconduction in amorphous materials, as used in Stan Ovshinsky's processes.Long range + structural and electronic interactions produce "antenna" effects, which are sensitive to very weak fields, + whether they originate inside or outside of the organism. Magnetobiology is often treated as a + pseudo-science or pathological science, because "real science" considers heating and chemical bond reactions + to be the only possible effects of low energy fields or radiation. Solco Tromp, beginning in the 1930s, + showed that cells behave like liquid crystals, and that liquid crystals can respond to very low electrical + and magnetic fields.If the adsorption potential structures the water in its region of space, this + interfacial water is now a new phase, with different physical properties, including new catalytic + properties, such as those recognized by the clay investigators (which increased its ability to dissolve the + clay minerals).Several versions of Langmuir's Pathological Science talk have been published, some of them + adding new examples, including "polywater." Langmuir died in 1957, and the first example of polywater was + observed by N.N. Fedyakin was observed in 1961. When finely drawn quartz or Pyrex glass capillary tubes + (with inside diameter of up to a tenth of a millimeter) are suspended in a container with the air pressure + reduced, above a container of distilled water, so that they are exposed to pure water vapor at room + temperature, after a period of an hour or more (sometimes days or weeks were required) a small drop of + liquid condenses inside some (a small percentage) of the capillary tubes. Above some of the original drops, + a second drop sometimes appeared, that would enlarge as the first drop shrank. This separation of water into + two fractions was itself anomalous, and the upper drop was found to be denser than normal water. Many people + began studying its properties. Fedyakin found that its thermal expansion was greater, and its vapor pressure + lower, than ordinary water. Others found that it had a higher refractive index, viscosity, and surface + tension, as well as greater density, than ordinary water. Birefringence (the splitting of a beam of light + into two rays when it passes through an ordered material) was observed in the anomalous water, and this + usually indicates the presence of a polymer (Fedyakin, et al., 1965; Willis et al., 1969; Lippincott, et + al., 1969) or crystallinity. The water associated with clay is also birefringent (Derjaguin and + Greene-Kelly, 1964), and its properties are different when the clay absorbs it from the vapor phase or from + liquid water.Hysteresis is a lag in the behavior of a system, resulting when the internal state of the + system is altered by an action, so that it responds differently to a repetition of that action; it's the + memory of a system that exists only when the system has internal structure. For example, a gas has + relatively little hysteresis. Perfect elasticity is one extreme of an ordered solid, but most solids have + some hysteresis, in which the deformed material fails to spring back immediately. Hysteresis of adsorption + can be seen at the edges of a drop of water on a tilted surface, with a steeper contact angle on the newer + contact at the lower edge, showing a reluctance of the water to wet a new surface, a lower contact angle + where the drop is pulling away from the upper surface, a reluctance to break the contact. The same is seen + at the edges of an evaporating-shrinking drop, or a growing drop. Everyone perceives this memory function of + water.Boris Deryagin studied both the elasticity and the hysteresis of water near surfaces, and both + approaches showed that it contained internal structure. Many dogmatic professors denied that water could + show elasticity or "memory," because of their interpretive system/mental rigidity. When Fedyakin got the + help of Deryagin's lab in analyzing the anomalous material, many different methods of purifying the glass + and the water and the vessel were tried, and its properties were analyzed in many different ways. When + Deryagin first described the material at a conference in Europe, there was great interest, and eventually + hundreds of people began investigating it. A British laboratory was the first to get a sample of Deryagin's + material in 1966, and their tests confirmed Deryagin's. The US Bureau of Standards, having the best + analytical instruments in the world (including a microscope spectrometer), studied it carefully. They + (Lippincott, Stromberg, Grant, & Cessac, 1969) found that its bonds were stronger than those in ordinary + water, and they compared its absorption spectrum (by computer) with those of 100,000 known substances, and + found that it corresponded with nothing previously known. It didn't have the absorption band of normal + water. When it evaporated, it left no visible residue, and it turned into ordinary water when heated. They + concluded that the physical structure that would best fit its absorption spectrum was a polymerized form of + water, so they called it "polywater." Later, Lippincott and others (Page, et al., 1970; Petsko, 1970) did + proton magnetic resonance analyses that showed a difference of polywater from normal water in the hydrogen + bonding, a "deshielding" of the protons, meaning that the electrons were arranged differently in the + molecules.In 1969 there were many threats to the dominant paradigm, and many people were demanding a change + in the government's funding priorities. The public excitement about polywater following the many + confirmations of its existence was disturbing to the defenders of the paradigm. Philip Abelson, the chief + editor of Science magazine, used the magazine to further his political beliefs. Denis Rousseau, a young + researcher at Bell Labs (who now writes about pathological science), published a series of articles in + Science describing his tests of polywater. He played tennis until his tee-shirt was soaked with sweat, then + extracted and concentrated the sweat into a small gummy pellet. He reported that the infrared spectrum of + the sweat concentrate (largely sodium lactate) was very similar to that of polywater. One of the techniques + he used to identify impurities (electron spectroscopy) requires a high vacuum, so there couldn't be any + normal water present. The water associated with ionic impurities is driven off at low temperatures compared + to the temperature needed to decompose the anomalous water.Although Rousseau's "explanation" was ludicrous, + it was just the thing the professors needed to prevent further challenges to their paradigm. Although + Deryagin published more evidence of the purity of the anomalous water in 1972, by 1973 the mass media, + including Science magazine, were saying that polywater didn't exist, and that Deryagin had admitted that he + was mistaken. But polywater was Lippincott's term, and what Deryagin said was that silica was the only + impurity that could be identified in the anomalous material. There are many antecedents to anomalous water + in the literature. In the 1920s, W.A. Patrick of Johns Hopkins and J. L. Shereshefsky at Howard university + investigated the properties of water in fine capillary tubes and found that the vapor pressure wasn't the + same as that of normal water. (This is what would have been expected, if Polanyi's adsorption isotherm had + been accepted.) The density of water in clay has been found to be slightly less than normal. This water + bound to clay requires a high temperature to eliminate, similar to the decomposition temperature of + polywater. The catalytic properties of interfacial water in clay are recognized, causing it to solublize + components of the clay. So it's hard to imagine that there wouldn't be some silica in the material formed in + quartz or glass capillary tubes.The only thing pathological about the polywater episode was the + extreme effort that was made to stigmatize a whole category of research, to restore faith in the old + doctrine that insisted there are no long range ordering processes anywhere in the universe. The + successful campaign against polywater strengthened the mainstream denial of the evidence of ordering in + interfacial and intracellular water, kept the doctrine of the lipid bilayer cell membrane alive, and up + until the present has prevented the proper use of MRI scans in medical diagnosis.In 1946, while the + government was studying the way nuclear fallout was influenced by the weather, a group at GE, led by + Langmuir, began experimenting with weather control by means of "cloud seeding." Langmuir observed that the + energy in a cloud system was greater than that in an atomic bomb, and that by seeding clouds in Europe, + disastrous weather effects could be created in the Soviet Union. The GE group convinced the Pentagon to + become involved in weather control. (The physicist Ross Gunn was transferred directly from work on the + atomic bomb to direct the cloud seeding project.) In one of Langmuir's seeding experiments, he claimed that + he had changed the direction of a hurricane moving toward the U.S. When a young researcher pointed out that + the weather service had predicted exactly that change of direction, based on the temperatures of ocean + currents, Langmuir became angry, and told the man that he wasn't going to explain it to him, because he was + too stupid to understand. Langmuir's attitude toward science was exactly what GE wanted; his career and + reputation were part of the corporation's public relations and business plan. Science was whatever GE + thought was good for their business. That science was pathological, sometimes by Langmuir's own defining + features, most of the time by the effects it has had on society. The Manhattan Project was central to GE's + business plan, and when the bomb project was completed GE and the Atomic Energy Commission found that the + same subsidies could be used to develop nuclear generators of electricity. Following Edison's pioneering + work with x-rays, x-ray imaging machines had become very profitable for GE. It was important to assure the + public that medical, industrial, and military radiation was well understood, well controlled, safe, and + essential for the general welfare. In their view, if every woman could have access to GE's x-ray mammograms, + for example, almost all breast cancers could be cured. The radiation exposure from living near a GE nuclear + power generator is infinitesimal compared to living in Denver or flying in an airplane. (There is some + discussion of these issues in my January, 2011 newsletter, "Radiation and growth.") Public relations + involves everything from "basic research" to television advertising.If nuclear energy is as safe as the + industry and governments say it is, the reactors should be located in the centers of large cities, because + transmitting electric power long distances is presently wasting 50% of the power (Hirose Takashi, The + Nuclear Disaster that could destroy Japan...and the world, 2011). Admiral Rickover, influential advocate of + nuclear power, said "...every time you produce radiation, [a] horrible force [is unleashed,] and I think + there the human race is going to wreck itself. [We must] outlaw nuclear reactors" (January, 1982 + congressional testimony) Helen Caldicott says Fukushima is many times worse than Chernobyl. The radioactive + cesium in German mushrooms and truffles hasn't decreased 25 years after Chernobyl, and the German government + is spending increasing amounts to compensate hunters for the wild boars (who eat truffles) that must be + disposed of as radioactive waste.(2)General Electric sent its condolences to the + people of Japan, and said the reactors of that design had functioned well for 40 years; they didn't mention + that Unit I at Fukushima had been scheduled to be shut down on March 26, 2011, the end of its 40 year life + expectancy. In late March, as the accident continued, Tepco applied for a permit to build two new reactors + at the Fukushima site. In the US, the government continues its loan guarantee policy to subsidize new + reactor construction. After many years of working with his metalized slides, Alexandre Rothen found that + their activity, the strength of their long-range influence, varied with a 24 hour cycle, and that their + activity could also be destroyed or restored by putting them in a magnetic field, parallel or perpendicular + to the surface. Around the same time, a Russian biochemist, Simon Shnoll, noticed that there were cyclic + changes in well defined enzymic reactions. Like Rothen, Shnoll did experiments that showed that the earth's + motion (relative to the stars) affected measurements in the laboratory, even measurements of alpha particles + produced by nuclear fission. Organized matter, whether it's cellular or in the crystalline solid state, is + susceptible to surrounding conditions.In 1971 or '72 I learned of H.C. Dudley's idea of a "neutrino sea," + that he suggested might be equivalent to the "luminiferous ether" that had previously been used to explain + light and electromagnetism. I wrote to him, asking if he thought neutrinos could be involved in biological + ordering processes by resonating with matter under some circumstances. He had been developing a theory, in + which atomic nuclei might interact with a neutrino "ether," in ways that could affect the decay rate of the + unstable isotopes, and so it didn't seem unreasonable to him that biological structures might also interact + with neutrinos. In October, 1972, he published a purely theoretical article in which he explained that + nuclear reactors might under some conditions become dangerously unstable. I had earlier seen a newspaper + article about an experiment by a physicist, J.L. Anderson, in which radioactive carbon-14 didn't follow the + normal rules of random decay, when the isotope was incorporated into an oil, which was spread in a monolayer + on a metal surface. By chance, Anderson's experimental article was published simultaneously with Dudley's + theoretical article, though neither one knew of the other's work. Nearly all physicists said his results + weren't possible, because the small forces involved in adsorbing an oil to a metal surface were + infinitesimal compared to the force needed to cause nuclear reactions. Over the next few years, Dudley and + others did some experiments that appeared to confirm Anderson's results, showing that the rate of nuclear + reactions can be modified by mild changes in the physical state of the unstable elements.Anderson's and + Dudley's work didn't get much attention from the public, so there was no need for the defenders of the + dominant paradigm to attack it. There was no financial support for continuing their research.Behind the + industries' assurances that "low level" radiation is safe, whether it's ionizing radiation, microwave or + broadcast frequency electromagnetic radiation, is their reductionist approach to physics, chemistry, and + biology. Those doctrines no longer have the prestige that they once did, but their pathological, + authoritarian "science" culture is being sustained by the influence of corporations on mass culture.With the + institutions of research and education controlled by pharmaceutical, military and industrial interests for + their own benefit, fundamental progress in knowledge is a threat to the system. NOTES1. From Einstein's 1926 + letter to Max Born: "Quantum mechanics is very worthy of regard. But an inner voice tells me that this is + not yet the right track. The theory yields much, but it hardly brings us closer to the Old One's secrets. I, + in any case, am convinced the He does not play dice." Quoted in P. Busch and G. Jaeger, "Unsharp quantum + reality," 4 May 2010.2. None of the major institutions in the US are providing basic information about + protection from Fukushima's radioactive fallout. Eating foods produced before the arrival of the radioactive + rain, feeding old foods to chickens and milk animals, and keeping your metabolic rate high, are the main + defenses. Eventually, fertilizing crops with mined minerals, and enriching the atmosphere with carbon from + coal will dilute the radioactive isotopes from the nuclear accidents.

REFERENCES

DM Anderson, Role of interfacial water and water in thin films in the origin of life, + http://history.nasa.gov/CP-2156/ch1.4.htmDM Anderson and AR Tice, 1970, Low-temperature phases + of interfacial water in clay-water systems, + Crrel Research Reports, Army Dept, US, Res Rpt 290. "The low temperature exotherms do not depend + critically upon water content, but clearly they are related to clay mineral and exchangeable cation type. + The evolution of heat in this temperature range probably corresponds to a phase change in the interfacial + water.")J. Physical Cehmistry 76(4), 1976, "Non-Poisson distributions observed during counting of + certain carbon-14 labeled (sub) monolayers," Anderson JL.Biophys. Chem. 113 (2005): 245-253, + Structural and kinetic effects of mobile phone microwaves on acetylcholinesterase activity, + Barteri M, Pala A, Rotella S.J. Chem. Phys. 1, 515), 1933, Bernal JD & Fowler RH.J Cell Biol 1964, + 127(1):117-128. Electric field-directed fibroblast locomotion involves cell surface molecular + reorganization and is calcium independent, Brown MJ and Loew LM.Nature 1965 208(5016):1183-7, + Principles of cell motility: the direction of cell movement and cancer invasion, + Carter SB.Nature 1967 213: 256-60, Haptotaxis and mechanism of cell motility, + Carter SB.Popular Science, June 1973, How you can grow your own polywater, PA Christian and + LH Berka: "Some experts claim this rare substance doesn't exist. Yet here's how you can + harvest enough of it for own experiments." Pyrex thermometer tubing from a mail-order scientific supply + store ....Biophysical Journal 9 (1969),303-319, Nuclear magnetic resonance evidence using D2O for + structured water in muscle and brain, + Cope FW.Langmuir 3(5): 607-612 (1987), Structure of water in thin layers, Deryagin + BV, Churaev NV.Langmuir 3(5): 601-606 (1987), Modern state of the investigation of long-range + surface forces, + Deryagin BV.Trans. Faraday Soc. 60 (1964: 449-455, Birefringence of thin liquid + films, Derjaguin BV and Greene-Kelly R.Pure & Appl. Chem. 61(11) (1989): 1955-1958, Influence of surface forces on the formation of structural peculiarities of the boundary layers of liquids + and boundary phases, + Derjaguin BV. "The surface forces acting beyond the range of boundary monolayers, are able to + change the concentration of dissolved ions and molecules.Trans. Faraday Soc. 60, 449 (1964), Reversible and irreversible modification of the properties of liquids under the influence of a lyophilic + surface, Derjaguin BV and Green-Kelly R. "Evidence is given of the reversible character of the + modification of the properties of liquids under the action of surface forces." (Lyophopic substrate, a few + molecules thick.) "In other cases, e.g. water-glass, water-quartz, fatty acids-metals, the substrate alters + the structure of the liquid and the properties depending on it to a depth of many tens or hundreds of + monolayers." (Lyophilic substrate). (the electroviscous effect, proportional to the square of the + zeta-potential).Fed Proc Transl Suppl. 1965 24(3):431-3, Effect of constant magnetic field on motor + activity of birds, + El'darov AL & Kholodov YA.Physics A: Statistical and Theoretical Physics 172 (1-2), + 161-173. The structure and properties of vicinal water: Lessons from statistical geometry, + Etzler FM, Ross RF, Halcomb RA, (3% greater density, 25% greater heat capacity.Dokl. Akad. Nauk. SSSR 165 + (1965): 878, Fedyakin N.N.FEBS Lett. 367 (1995): 53-55, Changes in the state of water, induced by + radiofrequency electromagnetic fields, Fesenko EE and Gluvstein A.Ya.D. Green-Kelly, B.V. + Derjaguin, Research in Surface Forces vol. 2, p. 117, Consultants Bureau, NY (1966). + (Birefringence of water near surfaces, in layers up to 200 A thick. Also birefringence of the boundary + layers of benzene derivatives.)Nature (submitted 1969) Hazlewood CF, Nichols BL, Chamberlain NF.Science 164 + (1969), p. 1482, Lippincott ER.Med. Hypotheses 66 (2006) 518-526, Cell hydration as the primary + factor in carcinogenesis: A unifying concept, McIntyre GI.Med. Hypothese 69 (2007): 1127-1130, + Increased cell hydration promotes both tumor growth and metastasis: A biochemical mechanism + concsistent with genetic signatures, McIntyre, GI.J Chem Phys 123, 174708, 2005, + Stability of Ca-montmorillonite hydrates: A computer simulation study, + Odriozola G & JF Aguilar JF.Tranropesactions of the Faraday Society, vol. XLII B, 1946, "The composition and swelling properties of haemoglobin crystals," Perutz M.Science 171(3967), + 170-172, "Polywater" and sweat: Similarities between the infrared spectra, D.L. + Rousseau,Biochim Biophys Acta 1975; 403(1):89-97, Synchronous reversible alterations in enzymatic + activity (conformational fluctuations) in actomyosin and creatine kinase preparations,Shnoll + SE, Chetverikova EP.Szent-Gyorgyi, A., 1957, Bioenergetics, Academic Press, Inc. New + York.Prog. Polym. Sci. 20 (1995): 1121-1163, High and low-density water in gels, Wiggins + PM.Nature 222, 159-161, 1969, "Anomalous" Water, Willis E, GK Rennia, C Smart BA Pethica. +

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+ © Ray Peat Ph.D. 2012. All Rights Reserved. www.RayPeat.com +

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+ Phosphate, activation, and aging +

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+ Recent publications are showing that excess phosphate can increase inflammation, tissue atrophy, + calcification of blood vessels, cancer, dementia, and, in general, the processes of aging. This + is especially important, because of the increasing use of phosphates as food additives. +
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+ Previously, the complications of chronic kidney disease, with increased serum phosphate, + were considered to be specific for that condition, but the discovery of a + phosphate-regulating gene named klotho (after one of the Fates in Greek mythology) has + caused a lot of rethinking of the biological role of phosphate. In the 19th century, + phosphorus was commonly called brain food, and since about 1970, its involvement in cell + regulation has become a focus of reductionist thinking. ATP, adenosine triphosphate, is + seen as the energy source that drives cell movement as well as the "pumps" that maintain + the living state, and as the source of the cyclic AMP that is a general activator of + cells, and as the donor of the phosphate group that activates a great number of proteins + in the "phosphorylation cascade." When tissues calcified in the process of aging, + calcium was blamed (ignoring the existence of calcium phosphate crystals in the + tissues), and low calcium diets were recommended. Recently, when calcium supplements + haven't produced the intended effects, calcium was blamed, disregarding the other + materials present in the supplements, such as citrate, phosphate, orotate, aspartate, + and lactate. +
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+ I have a different perspective on the "phosphorylation cascade," and on the other functions of + phosphate in cells, based largely on my view of the role of water in cell physiology. In the + popular view, a stimulus causes a change of shape in a receptor protein, causing it to become an + active enzyme, catalyzing the transfer of a phosphate group from ATP to another protein, causing + it to change shape and become activated, and to transfer phosphate groups to other molecules, or + to remove phosphates from active enzymes, in chain reactions. This is standard biochemistry, + that can be done in a test tube. +
+
+ Starting around 1970, when the involvement of phosphorylation in the activation of enzymes in + glycogen breakdown was already well known, people began noticing that the glycogen phosphorylase + enzyme became active immediately when the muscle cell contracted, and that phosphorylation + followed the activation. Phosphorylation was involved in activation of the enzyme, but if + something else first activated the enzyme (by changing its shape), the addition of the phosphate + group couldn't be considered as causal, in the usual reductionist sense. It was one participant + in a complex causal process. I saw this as a possible example of the effect of changing water + structure on protein structure and function. This view of water questions the relevance of test + tube biochemistry. +
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+ Enzymes are known which suddenly become inactive when the temperature is lowered beyond a certain + point. This is because soluble proteins arrange their shape so that their hydrophobic regions, + the parts with fat-like side-chains on the amino acids, are inside, with the parts of the chain + with water-soluble amino acids arranged to be on the outside, in contact with the water. The + "wetness" of water, its activity that tends to exclude the oily parts of the protein molecule, + decreases as the temperature decreases, and some proteins are destabilized when the relatively + hydrophobic group is no longer repelled by the surrounding cooler water.  +
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+ In the living cell, the water is all within a very short distance of a surface of fats or + fat-like proteins. In a series of experiments, starting in the 1960s, Walter + Drost-Hansen showed that, regardless of the nature of the material, the water near a + surface is structurally modified, becoming less dense, more voluminous. This water is + more "lipophilic," adapting itself to the presence of fatty material, as if it were + colder. This change in the water's properties also affects the solubility of ions, + increasing the solubility of potassium, decreasing that of sodium, magnesium, and + calcium (Wiggins, 1973). +
+
+
+  When a muscle contracts, its volume momentarily decreases (Abbott and Baskin, 1962). Under + extremely high pressure, muscles contract. In both situations, the work-producing + process of contraction is associated with a slight reduction in volume. During + contraction of a muscle or nerve, heat is given off, causing the temperature to rise. + During relaxation, recovering from excitation, heat is absorbed (Curtin and Woledge, + 1974; Westphal, et al., 1999; Constable, et al. 1997). In the case of a nerve, following + the heating produced by excitation, the temperature of the nerve decreases below the + starting temperature (Abbot, et al., 1965). Stretching a muscle causes energy to be + absorbed (Constable, et al., 1997). Energy changes such as these, without associated + chemical changes, have led some investigators to conclude that muscle tension generation + is "entropy driven" (Davis and Rodgers, 1995).  +
+
+
+  Kelvin's description (1858) of the physics of water in a soap bubble, "…if a film such as a + soap-bubble be enlarged . . . it experiences a cooling effect . . . ," describes the + behavior of nerves and muscles, absorbing energy or heat when they are relaxing (or + elongating), releasing it when they are excited/contracting.  +
+
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+ Several groups of experimenters over the last 60 years have tried to discover what happens + to the missing heat; some have suggested electrical or osmotic storage, and some have + demonstrated that stretching generates ATP, arguing for chemical storage. Physical + storage in the form of structural changes in the water-protein-lipid system, interacting + with chemical changes such as ATP synthesis, have hardly been investigated. +
+
+ Early studies of muscle chemistry and contraction found that adding ATP to a viscous + solution of proteins extracted from muscle reduced its viscosity, and also that the loss + of ATP from muscle caused its hardening, as in rigor mortis; if the pH wasn't too + acidic, the dead muscle would contract as the ATP content decreased. Szent-Gyorgyi found + that a muscle hardened by rigor mortis became soft again when ATP was added.  +
+
+
+  Rigor mortis is an extreme state of fatigue, or energy depletion. Early muscle studies + described the phenomenon of "fatigue contracture," in which the muscle, when it reaches + the point at which it stops responding to stimulation, is maximally contracted (this has + also been called delayed relaxation). Ischemic contracture, in the absence of blood + circulation, occurs when the muscle's glycogen is depleted, so that ATP can no longer be + produced anaerobically (Kingsley, et al., 1991). The delayed relaxation of hypothyroid + muscle is another situation in which it is clear that ATP is required for relaxation. + (In the Achilles tendon reflex test, the relaxation rate is visibly slowed in + hypothyroidism.) A delayed T wave in the electrocardiogram, and the diastolic + contracture of the failing heart show the same process of delayed relaxation. + Supplementing the active thyroid hormone, T3, can quickly restore the normal rate of + relaxation, and its beneficial effects have been demonstrated in heart failure + (Pingitore, et al., 2008; Wang, et al., 2006; Pantos, et al., 2007; Galli, et al., + 2008). +
+
+
+  A large part of the magnesium in cells is bound to ATP, and the magnesium-ATP complex is a + factor in muscle relaxation. A deficiency of either ATP or magnesium contributes to + muscle cramping. When a cell is stimulated, causing ATP to release inorganic phosphate, + it also releases magnesium. Above the pH of 6.7, phosphate is doubly ionized, in which + state it has the same kind of structural effect on water that magnesium, calcium, and + sodium have, causing water molecules to be powerfully attracted to the concentrated + electrical charge of the ion. Increasing the free phosphate and magnesium opposes the + effect of the surfaces of fats and proteins on the water structure, and tends to + decrease the solubility of potassium in the water, and to increase the water's + "lipophobic" tendency to minimize its contacts with fats and the fat-like surface of + proteins, causing the proteins to rearrange themselves.  +
+
+
+  These observations relating to the interactions of water, solutes and proteins in muscles + and nerves provide a coherent context for understanding contraction and conduction, + which is lacking in the familiar descriptions based on membranes, pumps, and + cross-bridges, but I think they also provide a uniquely useful context for understanding + the possible dangers of an excess of free phosphate in the body. +
+
+
+  A few people (M. Thomson, J. Gunawardena, A.K. Manrai) are showing that principles of + mass-action help to simplify understanding the networks of phosphorylation and + dephosphorylation that are involved in cell control. But independently from the + phosphorylation of proteins, the presence of phosphate ion in cell water modifies the + cell's ion selectivity, shifting the balance toward increased uptake of sodium and + calcium, decreasing potassium, tending to depolarize and "activate" the cell. +
+
+
+  About 99% of the publications discussing the mechanism of muscle contraction fail to + mention the presence of water, and there's a similar neglect of water in discussions of + the energy producing processes in the mitochondrion. The failure of mitochondrial energy + production leads to lipid peroxidation, activation of inflammatory processes, and can + cause disintegration of the energy producing structure. Increased phosphate decreases + mitochondrial energy production (Duan and Karmazyn, 1989), causes lipid peroxidation + (Kowaltowski, et al., 1996), and activates inflammation, increasing the processes of + tissue atrophy, fibrosis, and cancer. +
+
+
+  For about twenty years it has been clear that the metabolic problems that cause calcium to + be lost from bones cause calcium to increase in the soft tissues, such as blood vessels. + The role of phosphate in forming calcium phosphate crystals had until recently been + assumed to be passive, but some specific "mechanistic" effects have been identified. For + example, increased phosphate increases the inflammatory cytokine, osteopontin + (Fatherazi, et al., 2009), which in bone is known to activate the process of + decalcification, and in arteries is involved in calcification processes (Tousoulis, et + al., 2012). In the kidneys, phosphate promotes calcification (Bois and Selye, 1956), and + osteopontin, by its activation of inflammatory T-cells, is involved in the development + of glomerulonephritis, as well as in inflammatory skin reactions (Yu, et al., 1998). + High dietary phosphate increases serum osteopontin, as well as serum phosphate and + parathyroid hormone, and increases the formation of tumors in skin (Camalier, et al., + 2010).  Besides the activation of cells and cell systems, phosphate (like other + ions with a high ratio of charge to size, including citrate) can activate viruses + (Yamanaka, et al., 1995; Gouvea, et al., 2006). Aromatase, the enzyme that synthesizes + estrogen, is an enzyme that's sensitive to the concentration of phosphate (Bellino and + Holben, 1989). +
+
+
+  More generally, increased dietary phosphate increases the activity of an important + regulatory enzyme, protein kinase B, which promotes organ growth. A high phosphate diet + increases the growth of liver (Xu, et al., 2008) and lung (Jin, et al., 2007), and + promotes the growth of lung cancer (Jin, et al., 2009). An extreme reduction of + phosphate in the diet wouldn't be appropriate, however, because a phosphate deficiency + stimulates cells to increase the phosphate transporter, increasing the cellular uptake + of phosphate, with an effect similar to the dietary excess of phosphate, i.e., promotion + of lung cancer (Xu, et al., 2010). The optimum dietary amount of phosphate, and its + balance with other minerals, hasn't been determined. +
+
+
+  While increased phosphate slows mitochondrial energy production, decreasing its + intracellular concentration increases the respiratory rate and the efficiency of ATP + formation. A "deficiency" of polyunsaturated fatty acids has this effect (Nogueira, et + al., 2001), but so does the consumption of fructose (Green, et al., 1993; Lu, et al., + 1994). +
+
+ In a 1938 experiment (Brown, et al.) that intended to show the essentiality of unsaturated fats, a + man, William Brown, lived for six months on a 2500 calorie diet consisting of sucrose syrup, a + gallon of milk (some of it in the form of cottage cheese), and the juice of half an orange, + besides some vitamins and minerals. The experimenters remarked about the surprising + disappearance of the normal fatigue after a day's work, as well as the normalization of his high + blood pressure and high cholesterol, and the permanent disappearance of his frequent life-long + migraine headaches. His respiratory quotient increased (producing more carbon dioxide), as well + as his rate of resting metabolism. I think the most interesting part of the experiment was that + his blood phosphate decreased. In two measurements during the experimental diet, his fasting + plasma inorganic phosphorus was 3.43 and 2.64 mg. per 100 ml. of plasma, and six month after he + had returned to a normal diet the number was 4.2 mg/100 ml. Both the deficiency of the + "essential" unsaturated fatty acids, and the high sucrose intake probably contributed to + lowering the phosphate. +
+
+
+  In 2000, researchers who were convinced that fructose is harmful to the health, reasoned + that its harmful effects would be exacerbated by consuming it in combination with a diet + deficient in magnesium. Eleven men consumed, for six months, test diets with high + fructose corn syrup or starch, along with some fairly normal U.S. foods, and with either + extremely low magnesium content, or with slightly deficient magnesium content. The + authors' conclusion was clearly stated in the title of their article, that the + combination adversely affects the mineral balance of the body.  +
+
+
+  However, looking at their results in the context of these other studies of the effects of + fructose on phosphate, I don't think their conclusion is correct. Even on the extremely + low magnesium intake, both their magnesium and calcium balances were positive, meaning + that on average their bodies accumulated a little magnesium and calcium, even though men + aged 22 to 40 presumably weren't growing very much. To steadily accumulate both calcium + and magnesium, with the calcium retention much larger than the magnesium, the minerals + were probably mostly being incorporated into their bones. Their phosphate balance, + however, was slightly negative on the "high fructose" diet. If the sugar was having the + same effect that it had on William Brown in 1938 (and in animal experiments), some of + the phosphate loss was accounted for by the reduced amount in blood and other body + fluids, but to continue through the months of the experiment, some of it must have + represented a change in the composition of the bones. When there is more carbon dioxide + in the body fluids, calcium carbonate can be deposited in the bones (Messier, et al., + 1979). Increased carbon dioxide could account for a prolonged negative phosphate + balance, by taking its place in the bones in combination with calcium and + magnesium.  +
+
+
+  Another important effect of carbon dioxide is in the regulation of both calcium and + phosphate, by increasing the absorption and retention of calcium (Canzanello, et al., + 1995), and by increasing the excretion of phosphate. Increased carbon dioxide (as + dissolved gas) and bicarbonate (as sodium bicarbonate) both increase the excretion of + phosphate in the urine, even in the absence of the parathyroid hormone. Below the normal + level of serum bicarbonate, reabsorption of phosphate by the kidneys is greatly + increased (Jehle, et al., 1999). Acetazolamide increases the body's retention of carbon + dioxide, and increases the amount of phosphate excreted in the urine.  +
+
+
+ Much of the calcium dissolved in the blood is in the form of a complex of calcium and bicarbonate, + with a single positive charge (Hughes, et al., 1984). Failure to consider this complexed form of + calcium leads to errors in measuring the amount of calcium in the blood, and in interpreting its + physiological effects, including its intracellular behavior. Hyperventilation can cause cramping + of skeletal muscles, constriction of blood vessels, and excitation of platelets and other cells; + the removal of carbon dioxide from the blood lowers the carbonic acid, changing the state and + function of calcium. Hyperventilation increases phosphate and parathyroid hormone, and decreases + calcium (Krapf, et al., 1992). +
+
+
+ Since estrogen tends to cause hyperventilation, lowering carbon dioxide, its role in phosphate + metabolism should be investigated more thoroughly. Work by Han, et al. (2002) and Xu, et al. + (2003) showed that estrogen increases phosphate reabsorption by the kidney, but estrogen also + increases cortisol, which decreases reabsorption, so the role of estrogen in the whole system + has to be be considered.  +
+
+
+  This calcium solubilizing effect of bicarbonate, combined with its phosphaturic effect, + probably accounts for the relaxing effect of carbon dioxide on the blood vessels and + bronchial smooth muscles, and for the prevention of vascular calcification by the + thyroid hormones (Sato, et al., 2005, Tatar, 2009, Kim, et al., 2012). Distensibility of + the blood vessels and heart, increased by carbon dioxide, is decreased in + hypothyroidism, heart failure, and by phosphate.  +
+
+
+  While fructose lowers intracellular phosphate, it also lowers the amount that the intestine + absorbs from food (Kirchner, et al.,2008), and the Milne-Nielsen study suggests that it + increases phosphate loss through the kidneys. The "anti-aging" protein, klotho, + increases the ability of the kidneys to excrete phosphate (Dërmaku-Sopjani, et al., + 2011), and like fructose, it supports energy production and maintains thermogenesis + (Mori, et al., 2000).  +
+
+
+  Lowering the amount of phosphate in the blood allows the parathyroid hormone to decrease. + While the parathyroid hormone also prevents phosphate reabsorption by the kidneys, it + causes mast cells to release serotonin (and serotonin increases the kidneys' + reabsorption of phosphate), and possibly has other pro-inflammatory effects.  For + example, deleting the PTH gene compensates for the harmful (accelerated calcification + and osteoporosis) effects of deleting the klotho gene, apparently by preventing the + increase of osteopontin (Yuan, et al., 2012). +
+
+
+  Niacinamide is another nutrient that lowers serum phosphate (Cheng, et al., 2008), by + inhibiting intestinal absorption (Katai, et al., 1989), and also by reducing its + reabsorption by the kidneys (Campbell, et al., 1989). Niacinamide's reduction of free + fatty acids by inhibiting lipolysis, protecting the use of glucose for energy, might be + involved in its effect on phosphate (by analogy with the phosphate lowering action of a + deficiency of polyunsaturated fatty acids). Aspirin is another antilipolytic substance + (de Zentella, et al., 2002) which stimulates energy production from sugar and lowers + phosphate, possibly combined with improved magnesium retention (Yamada and Morohashi, + 1986). +
+
+
+  A diet that provides enough calcium to limit activity of the parathyroid glands, and that + is low in phosphate and polyunsaturated fats, with sugar rather than starch as the main + carbohydrate, possibly supplemented by niacinamide and aspirin, should help to avoid + some of the degenerative processes associated with high phosphate: fatigue, heart + failure, movement discoordination, hypogonadism, infertility, vascular calcification, + emphysema, cancer, osteoporosis, and atrophy of skin, skeletal muscle, intestine, + thymus, and spleen (Ohnishi and Razzaque, 2010; Shiraki-Iida, et al., 2000; Kuro-o, et + al., 1997; Osuka and Razzaque, 2012). The foods naturally highest in phosphate, relative + to calcium, are cereals, legumes, meats, and fish. Many prepared foods contain added + phosphate. Foods with a higher, safer ratio of calcium to phosphate are leaves, such as + kale, turnip greens, and beet greens, and many fruits, milk, and cheese. Coffee, besides + being a good source of magnesium, is probably helpful for lowering phosphate, by its + antagonism to adenosine (Coulson, et al., 1991). +
+
+
+ Although increased phosphate generally causes vascular calcification (increasing rigidity, with + increased systolic blood pressure), when a high level of dietary phosphate comes from milk and + cheese, it is epidemiologically associated with reduced blood pressure (Takeda, et al., + 2012). +
+
+
+  Phosphate toxicity offers some interesting insights into stress and aging, helping to + explain the protective effects of carbon dioxide, thyroid hormone, sugar, niacinamide, + and calcium. It also suggests that other natural substances used as food additives + should be investigated more thoroughly. Excessive citric acid, for example, might + activate dormant cancer cells (Havard, et al., 2011), and has been associated with + malignancy (Blüml, et al., 2011). Nutritional research has hardly begun to investigate + the optimal ratios of minerals, fats, amino acids, and other things in foods, and how + they interact with the natural toxicants, antinutrients, and hormone disrupters in many + organisms used for food. +
+
+
+  

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+
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+ J Pharm Pharmacol. 2002 Apr;54(4):577-82. Non-steroidal anti-inflammatory drugs inhibit + epinephrine- and cAMP-mediated lipolysis in isolated rat adipocytes. de Zentella PM, + Vázquez-Meza H, Piña-Zentella G, Pimentel L, Piña E. +
+

+ + © Ray Peat Ph.D. 2013. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/physiology-texts-and-the-real-world.html b/raypeat-articles/processed/physiology-texts-and-the-real-world.html new file mode 100644 index 0000000..e0bc788 --- /dev/null +++ b/raypeat-articles/processed/physiology-texts-and-the-real-world.html @@ -0,0 +1,275 @@ + + + +

+ +

+

Physiology texts and the real world

+
+ Hospital accidents kill more people than highway accidents. But when people die while they are receiving + standard, but irrational and antiscientific treatments and “support,” the deaths aren’t counted as accidents. + The numbers are large. Medical training and medical textbooks bear great responsibility for those unnecessary + deaths. Most medical research is done under the influence of mistaken assumptions, and so fails to correct the + myths of medical training. If the “consumers” or victims of medicine are willing to demand concrete + justifications before accepting “standard procedures,” they will create an atmosphere in which medical mythology + will be a little harder to sustain. +
+ + A sentence taken out of context is likely to be misleading. A chemical equation that is concerned only with the + reactants, catalyst, and product, can be misleading, and its industrial application is likely to produce + devastation and pollution along with the intended product. In nature and industry, the reactants, products, and + energy changes are linked to the ecology and to the economy. In physiological chemistry, events in the organism + are linked to the environment so closely that food, water, air, soil, and pollution form a firmly linked + functional system. But “medical physiology” has evolved as a separate thing, in which formulas that describe + specific situations are linked to each other by fragmentary schemes, terminology, and computer models. This + jerrybuilt scheme is even more roughly set into a hypothetical environment of “the origin of life,” “evolution,” + “inheritance,” “society,” and a few other perfunctory contextualizations that have no more relevance to the + subject than do the literary epigraphs that are often used at the beginning of chapters in medical books, to + signify that the author isn’t just a technical hack. This physiological mythology has made possible a practice + of medicine in which “genes” and “a virus” are regularly invoked to explain things that can’t be remedied, and + in which any fleshy body is described as “well nourished,” and in which malnutrition and poisoning by pollutants + are systematically dismissed as explanations for sicknesses, while thousands of different drugs are administered + according to instructions given by their salesmen. It is also deeply linked to attitudes that have turned the + practice of medicine into the surest way for an individual to get rich and retire early. It creates a sense of + confidence that the physician is doing the right thing, because there is a little physiological rationale for + everything. When a practice is replaced by its opposite, there is also a rationale for + that. In fact, medical textbooks are written to rationalize the highly arbitrary + practices of the industry. If, for some reason, perpetual motion machines had been as successful economically as + steam engines were, laws of thermodynamics would have been written to describe them, just as thermodynamic laws + were invented to describe the theory of steam engines. It was odd and interesting when a vice presidential + candidate stepped to the podium several years ago and asked “who am I? What am I doing here?” But those + questions are really of the greatest importance and interest, and physiology should be an attempt to understand + more fully what we are, what we are doing, and how we are doing it. When we have comprehensive answers to those + questions, then we will be in a position to create systematically valid solutions for our problems. For + physiology, the equivalent of medicine’s “first do no harm” would be “first, don’t believe unfounded doctrines.” + Accepting that principle puts a person into a critical attitude, and experiments can become actually + “empirical,” an extension of experience that allows you to perceive new things, rather than “testing + hypotheses.” Unless a hypothesis is a generalization from real experience, rather than a deduction from a + doctrine, progress is likely to be very slow. A first step in developing a critical attitude is to identify the + idols that stand in the way of real understanding. + Immunity, intelligence, appetites, tumor growth, aging, the proper development of organs—everything that + we think of as the biological foundations of health and sickness—will be misinterpreted if there are + fundamental misconceptions about physiology. + + Physiology is the study of the vital functions of organisms, but especially when talking about “pathologic + physiology,” great emphasis in physiology textbooks is given to the processes that maintain homeostasis of + the milieu interieur, or the constancy of composition of the “fluid in which tissue cells are + bathed.” Since cells are embedded in a gel-like matrix, “connective tissue,” the connective tissue should have + some serious attention in physiology courses, but in practice its composition is described, and then the rest of + physiology treats it as the “extracellular space.” Only specialists in the extracellular matrix are likely to + take it seriously as a factor in physiology. If medical physiologists are likely to think of cells as being + “bathed in fluid” which fills the empty spaces around the cells, they are also likely to think of the cell’s + interior as a watery solution which “fills the space enclosed by the cell membrane.” It is this image of the + organism that has made traditional biochemistry possible, since enzymes extracted from cells and dissolved in + water had been thought to function the way they function in the living state. But the living cell isn’t like a + tiny water-filled test-tube. + Some of the points that should be considered in a realistic (and therefore coherent) physiology + text: + Connective tissues, ground substance— making a multicell organism--secreting the right amount, + modifying/maintaining it, responding to the scaffolding--where the crucial milieu interieur is. + Cellular energy, a structural idea—a finely organized catalyst, a readiness for work, and + conditions that determine the equilibrium of reactions. + The dimensions of the organism range from cellular fields to organismic intentions, via + functional systems. + Physiology should be understood in terms of its geochemical setting, because otherwise + basic definitions will be built up in the belief that life is discontinuous from its physical environment, + separated by membranes, and maintained by the expense of energy mainly to preserve gradients across those + membranes; while in actuality the chemical energy released by living substance is spent in + renewing structures, and the gradients are mainly passive physical-chemical consequences of structure. The + spontaneous polymerization that occurs under volcanic conditions creates substances with intrinsic functions. + The living state is a substance that is always being renewed as it interacts with its environment, and from the + larger persepective, it is an evolving catalyst that modifies the environment so that the whole system + approaches equilibrium with the energy that flows through it. Since the evolving system stores energy in its + structure, the cosmic energy sources and sinks are at the boundaries of the system, and are the only questions + that (so far) transcend the issue of life in its environment. The chemistry of the planet is tied up with cosmic + energy, but the nature of the system as a whole is still relatively unexplored. If plants are bracketed by the + sun, carbon dioxide and water, animals are bracketed by sugar and oxygen. + Acid-base regulation--selectivity; physical chemistry of coral, bone; + kidney, lung; roles of oxygen, carbon dioxide and protein. + An Arrhenius base is something which produces hydroxide ions when it’s dissolved in water. + Metal, an element that forms a base by combining with a hydroxyl group (or groups). + Base, an electropositive element (cation) that combines with an anion to form a salt; a + compound ionizing to yield hydroxyl ion. + Electropositive atoms tend to lose electrons. + Electronegative atoms, such as oxygen, chlorine, and fluorine, tend to take up an electron and + to become negatively ionized.  + Definitions of Arrhenius and Lewis for acids and bases. It’s important to keep both sides + of an ionizable compound in mind, and to pay more attention to electrons than to protons. + A Lewis acid is an electron acceptor. + Alkali reserve, (Stedman’s phrase:) “the basic ions, mainly the bicarbonates” (bicarbonates of this or + that; there is no abstract “bicarbonate.”) + Carbon dioxide is a neutral Lewis acid, that associates with the hydroxide ion. (This + observation may be shocking to people who have thought too long in terms of abstract “bicarbonate.”) + Carbon dioxide regulates water, minerals, energy and cellular stability, excitation, and + efficiency. + Cellular respiration regulates both energy and substance disposition. + Respiration regulates osmotic/oncotic pressure, including the hydration (and dehydration) of the + extracellular matrix. + Electrons, positive charges, electronegativity, and induction: The unity of metabolism and + signalling interactions; hormones are physical-chemical agents, not information carriers. Electrets, + piezoelectricity, and crystal/bond stresses are relevant to physiology; the behavior of ionic materials in bulk + water provides misleading images for physiology. Space charges are more relevant to physiology than fluxes in + ion channels. + Inductive effect: an electronic effect transmitted through bonds in an organic compound + due to the electronegativity of substituents.  + Cooperative adsorption interacts with inductive effects producing coherent, systemic + changes and stabilities. + Steroids, peptides, biogenic amines, and other things considered as hormones and + transmitters, are active as modifiers of adsorption, induction, and metabolic pathways. Their structural effects create, or inhibit, phase transitions in cells. Synergies of + radiation, estrogen, and hypoxia are intelligible in terms of phase instability. + Alkaloids: organic substances occurring naturally, which are basic, forming salts with + acids. The basic group is usually an amino function. + The disposition of electrons in cells and tissues is a global phenomenon, integrating + metabolism, pH, osmolarity, and sensitivity. Excitation creates a field of alkalinity. + Cellular differentiation; developmental fields, polarities. + Regulation of water; electroosmosis; edema in relation to cellular energy. + Vicinal water, all water near surfaces, most of the water in cells, has special properties. + Needs on the cellular level guide the organism’s adaptations. + Functional systems, multilevel adaptive integrations, in which many “systems” and cell + types are organized according to activity and needs, leading to anatomical and functional changes. + Energy and relaxation, cellular inhibition, a structural state involving the entire cell + substance. High energy phosphate bonds explain nothing about the cell’s energy. + Multilevel self-regulation; cell intelligence, organic compensations (function producing + structure, organ regeneration, vascular neogenesis, stem cell functions, immunity/morphogenesis, + tubercles/tumors, fat/fiber/muscle/phagocytosis) permits highly organized and novel adaptive responses, which + are goal-directed rather than mechanistically “programmed” from the genes. + Sensitivity and motility—plants and animals, subtle cues, rhythms, motivations. + Adaptation—learning, intention, and stress. + Light, energy, motion; pigments and electron donor-acceptor bonds. + Acceptor of action, innate and learned models of reality. Intentionality is involved in + “reflexes.” + Digestion—bowel and liver; immune system and nervous system; need and intepretation, analysis; approximation and assimilation. Intestinal flora and detoxifying. Detoxifying fatty acids, estrogen, insulin, nerve chemicals, etc.   + Nutrition—appetite and satisfaction.  + Reproduction, puberty, menopause; how they are affected by the environment. + Humor, curiosity, exploratory and inventive potentials and need.  + Growth and aging; energy, individualization and generalization; mitosis and meiosis, germ + cells. + Nurse cells, their interactions in various organs. + Chalones, wound hormones, phagocytes, regeneration, nerve products; inhibition of growth + by nerves. Frog extracts in development. Anatomy is a dynamic system, whose integration is part of physiology. + Inflammations and tumors are systemic events, in causes and effects. + Inflammation, edema, fibrosis, calcification, and atrophy--the basic pathology. + Organisms relate to the biosphere as factors in the creation of new equilibria. + + Between 1947 and 1956, Arthur C. Guyton, of Ole Miss, wrote a textbook of medical physiology, and one of his + students, J. E. Hall, has added chapters to it. It is the most widely used physiology textbook in the world. It + may be more influential than the bible, since it has shaped the behavior of millions of doctors, affecting + billions of people. Its success probably has something to do with Guyton’s unusual personal experience. After + graduating from Harvard Medical School and, along with others from Harvard, working in germ warfare,* he + contracted polio, and returned to Mississippi. As someone moving from the centers of excellence and power to the + most backward state in the nation, instead of using textbooks he wrote handouts for the classes he taught there, + devising what he thought were plausible explanations for everything in physiology. A personalized perspective + and desire to keep things simple made the book, based on those handouts, readable and popular.  The + circulatory system, and the movement of fluids in the body, are at the center of physiology, so it is of + interest that Guyton believed that, in the “spaces around cells,” there is a negative pressure, a partial + vacuum, that sucks fluid out of the capillaries. He believed that this suction would balance a column of 5 or 10 + mm of mercury. The rib cage, and the force of the diaphragm muscle, can maintain a negative pressure around the + lungs, preventing their elastic collapse, but there is no such shell around the rest of the body; if elastic + fibers of connective tissue could be anchored to such a shell, then such a suction/vacuum would be + conceivable.  Hydrostatic and osmotic pressures interact in tissues, but even the hydrostatic forces + produced by the heartbeat are known only approximately, as estimates, on the microscopic level. The belief in + subatmospheric interstitial pressure is unreasonable on its face, and measurements are so inaccurate in the + microcirculation that its disproof would be somewhat like proving that fairies aren’t responsible for the + Brownian motions seen under a microscope. The oncotic/osmotic behavior of proteins in the blood and + extracellular (the term interstitial implies the presence of empty spaces + which aren’t really there) fluid is usually, in medical physiology, assumed to be a fixed quantity determined by + the nature of the polymer. Swelling and syneresis (contraction) of gels, with the absorption or release of + water, are strongly influenced by the electrical properties of the system, which includes solvent water, bound + water, and small solutes and ions as well as the polymers. Changes in pH and ionic strength and temperature, and + the presence of solutes modifying the polymer’s affinity for water, affect the osmotic behavior of the polymer, + and of gels formed by such polymers. Since the extracellular spaces are mainly filled with solid gels, Guyton’s + image of simple fluids entering and leaving these “spaces” reveals a major conceptual error, and that error has + been widely propagated by medical professors. If a person imagines open spaces, interstices, between cells, then + the question of the fluid pressure in these chambers seems reasonable, and the factors that produce edema will + be thought of mechanically. But if we call the material between cells the “extracellular matrix,” and recognize + its relatively solid gel nature, we will see the problem of edema in physical-chemical terms, rather than as a + problem of simple hydraulics. [*Biographical side-lights: Guyton graduated from Ole Miss + in 1939, got his medical degree from Harvard in 1943, where the department of bacteriology had a grant to study + the polio virus, and where he worked with people “involved in the war effort,” and then from 1944 to 1946 was + involved in germ warfare research, mainly at Camp Detrick. Camp Detrick had been established as the center for + chemical and biological warfare research, and a test site was established in Mississippi in 1943. Guyton’s first + paper was on aerosol research (published in 1946), and studies at that time were being done to improve the + spreading of germs in aerosols. Bacterial aerosols were tested on the public in San Francisco, in 1950. Guyton’s + Harvard colleagues established a polio research lab at Children’s Hospital Medical Center. When he left the + navy, after working at Camp Detrick, Guyton resumed work at Mass General, and contracted polio before he + finished his residency.]  + + Idols of medical physiology, foundations and cornerstones for the landfill, some things you shouldn’t + know about physiology: + Genes control the cell, the organism is its genome, the nucleus regulates the cytoplasm. Information flowing + from the genes produces and maintains the organism. Acquired traits aren’t passed on; mutations are random, the + genome doesn’t acquire information from the organism or environment, the germ-line is isolated. Physiology is + bounded by the informational function of genes. The cell is a drop of water containing dissolved chemicals + enclosed in a membrane.  Random diffusion governs energy metabolism, gene induction, and other + intracellular events. Enzyme reactions occur when dissolved molecules randomly diffusing come into contact with + a suitable enzyme, as described by the Michaelis-Menton equation. The Donnan equilibrium explains cellular + electrical behavior, and since ions are distributed across the membrane by active transport, the membrane + potential is maintained by the expense of metabolic energy. Water is just a peculiar solvent. Water structure + changes only at extremes of temperature. Cells are perfect osmometers. There are empty spaces between cells. The + membrane regulates the composition of the cytoplasm, with pumps and pores and channels. Cells must produce + enough energy to keep the pumps running. Membrane receptors regulate cell responses. Cells are activated by + receptors, and physical forces for which there are no receptors have no effect on cells except when they are + above a threshold at which they cause discrete chemical changes. The nervous system is hard-wired. Brain and + heart cells don’t regenerate. There is an immune system, whose function is to destroy pathogens, with + inflammation as one of its functions, and its specific reactions are determined by the selection of clones which + were generated by random mutations; an autonomic nervous system, which regulates visceral reflexes by + innervating, via receptors, smooth muscle, heart muscle, and glands; an endocrine system, regulated mainly by + negative feedback, that produces hormone molecules that carry messages to the receptors in certain target + tissues. Inflammation is produced by germs, and is a defensive reaction of the immune system, and so is good. + (Sterile inflammation is too confusing to include within the ambit of medical physiology, since it is associated + with serious harm to the organism. The roles in inflammation of the nervous and endocrine systems and kidneys + and membrane pumps and osmoregulation aren’t discussed in polite books.) During development, cells are organized + into systems, and they don’t change their type. In the case of germ cells, their type is determined before they + exist. Cells are able to undergo only about 50 divisions, and most of those divisions are used up in producing + an adult organism. The committed nature of the organism’s cells and anatomy make radical functional adaptation + impossible. Hormones and transmitter substances act only through specific receptor molecules. High energy + phosphate bonds in compounds such as ATP provide energy to molecular pumps and motors.  Molecular forces + act only locally. Pathologies are primarily local: Inflammations and tumors have local causes, and their effects + are local. Specific and local treatments are ideal. Circulation is treated as a plumbing problem, tumors as + clones of defective cells. Consciousness is produced by nervous signals that transmit information, and can be + compared with the handling of information by computers. Excitation and inhibition are functions of cell + membranes. Artificial intelligence research into computational and nerve net systems is as much a part of + research into the physiology of consciousness as computer modeling of feedback systems is a form of research + into endocrine physiology and immunology. Estrogen, testosterone, thyroid, prolactin, serotonin, adrenalin, + prostaglandins, etc., are carriers of information in an informational system. Cyclic functions and behaviors are + governed by genes. The existence of hard-wired informational receptor systems and gene-induction systems is + necessary because of the random diffusional nature of the other cellular processes and materials. + Essentially, an organism consists of random inert matter given form and activity by the imposition + of genetic information accumulated through random mutations. + (There are really people who still believe those things.) + A NOTE ON SCIENTIFIC REVOLUTIONS: + If scientific revolutions depended on "the authorities," then the Copernican revolution would be dated from the + Pope's apology. The fact that the major journals are controlled by antiscientific dimwits helps to define where + science exists. Gilbert Ling's revolution in cell physiology has been moved along by the existence of the + journal, Physiological Chemistry and Physics (and medical NMR). Michael Polanyi, in Personal + Knowledge, maybe even more than Thomas Kuhn did in his famous book (Structure of + Scientific Revolutions), helped to solidify the belief that there is a real international monolithic + "community of science." Even though Polanyi, working "in isolation" in Hungary created his general and elegant + adsorption isotherm, he didn't teach it to his own students, because of his belief in that community of science, + which ridiculed his work because it wasn't based on their (false) assumptions about the electrical nature of + matter.   The linguistic and cultural isolation of Hungary and Russia from Europe has permitted them to + evolve distinctive scientific cultures. C.C. Lindegren, in Cold War in Biology, showed that political forces in + the U.S. and England suppressed anti-Mendelian ideas by identifying them as subversive, imposing the Central + Dogma of genetics.  But even within an authoritarian national tradition, there are little communities of + science, where the real development of thought can take place. Perceptions that are clear and useful are the + real revolutions in science, and the rest of it has to do with social and financial commitments. Even in the + short time since Kuhn wrote his book, the status of medicine has changed significantly, putting it right up with + militarism and the energy industry as a source of political and economic power. The authoritarian monolith that + has been known as the community of science has become increasingly (even in areas such as astronomy, where + commercial interests aren't so crudely involved) a structure of cultural propaganda maintained by bullying and + fraud. Since the "normal science" in these authoritarian settings is dedicated to evading the truth, it becomes + almost a guide to where to look for the truth. It's sort of analogous to the "mystery" of why breast cancer + mortality is lowest in the poorest part of the U.S., Appalachia, and highest in the richest regions: the medical + industry goes where the money is, taking death with it. Science, like health, thrives on the neglect of the + corrupt industry.  I have always felt that the cybernetic definition of communication as the transfer of + something that makes a difference should be applied to speech and writing. As a student and teacher, I saw that + information which made a difference was the essence of intellectual excitement and growth. But making a + difference is exactly what university administrators and journal editors don't want.  © Ray Peat Ph.D. + 2014. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/progesterone-deceptions.html b/raypeat-articles/processed/progesterone-deceptions.html new file mode 100644 index 0000000..8bfaf59 --- /dev/null +++ b/raypeat-articles/processed/progesterone-deceptions.html @@ -0,0 +1,245 @@ + + + + The Progesterone Deceptions + + + +

+ The Progesterone Deceptions +

+ +

+ In the 1930s, it was demonstrated that estrogen, even in small doses, produced abortions, and that when it + is given early enough, even a very small dose will prevent implantation of the fertilized embryo. + Progesterone was known, by the early 1940s, to protect against the many toxic effects of estrogen, including + abortion, but it was also known as nature's contraceptive, since it can prevent pregnancy without harmful + side-effects, by different mechanisms, including prevention of sperm entry into the uterus. That is, + progesterone prevents the miscarriages which result from excess estrogen (1,2), but if used before + intercourse, it prevents conception, and thus is a true contraceptive, while estrogen is an abortifacient, + not a contraceptive. +

+

+ In the 1950s, there was a search for chemicals which would prevent ovulation. According to Carl Djerassi (), + drug companies were extremely reluctant to risk a religious backlash against their other products, and so + hesitated to market contraceptives. Obviously, the induction of monthly abortions would have been even + harder to sell. +

+ +

+ According to Djerassi (3), "Until the middle 1940s ti was assumed that progesterone's biological activity + was extremely specific and that almost any alteration of the molecule would diminish or abolish its + activity." This would obviously discourage interest from the drug companies, who could patent a substance + which they had chemically modified, but could not patent a simple natural substance. However, many + substances--even non-steroidal chemicals--were known to have estrogenic action. (4) +

+

+ By 1942, Hans Selye had demonstrated that natural steroids retain their activity when administered orally. + But every drug company with a steroid patent had an obvious interest in having the public believe that there + is a reason that the natural steroids cannot be conveniently used. The doctrine that natural steroids are + destroyed by stomach acid appeared, was promoted, and was accepted--without any supporting evidence. In the + manufacture of progesterone, the precursor steroid is boiled in hydrochloric acid to free it from its + glucose residue. No one seriously believed that stomach acid hurts progesterone, except the public--and the + doctors, who had seen the claim in their medical journals, and had heard it from drug salesmen. +

+

+ The myth stopped the use of the cheap tablets of progesterone, as tablets of the synthetic "progestins" came + on the market, at a much higher price. Doctors who insisted on using real progesterone were forced to buy it + in an injectable form. As a result, solubility became an issue. Progesterone is extremely insoluble in + water, and, though it is vastly more soluble in vegetable oil than in water, it does not stay in solution at + room temperature even at the low concentration of 1 part in 1000 parts of a typical vegetable oil. +

+

+ When people speak of an allergy to progesterone (or even to penicillin) they generally are not aware of the + presence of a very toxic solvent.(5) For a time, progesterone was often sold dissolved in benzyl benzoate. + The Physician's Desk Reference warned of possible allergic reactions to progesterone. Now, it is supposedly + sold dissolved in vegetable oil, with about 10% benzyl alcohol as--supposedly--a "bacteriostatic agent." +

+

+ Bacteriostatic water contains 0.9% to 1.9% benzyl alcohol, and can irreversibly harm nerves. (6,7) Its use + in hospitals killed thousands of babies. Awareness of benzyl alcohol's toxicity goes back to 1918 at least; + it was proposed as an effective insecticide, and was found to be toxic to many animal systems. The safe + systemic dose (7) is exceeded with an injection of 150 mg. of progesterone, yet the local concentration is + far higher. It can cause a severe reaction even when used at a lower concentration, in bacteriostatic water. + (5) +

+ +

+ Other alcohols, including ethanol, have been used as solvents, but since they (ethanol even more than benzyl + alcohol) have an affinity for water, the solution decomposes in contact with tissue water. +

+

+ In spite of the toxicity of the vehicle, several beneficial effects can be obtained with injected + progesterone, in serious conditions such as epilepsy or caner of the breast or uterus. Many researchers have + commented on the very obvious difficulty of giving very large amounts of progesterone. (8) My comparisons of + oral progesterone in tocopherol with other forms and methods of administration show a roughly similar + efficiency for oral and inject progesterone, and about 1/20 the effect for suppositories. Crystals of + progesterone are visible in the suppositories I have examined, and this material is obviously wasted. +

+

+ An old theory of vitamin E's mechanism of action in improving fertility was that it spares progesterone.(9) + It is established that some of the effects of vitamin E and progesterone are similar, for example, both + prevent oxygen waste and appear to improve mitochondrial coupling of phosphorylation with respiration. I + suspected that if they actually both work at the same mitochondrial site, then they must have a high mutual + solubility. +

+

+ Knowing the long-standing problem of administering large doses of progesterone without a toxic solvent, I + applied for and was granted a patent for the composition of progesterone in tocopherol. One of my reasons + for publishing in the form of patents is that I have had many years of experience in having my discoveries + taken up by others without acknowledgment, if they are compatible with conventional prejudices. Typically, + an editor rejects a paper, and then a few months later publishes a very similar paper by someone else. My + dissertation research, which established that an estrogen excess kills the embryo by suffocation, and that + progesterone protects the embryo by promoting the delivery of both oxygen and glucose, didn't strike a + responsive chord in the journals which are heavily influenced by funds from the drug industry. +

+

+ According to a consultant for a major medical journal, the idea ""of dissolving progesterone, a fat soluble + steroid hormone, in vitamin E which is then incorporated into chylomicrons absorbed via the lymphatics, and + thus avoids the liver on the so called first pass" "is so simple it is amazing that the pharmaceutical + companies have not jumped on it." (A more sophisticated writer might have said ""stomped on it.") +

+

+ In the powder form, direct and intimate contact with a mucous membrane allows lipid phase to lipid phase + transfer of progesterone molecules. Instead of by-passing the liver, much of the progesterone is picked up + in the portal circulation, where a major part of it is glucuronidated, and made water soluble for prompt + excretion. +

+ +

+ Since this glucuronide form cross-reacts to some extent with the ordinary progesterone in the assay process, + and since 50% of the ordinary free progesterone is carried inside the red blood cells (10,11), and 50% is + associated with proteins in the plasma, while the glucuronide hardly enters the red blood cells at all, it + is better to judge by clinical efficacy when comparing different oral forms. My comparisons show several + times higher potency in the tocopherol composition than in powder form. +

+

+ Since progesterone's use as a drug antedates the 1938 law requiring special federal approval, its legal + status is similar to that of thyroid hormone. Unfortunately, for both thyroid and progesterone, there is a + tendency to cut corners for the sake of a bigger profit margin. +

+

+ For example, steroid acetates are generally a little cheaper than the simple natural steroid. Some people + assume that an acetate or butyrate can be substituted for the steroid itself. This can cause dangerous + reactions. +

+

+ Medroxyprogesterone acetate is considered a progestin (though it is not supportive of gestation), because it + modifies the uterus in approximately the wasy progesterone does, but it is luteolytic, and lowers the + ovaries' production of progesterone while progesterone itself has a positive effect on the corpus luteum, + stimulating progesterone synthesis. Defining "progestin" in a narrow way allows many synthetics to be sold + as progestogens, though some of them are strongly estrogenic, allowing them to function as + contraceptives--it is odd that contraceptives and agents which suppress progesterone synthesis should be + officially called "supported of pregnancy." It is probably partly the acetate group in the + medroxyprogesterone acetate molecule which makes it bind firmly to receptors, yet causes it to block the + enzymes which would normally be involved in progesterone metabolism. (I think testosterone, even, might be a + safer progestin than medroxyprogesterone acetate.) Pregnenolone acetate similarly blocks the enzymes which + normally metabolize pregnenolone. (12) In aspirin, it has been found that it is the acetyl group which (by a + free radical action) blocks an enzyme involved in prostaglandin synthesis. +

+

+ If the category called "progestogens" or "progestins" is to be defined on the basis of a single tissue + reaction, then it is possible to classify progesterone with the toxic synthetic substances, but then it + becomes highly deceptive to imply that progesterone is just a progestin, or that + it has any of the other properties + + of the toxic synthetics, but this continues to be done. The warnings about "progestins causing birth + defects," for example, cause epileptic women t use conventional anti-seizure drugs (all of which cause birth + defects) during pregnancy, and to avoid natural progesterone, which generally could control their seizures. + Thus, a false message attached to progesterone creates precisely the harm it claims to want to prevent. In + my communications with the regulatory agencies, I have concluded that their attempts to deceive are too + blatant to ascribe to incompetence. Whether it's the Forest Service the FDA, the principle is the same: The + regulatory agencies have been captured by the regulated industries. +

+

+ Another place to cut costs is in the tocopherol. Tocopherol acetate does have vitamin E activity, but sine + it is only about half as efficiently absorbed as the simple tocopherol (13), it is a mistake to save a few + dollars an ounce, at the expense of losing half of the therapeutic effect. People who have compared natural + progesterone in natural tocopherols with other compositions have insisted that the other compositions must + not contain progesterone. +

+

+ The taste of natural vitamin E is stronger than that of the synthetic forms, but since the mixture is + absorbed by any tissue it contacts, including various parts of the bowel, it can be taken in a capsule. If a + small amount of olive oil is used with it, absorption through the skin is very rapid. Many women use it + vaginally, spread onto a diaphragm, to hold it in contact with the membranes. The efficiency of absorption + by all routes is so high that patients should be warned against its anesthetic effect, until their dosage + requirement is known approximately. Some physicians prefer concentrations higher than 10%, but the risk of + accidental drunkenness or anesthesia is higher with the stronger solutions. +

+

+ It is an indication of the tocopherol solution's high availability that medical researchers such as Roy + Hertz (8), who thought they were administering maximal doses by combining injections with suppositories, + never mentioned the problem of an anesthetic effect from an overdose. Similarly, it si evidence of the + extremely poor availability of the micropulverized progesterone that the researchers have administered + hundreds of milligrams per day, without mentioning the symptoms of an overdose. Because of the difficulties + involved in scientifically studying the clinical effectiveness of various formulations, I think the most + practical way of evaluating the effectiveness of different progesterone formulations is to measure the + amount extractable from the red blood cells, a few hours after the peak serum level has been reached. This + will reasonably reflect the amounts reaching brain cells, adrenal glands, and the various other cells on + which progesterone has its therapeutic action. +

+ +

REFERENCES

+ +

+ 1. A A. Gidley-Baird, et aI., Failure of implantation in human in vitro fertilization and embryo transfer + patients: the effects of altered progesterone/estrogen ratios in humans and mice, Fertility and Sterility + 45(1): 69-74, 1986. +

+

+ 2. J. L. Yovich, et aI., Early luteal serum progesterone concentrations are higher in pregnancy cycles, + Fertility and Sterility 44 (1): 185-189, 1985. +

+

+ 3. C. Djerassi, The making of the pill, Science 84: 127-129, 1984. +

+

+ 4. R. Kehl, Les Glandes Endocrines, Presses Universitaires de France, Paris, 1952. +

+

+ 5. J. A. Grant, et aI., New England Journal of Medicine 306(2): 108, 1982, Unsuspected benzyl alcohol + hypersensitivity. +

+

+ 6. T. E. Feasby, et aI., Neurotoxicity of bacteriostatic water, New England Journal of Medicine 308(6): + 966-7, 1983. +

+ +

+ 7. E. T. Kimura, et aI., Parenteral toxicity studies with benzyl a1cohol,Toxicol Appl Pharmacol18: 60-68, + 1971. +

+

+ 8. A. White, editor, Symposium on Steroids in Experimental and Clinical Practice, The Blakiston Co., N.Y., + 1951, p. 401. +

+

+ 9. A. Fraschini, II Metodo Biologico di Rinvigorimento, Edizioni Minerva Medica, Milan, 1954. +

+

+ 10. E. Mulder, et aI., Metabolism of free and conjugated steroids by intact and haemolysed mammalian + erythrocytes, Biochim. Biophys. Acta 263: 290-297, + 1972. +

+

+ 11. M. Holzbauer, The association of steroids with blood cells in vivo, J. of Steroid Biochemistry 3: + 579-592, 1972. +

+

+ 12. S. Lieberman, et aI., A heuristic proposal for understanding steroidogenic processes, Endocrine Reviews + 5(1): 128-148, 1984. +

+

+ 13. L. J. Machlin and E. Gabriel, Kinetics of tissue alpha-tocopherol uptake and depletion, following + administration of high levels of +

+ +

+ vitamin E, p. 48 in annals of the N.Y. Academy of Science 393,B. Lubin and I. J. Machlin, editors, New York, + 1982. +

+ + © Ray Peat Ph.D. 2007. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/progesterone-summaries.html b/raypeat-articles/processed/progesterone-summaries.html new file mode 100644 index 0000000..f2f4843 --- /dev/null +++ b/raypeat-articles/processed/progesterone-summaries.html @@ -0,0 +1,207 @@ + + + + Progesterone Summaries + + + +

+ Progesterone Summaries +

+ + +

PROGESTERONE INFORMATION

+

+ Sixty years ago, progesterone was found to be the main hormone produced by the ovaries. Since it was + necessary for fertility and for maintaining a healthy pregnancy, it was called the "pro-gestational + hormone," and its name sometimes leads people to think that it isn't needed when you don't want to get + pregnant. In fact, it is the most protective hormone the body produces, and the large amounts that are + produced during pregnancy result from the developing baby's need for protection from the stressful + environment. Normally, the brain contains a very high concentration of progesterone, reflecting its + protective function for that most important organ. The thymus gland, the key organ of our immune system, is + also profoundly dependent of progesterone. +

+ +

+ In experiments, progesterone was found to be the basic hormone of adaptation and of resistance to stress. + The adrenal glands use it to produce their antistress hormones, and when there is enough progesterone, they + don't have to produce the potentially harmful cortisol. In a progesterone deficiency, we produce too much + cortisol, and excessive cortisol causes osteoporosis, aging of the skin, damage to brain cells, and the + accumulation of fat, especially on the back and abdomen. +

+

+ Experiments have shown that progesterone relieves anxiety, improves memory, protects brain cells, and even + prevents epileptic seizures. It promotes respiration, and has been used to correct emphysema. In the + circulatory system, it prevents bulging veins by increasing the tone of blood vessels, and improves the + efficiency of the heart. It reverses many of the signs of aging in the skin, and promotes healthy bone + growth. It can relieve many types of arthritis, and helps a variety of immunological problems. +

+

+ If progesterone is taken dissolved in vitamin E, it is absorbed very efficiently, and distributed quickly to + all of the tissues. If a woman has ovaries, progesterone helps them to regulate themselves and their hormone + production. It helps to restore normal functioning of the thyroid and other glands. If her ovaries have been + removed, progesterone should be taken consistently to replace the lost supply. A progesterone deficiency has + often been associated with increased susceptibility to cancer, and progesterone has been used to treat some + types of cancer. +

+

+ It is important to emphasize that progesterone is not just the hormone of pregnancy. To use it only "to + protect the uterus" would be like telling a man he doesn't need testosterone if he doesn't plan to father + children, except that progesterone is of far greater and more basic physiological significance than + testosterone. While men do naturally produce progesterone, and can sometimes benefit from using it, it is + not a male hormone. Some people get that impression, because some physicians recommend combining estrogen + with either testosterone or progesterone, to protect against some of estrogen's side effects, but + progesterone is the body's natural complement to estrogen. Used alone, progesterone often makes it + unnecessary to use estrogen for hot flashes or insomnia, or other symptoms of menopause. +

+

+ When dissolved in vitamin E, progesterone begins entering the blood stream almost as soon as it contacts any + membrane, such as the lips, tongue, gums, or palate, but when it is swallowed, it continues to be absorbed + as part of the digestive process. When taken with food, its absorption occurs at the same rate as the + digestion and absorption of the food. +

+ +

+ PROGESTERONE SUPPLEMENTATION +

+

+ SYMPTOMATIC: For tendonitis, bursitis, arthritis, sunburn, etc., progesterone in vitamin E can be applied + locally after a little olive oil has been put on the skin to make it easier to spread the progesterone + solution. For migraines, it has been taken orally just as the symptoms begin. +

+

+ FOR PMS: The normal pattern of progesterone secretion during the month is for the ovaries to produce a large + amount in the 2nd two weeks of the menstrual cycle, (i.e., day 14 through day 28) beginning at + ovulation and ending around the beginning of menstruation, and then to produce little for the following two + weeks. An average person produces about 30 milligrams daily during the 2nd two weeks. The + solution I have used contains approximately 3 or 4 milligrams of progesterone per small drop. Three to four + drops, or about 10 to 15 milligrams of progesterone, is often enough to bring the progesterone level up to + normal. That amount can be taken days 14 through 28 of the menstrual cycle; this amount may be repeated once + or twice during the day as needed to alleviate symptoms. Since an essential mechanism of progesterone's + action involves its opposition to estrogen, smaller amounts are effective when estrogen production is low, + and if estrogen is extremely high, even large supplements of progesterone will have no clear effect; in that + case, it is essential to regulate estrogen metabolism, by improving the diet, correcting a thyroid + deficiency, etc. (Unsaturated fat is antithyroid and synergizes with estrogen.) +

+

+ PERIMENOPAUSAL: The symptoms and body changes leading up to menopause are associated with decreasing + production of progesterone, at a time when estrogen may be at a lifetime high. The cyclic use of + progesterone, two weeks on, two weeks off, will often keep the normal menstrual cycle going. Three to our + drops, providing ten or twelve milligrams of progesterone, is typical for a day, but some women prefer to + repeat that amount. Progesterone is always more effective when the diet contains adequate protein, and when + thee isn't an excessive amount of unsaturated fat in the diet.. +

+ +

+ POSTMENOPAUSAL: Some women continue the cyclic use of progesterone ater menopause, because the pituitary + gland and brain may continue to cycle long after menstruation has stopped, and progesterone is an important + regulator of pituitary and brain function. The cycling pituitary affects the adrenal glands and other + organs, and progesterone tends to protect against the unopposed actions of prolactin, cortisol, and adrenal + androgenic hormones. Progesterone's effects on the pituitary apparently contribute to its protective effect + against osteoporosis, hypertension, hirsutism, etc. But some women prefer to use progesterone without + interruption after the menopause, for its protective antistress effects. Slender people usually find that + two or three drops are enough, but this amount may be repeated once or twice as needed to relieve symptoms. + Adequate protein in the diet and good thyroid function help the body to produce its own progesterone; even + if the ovaries have been removed, the adrenal glands and brain continue to produce progesterone. +

+ + DOSAGE OF PROGESTERONE +

+ Since progesterone has none of the harmful side effects of other hormones (except for alteration of the + menstrual cycle if it is taken at the wrong time of month), the basic procedure should be to use it in + sufficient quantity to make the symptoms disappear, and to time its use so that menstrual cycles are not + disrupted. This normally means using it only between ovulation and menstruation unless symptoms are + sufficiently serious that a missed period is not important. The basic idea of giving enough to stop the + symptoms can be refined by some information on a few of the factors that condition the need for + progesterone. +

+

+ If a person has an enlarged thyroid gland, progesterone promotes secretion and unloading of the stored + "colloid," and can bring on a temporary hyperthyroid state. This is a corrective process, and in itself + isn't harmful. A thyroid supplement should be used to shrink the goiter before progesterone is given. Normal + amounts of progesterone facilitate thyroid secretion, while a deficiency, with unopposed estrogen, causes + the thyroid to enlarge. The production of euphoria has been mentioned as a side effect, but I think euphoria + is simply an indication of a good physiological state. (The history of official medical attitudes toward + euphoria is a subject that deserves more attention.) Very large doses that are given in vitamin E solution, + allowing complete absorption, can reach the level that is sometimes achieved late in pregnancy, producing + both euphoria and a degree of anesthesis. To avoid unexpected anesthesia, the correct dose should be + determined by taking about 10 mg. at a time allowing it to spread into the membranes of the mouth, and + repeating the dose after 10 minutes until the symptoms are controlled. +

+ +

+ An excessive estrogen/progesterone ratio is more generally involved in producing or aggravating symptoms + than either a simple excess of estrogen or a deficiency of progesterone, but even this ratio is conditioned + by other factors, including age, diet, other steroids, thyroid, and other hormones. The relative estrogen + excess seems to act by producing tissue hypoxia (as reported in my dissertation, University of Oregon, + 1972), and this is the result of changes induced by estrogen in alveolar diffusion, peripheral vascular + changes, and intracellular oxygen wastage. +

+

+ Hypoxia in turn produces edema (as can be observed in the cornea when it is deprived of oxygen, as by a + contact lens) and hypoglycemia (e.g., diminished ATP acts like insulin), because glycolysis must increase + greatly for even a small deficiency of oxygen. Elevated blood lactic acid is one sign of tissue hypoxia. + Edema, hypoglycemia, and lactic academia can also be produced by other "respiratory" defects, including + hypothyroidism, in which the tissue does not use enough oxygen. In hypoxia, the skin will be bluer (in thin + places, such as around the eyes), than when low oxygen consumption is the main problem. Low thyroid is one + cause of excess estrogen, and when high estrogen is combined with low thyroid, the skin looks relatively + bloodless. +

+

+ Symptoms in cycling women are most common around ovulation and in the premenstrual week, when the + estrogen/progesterone ratio is normally highest. At puberty, in the early twenties and in the late thirties + and menopause are the ages when the ratio is most often disturbed--and these are also the ages when thyroid + disorders are commonest in women. +

+

+ The individual who suffers from one aspect of the progesterone (and/or thyroid) deficiency will tend to + develop other problems at different times. With cyclic depressions or migraine headaches at age 22, there + will possibly be breast disease later, and often there will be problems with pregnancy. These people with a + history of sever symptoms are the ones most likely to have severe problems around menopause. Prenatal + exposure to poorly balanced hormones seems to predispose the child to later hormone problems. +

+

+ Excess stress (which can block progesterone synthesis and elevate estrogen) may bring on symptoms in someone + who never had them. Spending a summer in Alaska, with an unusually long day, may relieve the symptoms of a + chronic sufferer. Dark cloudy winters in England or the Pacific Northwest are powerful stressors, and cause + lower production of progesterone in women, and testosterone in men. Toxins can produce similar symptoms, as + can nutritional deficiencies. A very common cause of an estrogen excess is a dietary protein deficiency--the + liver simply cannot detoxify estrogen when it is under-nourished. +

+ +

+ With a diet high in protein (e.g., at least 70-100 grams per day, including eggs) and vitamin A (not + carotene), I have found that the dose of progesterone can be reduced each month. Using thyroid will usually + reduce the amount of progesterone needed. Occasionally, a woman won't feel any effect even from 100 mg. of + progesterone; I think this indicates that they need to use thyroid and diet, to normalize their estrogen, + prolactin, and cortisol. +

+

+ Progesterone stimulates the ovaries and adrenals to produce progesterone, and it also activates the thyroid, + so one dose can sometimes have prolonged effects. It shouldn't be necessary to keep using progesterone + indefinitely, unless the ovaries have been removed. In slender post-menopausal women, 10 mg. per day is + usually enough to prevent progesterone deficiency symptoms. +

+

+ In a 10% solution of progesterone in vitamin E, one drop contains about three milligrams of progesterone. + Normally, the body produces 10 to 20 milligrams per day. A dose of 3 or 4 drops usually brings the blood + levels up to the normal range, but this dose can be repeated several times during the day if it is needed to + control symptoms. +

+

+ For general purposes, it is most economical and effective to take progesterone dissolved in vitamin E + orally, for example taking a few drops on the lips and tongue, or rubbing it into the gums. (It is good for + the general health of the gums.) These membranes are very thin, and the progesterone quickly enters the + blood. When it is swallowed, the vitamin E allows it to be absorbed through the walls of the stomach and + intestine, and it can be assimilated along with food, in the chylomicrons, permitting it to circulate in the + blood to all of the organs before being processed by the liver. These droplets are smaller than red blood + cells, and some physicians seem to forget that red blood cells pass freely through the liver. +

+

+ For the topical treatment of sun damaged skin, or acne, wrinkles, etc. the oil can be applied directly to + the affected area. +

+ + © Ray Peat Ph.D. 2007. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/prostate-cancer.html b/raypeat-articles/processed/prostate-cancer.html new file mode 100644 index 0000000..58ac30a --- /dev/null +++ b/raypeat-articles/processed/prostate-cancer.html @@ -0,0 +1,515 @@ + + + +

+ +

+
+ +

+ "...simultaneous treatment of intact...rats with testosterone and estradiol-17beta for 16 weeks + consistenly induced a putative precancerous lesion, termed dysplasia, in the dorsolateral prostate of + all animals.  Since treatment of rats with androgen alone did not elicit the same response, we + concluded that estrogen played a critical role in the genesis of this proliferative + lesion."       Shuk-mei Ho and M. Yu, in "Selective increase in + type II estrogen-binding sites in the dysplastic dorsolateral prostates of Noble rats," Cancer + Research 53, 528-532, 1993. +

+

+

Prostate Cancer

+

+ It was noticed several decades ago that estrogen causes the prostate gland to enlarge in experimental + animals, but by then an oversimplified view of the sex hormones was already well established, that led + people to say that "estrogen causes the female organs to grow, and testosterone causes the male organs to + grow."  Logically extending this mistaken idea led many of the same people to suppose that the + "hormones of one sex would inhibit the growth of the reproductive organs of the other sex." +

+

+ When a friend of mine was told he had prostate cancer, though he had had no symptoms, and should receive + large doses of estrogen, I reviewed the literature, to see whether his doctor might have seen something I + had neglected.  Since that time, I have found it necessary to use quotation marks around the phrases + "medical research" and "medical science," because there is a certain kind of "research" performed within the + medical profession which is peculiar to that profession. +

+

+ When I read through the studies cited by the current articles as the basis for using estrogen to treat + prostate cancer, I saw that the decisive "research" had consisted of mailing a questionnaire to physicians + asking them if they thought it was reasonable to administer estrogen to these patients on the basis of its + opposition to testosterone, which was considered to be responsible for the growth of the prostate + gland.  Many physicians answered the questionnaire affirmatively. +

+

+ If the questioner's purpose was to determine his legal status in using a treatment, his research method was + appropriate, to see whether the treatment seemed reasonable to others in the profession.  Legally, a + physician is safe if he can count on others to testify that his practice is standard.  Unfortunately, + for generations his study of the opinions of his peers became the "evidence" of the value of the estrogen + treatment.  Phrases such as "it is indicated," "treatment of choice," and "standard practice" are used + in medicine, as part of the pseudo-scientific mystique of the profession.  Physicans who attempt to + base their practice on methods that have a sound scientific basis are likely to find that they are violating + the norms of their profession. +

+

+ More than 25 years ago, when I started pointing out that deliberate misrepresentation had been involved in + the continued designation of estrogen as "the female hormone," used as a basis for "hormone replacement + therapies," I saw that it was hard for people to sustain a critical attitude toward language.  Language + is prior to judgment, law, science, reason.  Those who define the terms set the rules. +

+

+ By the mid-1980s, some studies had shown that estrogen treatment didn't prolong the survival of prostate + cancer patients at all, but it was argued that the patients who received estrogen were happier than those + who didn't. +

+

+ Apparently, many physicians who were experts in conventional cancer treatment hadn't been impressed by the + happiness of their patients who were receiving estrogen, because a survey at a conference of physicians + found that many of them would choose to have no treatment if they learned they had prostate cancer.  + And more recently, there have been recommendations that older patients shouldn't be treated aggressively, + because their cancers are usually so slow growing that they are likely to die of something else related to + old age. +

+

+ In spite of the articles I showed my friend, and my warning that estrogen can cause strokes and heart + attacks, he decided to take the estrogen treatment.  Within a few days he began suffering from asthma + and disturbed sleep.  Then he had a series of strokes and died.  +

+

+ Since it was known that estrogen treatment was dangerous for men, and that it increases blood clotting and + vascular spasms, there had to be some overriding belief that led to its general use in treating prostate + cancer.  That belief seems to be that "estrogen, the female hormone, opposes testosterone, the male + hormone, which is responsible for the growth--and therefore for the cancerization--of the prostate + gland."  Everything is wrong with that sentence, but you can find every part of the belief present and + functioning in the medical literature.  Just to give some context to the association of growth and + cancerization, I should mention that Otto Warburg observed that all of the carcinogenic factors he studied + caused tissue atrophy before cancer appeared.  Another important contextual + point is that every hormone does many things, and every endocrine gland produces + multiple hormones. +

+

+ Since the time of Brown-Sequard and Eugen Steinach, it has been accepted that declining testicular function + is a common feature of aging, and testosterone was probably the first hormone that was clearly found to + decrease consistently with aging.  (Vermeulen, et al., 1972, 1979.)  +

+

+ It has seemed odd to many people that enlargement of the prostate should occur mainly in older men, if + testosterone is the hormone that causes its growth, and estrogen is antagonistic to its growth.  The + nature of the growth of the old man's prostate is very different from its natural growth in youth. +

+

+ It was also recognized decades ago that estrogen rises in men during old age (Pirke and Doerr, 1975), as it + rises in stress, disease, malnutrition, and hypothyroidism (which are also associated with old age).  + Estrogen is produced in fat (Siiteri, and MacDonald, 1973, Vermeulen, 1976) which tends to increase with + age, when thyroid and progesterone are deficient.  The conversion of testosterone to estrogen occurs in + the testicle itself, but this conversion is also inhibited by the favorable hormonal environment of + youth.  The active thyroid hormone, T3 + , declines with aging, and this necessarily lowers production of pregnenolone + and progesterone.  Increasingly, in both sexes, it appears that DHEA may rise during stress as a result + of a deficiency of thyroid, progesterone, and pregnenolone. +

+

+ In 1786, John Hunter reported that castration causes a decrease in the size of the prostate gland, and by + the end of the 19th century castration was being advocated for treating enlargement of the prostate.  + In aging men, the prostate gland (both central and peripheral zones) atrophies, and it is within the + atrophic gland that cancer cells can be found.  Nodular, noncancerous enlargement may occur, with or + without cancer.  In 1935, an autopsy study showed carcinoma in the prostates of 30% of men by the age + of 50.  Proliferation of ductal and epithelial tissue is closely associated with prostate cancer, a + situation similar to that of the cancerous or precancerous breast.  (Simpson, et al., 1982; Wellings, + et al., 1975; Jensen, et al., 1976.)  The high probability of "epitheliosis" in association with cancer + was seen in women in their early 40s, and in women over 60. (Simpson, et al.)  (Epitheliosis just + refers to an exaggerated proliferation of epithelial cells, the cells covering all surfaces, including the + lining of glands, and things as simple as irritation and vitamin A deficiency can cause these cells to + proliferate.)  In the breast, the proliferative epitheliosis is clearly caused by estrogenic + stimulation.  The antagonism between estrogen and vitamin A in controlling epithelial proliferation + (and possibly other cell types: Boettger-Tong and Stancel, 1995) is clear wherever it has + been tested; vitamin A restrains epithelial proliferation.  (Wherever estrogen is a + factor in the development of abnormal tissue, vitamin A supplementation would seem beneficial.) +

+

+  In aging women and men, as the breasts and prostate atrophy, their estrogen/antiestrogen + ratio increases. +

+

+ In men with prostate cancer, the fluid secreted by the prostate contains significantly more estradiol than + the fluid from men without cancer (Rose, et al., 1984).  This is analogous to observations made in + women with breast cancer. +

+

+ The pituitary hormones have diverse functons, including effects on epithelial tissues, other than their + "classical" functions.  Growth hormone, ACTH (Lostroh and Li, 1957), and ACTH with prolactin (Tullner, + 1963) stimulate prostate growth.  Prolactin--which is increased by estrogen--stimulates growth of the + rat's lateral prostate (Holland and Lee, 1980), and stimulates the growth of human prostate epithelial + cells in vitro (Syms, et al., 1985).  LH (luteinizing hormone) increases when + progesterone or testosterone is deficient, and growth hormone and prolactin (which are closely associated in + evolution) both increase under a variety of stressful situations, and with estrogenic + stimulation.  Prostate cancer patients who had higher levels of LH and  + lower testosterone +  died most quickly.  (Harper, et al., 1984.)  Also, a  + high ratio of testosterone to estradiol or of testosterone to prolactin +  corresponded to better survival (Rannikko, et al., 1981.)  Considered separately, patients + with  + higher testosterone levels had a better prognosis +  than those with lower levels, and patients with lower growth hormone levels did + better than those with higher growth hormone levels. (Wilson, et al., 1985.)  Has anyone ever tried + testosterone therapy for prostate cancer?  Or, more practically, a generalized antiestrogenic therapy, + using thyroid, progesterone, and pregnenolone?  Other drugs (naloxone, bromocriptine, + gonadotropin-releasing hormone agonists, and anti-growth hormone druges, e.g.) are available to regulate the + pituitary hormones, and might be useful therapeutically or preventively.  (See Blaakaer, et al., + 1995.)  Biskind and Biskind's work (1944) with ovarian tumors might be relevant to both testicular and + prostate cancer. +

+

+ Abnormal patterns of pituitary hormones reflect stress and hormonal imbalance, but they are also directly + involved in widespread changes in tissue content of glycoproteins.  The prostate is specialized to + secrete large amounts of mucin.  The endocrine physiology of prostate mucin secretion is poorly + understood, but it is likely that there are interactions between growth-regulatory and secretion-regulatory + systems. +

+

+ In recent years, prostate cancer has been one of the fastest increasing kinds of cancer, and it isn't + apparent that increased treatment has had an effect in lowering the death rate.  The postwar baby-boom + (following the baby-bust of the great depression) created an abnormal age-structure of the population, that + has been used to argue that the war against cancer is being won.  Increasing environmental estrogens + are known to cause many reproductive abnormalities, and their contribution to prostate cancer would get more + attention if estrogen's role in prostate disease were better known.  Environmental estrogens are + clearly responsible for genital deformities and sterility in many species of wild animals, but when the + causal link is made between estrogens and human abnormalities, the estrogen industry sends its shills in to + create controversy and confusion.  Even the effects of estrogens in sewage, known for decades, are + treated as State Secrets:  "There had been reports of hermaphroditic fishes in one or two rivers, and + government investigators had been studying them since the late 1970s.  But no one had been + aware of the work because it was classified." (Lutz, 1996.) +

+

+ Testicular cancer is easy to diagnose, and its incidence has clearly increased (100% in white men, 200% in + black men) since 1950.  Undescended testicles, urethral abnormalities, etc., similar to those seen in + DES sons and in wild animals, have also increased.  So the tremendous increase in the death rate from + prostate cancer during the same time has a meaningful context. +

+

+ Although the animal studies showed that estrogen treatment promotes enlargement of the prostate, it was + possible to suppose that the human prostate's growth might be stimulated only by testosterone, until tests + were done in vitro to determine the effects of hormones on cell division. +

+

+ In human prostate slices, several hormones (including insulin, and probably prolactin) stimulated cell + division; testosterone did not, under these experimental conditions. + (McKeehan, et al., 1984.) Contrary to the stereotyped ideas, there are suggestions that supplementary + androgens could control prostate cancer (Umekita, et al., 1996), and that antagonists to prolactin and + estrogen might be appropriately used in hormonal therapy (for example, Wennbo, et al., 1997; Lane, et al., + 1997). +

+

+ By the age of 50, men often show an excess of both prolactin and estrogen, and a deficiency of thyroid and + testosterone.  This is the age at which enlargement of the prostate often becomes noticeable. +

+

+ Estrogen's role in prostate growth and cancerization is clear:  "...simultaneous treatment of intact...rats with testosterone and estradiol-17beta for 16 weeks consistenly + induced a putative precancerous lesion, termed dysplasia, in the dorsolateral prostate of all animals.  + Since treatment of rats with androgen alone did not elicit the same response, we concluded that estrogen + played a critical role in the genesis of this proliferative lesion."  (Ho and Yu.) +

+

+ Progesterone and pregnenolone also decline in aging men.  Several studies using synthetic progestins + have shown that they effectively shrink the hypertrophic prostate, and the saw palmetto remedy for prostate + enlargement has been reported to contain pregnenolone, or something similar to it.  These materials + might be expected to reduce conversion of testosterone or other androgens to estrogen. +

+

+ The prostaglandins were discovered in prostatic fluid, where they occur in significant concentrations.  + They are so deeply involved with the development of cancers of all sorts that aspirin and other + prostaglandin inhibitors should be considered as a basic part of cancer therapy.  The prostaglandins + have local and systemic effects that promote cancer growth.  ("The prostaglandins and related + eicosanoids synthesized from polyunsaturated fatty acid precursors have been implicated as modulators + of tumor metastasis, host immunoregulation, tumor promotion, and cell proliferation."  Hubbard, et al., 1988.) +

+

+ Estrogens cause elevation of free fatty acids, and  there are many interactions between the unsaturated + fatty acids and estrogen, including their metabolism to prostaglandins, and their peroxidation.  + Estrogen's roles as free-radical promoter, DNA toxin, carcinogen, tumor promotor, modifier of tissue growth + factors, anti-thymic hormone, etc., as well as its local effects on the prostate gland, have to be kept in + mind.  Most of the interest in studying estrogen's contributions to prostate cancer relates to the + existence of estrogen receptors in various parts of the prostate.  While that is interesting, it tends + to distract attention from the fact that many of estrogen's most important actions don't involve the + "receptors."  A direct excitatory action on prostate cells, and indirect actions by way of the pituitary, pancreas, thyroid, adrenal, fatty acids, + prostaglandins, histamine and circulation are probably essential parts of the cancerization process. +

+

+ The unsaturated fatty acids, but not the saturated fatty acids, free estrogen from the serum proteins that + bind it, and increase its availability and activity in tissue cells. +

+ +

+ Thyroid supplementation, adequate animal protein, trace minerals, and vitamin A are the first things to + consider in the prevention of prostate hypertrophy and cancer.  Nutritional and endocrine support can + be combined with rational anticancer treatments, since there is really no sharp line between different + approaches that are aimed at achieving endocrine and immunological balance, without harming anything. +

+

+ Avoiding tissue atrophy is very closely related to promoting healthy regeneration.  These processes + require efficient energy production, and an appropriate balance between stimulation and resources.  + Growth hormone is sometimes recommend to correct tissue atrophy, but the evidence seems reasonably clear + that it is a factor in the promotion of tumefaction of the prostate.  The only study I have seen + suggesting that it might be beneficial in prostatic cancer was a 14 day experiment done in female + rats.  Numerous publications suggest that blocking growth hormone is beneficial in treating prostate + cancer; in future newsletters I will be discussing the evidence that growth hormone, like + estrogen, cortisol, and unsaturated fats, tends to promote degenerative changes of aging - Growth hormone: Hormone of Stress, Aging, and Death? +

+

 

+

    

REFERENCES

+

 

+

+ M.C. Audy, et al., "17beta-Estradiol stimulates a rapid Ca2+ influx in LNCaP human prostate cancer + cells," Eur. J. Endocrionol.135, 367-373, 1996. +

+

+ M. S. Biskind and G. S. Biskind, "Development of tumors in the rat ovary after transplantation into + the spleen," Proc. Soc. Exp. Biol. Med. 55, 176-179, 1944. +

+

+ J. Blaakaer, et al., "Gonadotropin-releasing hormone agonist suppression of ovarian tumorigenesis in + mice of the Wx/Wv genotype," Biol. of Reprod. 53, 775-779, 1995. +

+

+ Clinton, SK Mulloy AL, Li SP, Mangian HJ, Visek WJ, J Nutr 1997 Feb;127(2):225-237 "Dietary fat and + protein intake differ in modulation of prostate tumor growth, prolactin secretion and metabolism, and + prostate gland prolactin binding capacity in rats."  +

+

+ J. R. Drago, "The induction of Nb rat prostatic carcinomas," Anticancer Res. 4, 255-256, 1984. +

+

+ J. Geller, et al., "The effect of cyproterone acetate on adenocarcinoma of the prostate," Surg. Gynec. + Obst. 127, 748-758, 1968. +

+

+ J. Geller, J. Fishman, and T. L. Cantor, "Effect of cyproterone acetate on clinical, endocrine and + pathological features of benign prostatic hypertrophy," J. Steroid Biochemistry 6, 837-843, 1975. +

+

+ Ho, Shuk-mei, and M. Yu, "Selective increase in type II estrogen-binding sites in the dysplastic + dorsolateral prostates of Noble rats," Cancer Research 53, 528-532, 1993.  "...simultaneous + treatment of intact...rats with testosterone and estradiol-17beta for 16 weeks consistenly induced a + putative precancerous lesion, termed dysplasia, in the dorsolateral prostate of all animals.  Since + treatment of rats with androgen alone did not elicit the same response, we concluded that estrogen + played a critical role in the genesis of this proliferative lesion." +

+

+ M. E. Harper, et al., "Carcinoma of the prostate: relationship of pretreatment hormone levels to + survival," Eur. J. Cancer Clin. Oncol. 20, 477-482, 1984. +

+

+ J. M. Holland and C. Lee, "Effects of pituitary grafts on testosterone stimulated growth of rat + prostate," Biol. Reprod. 22, 351-355, 1980. +

+

+ W. C. Hubbard, et al., "Profiles of prostaglandin biosynthesis in sixteen established cell lines + derived from human lung, colon, prostate, and ovarian tumors," Cancer Research 48, 4770-4775, + 1988.  "The prostaglandins and related eicosanoids synthesized from polyunsaturated fatty acid + precursors have been implicated as modulators of tumor metastasis, host immunoregulation, tumor + promotion, and cell proliferation." +

+

+ Izes JK, Zinman LN, Larsen CR, Urology 1996 May;47(5):756-759 "Regression of large pelvic desmoid + tumor by tamoxifen and sulindac,"  "A 54-year-old man was evaluated for symptoms of bladder outlet + obstruction. Evaluation revealed a 10 by 9.8-cm tumor composed of bland, fibroblastic, poorly cellular + material adjacent to the prostate. Administration of a course of antiestrogen (tamoxifen) and + a nonsteroidal anti-inflammatory agent (sulindac) resulted in prompt relief of symptoms and a slow + decrease in the size of the tumor as measured by computed tomography. After 54 + months of therapy, the tumor was undetectable clinically and dramatically reduced in size as seen on + computed tomography. Data on the natural history of desmoid tumors and the efficacy of various + therapeutic strategies are reviewed. +

+

+ Jungwirth A, Schally AV, Pinski J, Halmos G, Groot K, Armatis P, Vadillo-Buenfil M., Br J Cancer + 1997;75(11):1585-1592, "Inhibition of in vivo proliferation of androgen-independent prostate cancers by + an antagonist of growth hormone-releasing hormone." +

+

+ Kroes R; Teppema JS Development and restitution of squamous metaplasia in the calf prostate after a + single estrogen treatment. An electron microscopic study.  Mol Pathol, 1972 Jun, 16:3, + 286-301. +

+

+ Lane KE, Leav I, Ziar J, Bridges RS, Rand WM, Ho SM, Carcinogenesis 1997 Aug;18(8):1505-1510  + "Suppression of testosterone and estradiol-17beta-induced dysplasia in the dorsolateral prostate of + Noble rats by bromocriptine." "We, and others, have previously described the histological changes that + occur in the prostate gland of intact Noble (NBL) rats following prolonged hormonal treatment. + Dysplasia, a pre-neoplastic lesion, develops specifically in the dorsolateral prostates (DLPs) of NBL + rats treated for 16 weeks with a combined regimen of testosterone (T) and estradiol-17beta (E2) (T + + E2-treated rats).  + Concurrent with DLP dysplasia induction, the dual hormone regimen also elicits hyperprolactinemia, in + addition to an elevation of nuclear type II estrogen binding sites (type II EBS), no alteration in + estrogen receptors (ER), and marked epithelial cell proliferation in the dysplastic foci. +  The aim of this study was to investigate whether the dual hormone action is mediated via + E2-induced hyperprolactinemia. Bromocriptine (Br), at a dose of 4 mg/kg body wt per day, was used to + suppress pituitary prolactin (PRL) release. Serum PRL levels were lowered from values of 341 +/- 50 + ng/ml in T + E2-treated rats to 32 +/- 10 ng/ml in Br co-treated animals. The latter values were + comparable to those in untreated control rats. In addition, Br co-treatment effectively inhibited the + evolution of dysplasia (six out of eight rats)  + and the often associated inflammation +  (five out of eight rats) in most animals. In contrast, Br co-treatment did not suppress the T + + E2-induced type II EBS elevation nor alter ER levels in the DLPs of these rats, when compared with T + + E2-treated rats. These data extend the many previous studies that have detailed marked influences + of  + PRL on rat prostatic functions. However, the current study is the first to implicate PRL in prostatic + dysplasia induction in vivo. + " +

+

+ I. Leav, et al., "Biopotentiality of response to sex hormones by the prostate of castrated or + hypophysectomized dogs:  Direct effects of estrogen," Am. J. Pathol., 93, 69-92, 1978. +

+

+ H. C. Levine, et al., "Effects of the addition of estrogen to medical castration on prostatic size, + symptoms, histology and serum prostate specific antigen in 4 men with benign prostatic hypertrophy," J. Urol. 146, 790-93, 1991. +

+

Diana Lutz, The Sciences, January/February 1996.

+

+ W. L. McKeehan, et al., "Direct mitogenic effects of insulin, epidermal growth factor, glucocorticoid, + cholera toxin, unknown pituitary factors and possibly prolactin,but not androgen, on normal rat prostate epithelial cells in serum-free, primary cell culture," Cancer Res. 44(5), + 1998-2010, 1984. +

+

+ Nevalainen MT, Valve EM, Ingleton PM, Nurmi M, Martikainen PM, Harkonen PL, J Clin Invest 1997 Feb + 15;99(4):618-627 "Prolactin and prolactin receptors are expressed and functioning in human prostate." + "The highest density of prolactin receptors was detected in the secretory epithelial cells by + immunohistochemistry. Finally, we report that prolactin is locally produced in human prostate + epithelium, as evidenced by marked prolactin immunoreactivity in a significant portion of prostate + epithelial cells, with parallel expression of prolactin mRNA in human prostate. Collectively, these data + provide significant support for the existence of an autocrine/paracrine loop of prolactin in the human + prostate and may shed new light on the involvement of prolactin in the etiology and progression of + neoplastic growth of the prostate." +

+

+ A. J. Lostroh and C. H. Li, "Stimulation of the sex accessories of hypophysectomised male rat by + non-gonadotrophin hormones of the pituitary gland," Acta endocr. Copenh. 25, 1-16, 1957. +

+

+ F. B. Merk, et al., "Multiple phenotypes of prostatic glandular cells in castrated dogs after + individual or combined treatment with androgen and estrogen," Lab. Invest. 54, 42-46, 1986. +

+

+ Pirke, K.M. and P. Doerr, "Age related changes in free plasma testosterone, dihydrotesterone, and + oestradiol," Acta endocr. Copenh. 89, 171-178, 1975 +

+

+ S. Rannikko, et al., "Hormonal patterns in prostatic cancer 1. Correlation with local extent of + tumour, presence of metastases and grade of differentiation," Acta endocr. Copenh. 98, 625-633, + 1981. +

+

+ P. H. Rolland, et al., "Prostaglandins in human breast cancer:  Evidence suggesting that an + elevated prostaglandin production is a marker of metastatic potential for neoplastic cells," J. Natl. + Cancer Inst. 64, 1061-1070, 1980. +

+

+ D. P. Rose, et al., "Hormone levels in prostatic fluid from healthy Finns and prostate cancer + patients," Eur. J. Cancer clin. Oncol. 20, 1317-1319, 1984. +

+

+ L. M. Schuman, et al., "Epidemiologic study of prostatic cancer:  Preliminary report," Cancer + Treat. Rep. 61, 181-186, 1977. +

+

+ Siiteri, P.K. and P. C. MacDonald, "Role of extraglandular estrogen in human endocrinology," In + Handbook of Physiology, section 7, Endocrinology Vol II (Eds. S. R. Geiger, et al.,) pp. 615-629, + Williams & Wilkins, Baltimore. +

+

+ H. W. Simpson, et al., "Bimodal age-frequency distribution of epitheliosis in cancer mastectomies, + Cancer 50, 2417-2422, 1982; S. R. Wellings, et al., "Atlas of subgross pathology of the human breast + with special reference to possible precancerous lesions," J. Nat. Cancer Inst. 55, 231-273, 1975; H. M. + Jensen, et al., "Preneoplastic lesions in the human breast," Science, N.Y. 191, 295-297,1976. +

+

+ Sugimura Y, Sakurai M, Hayashi N, Yamashita A, Kawamura J., Prostate 1994;24(1):24-32  + "Age-related changes of the prostate gland in the senescence-accelerated mouse." "Wet weight and numbers + of ductal tips in ventral and dorsolateral prostate glands in senescence accelerated-prone (SA-P) mice + were significantly smaller than those of senescence accelerated-resistant (SA-R) mice, although the + changes of patterns of gross ductal morphology were virtually identical in these groups. High + incidence of stromal hyperplasia with fibrosis and inflammation was observed...." + "These data suggest that the aging process occurs heterogeneously within the prostate gland, and + that SA-P mice may be an important model for the study of age-related changes in the prostate + gland." +

+

+ W. W. Tullner, "Hormonal factors in the adrenal-dependent growth of the rat ventral prostate," Nat. + Cancer Inst. Monograph 12, 211-223, 1963. +

+

+ Umekita Y, Hiipakka RA, Kokontis JM, Liao S, Proc Natl Acad Sci U S A 1996 Oct + 15;93(21):11802-11807  "Human prostate tumor growth in athymic mice: inhibition by androgens and + stimulation by finasteride," "When the human prostate cancer cell line, LNCaP 104-S, the growth of which + is stimulated by physiological levels of androgen, is cultured in androgen-depleted medium for > 100 + passages, the cells, now called LNCaP 104-R2, are proliferatively repressed by low concentrations of + androgens. LNCaP 104-R2 cells formed tumors in castrated male athymic nude mice. Testosterone + propionate (TP) treatment prevented LNCaP 104-R2 tumor growth and caused regression of established + tumors in these mice. Such a tumor-suppressive effect was not observed with tumors + derived from LNCaP 104-S cells or androgen receptor-negative human prostate cancer PC-3 cells. 5 + alpha-Dihydrotestosterone, but not 5 beta-dihydrotesto- sterone, 17 + beta-estradiol, or medroxyprogesterone acetate, also inhibited LNCaP 104-R2 tumor + growth. Removal of TP or implantation of finasteride, a 5 alpha-reductase inhibitor, in nude mice + bearing TP implants resulted in the regrowth of LNCaP 104-R2 tumors. Within 1 week after TP + implantation, LNCaP 104-R2 tumors exhibited massive necrosis with severe hemorrhage. Three weeks + later, these tumors showed fibrosis with infiltration of chronic inflammatory cells and scattered + carcinoma cells exhibiting degeneration. TP treatment of mice with LNCaP 104-R2 tumors reduced tumor + androgen receptor and c-myc mRNA levels but increased prostate-specific antigen in serum- and + prostate-specific antigen mRNA in tumors. Although androgen ablation has been the + standard treatment for metastatic prostate cancer for > 50 years, our study shows that androgen + supplementation therapy may be beneficial for treatment of certain types of human prostate cancer + and that the use of 5 alpha-reductase inhibitors, such as finasteride or anti-androgens, in the + general treatment of metastatic prostate cancer may require careful assessment." +

+

+ A. Vermeulen, "Testicular hormonal secretion and aging in males," in Benign prostatic hyperplasia (J. + T. Grayhack, et al., eds), pp. 177-182, DHEW Publ. No. (NIH) 76-1113, 1976. +

+

+ A. Vermeulen, et al., "Testosterone secretion and metabolism in male senescence," J. Clin. Endocr. + Metab. 34, 730-735, 1972. +

+

+ A. Vermeulen, et al., "Hormonal factors related to abnormal growth of the prostate," in Prostate + Cancer (D. S. Coffey and J. T. Issacs, eds). UICC Technical Workshop Series, Vol 48, 81-92, UICC, + Geneva. +

+

+ S. Zuckerman and J. R. Groome, "The aetiology of benign enlargement of the prostate in the dog," J. + Pathol. Bact. 44, 113-124, 1937. +

+

+ B. Zumoff, et al., "Abnormal levels of plasma hormones in men with prostate cancer:  Evidence + toward a 'time-defense' theory," The Prostate 3, 579-588, 1982. +

+

+ M. Wehling, "Non-genomic steroid action--take a closer look, it's not rare!" Eur. J. of Endorinol. + 135, 287-288, 1996. +

+

+ Wennbo H, Kindblom J, Isaksson OG, Tornell J., Endocrinology 1997 Oct;138(10):4410-4415. "Transgenic + mice overexpressing the prolactin gene develop dramatic enlargement of the prostate gland,"  "An + altered endocrine status of elderly men has been hypothesized to be important for development of + prostate hyperplasia. The present study addresses the question whether increased PRL expression is of + importance for development of prostate hyperplasia in mice. Three lines of PRL transgenic mice were + generated having serum levels of PRL of approximately 15 ng/ml, 100 ng/ml, and 250 ng/ml, respectively. + These mice developed dramatic enlargement of the prostate gland, approximately 20 times the normal + prostate weight and they had a 4- to 5-fold increased DNA content. Histologically, the prostate glands + in the transgenic mice were distended from secretion, and the amount of interstitial tissue was + increased. The levels oftestosterone and IGF-I were increased in the PRL transgenic animals. In mice + overexpressing the bovine GH gene, displaying elevated IGF-I levels, the prostate gland was slightly + larger compared with normal mice, indicating that the effect of PRL was not primarily mediated through + elevated plasma IGF-I levels. "The present study suggests that PRL is an important factor in the + development of prostate hyperplasia acting directly on the prostate gland or via + increased plasma levels of testosterone." +

+

 

+ + © Ray Peat Ph.D. 2013. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/protective-co2-aging.html b/raypeat-articles/processed/protective-co2-aging.html new file mode 100644 index 0000000..780a76a --- /dev/null +++ b/raypeat-articles/processed/protective-co2-aging.html @@ -0,0 +1,326 @@ + + + +

+ +

+ Protective CO2 and aging +

The therapeutic effects of increasing carbon dioxide are being more widely recognized in recent years. Even + Jane Brody, the NY Times writer on health topics, has favorably mentioned the use of the Buteyko method for + asthma, and the idea of "permissive hypercapnia" during mechanical ventilation, to prevent lung damage from + excess oxygen, has been discussed in medical journals. But still very few biologists recognize its role as a + fundamental, universal protective factor. I think it will be helpful to consider some of the ways carbon dioxide + might be controlling situations that otherwise are poorly understood. The brain has a high rate of oxidative + metabolism, and so it forms a very large proportion of the carbon dioxide produced by an organism. It also + governs, to a great extent, the metabolism of other tissues, including their consumption of oxygen and + production of carbon dioxide or lactic acid. Within a particular species, the rate of oxygen consumption + increases in proportion to brain size, rather than body weight. Between very different species, the role of the + brain in metabolism is even more obvious, since the resting metabolic rate corresponds to the size of the brain. + For example, a cat"s brain is about the size of a crocodile"s, and their oxygen consumption at rest is similar, + despite their tremendous difference in body size.Stress has to be understood as a process that develops in time, + and the brain (especially the neocortex and the frontal lobes) organizes the adaptive and developmental + processes in both the spatial and temporal dimensions. The meaning of a situation influences the way the + organism responds. For example, the stress of being restrained for a long time can cause major gastrointestinal + bleeding and ulcerization, but if the animal has the opportunity to bite something during the stress (signifying + its ability to fight back, and the possibility of escape) it can avoid the stress ulcers. The patterning of the + nervous activity throughout the body governs the local ability to produce carbon dioxide. When the cortex of the + brain is damaged or removed, an animal becomes rigid, so the cortex is considered to have a "tonic inhibitory + action" on the body. But when the nerves are removed from a muscle (for example, by disease or accident), the + muscle goes into a state of constant activity, and its ability to oxidize glucose and produce carbon dioxide is + reduced, while its oxidation of fatty acids persists, increasing the production of toxic oxidative fragments of + the fatty acids, which contributes to the muscle"s atrophy.The organism"s intentions, expectations, or plans, + are represented in the nervous system as a greater readiness for action, and in the organs and tissues + controlled by the nerves, as an increase or decrease of oxidative efficiency, analogous to the differences + between innervated and denervated muscles. This pattern in the nervous system has been called "the acceptor of + action," because it is continually being compared with the actual situation, and being refined as the situation + is evaluated. The state of the organism, under the influence of a particular acceptor of action, is called a + "functional system," including all the components of the organism that participate most directly in realizing + the intended adaptive action.The actions of nerves can be considered anabolic, because during a stressful + situation in which the catabolic hormones of adaption, e.g., cortisol, increase, the tissues of the functional + system are protected, and while idle tissues may undergo autophagy or other form of involution, the needs of the + active tissues are supplied with nutrients from their breakdown, allowing them to change and, when necessary, + grow in size or complexity. The brain"s role in protecting against injury by stress, when it sees a course of + action, has a parallel in the differences between concentric (positive, muscle shortening) and eccentric + (negative, lengthening under tension) exercise, and also with the differences between innervated and denervated + muscles. In eccentric exercise and denervation, less oxygen is used and less carbon dioxide is produced, while + lactic acid increases, displacing carbon dioxide, and more fat is oxidized. Prolonged stress similarly decreases + carbon dioxide and increases lactate, while increasing the use of fat.Darkness is stressful and catabolic. For + example, in aging people, the morning urine contains nearly all of the calcium lost during the 24 hour period, + and mitochondria are especially sensitive to the destructive effects of darkness. Sleep reduces the destructive + catabolic effects of darkness. During the rapid-eye-movement (dreaming) phase of sleep, breathing is inhibited, + and the level of carbon dioxide in the tissues accumulates. In restful sleep, the oxygen tension is frequently + low enough, and the carbon dioxide tension high enough, to trigger the multiplication of stem cells and + mitochondria.Dreams represent the "acceptor of action" operating independently of the sensory information that + it normally interacts with. During dreams, the brain (using a system called the Ascending Reticular Activating + System) disconnects itself from the sensory systems. I think this is the nervous equivalent of + concentric/positive muscle activity, in the sense that the brain is in control of its actions. The active, + dreaming phase of sleep occurs more frequently in the later part of the night, as morning approaches. This is + the more stressful part of the night, with cortisol and some other stress hormones reaching a peak at dawn, so + it would be reasonable for the brain"s defensive processes to be most active at that time. The dreaming process + in the brain is associated with deep muscle relaxation, which is probably associated with the trophic + (restorative) actions of the nerves.In ancient China the Taoists were concerned with longevity, and according to + Joseph Needham (Science and Civilization in China) their methods included the use of herbs, minerals, + and steroids extracted from the urine of children. Some of those who claimed extreme longevity practiced + controlled breathing and tai chi (involving imagery, movement, and breating), typically in the early morning + hours, when stress reduction is most important. As far as I know, there are no studies of carbon dioxide levels + in practitioners of tai chi, but the sensation of warmth they typically report suggests that it involves + hypoventilation.In the 1960s, a Russian researcher examined hospital records of measurements of newborn babies, + and found that for several decades the size of their heads had been increasing. He suggested that it might be + the result of increasing atmospheric carbon dioxide. The experiences and nutrition of a pregnant animal are + known to affect the expression of genes in the offspring, affecting such things as allergies, metabolic rate, + brain size, and intelligence. Miles Storfer (1999) has reviewed the evidence for epigenetic environmental + control of brain size and intelligence. The main mechanisms of epigenetic effects or "imprinting" are now known + to involve methylation and acetylation of the chromosomes (DNA and histones).Certain kinds of behavior, as well + as nutrition and other environmental factors, increase the production and retention of carbon dioxide. The + normal intrauterine level of carbon dioxide is high, and it can be increased or decreased by changes in the + mother"s physiology. The effects of carbon dioxide on many biological processes involving methylation and + acetylation of the genetic material suggest that the concentration of carbon dioxide during gestation might + regulate the degree to which parental imprinting will persist in the developing fetus. There is some evidence of + increased demethylation associated with the low level of oxygen in the uterus (Wellman, et al., 2008). A high + metabolic rate and production of carbon dioxide would increase the adaptability of the new organism, by + decreasing the limiting genetic imprints.A quick reduction of carbon dioxide caused by hyperventilation can + provoke an epileptic seizure, and can increase muscle spasms and vascular leakiness, and (by releasing serotonin + and histamine) contribute to inflammation and clotting disorders. On a slightly longer time scale, a reduction + of carbon dioxide can increase the production of lactic acid, which is a promoter of inflammation and fibrosis. + A prolonged decrease in carbon dioxide can increase the susceptibility of proteins to glycation (the addition of + aldehydes, from polyunsaturated fat peroxidation or methylglyoxal from lactate metabolism, to amino groups), and + a similar process is likely to contribute to the methylation of histones, a process that increases with aging. + Histones regulate genetic activity.With aging, DNA methylation is increased (Bork, et al., 2009). I + suggest that methylation stabilizes and protects cells when growth and regeneration aren"t possible (and + that it"s likely to increase when CO2 isn"t available). + Hibernation (Morin and Storey, 2009) and sporulation (Ruiz-Herrera, 1994; Clancy, et al., 2002) appear + to use methylation protectively.Parental stress, prenatal stress, early life stress, and even stress in + adulthood contribute to "imprinting of the genes," partly through methylation of DNA and the histones. + Methionine and choline are the main dietary sources of methyl donors. Restriction of methionine has many + protective effects, including increased average (42%) and maximum (44%) longevity in rats (Richie, et al., + 1994). Restriction of methyl donors causes demethylation of DNA (Epner, 2001). The age + accelerating effect of methionine might be related to disturbing the methylation balance, inappropriately + suppressing cellular activity. Besides its effect on the methyl pool, methionine inhibits thyroid function and + damages mitochondria. The local concentration of carbon dioxide in specific tissues and organs can be adjusted + by nervous and hormonal activation or inhibition of the carbonic anhydrase enzymes, that accelerate the + oonversion of CO2 to carbonic acid, H2CO3. The activity of carbonic anhydrase can determine the density and + strength of the skeleton, the excitability of nerves, the accumulation of water, and can regulate the structure + and function of the tissues and organs. Ordinarily, carbon dioxide and bicarbonate are thought of only in + relation to the regulation of pH, and only in a very general way. Because of the importance of keeping the pH of + the blood within a narrow range, carbon dioxide is commonly thought of as a toxin, because an excess can cause + unconsciousness and acidosis. But increasing carbon dioxide doesn"t necessarily cause acidosis, and acidosis + caused by carbon dioxide isn"t as harmful as lactic acidosis.Frogs and toads, being amphibians, are especially + dependent on water, and in deserts or areas with a dry season they can survive a prolonged dry period by + burrowing into mud or sand. Since they may be buried 10 or 11 inches below the surface, they are rarely found, + and so haven"t been extensively studied. In species that live in the California desert, they have been known to + survive 5 years of burial without rainfall, despite a moderately warm average temperature of their surroundings. + One of their known adaptations is to produce a high level of urea, allowing them to osmotically absorb and + retain water. (Very old people sometimes have extremely high urea and osmotic tension.)Some laboratory studies + show that as a toad burrows into mud, the amount of carbon dioxide in its tissues increases. Their skin normally + functions like a lung, exchanging oxygen for carbon dioxide. If the toad"s nostrils are at the surface of the + mud, as dormancy begins its breathing will gradually slow, increasing the carbon dioxide even more. Despite the + increasing carbon dioxide, the pH is kept stable by an increase of bicarbonate (Boutilier, et al., 1979). A + similar increase of bicarbonate has been observed in hibernating hamsters and doormice.Thinking about the long + dormancy of frogs reminded me of a newspaper story I read in the 1950s. Workers breaking up an old concrete + structure found a dormant toad enclosed in the concrete, and it revived soon after being released. The concrete + had been poured decades earlier. Although systematic study of frogs or toads during their natural buried + estivation has been very limited, there have been many reports of accidental discoveries that suggest that the + dormant state might be extended indefinitely if conditions are favorable. Carbon dioxide has antioxidant + effects, and many other stabilizing actions, including protection against hypoxia and the excitatory effects of + intracellular calcium and inflammation (Baev, et al., 1978, 1995; Bari, et al., 1996; Brzecka, 2007; Kogan, et + al., 1994; Malyshev, et al., 1995).When mitochondria are "uncoupled," they produce more carbon dioxide than + normal, and the mitochondria produce fewer free radicals. Animals with uncoupled mitochondria live longer than + animals with the ordinary, more efficient mitochondria, that produce more reactive oxidative fragments. One + effect of the high rate of oxidation of the uncoupled mitochondria is that they can eliminate polyunsatured + fatty acids that might otherwise be integrated into tissue structures, or function as inappropriate regulatory + signals.Birds have a higher metabolic rate than mammals of the same size, and live longer. Their tissues contain + fewer of the highly unsaturated fatty acids. Queen bees, which live many times longer than worker bees, have + mainly monounsaturated fats in their tissues, while the tissues of the short-lived worker bees, receiving a + different diet, within a couple of weeks of hatching will contain highly unsaturated fats.Bats have a very high + metabolic rate, and an extremely long lifespan for an animal of their size. While most animals of their small + size live only a few years, many bats live a few decades. Bat caves usually have slightly more carbon dioxide + than the outside atmosphere, but they usually contain a large amount of ammonia, and bats maintain a high serum + level of carbon dioxide, which protects them from the otherwise toxic effects of the ammonia. The naked mole + rat, another small animal with an extremely long lifespan (in captivity they have lived up to 30 years, 9 or 10 + times longer than mice of the same size) has a low basal metabolic rate, but I think measurements made in + laboratories might not represent their metabolic rate in their natural habitat. They live in burrows that are + kept closed, so the percentage of oxygen is lower than in the outside air, and the percentage of carbon dioxide + ranges from 0.2% to 5% (atmospheric CO2 is about 0.038). The temperature and humidity in their burrows can be + extremely high, and to be very meaningful their metabolic rate would have to be measured when their body + temperature is raised by the heat in the burrow.When they have been studied in Europe and the US, there has been + no investigation of the effect of altitude on their metabolism, and these animals are native to the high plains + of Kenya and Ethiopia, where the low atmospheric pressure would be likely to increase the level of carbon + dioxide in their tissues. Consequently, I doubt that the longevity seen in laboratory situations accurately + reflects the longevity of the animals in their normal habitat.Besides living in a closed space with a high + carbon dioxide content, mole rats have another similarity to bees. In each colony, there is only one female that + reproduces, the queen, and, like a queen bee, she is the largest individual in the colony. In beehives, the + workers carefully regulate the carbon dioxide concentration, which varies from about 0.2% to 6%, similar to that + of the mole rat colony. A high carbon dioxide content activates the ovaries of a queen bee, increasing her + fertility.Since queen bees and mole rats live in the dark, I think their high carbon dioxide compensates for the + lack of light. (Both light and CO2 help to maintain oxidative metabolism and inhibit lactic acid formation.) + Mole rats are believed to sleep very little. During the night, normal people tolerate more CO2, and so breathe + less, especially near morning, with increased active dreaming sleep. A mole rat has never been known to develop + cancer. Their serum C-reactive protein is extremely low, indicating that they are resistant to inflammation. In + humans and other animals that are susceptible to cancer, one of the genes that is likely to be silenced by + stress, aging, and methylation is p53, a tumor-suppressor gene. If the intrauterine experience, with low oxygen + and high carbon dioxide, serves to "reprogram" cells to remove the accumulated effects of age and stress, and so + to maximize the developmental potential of the new organism, a life that"s lived with nearly those levels of + oxygen and carbon dioxide might be able to avoid the progressive silencing of genes and loss of function that + cause aging and degenerative diseases.Several diseases and syndromes are now thought to involve abnormal + methylation of genes. Prader-Willi sydrome, Angelman"s syndrome, and various "autistic spectrum disorders," as + well as post-traumatic stress disorder and several kinds of cancer seem to involve excess methylation. Moderate + methionine restriction (for example, using gelatin regularly in the diet) might be practical, but if increased + carbon dioxide can activate the demethylase enzymes in a controlled way, it might be a useful treatment for the + degenerative diseases and for aging itself. The low carbon dioxide production of hypothyroidism (e.g., Lee and + Levine, 1999), and the respiratory alkalosis of estrogen excess, are often overlooked. An adequate supply of + calcium, and sometimes supplementation of salt and baking soda, can increase the tissue content of CO2. + +

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Fiziol Zh Im I M Sechenova 1995 Feb;81(2):47-52. + [The unknown physiological role of carbon dioxide]. Baev VI, Vasil'eva IV, L'vov SN, Shugalei IV + [The data suggests that carbon dioxide is a natural element of the organism antioxidant defence system. ion + poisoning].Stroke. 1996 Sep;27(9):1634-9; discussion 1639-40. Differential effects of short-term hypoxia + and hypercapnia on N-methyl-D-aspartate-induced cerebral vasodilatation in piglets. Bari F, Errico + RA, Louis TM, Busija DW.Vojnosanit Pregl. 1996 Jul-Aug;53(4):261-74. [Carbon dioxide inhibits the + generation of active forms of oxygen in human and animal cells and the significance of the phenomenon in + biology and medicine] [Article in Serbian] Boljevic S, Kogan AH, Gracev SV, Jelisejeva SV, Daniljak + IG.J Exp Biol. 1979 Oct;82:357-65. Acid-base relationships in the blood of the toad, Bufo marinus. III. + The effects of burrowing. + Boutilier RG, Randall DJ, Shelton G, Toews DP.Acta Neurobiol Exp (Wars). 2007;67(2):197-206. Role of hypercapnia in brain oxygenation in sleep-disordered breathing. Brzecka A. Adaptive mechanisms + may diminish the detrimental effects of recurrent nocturnal hypoxia in obstructive sleep apnea (OSA). The + potential role of elevated carbon dioxide (CO2) in improving brain oxygenation in the patients with severe OSA + syndrome is discussed. CO2 increases oxygen uptake by its influence on the regulation of alveolar ventilation + and ventilation-perfusion matching, facilitates oxygen delivery to the tissues by changing the affinity of + oxygen to hemoglobin, and increases cerebral blood flow by effects on arterial blood pressure and on cerebral + vessels. Recent clinical studies show improved brain oxygenation when hypoxia is combined with hypercapnia. + Anti-inflammatory and protective against organ injury properties of CO2 may also have therapeutic importance. + These biological effects of hypercapnia may improve brain oxygenation under hypoxic conditions. This may be + especially important in patients with severe OSA syndrome.Ageing Res Rev. 2009 Oct;8(4):268-76. Epub 2009 Apr 1. + The role of epigenetics in aging and age-related diseases. Calvanese V, Lara E, Kahn A, Fraga + MF.Rev Esp Geriatr Gerontol. 2009 Jul-Aug;44(4):194-9. Epub 2009 Jul 3. [Effect of restricting amino + acids except methionine on mitochondrial oxidative stress.] + [Article in Spanish] Caro P, G"mez J, S"nchez I, L"pez-Torres M, Barja G.Cell Metab. 2007 + Jan;5(1):21-33. A central thermogenic-like mechanism in feeding regulation: an interplay between arcuate + nucleus T3 and UCP2. Coppola A, Liu ZW, Andrews ZB, Paradis E, Roy MC, Friedman JM, Ricquier D, + Richard D, Horvath TL, Gao XB, Diano S.Ter Arkh. 1995;67(3):23-6. [Changes in the sensitivity of + leukocytes to the inhibiting effect of CO2 on their generation of active forms of oxygen in bronchial asthma + patients] Daniliak IG, Kogan AKh, Sumarokov AV, Bolevich S.Cell Metab. 2007 Dec;6(6):497-505. + Respiratory uncoupling in skeletal muscle delays death and diminishes age-related disease. + Gates AC, Bernal-Mizrachi C, Chinault SL, Feng C, Schneider JG, Coleman T, Malone JP, Townsend RR, Chakravarthy + MV, Semenkovich CF.Endocr Pract. 2009 Jun 2:1-13. + Fibrotic Appearance of Lungs in Severe Hypothyroidism is Reversible with Thyroxine Replacement. + George JT, Thow JC, Rodger KA, Mannion R, Jayagopal V.J Bioenerg Biomembr. 2009 Jun;41(3):309-21. Epub 2009 Jul + 25. Effect of methionine dietary supplementation on mitochondrial oxygen radical generation and + oxidative DNA damage in rat liver and heart. + Gomez J, Caro P, Sanchez I, Naudi A, Jove M, Portero-Otin M, Lopez-Torres M, Pamplona R, Barja G.Proc + Natl Acad Sci U S A. 1996 Jul 23;93(15):7612-7. Increased tricarboxylic acid cycle flux in rat brain + during forepaw stimulation detected with 1H[13C]NMR. + Hyder F, Chase JR, Behar KL, Mason GF, Siddeek M, Rothman DL, Shulman RG.Can J Neurol Sci. 1979 + May;6(2):105-12. The effects of partial chronic denervation on forearm metabolism. Karpati G, + Klassen G, Tanser P.Biull Eksp Biol Med. 1994 Oct;118(10):395-8. [CO2--a natural inhibitor of active + oxygen form generation by phagocytes] Kogan AKh, Manuilov BM, Grachev SV, Bolevich S, Tsypin AB, + Daniliak IG.Izv Akad Nauk Ser Biol. 1997 Mar-Apr;(2):204-17. + [Carbon dioxide--a universal inhibitor of the generation of active oxygen forms by cells (deciphering one + enigma of evolution)] + Kogan AKh, Grachev SV, Eliseeva SV, Bolevich S.Vopr Med Khim. 1996 Jul-Sep;42(3):193-202. + [Ability of carbon dioxide to inhibit generation of superoxide anion radical in cells and its biomedical + role] Kogan AKh, Grachev SV, Eliseeva SV, Bolevich S.Dokl Akad Nauk. 1996 May;348(3):413-6. [New evidence for the inhibitory action of CO2 on generation of superoxide anion radicals by phagocytes in + various tissues. (Mechanism of bio- and eco-effects of CO2)] + Kogan AKh, Grachev SV, Bolevich S, Eliseeva SV.Biull Eksp Biol Med. 1996 Apr;121(4):407-10. [Carbon dioxide gas inhibition of active forms of oxygen generation by cells in the internal organs and its + biological significance] Kogan AKh, Grachev SV, Eliseeva SV.Fiziol Cheloveka. 1995 + Jul-Aug;21(4):128-36. [CO2--a natural inhibitor of the generation of active species of oxygen in + phagocytes] Kogan AKh, Manuilov BM, Grachev SV, Bolevich S, Tsypin AB, Daniliak IG.Patol + Fiziol Eksp Ter. 1995 Jul-Sep;(3):34-40. [Comparative study of the effect of carbon dioxide on the + generation of active forms of oxygen by leukocytes in health and in bronchial asthma] Kogan AKh, + Bolevich S, Daniliak IG.Can J Anaesth. 1999 Feb;46(2):185-9. Acute respiratory alkalosis associated with + low minute ventilation in a patient with severe hypothyroidism. Lee HT, Levine M.Tl128@columbia.edu + PURPOSE: Patients with severe hypothyroidism present unique challenges to anesthesiologists and demonstrate much + increased perioperative risks. Overall, they display increased sensitivity to anesthetics, higher incidence of + perioperative cardiovascular morbidity, increased risks for postoperative ventilatory failure and other + physiological derangements. The previously described physiological basis for the increased incidence of + postoperative ventilatory failure in hypothyroid patients includes decreased central and peripheral ventilatory + responses to hypercarbia and hypoxia, muscle weakness, depressed central respiratory drive, and resultant + alveolar hypoventilation. These ventilatory failures are associated most frequently with severe hypoxia and + carbon dioxide (CO2) retention. The purpose of this clinical report is to discuss an interesting and unique + anesthetic presentation of a patient with severe hypothyroidism. CLINICAL FEATURES: We describe an unique + presentation of ventilatory failure in a 58 yr old man with severe hypothyroidism. He had exceedingly low + perioperative respiratory rate (3-4 bpm) and minute ventilation volume, and at the same time developed primary + acute respiratory alkalosis and associated hypocarbia (P(ET)CO2 approximately 320-22 mmHg). CONCLUSION: Our + patient's ventilatory failure was based on unacceptably low minute ventilation and respiratory rate that was + unable to sustain adequate oxygenation. His profoundly lowered basal metabolic rate and decreased CO2 + production, resulting probably from severe hypothyroidism, may have resulted in development of acute respiratory + alkalosis in spite of concurrently diminished minute ventilation.Anal Bioanal Chem. 2008 Jan;390(2):679-88. Epub + 2007 Oct 27. The structural modification of DNA nucleosides by nonenzymatic glycation: an in vitro study + based on the reactions of glyoxal and methylglyoxal with 2'-deoxyguanosine. Li Y, Cohenford MA, + Dutta U, Dain JA.Biull Eksp Biol Med. 1995 Jun;119(6):590-3. [Adaptation to high altitude hypoxia + facilitates a limitation of lipid peroxidation activation in inflammation and stress] [Article in + Russian]Malyshev VV, Vasil'eva LS, Belogorov SB, Nefedova TV.Am J Physiol Regul Integr Comp + Physiol. 2007 Sep;293(3):R1159-68. Epub 2007 Jun 20.Denervation-induced skeletal muscle atrophy is + associated with increased mitochondrial ROS production. Muller FL, Song W, Jang YC, Liu Y, Sabia M, + Richardson A, Van Remmen H.Radiobiologiia. 1984 Jan-Feb;24(1):29-34. [Enzyme activity of glutamic acid + metabolism and the Krebs cycle in the brain of rats laser-irradiated against a background of altered + adrenoreceptor function] [Article in Russian] + Pikulev AT, Dzhugurian NA, Zyrianova TN, Lavrova VM, Mostovnikov VA.Rejuvenation Res.2007 Dec12; + :18072884, Exploring Overlooked Natural Mitochondria-Rejuvenative Intervention: The Puzzle of Bowhead + Whales and Naked Mole Rats. + Prokopov A.F.Proceedings of the Japan Academy. Ser. B: Physical and Biological Sciences Vol.78, + No.10(2002)pp.293-298. DNA methylation and Lamarckian inheritance, Sano H.Biol Chem. 2009 + Nov;390(11):1145-53. The epigenetic bottleneck of neurodegenerative and psychiatric diseases. + Sananbenesi F, Fischer A. The orchestrated expression of genes is essential for the development and + survival of every organism. In addition to the role of transcription factors, the availability of genes for + transcription is controlled by a series of proteins that regulate epigenetic chromatin remodeling. The two most + studied epigenetic phenomena are DNA methylation and histone-tail modifications. Although a large body of + literature implicates the deregulation of histone acetylation and DNA methylation with the pathogenesis of + cancer, recently epigenetic mechanisms have also gained much attention in the neuroscientific community. In + fact, a new field of research is rapidly emerging and there is now accumulating evidence that the molecular + machinery that regulates histone acetylation and DNA methylation is intimately involved in synaptic plasticity + and is essential for learning and memory. Importantly, dysfunction of epigenetic gene expression in the brain + might be involved in neurodegenerative and psychiatric diseases. In particular, it was found that inhibition of + histone deacetylases attenuates synaptic and neuronal loss in animal models for various neurodegenerative + diseases and improves cognitive function. In this article, we will summarize recent data in the novel field of + neuroepigenetics and discuss the question why epigenetic strategies are suitable therapeutic approaches for the + treatment of brain diseases.Ukr Biokhim Zh 1994 Jan-Feb;66(1):109-12. [Protective effect of sodium + bicarbonate in nitrite ion poisoning]. Shugalei IV, L'vov SN, Baev VI, Tselinskii IVAm J Respir + Crit Care Med. 2000 Mar;161(3 Pt 1):891-8. Modulation of release of reactive oxygen species by the + contracting diaphragm. Stofan DA, Callahan LA, DiMarco AF, Nethery DE, Supinski GS.Ecology: Vol. + 50, No. 3, pp. 492-494. Carbon Dioxide Retention: A Mechanism of Ammonia Tolerance in Mammals. + Studier EM and Fresquez AA. Sci Signal. 2009 Mar 31;2(64): pe17. Reversing DNA methylation: new insights + from neuronal activity-induced Gadd45b in adult neurogenesis. + Wu H, Sun YE. Neurogenesis in the adult mammalian brain involves activity-dependent expression of genes + critical for the proliferation of progenitors and for neuronal maturation. A recent study suggests that the + stress response gene Gadd45b (growth arrest and DNA-damage-inducible protein 45 beta) can be transiently induced + by neuronal activity and may promote adult neurogenesis through dynamic DNA demethylation of specific gene + promoters in adult hippocampus. These results provide evidence supporting the provocative ideas that active DNA + demethylation may occur in postmitotic neurons and that DNA methylation-mediated dynamic epigenetic regulation + is involved in regulating long-lasting changes in neural plasticity in mammalian brains.Patol Fiziol Eksp Ter. + 2005 Apr-Jun;(2):13-5. [The effect of the NMDA-receptor blocker MK-801 on sensitivity of the respiratory + system to carbon dioxide] Tarakanov IA, Dymetska A, Tarasova NN.Life Sci. 1997;61(5):523-35. + Effect of acidotic challenges on local depolarizations evoked by N-methyl-D-aspartate in the rat + striatum. Urenjak J, Zilkha E, Gotoh M, Obrenovitch TP. "Hypercapnia reduced NMDA-evoked responses + in a concentration-dependent manner, with 7.5 and 15 % CO2 in the breathing mixture reducing the depolarization + amplitude to 74 % and 64 % of that of the initial stimuli, respectively. Application of 50 mM NH4+ progressively + reduced dialysate pH, and a further acidification was observed when NH4+ was discontinued. Perfusion of NMDA + after NH4+ application evoked smaller depolarizations (56 % of the corresponding control, 5 min after NH4+ + removal), and this effect persisted for over 1 h." "Together, these results demonstrate that extracellular + acidosis, such as that associated with excessive neuronal activation or ischemia, inhibits NMDA-evoked responses + in vivo."Arch Int Physiol Biochim. 1977 Apr;85(2):295-304. Glutamate and glutamine in the brain of the + neonatal rat during hypercapnia. Van Leuven F, Weyne J, Leusen I.Pediatrics 1995 + Jun;95(6):868-874. Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: an experimental + study in the immature rat. Vannucci RC, Towfighi J, Heitjan DF, Brucklacher RMPediatr Res 1997 + Jul;42(1):24-29. Effect of carbon dioxide on cerebral metabolism during hypoxia-ischemia in the immature + rat. + Vannucci RC, Brucklacher RM, Vannucci SJSci. Signal., 31 March 2009 Vol. 2, Issue 64, p. pe17, Reversing DNA Methylation: New Insights from Neuronal Activity-Induced Gadd45b in Adult Neurogenesis + Wu H, Sun YI

+ © Ray Peat Ph.D. 2012. All Rights Reserved. www.RayPeat.com +

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+ + Regeneration and degeneration: Types of inflammation change with aging +

+

For about 100 years it has been popular to explain the degenerative diseases as the result of mutations + in the genes, a slow accumulation of "somatic mutations," as opposed to the "germ cell mutations" that are + involved in Huntington"s chorea and sickle cell anemia. Some people explained all the changes of aging on the + same basis, but 50 years ago, the somatic mutation theory of aging was clearly shown to be false. The + gene-mutation theory of cancer is more persistent, but the work of people like Harry Rubin has made it clear + that functional changes in cells that are becoming cancerous destabilize the chromosomes and cause defects to + appear in the genes, rather than the reverse.Older ways of understanding aging and degenerative disease are now + returning to the foreground. The developmental interactions of the organism with its environment, and the + interactions of its cells, tissues, and organs with each other, have again become the focus of biological aging + research. In place of the old belief that "we are defined and limited by our genes," the new perspective is + showing us that we are limited by our environment, and that our environment can be modified. As we react to + unsuitable environments, our internal environments become limiting for our cells, and instead of renewing + themselves, repairing damage, and preparing for new challenges, our cells find themselves in blind alleys. + Looking at aging in this way suggests that putting ourselves into the right environments could prevent aging.A + bird developing inside its eggshell illustrates the way organs and the environment interact. The chicken created + a very good environment for the early development of its young. When the egg is formed, it contains everything + needed to produce a chicken, except for oxygen and a steady warm temperature. But before the chick"s body has + finished developing, using yolk fat for energy, the glucose contained in the egg has been consumed, and at that + point the chick"s brain stops growing. A researcher who knew that brain growth in other kinds of animals + requires glucose, injected glucose (or glycine) into the developing eggs when the original glucose had been + depleted. The supplemental glucose allowed the chick"s brain to continue growing until it hatched. These chicks + had larger brains, containing more numerous cells. The same experimenters also found that progesterone increases + brain size, while corticosterone decreases it. Although the egg is a very good environment for the development + of chickens, these experiments showed that it isn"t the best that can be achieved. If the hen"s environment had + been different, it might have been able to provide as much glucose and progesterone as the experimenters did. + Mammals were able to develop bigger brains than birds, by gestating their offspring internally, allowing a + continuous supply of nutrients, such as glucose, and hormones such as progesterone. But the environment of the + mother still can profoundly affect the development of the offspring, by influencing her physiology.Another + factor involved in developing a large brain is the metabolic rate, which is closely associated with the + temperature. Birds have larger brains relative to their bodies than reptiles do, and birds maintain a + consistently high body temperature, sometimes as high as 110 degrees F, while reptiles" temperature varies + somewhat according to the temperature of their surroundings and their level of activity. Amphibians have much + lower metabolic rates, and are generally unable to live at the higher temperatures required by reptiles. The + high metabolic rate of a bird, combined with its development inside an egg, means that compromises are made. The + high rate of metabolism uses the stored energy rapidly, so the growth of the brain is limited. But their very + high body temperature maximizes the effectiveness of that brain. Birds, such as owls, parrots, and crows, that + hatch in a less developed, more dependent condition, are able to continue their brain growth, and have larger + brains than other birds, such as chickens. In birds and mammals, longevity generally corresponds to brain size + and metabolic rate. (For example, a pet crow, Tata, died at the age of 59 in 2006 in New York; parrots sometimes + live more than 100 years.) These (altricious) birds are the opposite of precocious, they preserve embryonic or + infantile traits into adulthood.For whole organisms or for single cells, development depends on the adequacy of + the environment. Temperature and the quality of nourishment are important, and by thinking about the other + special features of the growth processes during gestation, we might be able to find that some of the compromises + that are customarily made in our more mature lives aren"t necessary. One way of looking at aging is that it"s a + failure of regeneration or healing, related to changes in the nature of inflammation. In childhood, wounds heal + quickly, and inflammation is quickly resolved; in extreme old age, or during extreme stress or starvation, wound + healing is much slower, and the nature of the inflammation and wound closure is different. In the fetus, healing + can be regenerative and scarless, for example allowing a cleft palate to be surgically corrected without scars + (Weinzweig, et al., 2002).Fifty years ago, inflammation was seen as a necessary part of the healing process, but + now it is recognized as a cause of heart disease, diabetes, cancer, and aging itself. During the development of + the organism, the nature of healing changes, as the nature of inflammation changes. Early in life, healing is + regenerative or restorative, and there is little inflammation. In adulthood as the amount of inflammation + increases, healing fails to completely restore lost structures and functions, resulting in scarring, the + replacement of functional tissue with fibrous tissue. Identifiable changes in the nature of inflammation under + different conditions can explain some of these losses of healing capacity. Factors that limit inflammation and + fibrosis, while permitting tissue remodeling, could facilitate regeneration and retard aging.Several cytokines + (proteins that regulate cell functions) appear at much higher concentrations in adult tissues than in fetal + tissues (PDGF A, three forms of TGF, IGF 1, and bFGF; Wagner, et al., 2007), and when one of these (TGF-beta1) + is added to the healing fetus, it produces inflammation and fibrosis (Lanning, et al., 1999). Two + prostaglandins, PGE2 and PGF2a, potently produce inflammation in fetal rabbits, but not in adult rabbits. + (Morykwas, et al., 1994).Tissue injury that would produce inflammation in adults causes other signals in the + fetus that activate repair processes. When a cell is injured or stressed, for example when deprived of oxygen, + it becomes incontinent, and releases ATP into its surroundings. The extracellular ATP, and its breakdown + products, ADP, AMP, adenosine, and inorganic phosphate or pyrophosphate, stimulate cells in various ways. ATP + causes vasodilation, increasing circulation, and usually signals cells to divide, and can activate stem cells + (Yu, et al., 2010) The lactic acid produced by distressed cells also has signalling effects, including + vasodilation and stimulated division. Stressed cells digest their own proteins and other structural materials + (autophagy), and the breakdown products act as signals to guide the differentiation of their replacement cells. + Mobile phagocytes, ingesting the material of decomposing cells, are essential for guiding tissue restoration. In + adults, prostaglandins are known to be involved in many of the harmful effects of inflammation. They are formed + from the polyunsaturated fats, linoleic acid and arachidonic acid, which we are unable to synthesize ourselves, + so the adult"s exposure to the prostaglandins is influence by diet. Since the fetus is able to synthesize fat + from glucose, the newborn animal usually contains a high proportion of saturated fats and their derivatives, + such as stearic acid, oleic acid, and Mead acid, which can be synthesized from glucose or amino acids. Newborn + calves have very little polyunsaturated fat in their tissues, but even the small percentage of PUFA in milk + causes its tissues to gradually accumulate a higher percentage of PUFA as it matures. The fatty acids of newborn + humans, and other non-ruminants, reflect their mothers" diets more closely, but Mead acid is still present in + human newborns (Al, et al., 1990). In a study of prenatal learning (habituation rate), the experimenters found + that the relative absence of the supposedly essential fatty acids improved the short term and long term memory + of the fetus (Dirix, et al., 2009). The size of the baby was found to be negatively associated with the highly + unsaturated fatty acids DHA and AA (Dirix, et al., 2009), showing a general growth-retarding effect of these + environmentally derived fats.The embryo or fetus is enclosed in a germ-free environment, so it doesn"t need an + "immune system" in the ordinary sense, but it does contain phagocytes, which are an essential part of + development, in the embryo, as well as in the adult (Bukovky, et al., 2000). They are involved in removing + malignant cells, healing wounds, and remodeling tissues. In adults, the long-chain omega-3 fatty acids such as + DHA are known to be immunosuppressive, but in tests on monocytes from the umbilical cord blood of newborns, the + highly unsaturated fatty acids kill the monocytes that are so important for proper development and regeneration + (Sweeney, et al., 2001), and interfere with signals that govern their migration (Ferrante, et al., 1994). DHA is + now being sold with many health claims, including the idea that adding it to baby formula will improve their + eyesight and intelligence. As the consumption of PUFA has increased in the US and many other countries, the + incidence of birth defects has increased. The formation of excessive amounts of prostaglandin, or killing + macrophages, among other toxic effects, might be responsible for those visible anatomical changes during growth, + as well as for the subtler loss of regenerative capacity.In the adult, the PUFA and prostaglandins are known to + increase collagen synthesis. Serotonin and estrogen, which interact closely with PUFA, promote collagen + synthesis and fibrosis. In the fetus, hyaluronic acid, rather than collagen, is the main extracellular material + in wound repair (Krummel, et al., 1987). Both it and its decomposition products have important regulatory + "signal" functions in wound healing (Gao, et al., 2008), inflammation, and cell differentiation (Krasinski and + Tch"rzewski, 2007). Prostaglandins also inhibit local cell division (observed in the cornea, Staatz and Van + Horn, 1980), shifting responsibility for tissue repair to mobile cells, for example stem cells from the blood. + PUFA also interfere with the turnover of collagen by inhibiting proteolytic enzymes that are necessary for + tissue remodeling. These are among the changes that characterize scar formation, rather than the scarless + regeneration that can occur in the fetus. They also occur throughout the body with aging, as part of a + progressive fibrosis.Besides minimizing dietary PUFA, other things are known that will reduce the fibrosis + associated with injury, inflammation, or aging. Thyroid hormone, progesterone, and carbon dioxide all reduce + inflammation while facilitating normal tissue remodeling. Fibrosis of the heart and liver, which are often + considered to be unavoidably progressive, can be regressed by thyroid hormone, and various fibroses, including + breast, liver, and mesentery, have been regressed by progesterone treatment.The thyroid hormone is necessary for + liver regeneration, and the ability of the thyroid gland itself to regenerate might be related to the also great + ability of the adrenal cortex to regenerate--the cells of these endocrine glands are frequently stimulated, even + by intrinsic factors such as T3 in the thyroid, and seem to have an intrinsic stem-cell-like quality, + turning-over frequently. Secretion of stimulating substances is probably one of the functions of macrophages in + these glands (Ozbek & Ozbek, 2006) The failure to recognize the glands" regenerative ability leads to many + inappropriate medical treatments. The amount of disorganized fibrous material formed in injured tissue is + variable, and it depends on the state of the individual, and on the particular situation of the tissue. For + example, the membranes lining the mouth, and the bones and bone marrow, and the thymus gland are able to + regenerate without scarring. What they have in common with each other is a relatively high ratio of carbon + dioxide to oxygen. Salamanders, which are able to regenerate legs, jaw, spinal cord, retina and parts of the + brain (Winklemann & Winklemann, 1970), spend most of their time under cover in burrows, which besides + preventing drying of their moist skin, keeps the ratio of carbon dioxide to oxygen fairly high.The regeneration + of finger tips, including a well-formed nail if some of the base remained, will occur if the wounded end of the + finger is kept enclosed, for example by putting a metal or plastic tube over the finger. The humidity keeps the + wound from forming a dry scab, and the cells near the surface will consume oxygen and produce carbon dioxide, + keeping the ratio of carbon dioxide to oxygen much higher than in normal uninjured tissue. Carbon dioxide is + being used increasingly to prevent inflammation and edema. For example, it can be used to prevent adhesions + during abdominal surgery, and to protect the lungs during mechanical ventilation. It inhibits the formation of + inflammatory cytokines and prostaglandins (Peltekova, et al., 2010, Peng, et al., 2009, Persson & van den + Linden, 2009), and reduces the leakiness of the intestine (Morisaki, et al., 2009). Some experiments show that + as it decreases the production of some inflammatory materials by macrophages (TNF: Lang, et al., 2005), + including lactate, it causes macrophages to activate phagocytic neutrophils, and to increase their number and + activity (Billert, et al., 2003, Baev & Kuprava, 1997).Factors that are associated with a decreased level of + carbon dioxide, such as excess estrogen and lactate, promote fibrosis. Adaptation to living at high altitude, + which is protective against degenerative disease, involves reduced lactate formation, and increased carbon + dioxide. It has been suggested that keloid formation (over-growth of scar tissue) is less frequent at high + altitudes (Ranganathan, 1961), though this hasn"t been carefully studied. Putting an injured arm or leg into a + bag of pure carbon dioxide reduces pain and accelerates healing. In aging, the removal of inactive cells becomes + incomplete (Aprahamian, et al., 2008). It is this removal of cellular debris that is essential for regenerative + healing to take place. Degenerating tissue stimulates the formation of new tissue, but this requires adequate + cellular energy for phagocytosis, which requires proper thyroid function. "Hyperthyroidism" has been shown to + accelerate the process (Lewin-Kowalik, et al., 2002). The active thyroid hormone, T3, stimulates the removal of + inactive cells (Kurata, et al., 1980). Regenerative healing also requires freedom from substances that inhibit + the digestion of the debris. The great decline in proteolytic autophagy that occurs with aging (Del Roso, et + al., 2003) can be reduced by inhibiting the release of fatty acids. This effect is additive to the antiaging + effects of calorie restriction, suggesting that it is largely the decrease of dietary fats that makes calorie + restriction effective (Donati, et al., 2004, 2008).Niacinamide is a nutrient that inhibits the release of fatty + acids, and it also activates phagocytic activity and lowers phosphate. It protects against the development of + scars in spinal cord injuries, facilitates recovery from traumatic brain injury, and accelerates healing + generally. While it generally supports immunity, it"s protective against autoimmunity. It can cause tumor cells + to either mature or disintegrate, but it prolongs the replicative life of cultured cells, and protects against + excitotoxicity. The amounts needed seem large if niacinamide is thought of as "vitamin B3," but it should be + considered as a factor that compensates for our unphysiological exposure to inappropriate fats. Aspirin and + vitamin E are other natural substances that are therapeutic in "unnaturally" large amounts because of our + continual exposure to the highly unsaturated plant-derived n-3 and n-6 fats.When animals are made "deficient" in + the polyunsaturated fatty acids, their wounds heal, with normal or accelerated collagen synthesis, and with more + vigorous collagen breakdown (Parnham, et al., 1977). Their blood vessels are more resistant, preventing shock + that would otherwise be caused by many factors. All phases of development, from gestation to aging, are altered + by the presence of the unsaturated fats, and these effects correspond closely to the loss of the regenerative + capacity, the ability to replenish and restore tissues. If the very small amounts of polyunsaturated fats + reaching the fetus can retard growth and brain development (Liu and Borgman, 1977; Borgman, et al., 1975) and + function, it is apparently acting on some very important biological processes. The toxic effects of PUFA seen in + the animal studies probably have their equivalent in humans, for example the association of childhood + hyperactivity with a smaller brain. The incidence of the attention deficit-hyperactivity disorder is increasing + in the US, somewhat faster among girls than boys (Robison, et al.,2002). In schizophrenic teenagers, the brain + shrinks, suggesting an interaction of the hormones of puberty with environmental toxins or deficiencies. The + progressive accumulation of much larger amounts of these fats later in life, especially after the rate of growth + decreases, could be expected to cause even greater interference with those processes of development and + function. All tissues age, but the brain might be the least ambiguous organ to consider. The aging brain often + shrinks, and becomes more susceptible to excitotoxicity, which kills brain cells. Degenerative brain diseases, + such as Huntington"s chorea and Creutzfeld-Jacob disease, have been compared to the dementia of pellagra, in + which chorea and other excitatory processes are obvious. (Anti-glutamatergic drugs are beginning to be used + therapeutically, to restore some inhibitory balance in the degenerating brain.)Pellagra occurs about twice as + often in women as in men, and this is because estrogen activates an enzyme that alters metabolism of tryptophan, + blocking the formation of niacin. The alternative products include the excitotoxin, quinolinic acid, and some + carcinogens.Progesterone inhibits the activity of that enzyme. Progesterone also lowers brain serotonin + (Izquierdo, et al., 1978), decreases the excitatory carcinogens (Moursi, et al., 1970) and increases the + formation of niacin (Shibata, et al., 2003) The polyunsaturated fats, DHA, EPA, and linoleic acid activate the + conversion of tryptophan to quinolinic acid (Egashira, et al., 2003, 2004), and inhibit the formation of niacin + (Egashira, et al., 1995). The normal pathway from tryptophan to niacin leads to formation of + the coenzyme NAD, which is involved in a great variety of cellular processes, notably energy production, the + maintenance of the cellular differentiated state by regulating gene expression, and the activity of phagocytes. + Glucose and niacinamide work very closely with each other, and with the thyroid hormone, in the maintenance and + repair of cells and tissues. When one of these energy-producing factors is lacking, the changes in cell + functions -- a sort of pre-inflammatory state -- activate corrective processes. Energy depletion itself is an + excitatory state, that calls for increased fuel and oxygen. But when cells are exposed to PUFA, their ability to + use glucose is blocked, increasing their exposure to the fats. Saturated fats activate the pyruvate + dehydrogenase enzyme that is essential for the efficient use of glucose, while PUFA block it. (The MRL mouse + strain has a high regenerative ability, associated with a retained tendency to metabolize glucose rather than + fatty acids.) The negative energetic effects of PUFA include interfering with thyroid and progesterone. The + energy resources are suppressed, at the same time that the inflammatory signals are amplified, and many + regulatory pathways (including the replenishment of NAD from tryptophan) are diverted.In the fetus, especially + before the fats from the mother"s diet begin to accumulate, signals from injured tissue produce the changes that + lead quickly to repair of the damage, but during subsequent life, similar signals produce incomplete repairs, + and as they are ineffective they tend to be intensified and repeated, and eventually the faulty repair processes + become the main problem. Although this is an ecological problem, it is possible to decrease the damage by + avoiding the polyunsaturated fats and the many toxins that synergize with them, while increasing glucose, + niacinamide, carbon dioxide, and other factors that support high energy metabolism, including adequate exposure + to long wavelength light and avoidance of harmful radiation. As long as the toxic factors are present, increased + amounts of protective factors such as progesterone, thyroid, sugar, niacinamide, and carbon dioxide can be used + therapeutically and preventively. +

REFERENCES

Eur J Med Res. 2003 Aug 20;8(8):381-7. Dietary fatty acids and immune reactions in + synovial tissue. Adam O.Early Hum Dev. 1990 Dec;24(3):239-48. Biochemical EFA status of + mothers and their neonates after normal pregnancy. Al MD, Hornstra G, van der Schouw YT, + Bulstra-Ramakers MT, Huisjes HJ.Clin Exp Immunol. 2008 Jun;152(3):448-55. Epub 2008 Apr 16. Ageing is + associated with diminished apoptotic cell clearance in vivo.Aprahamian T, Takemura Y, Goukassian D, + Walsh K.Aviakosm Ekolog Med. 1997;31(6):56-9. [Functional activity of peripheral blood neutrophils of + rats during combined effects of hypoxia, hypercapnia and cooling] [Article in Russian] Baev VI, + Kuprava MV.Br J Nutr. 1984 Mar;51(2):219-24. Inhibition of tryptophan metabolism by oestrogens in the + rat: a factor in the aetiology of pellagra. Bender DA, Totoe L.Vascul Pharmacol. 2003 + Feb;40(2):119-25. Oxidative metabolism of peripheral blood neutrophils in experimental acute hypercapnia + in the mechanically ventilated rabbit. Billert H, Drobnik L, Podstawska D, Wlodarczyk M, Kurpisz + M.Am J Vet Res. 1975 Jun;36(6):799-805. Influence of maternal dietary fat upon rat pups. + Borgman RF, Bursey RG, Caffrey BC.Med Hypotheses. 2000 Oct;55(4):337-47. Dominant role of monocytes in + control of tissue function and aging. Bukovsky A, Caudle MR, Keenan JA.Exp Gerontol. 2003 + May;38(5):519-27. Ageing-related changes in the in vivo function of rat liver macroautophagy and + proteolysis. + Del Roso A, Vittorini S, Cavallini G, Donati A, Gori Z, Masini M, Pollera M, Bergamini E.Prostaglandins + Leukot Essent Fatty Acids. 2009 Apr;80(4):207-12. Fetal learning and memory: weak associations with the + early essential polyunsaturated fatty acid status. Dirix CE, Hornstra G, Nijhuis JG.Early Hum Dev. + 2009 Aug;85(8):525-30. Associations between term birth dimensions and prenatal exposure to essential and + trans fatty acids. Dirix CE, Kester AD, Hornstra G.Biochem Biophys Res Commun. 2008 Feb + 15;366(3):786-92. Epub 2007 Dec 17. In vivo effect of an antilipolytic drug (3,5'-dimethylpyrazole) on + autophagic proteolysis and autophagy-related gene expression in rat liver. Donati A, Ventruti A, + Cavallini G, Masini M, Vittorini S, Chantret I, Codogno P, Bergamini E.Biochim Biophys Acta. 2004 Nov + 8;1686(1-2):118-24. Differential effects of dietary fatty acids on rat liver + alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase activity and gene expression. + Egashira Y, Murotani G, Tanabe A, Saito K, Uehara K, Morise A, Sato M, Sanada H. Hepatic + alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD; formerly termed picolinic + carboxylase) [EC4.1.1.45] plays a key role in regulating NAD biosynthesis and the generation of quinolinate + (quinolinic acid) from tryptophan. Quinolinate is a potent endogenous excitotoxin of neuronal cells. We + previously reported that ingestion of fatty acids by rats leads to a decrease in their hepatic ACMSD activity. + However, the mechanism of this phenomenon is not clarified. We previously purified ACMSD and cloned cDNA + encoding rat ACMSD. Therefore, in this study, we examined the differential effect of fatty acids on ACMSD mRNA + expression by Northern blot. Moreover, we measured quinolinic acid concentration in rats fed on fatty acid. When + diets containing 2% level of fatty acid were given to male Sprague-Dawley rats (4 weeks old) for 8 days, + long-chain saturated fatty acids and oleic acid did not affect ACMSD mRNA expression in the liver. + Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) strongly suppressed the liver ACMSD mRNA expression. + In + rats fed with high linoleic acid diet for 8 days, serum quinolinic acid was significantly increased as + compared with the rats fed on a fatty acid-free diet under the condition of the approximately same calorie + ingestion. These results suggest that the transcription level of ACMSD is modulated by + polyunsaturated fatty acids, and suppressive potency of ACMSD mRNA is n-3 fatty acid family>linoleic acid + (n-6 fatty acid)>saturated fatty acid. Moreover, this study provides the information that a high + polyunsaturated fatty acid diet affects the production of quinolinic acid in serum by suppressing the ACMSD + activity.Int J Vitam Nutr Res. 2007 Mar;77(2):142-8. Dietary protein level and dietary interaction + affect quinolinic acid concentration in rats. Egashira Y, Sato M, Saito K, Sanada H. "In this + study, we examined whether dietary protein level, fatty acid type, namely saturated fatty acid and + polyunsaturated fatty acid, and their interaction affect serum quinolinic acid concentration in rats." Male + Sprague-Dawley rats (4-weeks old) were fed with 20% casein + 10% stearic acid diet (20C10S), 20% casein + 10% + linoleic acid diet (20C10L), 40% casein + 10% stearic acid diet (40C10S), or + 40% casein + 10% linoleic acid diet (40C10L) + for 8 days, and serum quinolinic acid concentration and ACMSD activity were determined. Serum + quinolinic acid concentration was significantly increased in the 40C10L +
+ Increased serum QA concentrations are probably due to a decreased ACMSD activity.Biochim + Biophys Acta. 2004 Nov 8;1686(1-2):118-24. Differential effects of dietary fatty acids on rat liver + alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase activity and gene expression. + Egashira Y, Murotani G, Tanabe A, Saito K, Uehara K, Morise A, Sato M, Sanada H.Int J Vitam Nutr Res. 2007 + Mar;77(2):142-8. Dietary protein level and dietary interaction affect quinolinic acid concentration in + rats. Egashira Y, Sato M, Saito K, Sanada H.Comp Biochem Physiol A Physiol. 1995 Aug;111(4):539-45. + Effect of dietary linoleic acid on the tryptophan-niacin metabolism in streptozotocin diabetic rats. + Egashira Y, Nakazawa A, Ohta T, Shibata K, Sanada H.Adv Exp Med Biol. 2003;527:671-4. Dietary + linoleic acid suppresses gene expression of rat liver alpha-amino-beta-carboxymuconate-epsilon-semialdehyde + decarboxylase (ACMSD) and increases quinolinic acid in serum. Egashira Y, Sato M, Tanabe A, Saito + K, Fujigaki S, Sanada H.J Clin Invest. 1994 Mar;93(3):1063-70. Neutrophil migration inhibitory + properties of polyunsaturated fatty acids. The role of fatty acid structure, metabolism, and possible second + messenger systems. Ferrante A, Goh D, Harvey DP, Robinson BS, Hii CS, Bates EJ, Hardy SJ, Johnson + DW, Poulos A.Clin Invest Med. 2008;31(3):E106-16. Hyaluronan oligosaccharides are potential stimulators + to angiogenesis via RHAMM mediated signal pathway in wound healing. Gao F, Yang CX, Mo W, Liu YW, + He YQ.Pharmacol Res Commun. 1978 Jul;10(7):643-56. Role of ACTH on the effect of medroxyprogesterone in + brain stem serotonin. Izquierdo JA, Savini C, Borghi E, Rabiller G, Costas S, Justel E.Postepy Hig + Med Dosw (Online). 2007 Nov 19;61:683-9. [Hyaluronan-mediated regulation of inflammation] + [Article in Polish] Krasinski R, Tch"rzewski H.J Pediatr Surg. 1987 Jul;22(7):640-4. Fetal response to + injury in the rabbit. Krummel TM, Nelson JM, Diegelmann RF, Lindblad WJ, Salzberg AM, Greenfield LJ, Cohen + IK.Acta Haematol. 1980;63(4):185-90. Thrombocytopenia in Graves' disease: effect of T3 on platelet + kinetics. + Kurata Y, Nishioeda Y, Tsubakio T, Kitani T.Clin Chim Acta. 1977 Sep 1;79(2):479-87. Influence + of glucose and inhibitors of glycolysis on release of total proteins and enzymes from human + leukocytes. Lahrichi M, Tarallo P, Houpert Y, Siest G.Am J Physiol Lung Cell Mol Physiol. 2005 + Jul;289(1):L96-L103. Epub 2005 Mar 18. + Effect of CO2 on LPS-induced cytokine responses in rat alveolar macrophages. Lang CJ, Dong P, + Hosszu EK, Doyle IR.J Pediatr Surg. 1999 May;34(5):695-700. TGF-beta1 alters the healing of cutaneous + fetal excisional wounds. Lanning DA, Nwomeh BC, Montante SJ, Yager DR, Diegelmann RF, Haynes + JH.Restor Neurol Neurosci. 2002;20(5):181-7. Experimental hyperthyroidism increases the effectiveness of + predegenerated peripheral nerve graft implantation into hippocampus of adult rats. Lewin-Kowalik J, + Golka B, Larysz-Brysz M, Swiech-Sabuda E, Granek A.Am J Vet Res. 1977 Oct;38(10):1657-9. Influence in + rats of dietary fats during the perinatal period: effects upon development and behavior of dams and + offspring. Liu YL, Borgman RF.Intensive Care Med. 2009 Jan;35(1):129-35. Hypercapnic + acidosis minimizes endotoxin-induced gut mucosal injury in rabbits. Morisaki H, Yajima S, Watanabe + Y, Suzuki T, Yamamoto M, Katori N, Hashiguchi S, Takeda J.Int J Tissue React. 1993;15(4):151-6. + Effects of prostaglandins and indomethacin on the cellular inflammatory response following surgical trauma + in fetal rabbits. Morykwas MJ, Perry SL, Argenta LC.Bull World Health Organ. 1970;43(5):651-61. + The influence of sex, age, synthetic oestrogens, progestogens and oral contraceptives on the excretion + of urinary tryptophan metabolites. Moursi GE, Abdel-Daim MH, Kelada NL, Abdel-Tawab GA, Girgis + LH.Int J Dev Neurosci. 2007 Dec;25(8):499-508. Signal transduction pathways associated with ATP-induced + proliferation of cell progenitors in the intact embryonic retina. Nunes PH, Calaza Kda C, + Albuquerque LM, Fragel-Madeira L, Sholl-Franco A, Ventura AL.Mikrobiyol Bul. 2006 Oct;40(4):325-32. [Histologic demonstration of adrenal macrophages as a member of mononuclear phagocytic system in guinea pig + models] [Article in Turkish] Ozbek A, Ozbek E.Prostaglandins. 1977 Oct;14(4):709-14. + Increased collagen metabolism in granulomata induced in rats deficient in endogenous prostaglandin + precursors. Parnham MJ, Shoshan S, Bonta IL, Neiman-Wollner S.Intensive Care Med. 2010 + May;36(5):869-78. Epub 2010 Mar 6. Hypercapnic acidosis in ventilator-induced lung injury. + Peltekova V, Engelberts D, Otulakowski G, Uematsu S, Post M, Kavanagh BP.J Surg Res. 2009 Jan;151(1):40-7. Epub + 2008 Apr 23. Heated and humidified CO2 prevents hypothermia, peritoneal injury, and intra-abdominal + adhesions during prolonged laparoscopic insufflations. Peng Y, Zheng M, Ye Q, Chen X, Yu B, Liu + B.Med Hypotheses. 2009 Oct;73(4):521-3. Epub 2009 Jul 8. Intraoperative field flooding with warm + humidified CO2 may help to prevent adhesion formation after open surgery. Persson M, van der Linden + J.British Medical Journal 1961 Feb. 4, 1:364. Keloids after B.C.G. Ranganathan KS.CNS Drugs. + 2002;16(2):129-37. Is attention deficit hyperactivity disorder increasing among girls in the US? Trends + in diagnosis and the prescribing of stimulants. Robison LM, Skaer TL, Sclar DA, Galin RS.Adv Exp + Med Biol. 2003;527:435-41. Increase in conversion of tryptophan to niacin in pregnant rats. + Shibata K, Fukuwatari T, Murakami M, Sasaki R.Invest Ophthalmol Vis Sci. 1980 Aug;19(8):983-6. The effects of aging and inflammation on corneal endothelial wound healing in rabbits.Staatz WD, Van + Horn DL.Pediatr Surg Int. 2001 May;17(4):254-8. + Polyunsaturated fatty acids influence neonatal monocyte survival. + Sweeney B, Puri P, Reen DJ. "PUFAs modulate apoptosis of certain tumour cells and cell lines. + Monocytes, which are major effector cells of the innate immune system, play a central role in the initiation, + development, and outcome of the immune response. They are crucial in the defence against invading pathogens and + are involved in the lysis of infected or malignant cells, wound healing, repair, and remodeling + of tissues. In the present study we investigated whether PUFAs might evoke apoptosis in newborn monocytes." "In + the absence of fatty acids, 30 +/- 4% of control cord monocytes underwent apoptosis or necrosis after 24 h + incubation. At a concentration of 50 microM, none of the PUFAs had a significant effect on monocyte cell + death,but at a dose of 100 microM, DHA resulted in 60 +/- 4% cell death (P < 0.05) while the other + PUFAs had no significant effect. In contrast, at higher concentrations (200 microM), all the PUFAs + significantly increased monocyte cell death (AA: 70 +/- 5%, DHA: 86 + +/- 2%, EPA: 70 +/- 4%). PUFAs thus exert a potent influence on cord monocyte cell survival in vitro. + Their effect is dose-dependent and DHA appears to be the most potent of the fatty acids tested. The influence of + PUFAs on neonatal monocyte-cell survival suggests a novel mechanism whereby PUFAs may modulate the immune + response."J Cell Mol Med. 2007 Nov-Dec;11(6):1342-51. Differential cytokine activity and morphology + during wound healing in the neonatal and adult rat skin. + Wagner W, Wehrmann M.Pharmacol Res Commun. 1978 Jul;10(7):643-56. Role of ACTH on the effect of + medroxyprogesterone in brain stem serotonin. Izquierdo JA, Savini C, Borghi E, Rabiller G, Costas + S, Justel E.J Cell Mol Med. 2007 Nov-Dec;11(6):1342-51. Differential cytokine activity and morphology + during wound healing in the neonatal and adult rat skin. + Wagner W, Wehrmann M.Plast Reconstr Surg. 2002 Jun;109(7):2355-62. The fetal cleft palate: III. + Ultrastructural and functional analysis of palatal development following in utero repair of the congenital + model. Weinzweig J, Panter KE, Spangenberger A, Harper JS, McRae R, Edstrom LE.Z Mikrosk Anat + Forsch 1970 Jan. 82(2): 149-71. [Experimental studies on the regeneration of the telencephalon of + Ambystoma mexicanum after the resection of both hemispheres] E Winkelmann, A Winkelmann.Am J + Physiol Cell Physiol. 2010 Mar;298(3):C457-64. Shockwaves increase T-cell proliferation and IL-2 + expression through ATP release, P2X7 receptors, and FAK activation. Yu T, Junger WG, Yuan C, Jin A, + Zhao Y, Zheng X, Zeng Y, Liu J.

+ © Ray Peat Ph.D. 2012. All Rights Reserved. www.RayPeat.com +

+ + diff --git a/raypeat-articles/processed/rosacea-inflammation-aging.html b/raypeat-articles/processed/rosacea-inflammation-aging.html new file mode 100644 index 0000000..4f50f4c --- /dev/null +++ b/raypeat-articles/processed/rosacea-inflammation-aging.html @@ -0,0 +1,1079 @@ + + + +

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+
+ Rosacea, inflammation, and aging: The inefficiency of stress +
+
+ Rosacea, or acne rosacea, has been defined as "vascular and follicular dilation involving the + nose and contiguous portions of the cheeks . . ." that may involve persistent erythema with + hyperplasia of sebaceous glands. Stedman's Medical Dictionary 23rd + edition. +
+
+
+ Light-skinned people, especially women between the ages of 30 and 50, sometimes develop a + persistent redness of their cheeks and nose. It may begin as a tendency to flush excessively, + but the blood vessels can become chronically dilated. Similar processes occur in dark-skinned + people less frequently. +
+
+ The eyes are sometimes involved, with redness of the exposed areas (conjuctival hyperemia). New + blood vessels develop in the area, and the flow of blood through the affected tissue is greatly + increased. The tissues become thickened and fibrotic, with the multiplication of fibroblasts and + the increased deposition of collagen. +
+
+ The cornea normally receives its oxygen from the air, and its nutrients from the aqueous humor. As + rosacea of the eye develops, the blood vessels surrounding the cornea become increasingly + visible, and, especially on the inner (nasal) side of the eye, the vessels tend to enlarge and + become tortuous. Rhinophyma, or potato nose, has been described as a late development of + rosacea. +
+
+ Too often, the medical reaction is to give the condition a name, and to distinguish its variants as + if they were different problems, and then to use the most direct means to eliminate the problem + they have defined. +
+
+ A typical attitude is that "Rosacea is an enigmatic disease with multiple exacerbations and + remissions, and, unfortunately, treatment is directed toward symptomatic control rather than + cure" (Randleman). +
+
+ Lasers or other radiation, caustic chemical abrasion, surgical planing and dermal shaves, and other + forms of surgery may be used to destroy the superficial blood vessels, and to reduce the + enlarged nose or other irregularities. A few decades ago, when rosacea was believed to be the + result of a local infection, antibiotics were used to treat it, and some of them, including + tetracycline, helped. It was discovered that some antibiotics have anti-inflammatory actions, + apart from their germicidal effects, and now it is very common to prescribe the chronic use of + tetracycline to suppress symptoms. +
+
+ Rosacea, and the fibrotic changes associated with it (pingueculae and pterygia in the eyes, + rhinophyma of the nose, etc.), are much more than "cosmetic" issues, involving the skin and eye + surface. If the invasive proliferation of blood vessels can be prevented, it's important to do + that, because, for example, pannus/neovascularization of the cornea can seriously impair + vision.  +
+
+ But possibly the strangest thing about the relationship of the medical profession to rosacea is + that its essential features, invasive neovascularization and fibrotic growth, are of great + interest when they occur elsewhere, and many physiological processes are known to regulate the + growth of blood vessels and fibroblasts, but nearly all the attention given to rosacea and + rhinophyma concerns control of symptoms for cosmetic effect. Rosacea is a physiological problem + that deserves consideration in the light of all that's known about physiology and developmental + biology. +
+
+ The increased incidence of rosacea after the age of 30, and the fact that it occurs most commonly + in the areas that are most exposed to sunlight (bald men sometimes develop it on the top of the + head), indicate that aging and irritation are essential causes. Stress, irritation (such as + produced by ultraviolet or ionizing radiation or free radicals), and aging are known to cause + disorganized growth of fibrous and vascular tissues in various parts of the body. The occurrence + of these processes at the surface, where the changes can be observed immediately, and without + invasive procedures, should have aroused wide interest among those who study kidney disease, + diabetes, and other degenerative diseases in which fibrosis and neovascularization play + important roles. +
+
+ A localized stress or irritation at first produces vasodilation that increases the delivery of + blood to the tissues, allowing them to compensate for the stress by producing more energy. Some + of the agents that produce vasodilation also reduce oxygen consumption (nitric oxide, for + example), helping to restore a normal oxygen tension to the tissue. Hypoxia itself (produced by + factors other than irritation) can induce vasodilation, and if prolonged sufficiently, tends to + produce neovascularization and fibrosis.  +
+
+ Sensitivity to the harmful effects of light can be increased by some drugs and by excess porphyrins + produced in the body (and by the porphyrin precursor, delta-amino levulinic acid), leading to + rosacea, so those factors should be considered, but too often alcohol (which can cause porphyrin + to increase) is blamed for rosacea and rhinophyma, without justification. There are many ways in + which poor health can increase light sensitivity. Some types of excitation produced by + metabolites (or by the failure of inhibitory metabolites) can produce vasodilation, involving + the release of nitric oxide (Cardenas, et al., 2000), setting off a series of potentially + pathological reactions, including fibrosis. The nitric oxide increases glycolysis while lowering + energy production. The excitatory metabolite glutamate, and nitric oxide, are both inhibited by + aspirin (Moro, et al., 2000). +
+
+ When blood flow in skin affected by rosacea was measured, circulation was 3 or 4 times higher than + normal (Sibenge & Gawkrodger, 1992), and oxygen tension may be increased. An inability to + extract oxygen from the blood, or to use it to produce energy, will produce the same hyperemia + that would be produced by a lack of oxygen. These measurements suggest that mitochondrial + defects would be the best place to look for a general cause of rosacea. +
+
+ When mitochondria are damaged, active cells produce increased amounts of lactic acid, even in the + presence of adequate oxygen. Otto Warburg identified this kind of metabolism, aerobic + glycolysis, as an essential feature of cancer, and showed that it could be produced by stress, + ionizing radiation, carcinogenic toxins, and even by a simple oxygen deficiency. Other + investigators around the same time showed that lactic acid produces vasodilation (for example, + in the cornea), and more recently it has been shown to promote the development of fibrosis, and + it has been called a "phlogogen," a promoter of inflammation.  +
+
+ Riboflavin, vitamin B2, is an essential component of the mitochondrial respiratory enzymes, and it + is very easily destroyed by light (blue light and especially ultraviolet). When it is excited by + high energy light, it can spread the damage to other components of the mitochondria, including + the cytochromes and the polyunsaturated fatty acids. The other B vitamins are affected when + riboflavin's actions are disturbed. +
+
+ Vitamin K is also extremely light sensitive, and it interacts closely with coenzyme Q in regulating + mitochondrial metabolism. For example, mitochondrial Complex-I, NADH-ubiquinone reductase, is + probably the most easily damaged part of the mitochondrion, and it is protected by vitamin K. + Vitamin E, coenzyme Q, and the polyunsaturated fatty acids are also light sensitive, and they + are more susceptible to free radical damage when vitamin K is deficient. +
+
+ Niacinamide, one of the B vitamins, provides energy to this mitochondrial system. Under stress and + strong excitation, cells waste niacinamide-NADH, but niacinamide itself has a sedative + antiexcitatory effect, and some of its actions resemble a hormone. Estrogen tends to interfere + with the formation of niacin from tryptophan. Tryptophan, rather than forming the sedative + niacin (pyridine carboxylic acid), can be directed toward formation of the excitatory quinolinic + acid (pyridine dicarboxylic acid) by polyunsaturated fatty acids. Excitation must be in balance + with a cell's energetic resources, and niacinamide can play multiple protective roles, + decreasing excitation, increasing energy production, and stabilizing repair systems. The state + of excitation and type of energy metabolism are crucial factors in governing cell functions and + survival. +
+
+ The polyunsaturated fatty acids, besides their interactions with estrogen and tryptophan + metabolism, promote excitation and decrease energy production in several other ways. For + example, they increase the excitatory effects of the glutamate pathways (Yu, et al., 1986; + Nishikawa, 1994), and their breakdown products inhibit mitochondrial respiration (Humphries, et + al., 1998; Picklo, et al., 1999; Lovell, et al., 2000). +
+
+ The excess excitation that produces nitric oxide and lactic acid lowers the energy production of + vascular cells, possibly enough to lower their contractile ability (Geng, et al., 1992), causing + vasodilation. When flushing is caused by a mismatch between energy supply and energy demand, + caffeine can decrease the vasodilation (Eikvar & Kirkebøen, 1998), but when vasodilation is + caused more physiologically by carbon dioxide, caffeine doesn't have that effect (Meno, et al., + 2005). In a study in which drinking hot water or coffee was compared with drinking + room-temperature coffee or caffeine, it was found that the hot liquids caused flushing, but cool + coffee and caffeine didn't. +
+
+ Caffeine increases cells' energy efficiency, and by opposing the effects of adenosine (secreted by + cells that are stressed and energy-depleted), it can inhibit vasodilation, angioneogenesis + (Merighi, et al., 2007; Ryzhov, et al., 2007), and fibrosis (Chan, et al., 2006).  +
+
+ One nearly ubiquitous source of inappropriate excitation and energy depletion is the endotoxin, + bacterial lipopolysaccharides absorbed from the intestine (Wang and White, 1999). That this + ubiquitous toxin has a role in rosacea is suggested by the observation that intestinal + stimulation, to speed transit through the bowel, immediately relieved symptoms (Kendall, 2002). + Increased cortisol (Simon, et al., 1998) and sepsis (Levy, 2007) interfere with mitochondrial + energy production. +
+
+ Simple nervous blushing or flushing is usually considered harmless, and when a person is + overheated, the reddening of the skin has the function of facilitating heat loss, to restore a + normal temperature. But even nerve-regulated flushing can involve a distinct interference with + mitochondrial respiration, and can stimulate the overgrowth of blood vessels.  +
+
+ Cancer's respiratory defect that Warburg identified, fermentation with lactic acid production even + in the presence of adequate oxygen, was the result of some kind of injury to the mitochondria. + He showed that one of the injuries that could produce aerobic glycolysis was a deficiency of + riboflavin. He observed that tumors generally were anoxic, and that cancers typically appeared + in the midst of tissue that was atrophying, and suggested that the cancer cells' survival was + favored by their ability to live without oxygen. This may be relevant to the observations of + many surgeons of a small cancer embedded in the fibrous tissue of large rhinophymas that have + been removed. +
+
+ The relatively high incidence of rosacea among women (some studies indicate that it may be 3 times + as common in women as in men) isn't likely to be the result of greater sun exposure, so it's + reasonable to look for hormonal causes. +
+
+ In old age, it's well recognized that men's estrogen level rises. But the estrogen industry has + convinced women that their estrogen declines as they get older. It's common knowledge that aging + rodents often go into "persistent estrus," and that their estrogen levels generally increase + with age (Parkening, et al., 1978; Anisimov and Okulov, 1981). Several studies in women have + shown that serum estrogen levels rise from the teens into the 40s (Musey, et al., 1987; + Wilshire, et al., 1995; Santoro, et al., 1996). +
+
+ Other studies show that serum and tissue estrogen concentrations are not concordant, and that some + tissues may contain several times as much estrogen as the serum (Jefcoate, et al., 2001). Local + irritation increases tissue estrogen content. +
+
+ The antiestrogens, especially progesterone, begin declining in the 30s, so that the rising estrogen + has more effect on the tissues during those years. These are the years in which the incidence of + rosacea rises suddenly. Rosacea develops later on average in men, whose estrogen levels rise + significantly at later ages. +
+
+ Estrogen's most immediate effect on cells is to alter their oxidative metabolism. It promotes the + formation of lactic acid. In the long run, it increases the nutritional requirements for the B + vitamins, as well as for other vitamins. It also increases the formation of aminolevulinic acid, + a precursor of porphyrin, and increases the risk of excess porphyrin increasing light + sensitivity. Both aminolevulinic acid and excess porphyrins are toxic to mitochondria, apart + from their photosensitizing actions. Nitric oxide, glutamate, and cortisol all tend to be + increased by estrogen. +
+
+ Veins and capillaries are highly sensitive to estrogen, and women are more likely than men to have + varicose veins, spider veins, leaky capillaries, and other vascular problems besides + rosacea.  Estrogen can promote angioneogenesis by a variety of mechanisms, including nitric + oxide (Johnson, et al., 2006). "Estrogens potentiate corticosteroid effects on the skin such as + striae, telangiectasiae, and rosacea dermatitis" (Zaun, 1981). Early forms of oral + contraceptives, high in estrogen, were found to increase acne rosacea more than three-fold + (Prenen & Ledoux-Corbusier, 1971). +
+
+ Lactic acid, produced under the influence of estrogen, nitric oxide, or other problems of energy + formation, besides causing vasodilation, also stimulates the growth of fibroblasts. Oxygen + deprivation, or damage to mitochondria, will increase lactic acid formation, and so it will + immediately cause vasodilation, and if the problem is prolonged, new blood vessels will grow, + and fibrous connective tissue will increase. Estrogen stimulates collagen synthesis, and it has + been associated with a variety of inflammatory and fibrotic conditions (for example, Cutolo, et + al., 2003. Payne, et al., 2006, suggest the use of the anti-estrogen, tamoxifen, to treat + rhinophyma.) +
+
+ The cornea normally contains more riboflavin even than the retina, which has a much higher rate of + metabolism. When the cornea isn't able to get enough oxygen from the air for its needs (and if + riboflavin is deficient, its need for oxygen is increased), surrounding blood vessels at first + dilate in response to the diffusing lactic acid, to increase the blood supply to the edges of + the cornea. If the problem is prolonged, the conjuctiva becomes chronically blood-shot, + hyperemic, and larger more visible blood vessels grow, surrounding the cornea, or even invading + the cornea. Many people, especially women, experienced problems of this sort from wearing + contact lenses, especially when the lenses were made of materials very impermeable to oxygen + (Dumbleton, et al., 2006). +
+
+ Sunlight, and mechanical obstruction of the cornea, produce very localized effects, but those local + effects are more likely to be harmful when there is a systemic nutritional deficiency or excess + of estrogen. When the systemic problem is very severe, the cheeks, nose, and eyes might not be + the first tissues to experience a functional disturbance.  +
+
+ The mitochondrial inhibition produced by the action of the parasympathetic nervous system + (occurring in simple blushing) can occur wherever those nerves act, and blood vessels in all + parts of the body are responsive to the acetylcholine secreted by those nerves. Sleep typically + involves a shift of dominance in the autonomic nervous system toward the parasympathetic nerves, + with vasodilation. Nosebleeds, especially in children, commonly occur during sleep (Jarjour + & Jarjour, 2005: high incidence in sleep, and association with migraine).  +
+
+ A 3 year-old child who had been having an average of 3 nosebleeds every day, during a nap and at + night, for several months, also had an extreme behavior problem. He became angry and sometimes + violent when he went a little longer than normal between meals. After an oral dose of about ten + milligrams of riboflavin, he was able to sleep without having another recurrence of the + nosebleeds, and his tantrums became rare. Apparently, the nerve-regulated vasodilation produced + by sleep, combined with a riboflavin deficiency, had been enough to produce nosebleeds. The + energy deficit resulting from a systemic riboflavin deficiency had probably been causing him to + be abnormally sensitive to glycogen depletion, producing sudden anger. In another individual, + the energy problem might have taken the form of a memory problem, or of a hemorrhage in the + brain or other essential organ. +
+
+ A 37 year old slightly alcoholic man with a bright red nose and cheeks was an amateur fiction + writer, but he was having trouble with his memory for words, and for everyday events. Even + conversationally, he had to struggle for relatively familiar words. On the suggestion that + riboflavin might help his memory, by allowing his brain cells to use oxygen more efficiently, he + had his doctor give him an intravenous injection of B vitamins. When I saw him the next day, his + conversation was perfectly fluent, and he obviously had easy access to a good vocabulary. Just + as noticeable was the normal color of his nose and cheeks. For a week, he had a daily injection + of the B vitamins, and his nose color and vocabulary stayed normal. But on the weekend, after + not having the shots for two days, his nose and cheeks were again maraschino cherry red, and his + speech was halting, as he struggled for words. He forgot the whole episode, and neglected to + return to the doctor for more of the vitamin injections. Ten years later, he had developed a + medium-sized potato nose, and had his heart valves replaced.  +
+
+ His vitamin requirements were apparently abnormally high. At first, the problems resulting from + damaged mitochondria seem mostly functional (flushing, mood, memory problems, etc.) and + variable, but chronically disturbed functions lead to structural, anatomical changes, as + prolonged stimulation alters tissue maintenance and growth. +
+
+ Abram Hoffer, who had been treating schizophrenia and senile dementia with niacin, accidentally + discovered that it cured his bleeding gums. That led to its use to treat heart disease. +
+
+ The "orthomolecular" ideas of Hoffer and Linus Pauling were developed in a context of biochemistry + governed by genetics, molecular biology, in which the goal was to provide a chemical that was + lacking because of a genetic defect in metabolism. Their idea of using nutrients as drugs has + led to many unphysiological practices, in which an isolated nutrient is supposed to have a + drug-like action, and if in isolation it doesn't act like a drug, then it should be used only + according to the normal genetically determined nutritional requirement. +
+
+ But in reality, nutritional requirements are strongly influenced by history and present + circumstances. For example, when corneal mitochondria have been damaged by riboflavin + deficiency, they have been found to subsequently require more than the normal amount of the + vitamin to function properly. And the presence of a certain amount of one nutrient often + increases or decreases the amount of other nutrients needed. +
+
+ When the interactions among energy expenditure and energy production, and cellular activation and + cellular inhibition, are taken into account, then it's clear that any particular problem is + likely to have many causes and many factors that could contribute to a cure. +
+
+ Lactate, glutamate, ammonium, nitric oxide, quinolinate, estrogen, histamine, aminolevulinate, + porphyrin, ultraviolet light, polyunsaturated fatty acids and endotoxin contribute to excitatory + and excitotoxic processes, vasodilation, angioneogenesis, and fibrosis.  +
+
+ Carbon dioxide, glycine, GABA, saturated fatty acids (for example, Nanji, et al., 1997), vitamin K, + coenzyme Q10, niacinamide, magnesium, red light, thyroid hormone, progesterone, testosterone, + and pregnenolone are factors that can be increased to protect against inappropriate cellular + excitation. +
+
+ All of the nutritional factors that participate in mitochondrial respiration contribute to + maintaining a balance between excessive excitation and protective inhibition. Riboflavin, + coenzyme Q10, vitamin K, niacinamide, thiamine, and selenium are the nutrients that most + directly relate to mitochondrial energy production.  +
+
+ Coffee is often avoided by people with rosacea, but it is a very good source of niacin and + magnesium, and caffeine has some of the same cell-protective functions as niacinamide. +
+
+ People suffering from rosacea have been found to be more likely than average to have suffered from + styes in childhood, to have varicose veins and spider veins, and to suffer from migraines and + depression.  +
+
+ Hypothyroidism has been identified as a factor in all of those. Good thyroid function is necessary + for resistance to bacterial infection, for regulation of blood sugar, neurotransmitters, and + hormones related to mood, and for the formation of progesterone. Progesterone regulates smooth + muscle tone, including the walls of veins, so that a deficiency allows veins to enlarge. It also + prevents overgrowth of fibrotic tissue, and in some contexts may inhibit angioneogenesis. +
+
+ GABA itself tends to raise body temperature (Ishiwata, et al., 2005), by controlling vasodilation, + and the factors such as progesterone which protect mitochondrial energy production are also + thermogenic, supporting the GABA system. Flushing, both by directly causing heat loss and by + reducing mitochondrial energy production, tends to lower body temperature. +
+
+ The sun-damaged areas in rosacea can be directly provided with some of the protective factors by + applying them topically. In the same way that topical lactate can cause vasodilation and + disturbed energy metabolism (Rendl, et al., 2001), topical niacinamide, progesterone, vitamin K, + and coenzyme Q10 can improve the metabolism and function of the local tissues. Riboflavin can + probably be useful when applied topically, but because of its extreme sensitivity to light, it + should usually be used only internally, unless the treated skin is covered to prevent exposure + to light. Topically applied caffeine, even after sun exposure, can reduce local tissue damage + (Koo, et al., 2007). Aspirin and saturated fats can also be protective when applied + topically. +
+
+ Some of the benefit from antibiotics probably results from the reduced endotoxin stress when + intestinal bacteria are suppressed. However, antibiotics can kill the intestinal bacteria that + produce vitamin K, so it's important to include that in the diet when antibiotics are + used. +
+
+ Some fibers, such as raw carrots, that are effective for lowering endotoxin absorption also contain + natural antibiotics, so regular use of carrots should be balanced by occasional supplementation + with vitamin K, or by occasionally eating liver or broccoli. +
+
+ Abram Hoffer's research was instrumental in getting niacin recognized as a heart protective drug, + but nearly everyone who prescribes it does so to lower blood lipids. That wasn't Hoffer's + understanding of its function. He thought it acted directly on blood vessels to protect their + integrity. During his studies of its effects on heart disease, he saw that it also lowered + cancer mortality, and so began treating cancer patients with it, with considerable success, but + there was no medical cliché that could allow the profession to follow in that + direction.  +
+
+ The arguments I have outlined for considering rosacea to be essentially a problem of metabolic + energy, and the mechanisms that I mention for restoring mitochondrial functions, might seem more + complex than Hoffer's orthomolecular views. However, this approach is actually much simpler + conceptually than any of the ideologies of drug treatment. It simply points out that certain + excitatory factors can interfere with energy production, and that there are opposing + "inhibitory" factors that can restore energy efficiency. Sometimes, using just one or two of the + factors can be curative. +
+
+ Because mitochondrial respiration is very similar in every kind of tissue, a physiological view of + rosacea could incline us toward considering the effects of these metabolic factors in other + organs during stress and aging--what would the analogous condition of rosacea and rhinophyma be + in the brain, heart, liver, or kidney? +
+
+
+

REFERENCES

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+
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+
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+
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+
+ www.emedicine.com/oph/topic115.htm +  Last Updated: May 14, 2007. Author: J Bradley Randleman, MD, Assistant Professor, + Department of Ophthalmology, Cornea, External Disease, and Refractive Surgery Section, + Emory University School of Medicine +
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 +
+
+ J Neurochem 1986 Oct;47(4):1181-9. Effects of arachidonic acid on glutamate and + gamma-aminobutyric acid uptake in primary cultures of rat cerebral cortical astrocytes and + neurons. Yu AC, Chan PH, Fishman RA. +
+
+ Med Monatsschr Pharm. 1981 Jun;4(6):161-5. [Skin changes from taking hormonal + contraceptives][Article in German] Zaun H. PIP: Hormonal contraceptives can induce + changes in the skin and its appendages. "Estrogens potentiate corticosteroid effects on the skin + such as striae, telangiectasiae, and rosacea dermatitis." +
+

 

+ + © Ray Peat Ph.D. 2013. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/ru486.html b/raypeat-articles/processed/ru486.html new file mode 100644 index 0000000..359cdfe --- /dev/null +++ b/raypeat-articles/processed/ru486.html @@ -0,0 +1,720 @@ + + RU486, Cancer, Estrogen, and Progesterone. + +

+ RU486, Cancer, Estrogen, and Progesterone. +

+ + Recently many people have been disturbed by reading claims that progesterone can cause cancer, or diabetes, or + autoimmune diseases, or heart disease, or Alzheimer's disease. A flurry of press conferences, and a few groups + of "molecular biologists" working on "progesterone receptors," and the results of studies in which Prempro + (containing a synthetic "progestin") increased breast cancer, have created great confusion and concern, at least + in the English speaking countries.

+

+ Wyeth, the manufacturer of Prempro, has been highly motivated to recover their sales and profits that + declined about 70% in the first two years after the Women's Health Initiative announced its results. When + billions of dollars in profits are involved, clever public relations can achieve marvelous things. +

+

+ Women and other mammals that are deficient in progesterone, and/or that have an + excess of estrogen, have a higher than average incidence of cancer. Animal experiments have shown that + administering progesterone could prevent cancer. Cells in the most cancer-susceptible tissues proliferate in + proportion to the ratio of estrogen to progesterone. When the estrogen dominance persists for a long time + without interruption, there are progressive distortions in the structure of the responsive organs--the + uterus, breast, pituitary, lung, liver, kidney, brain, and other organs--and those structural distortions + tend to progress gradually from fibroses to cancer. +

+

+ As a result of the early studies in both humans and animals, progesterone was used by many physicians to + treat the types of cancer that were clearly caused by estrogen, especially uterine, breast, and kidney + cancers. But by the 1950s, the drug industry had created the myth that their patented synthetic analogs of + progesterone were medically more effective than progesterone itself, and the result has been that + medroxyprogesterone acetate and other synthetics have been widely used to treat women's cancers, including + breast cancer. +

+ +

+ Unfortunately, those synthetic compounds have a variety of functions unlike progesterone, including some + estrogenic and/or androgenic and/or glucocorticoid and/or antiprogesterone functions, besides other special, + idiosyncratic side effects. The rationale for their use was that they were "like progesterone, only better." + The unpleasant and unwanted truth is that, as a group, they are seriously carcinogenic, besides being toxic + in a variety of other ways. Thousands of researchers have drawn conclusions about the effects of + progesterone on the basis of their experiments with a synthetic progestin. +

+

+ The earliest studies of estrogen and progesterone in the 1930s had the great advantage of a scientific + culture that was relatively unpolluted by the pharmaceutical industry. As described by Carla Rothenberg, the + massive manipulation of the medical, regulatory, and scientific culture by the estrogen industry began in + 1941. After that, the role of metaphysics, word magic, and epicycle-like models increasingly replaced + empirical science in endocrinology and cell physiology. +

+

+ As the estrogen industry began losing billions of dollars a year following the 2002 report from the Women's + Health Initiative regarding estrogen's toxicity, and as it was noticed that progesterone sales had increased + more than 100-fold, it was clear what had to be done--the toxic effects of estrogen had to be transferred to + progesterone. For more than 50 years, progesterone was recognized to be antimitotic and anti-inflammatory + and anticarcinogenic, but suddenly it has become a mitogenic pro-inflammatory carcinogen. +

+

+ Science used to involve confirmation or refutation of published results and conclusions. A different + experimenter, using the technique described in a publication, would often get a different result, and a + dialog or disputation would develop, sometimes continuing for years, before consensus was achieved, though + many times there would be no clear conclusion or consensus. +

+ +

+ In that traditional scientific environment, it was customary to recognize that a certain position remained + hypothetical and controversial until some new technique or insight settled the question with some degree of + clarity and decisiveness. People who cherry-picked studies to support their position, while ignoring + contradictory evidence, were violating the basic scientific principles of tentativeness and reasonableness. + Contradictory, as well as confirmatory, data have to be considered. +

+

+ But when a single experiment involves several people working for a year or more, at a cost of a million or + more dollars, who is going to finance an experiment that "would merely confirm" those results? The newly + developed techniques for identifying specific molecules are often very elaborate and expensive, and as a + result only a few kinds of molecule are usually investigated in each experiment. The results are open to + various interpretations, and most of those interpretations depend on results from other studies, whose + techniques, results, and conclusions have never been challenged, either. There is no significant source of + funding to challenge the programs of the pharmaceutical industry. +

+

+ The result is that the pronouncements of the principal investigator, and the repetitions of those + conclusions in the mass media, create a culture of opinion, without the foundation of multiple confirmations + that used to be part of the scientific process. The process has taken on many of the features of a cult, in + which received opinions are repeatedly reinforced by the investment of money and authority. Newspaper + reporters know that the team of investigators spent two years on their project, and the lead investigator + wears a white lab coat during the interview, so the reporters don't notice that the investigators' + conclusion is a non sequitur, supported by chains of non sequiturs. +

+

+ The public gets most of its information about science from the mass media, and the increasingly concentrated + ownership of the media contributes to the use of scientific news as an adjunct to their main business, + advertising and product promotion. The pharmaceutical industry spends billions of dollars annually on + direct-to-consumer advertising, so the big scientific news, for the media, is likely to be anything that + will increase their advertising revenue. +

+ +

+ Social-economic cults often simplify the thought processes required by the participants, by inventing a + scapegoat. The estrogen cult has decided that progesterone will be its scapegoat. +

+

+ Hans Selye argued that steroid hormones should be named by their origin, or by their chemical structural + names, rather than their effects, because each hormone has innumerable effects. To name a substance + according to its effects is to predict and to foreordain the discoveries that will be made regarding its + effects. +

+

+ The common system of hormonal names according to their putative effects has allowed ideology and + metaphysical ideas to dominate endocrinology. The worst example of metaphysical medicine was the use, for + more than 50 years, of "estrogen, the female hormone" to treat prostate cancer, in the belief that "male + hormones" cause the cancer, and that the female hormone would negate it. This word magic led to a vast + psychotic medical endeavor, that has only recently been reconsidered. +

+

+ Within the scheme of hormones understood according to their names, "hormone receptors" were proposed to be + the mechanism by which hormones produced their effects. Each hormone had a receptor. If another substance + bound more strongly than the hormone to its receptor, without producing the effects of the hormone, it was + called an antihormone. +

+ +

+ The industry of synthetic hormones used the ideology of unitary hormonal action to identify new substances + as pharmaceutical hormones, that were always in some way said to be better than the natural hormones--for + example by being "orally active," unlike natural hormones, supposedly. Physicians docilely went along with + whatever the drug salesmen told them. If a drug was classified as a "progestin" by a single reaction in one + animal tissue, then it had a metaphysical identity with the natural hormone, except that it was better, and + patentable. +

+

+ The natural hormones eventually were assigned any of the toxic properties that were observed for the + pharmaceutical products "in their class." If synthetic progestins caused heart disease, birth defects, and + cancer, then the "natural progestin" was assumed to do that, too. It's important to realize the impact of + logical fallacies on the medical culture. +

+ +

+ Like the hormones themselves, which metaphysically supposedly acted upon one receptor, to activate one gene + (or set of genes), the antihormones came to be stereotyped. If a particular hormonal action was blocked by a + chemical, then that substance became an antagonistic antihormone, and when its administration produced an + effect, that effect was taken to be the result of blocking the hormone for which it was "the antagonist." +

+

+ The "antiprogesterone" molecule, RU486, besides having some progesterone-like and antiestrogenic properties, + also has (according to Hackenberg, et al., 1996). some androgenic, antiandrogenic, and antiglucocorticoid + properties. Experiments in which it is used might have pharmaceutical meaning, but they so far have very + little clear biological meaning. +

+

+ Adding to the conceptual sloppiness of the "molecular biology" wing of endocrinology, the culture in which + pharmaceutical products had come to dominate medical ideas about hormones allowed the conventional + pharmaceutical vehicles to be disregarded in most experiments, both in vitro + + and in vivo. If progesterone was injected into patients mixed with sesame oil and benzyl alcohol, + then it often didn't occur to animal experimenters to give control injections of the solvent. For in + vitro + studies, in a watery medium, oil wouldn't do, so they would use an alcohol solvent, and again often forgot + to do a solvent control experiment. +

+

+ The importance of the solvent was seen by an experimenter studying the effect of vitamin E on age pigment in + nerves. It occurred to that experimenter to test the ethyl alcohol alone, and he found that it produced + almost the same effect as that produced by the solution of alcohol and vitamin E. Workers with hormones + often just assume that a little alcohol wouldn't affect their system. But when the effects of alcohol by + itself have been studied, many of the effects produced by very low concentrations happen to be the same + effects that have been ascribed to hormones, such as progesterone. +

+

+ In some cases, the solvent allows the hormone to crystallize, especially if the solvent is water-miscible, + and fails to distribute it evenly through the medium and cells as the experimenter assumed would happen, and + so the experimenter reports that the hormone is not effective in that kind of cell, even though the hormone + didn't reach the cells in the amount intended. +

+ +

+ These are four of the common sources of error about progesterone: (1) Saying that progesterone has produced + an effect which was produced by a different substance. (2) Saying that progesterone is the cause of a + certain effect, if an "anti-progesterone" chemical prevents that effect. (3) Saying that progesterone caused + something, when in fact the solvent caused it. And (4) saying that progesterone fails to do something, when + progesterone hasn't been delivered to the system being studied. +

+

+ Many years ago, experimenters who wanted to minimize the problems involved in administering progesterone in + toxic solvents found that, with careful effort, progesterone could be transferred to a protein, such as + albumin, and that the albumin-progesterone complex could be washed to remove the solvent. In this form, the + progesterone can be delivered to cells in a form that isn't radically different from the form in which it + naturally circulates in the body. Apparently, the labor involved discourages the widespread use of this + technique. +

+

+ Although the industry's early generalizations about estrogen and progesterone, defining them as "the female + hormone" and "the pregnancy hormone," were radically mistaken, some useful generalizations about their + effects were gradually being built up during the first few decades in which their chemical and physiological + properties were studied. +

+ +

+ Estrogen's name, derived from the gadfly, accurately suggests its role as an excitant, getting things + started. Progesterone's name, relating to pregnancy, is compatible with thinking of it as an agent of + calming and fulfillment. But these properties show up in every aspect of physiology, and the special cases + of female estrus and pregnancy can be properly understood only in the larger context, in which, for example, + progesterone is a brain hormone in both sexes and at all ages, and estrogen is an essential male hormone + involved in the sperm cell's function and male libido. +

+

+ Progesterone can, without estrogen, create the uterine conditions for implantation of an embryo (Piccini, + 2005, progesterone induces LIF; Sherwin, et al., 2004, LIF can substitute for estrogen), and it has many + other features that can be considered apart from estrogen, such as its regulation of salts, energy + metabolism, protein metabolism, immunity, stress, and inflammation, but without understanding its opposition + to estrogen, there will be no coherent understanding of progesterone's biological meaning. +

+

+ Both estrogen and progesterone are hydrophobic molecules (progesterone much more so than estrogen) which + bind with some affinity to many components of cells. Certain proteins that strongly bind the hormones are + called their receptors. +

+

+ Cells respond to stimulation by estrogen by producing a variety of molecules, including the "progesterone + receptor" protein. When progesterone enters the cell, binding to these proteins, the estrogenic stimulation + is halted, by a series of reactions in which the estrogen receptors disintegrate, and in which estrogen is + made water soluble by the activation of enzymes that attach sulfate or a sugar acid, causing it leave the + cell and move into the bloodstream, and by reactions that prevent its reentry into the cell by inactivating + another type of enzyme, and that suppress its de novo formation in the cell, and that oxidize it + into a less active form. Progesterone terminates estrogen's cellular functions with extreme thoroughness. +

+ +

+ A recent publication in Science + ("Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist," Poole, et al., + Dec. 1, 2006), with associated press conferences, reported an experiment in which a special kind of mouse + was prepared, which lacked two tumor-suppressing genes called BRCA and p53. +

+

+ One of the functions of the BRCA gene product is to repair genetic damage, and another function is to (like + progesterone) suppress the estrogen receptor and its functions. Estrogen, and some environmental + carcinogens, can suppress the BRCA gene product. Estrogen can also turn off the tumor suppressor protein, + p53. So it is interesting that a group of experimenters chose to produce a mouse that lacked both the normal + BRCA and p53 genes. They had a mouse that was designed to unleash estrogen's effects, and that modeled some + of the features of estrogen toxicity and progesterone deficiency. +

+

+ This mouse, lacking an essential gene that would allow progesterone to function normally, probably affecting + progesterone's ability to eliminate the estrogen receptor, also lacked the tumor suppressor gene p53, which + is required for luteinization (Cherian-Shaw 2004); + in its absence, progesterone synthesis is decreased, + estrogen synthesis is increased. +

+ +

+ (Chen, Y, et al., 1999: BRCA represses the actions of estrogen and its receptor, and, like + progesterone, activates the p21 promoter, which inhibits cell proliferation. Aspirin and vitamin D also act + through p21.) +

+

+ The mutant BRCA gene prevents the cell, even in the presence of progesterone, from turning off estrogen's + effects the way it should. The antiestrogenic RU486 (some articles below), which has some of progesterone's + effects (including therapeutic actions against endometrial and breast cancer), appears to overcome some of + the effects of that mutation. +

+

+ It might have been proper to describe the engineered mouse that lacked both the BRCA and the p53 genes as a + mouse in which the effects of estrogen excess and progesterone deficiency would be especially pronounced and + deadly. To speak of progesterone as contributing to the development of cancer in that specially designed + mouse goes far beyond bad science. However, that study makes sense if it is seen as preparation for the + promotion of a new drug similar in effect to RU486, to prevent breast cancer. +

+

+ The study's lead author, Eva Lee, quoted by a university publicist, said "We found that progesterone plays a + role in the development of breast cancer by encouraging the proliferation of mammary cells that carry a + breast cancer gene." But they didn't measure the amount of progesterone present in the animals. They didn't + "find" anything at all about progesterone. The "anti-progesterone" drug they used has been used for many + years to treat uterine, ovarian, and breast cancers, in some cases with progesterone, to intensify + its effects, and its protective effects are very likely the result of its antiestrogenic and anti-cortisol + effects, both of which are well established, and relevant. In some cases, it acts like progesterone, only + more strongly. +

+

+ "Other more specific progesterone blockers are under development," Lee notes. And the article in Science magazine looks like nothing more than the first advertisement for one that her husband, + Wen-Hwa Lee, has designed. +

+ +

+ According to publicists at the University of California, Irvine, "Lee plans to focus his research on + developing new compounds that will disrupt end-stage cancer cells. The goal is a small molecule that, when + injected into the blood stream, will act as something of a biological cruise missile to target, shock and + awe the cancerous cells." "In this research, he will make valuable use of a breast cancer model developed by + his wife." "She developed the model, and I will develop the molecule," Lee says. "We can use this model to + test a new drug and how it works in combination with old drugs." +

+

+ "Previously we blamed everything," Lee says of his eye cancer discovery. "We blamed electricity, we blamed + too much sausage - but in this case it's clear: It's the gene's fault." +

+ +

+ The things that these people know, demonstrated by previous publications, but that they don't say in the Science article, are very revealing. The retinoblastoma gene (and its protein product), a specialty of + Wen-Hwa Lee, is widely known to be a factor in breast cancer, and to be responsive to progesterone, RU486, + and p21. Its links to ubiquitin, the hormone receptors, proteasomes, and the BRCA gene are well known, but + previously they were seen as linking estrogen to cell proliferation, and progesterone to the inhibition of + cellular proliferation. +

+

+ By organizing their claims around the idea that RU486 is acting as an antiprogesterone, rather than as a + progesterone synergist in opposing estrogen, Eva Lee's team has misused words to argue that it is + progesterone, rather than estrogen, that causes breast cancer. Of the many relevant issues that their + publication ignores, the absence of measurements of the actual estrogen and progesterone in the animals' + serum most strongly suggests that the project was not designed for proper scientific purposes. +

+

+ They chose to use techniques that are perfectly inappropriate for showing what they claim to show. +

+

+ In the second paragraph of their article, Poole, et al., say "Hormone replacement therapy with progesterone + and estrogen, but not estrogen alone, has been associated with an elevation risk in postmenopausal women." + Aside from the gross inaccuracy of saying "progesterone," rather than synthetic progestin, they phrase their + comment about "estrogen alone" in a way that suggests an identity of purpose with the estrogen industry + apologists, who have been manipulating the data from the WHI estrogen-only study, clearly to lay the blame + on progesterone. (Women who took estrogen had many more surgeries to remove mammographically abnormal breast + tissue. This would easily account for fewer minor cancer diagnoses; despite this, there were more advanced + cancers in the estrogen group.) +

+

+ While the Poole, et al., group are operating within a context of new views regarding estrogen, progesterone, + and cancer, they are ignoring the greater part of contemporary thinking about cancer, a consensus that has + been growing for over 70 years: All of the factors that produce cancer, including breast + cancer, produce inflammation and cellular excitation. +

+

+ Progesterone is antiinflammatory, and reduces cellular excitation. +

+

+ Even within their small world of molecular endocrinology, thinking in ways that have been fostered by + computer technology, about gene networks, interacting nodes, and crosstalk between pathways, their model and + their arguments don't work. They have left out the complexity that could give their argument some weight. +

+ +

+ The medical mainstream has recognized for 30 years that progesterone protects the uterus against cancer; + that was the reason for adding Provera to the standard menopausal hormonal treatment. The new claim that + natural progesterone causes breast cancer should oblige them to explain why the hormone would have opposite + effects in different organs, but the mechanisms of action of estrogen and progesterone are remarkably + similar in both organs, even when examined at the molecular level. If "molecular endocrinologists" are going + to have interpretations diametrically opposed to classical endocrinology (if black is to be white, if apples + are to fall up), they will have to produce some very interesting evidence. +

+

+ Cancer is a malignant (destructive, invasive) tumor that kills the organism. The main dogma regarding its + nature and origin is that it differs genetically from the host, as a result of mutations. Estrogen causes + mutations and other forms of genetic instability, as well as cancer itself. Progesterone doesn't harm genes + or cause genetic instability. +

+

+ The speculative anti-progesterone school has put great emphasis on the issue of cellular proliferation, with + the reasoning that proliferating cells are more likely to undergo genetic changes. And synthetic progestins + often do imitate estrogen and increase cellular proliferation. People like the Lees are asserting as an + established fact that progesterone increases cellular proliferation. +

+

+ A paper by Soderqvist has been cited as proof that progesterone increases the proliferation of breast cells. + He saw more mitoses in the breasts during the luteal phase of the menstrual cycle, and said the slightly + increased mitotic rate was "associated with" progesterone. Of course, estrogen increased at the same time, + and estrogen causes sustained proliferation of breast cells, while progesterone stimulation causes only two + cell divisions, ending with the differentiation of the cell. (Groshong, et al., 1997, Owen, et al., 1998) +

+ +

+ One of the ways that progesterone stops proliferation and promotes differentiation is by keeping the + retinoblastoma protein in its unphosphorylated, active protective state (Gizard, et al., 2006) The effects + of estrogen and progesterone on that protein are reciprocal (Chen, et al., 2005). It's hard for me to + imagine that the Lees don't know about these hormonal effects on Wen-Hwa's retinoblastoma gene product. +

+

+ The inactivation of that protein by hyperphosphorylation is part of a general biological process, in which + activation of a cell (by injury or nervous or hormonal or other stimulation, including radiation) leads to + the activation of a large group of about 500 enzymes, phosphorylases, which amplify the stimulation, and + cause the cell to respond by becoming active in many ways, for example, by stopping the synthesis of + glycogen, and beginning its conversion to glucose to provide energy for the adaptive responses, that include + the activation of genes and the synthesis or destruction of proteins. Another set of enzymes, the + phosphatases, remove the activating phosphate groups, and allow the cell to return to its resting state. +

+

+ The "molecular" endocrinologists and geneticists are committed to a reductionist view of life, the view that + DNA is the essence, the secret, of life, and that it controls cells through its interactions with smaller + molecules, such as the hormone receptors. +

+

+ The idea of hormone receptors can be traced directly to the work of Elwood Jensen, who started his career + working in chemical warfare, at the University of Chicago. Jensen claims that an experiment he did in the + 1950s "caused the demise" of the enzymic-redox theory of estrogen's action, by showing that uterine tissue + can't oxidize estradiol, and that its only action is on the genes, by way of "the estrogen receptor." But + the uterus and other tissues do oxidize estradiol, and its cyclic oxidation and reduction is clearly + involved in some of estrogen's toxic and excitatory effects. +

+

+ For some reason, the military is still interested in hormone receptors. Lawrence National Weapons Laboratory + (with its giant "predictive science" computer) is now the site of some of the anti-progesterone research. +

+

+ Molecular biologists have outlined a chain of reactions, starting at the cell surface, and cascading through + a series of phosphorylations, until the genes are activated. The cell surface is important, because cells + are always in contact with something, and their functions and structure must be appropriate for their + location. But the reductionist view of a network of phosphorylating enzymes ignores some facts. +

+

+ Glycogen phosphorylase was the first enzyme whose activity was shown to be regulated by structural changes, + allosterism. The active form is stabilized by phosphorylation, but this process takes seconds or minutes to + develop, and the enzyme becomes active immediately when the cell is stimulated, for example in muscle + contraction, within milliseconds. This kind of allosteric activation (or inactivation) can be seen in a + variety of other enzymes, the cold-labile enzymes. A coherent change of the cell causes coordinated changes + in its parts. These processes of enzymic regulation are fast, and can occur throughout a cell, practically + simultaneously. Strict reductionists don't like to talk about them. "Network analysis" becomes irrelevant. +

+

+ While a cell in general is activated by a wave of phosphorylation, certain processes (including glycogen + synthesis) are blocked. When BRCA1 or retinoblastoma protein is hyperphosphorylated, its anti-estrogenic, + anti-proliferative functions are stopped. The communication between cells is another function that's stopped + by injury-induced phosphorylation. +

+

+ Estrogen generally activates phosphorylases, and inactivates phosphatases. Progesterone generally opposes + those effects. +

+

+ Phosphorylation is just one of the regulatory systems that are relevant to the development of cancer, and + that are acted on oppositely by estrogen and progesterone. To reduce the explanation for cancer to a gene or + two or three may be an attractive idea for molecular endocrinologists, but the idea's simplicity is + delusive. +

+

+ Each component of the cell contributes complexly to the cell's regulatory stability. Likewise, a drug such + as RU486 complexly modifies the cell's stability, changing thresholds in many ways, some of which synergize + with progesterone (e.g., supporting the GABA system), others of which antagonize progesterone's effects + (e.g., increasing exposure to prostaglandins). +

+ +

+ There are other proteins in cells, besides the "hormone receptors," that bind progesterone, and that + regulate cell functions globally. The sigma receptor, for example, that interacts with cocaine to excite the + cell, interacts with progesterone to quiet the cell. The sigma receptor is closely related functionally to + the histones, that regulate the activity of chromosomes and DNA, and progesterone regulates many processes + that control the histones. +

+

+ The GABA receptor system, and the systems that respond to glutamic acid (e.g., the "NMDA receptors") are + involved in the inhibitory and excitatory processes that restrain or accelerate the growth of cancer cells, + and progesterone acts through those systems to quiet cells, and restrain growth. +

+

+ The inhibitor of differentiation, Id-1, is inhibited by progesterone, activated by estrogen (Lin, et al., + 2000). Proteins acting in the opposite direction, PTEN and p21, for example, are activated by progesterone, + and inhibited by estrogen. +

+

+ The inflammatory cytokines, acting through the NFkappaB protein to activate genes, are generally oppositely + regulated by estrogen and progesterone. +

+ +

+ Prostaglandins, platelet activating factor, nitric oxide, peroxidase, lipases, histamine, serotonin, + lactate, insulin, intracellular calcium, carbon dioxide, osmolarity, pH, and the redox environment are all + relevant to cancer, and are affected systemically and locally by estrogen and progesterone in generally + opposing ways. +

+

+ About ten years ago, Geron corporation announced that it was developing products to control aging and + cancer, by regulating telomerase, the enzyme that lengthens a piece of DNA at the end of the chromosomes. + Their argument was that telomeres get shorter each time a cell divides, and that after about 50 divisions, + cells reach the limit identified by Leonard Hayflick, and die, and that this accounts for the aging of the + organism. Cancer cells are immortal, they said, because they maintain active telomerase, so the company + proposed to cure cancer, by selling molecules to inhibit the enzyme, and to cure aging, by providing new + enzymes for old people. However, Hayflick's limit was mainly the effect of bad culture methods, and the + theory that the shortening of telomeres causes aging was contradicted by the finding of longer telomeres in + some old people than in some young people, and different telomere lengths in different organs of the same + person. +

+

+ But it's true that cancer cells have active telomerase, and that most healthy cells don't. It happens that + telomerase is activated by cellular injury, such as radiation, that activates phosphorylases, and that it is + inactivated by phosphatases. Estrogen activates telomerase, and progesterone inhibits it. +

+

+ Molecular endocrinology is very important to the pharmaceutical industry, because it lends itself so well to + television commercials and corporate stock offerings. Monsanto and the Pentagon believe they can use + reductionist molecular biology to predict, manipulate, and control life processes, but so far it is only + their ability to damage organisms that has been demonstrated. +

+

+ Besides the early animal studies that showed experimentally that progesterone can prevent or cure a wide + variety of tumors, the newer evidence showing that progesterone is a major protective factor against even + breast cancer, would suggest that dishonest efforts to protect estrogen sales by preventing women from using + natural progesterone will be causing more women to develop cancer. +

+ +

+ The recent report that the incidence of breast cancer in the United States fell drastically between 2002 and + 2004, following the great decline in estrogen sales, shows the magnitude of the injury and death caused by + the falsifications of the estrogen industry--a matter of millions of unnecessary deaths, just in the years + that I have been working on the estrogen issue. The current campaign against progesterone can be expected to + cause many unnecessary cancer deaths (e.g., Plu-Bureau, et al., Mauvais-Jarvis, et al.), while distracting + the public from the culpability of the estrogen industry. +

+

+

REFERENCES

+

+

+ J Endocrinol. 2003 Oct;179(1):55-62. Overexpression of wild-type p53 gene renders MCF-7 breast + cancer cells more sensitive to the antiproliferative effect of progesterone. + Alkhalaf M, El-Mowafy AM. +

+

+ J Clin Endocrinol Metab. 1985 Apr;60(4):692-7. RU486, a progestin and glucocorticoid antagonist, + inhibits the growth of breast cancer cells via the progesterone receptor. + + + Bardon S, Vignon F, Chalbos D, Rochefort H. +

+

+ Mol Carcinog. 2003 Dec;38(4):160-9. Suppression of the transformed phenotype and induction of + differentiation-like characteristics in cultured ovarian tumor cells by chronic treatment with + progesterone. Blumenthal M, Kardosh A, Dubeau L, Borok Z, Schonthal AH. +

+

+ Contraception. 1998 Jul;58(1):45-50. Screening for antiproliferative actions of mifepristone. + Differential endometrial responses of primates versus rats. Burleigh DW, Williams RF, Gordon K, + Hsiu JG, Hodgen GD. +

+

+ Hum Reprod Update. 1998 Sep-Oct;4(5):570-83. Modulation of oestrogenic effects by progesterone + antagonists in the rat uterus. Chwalisz K, Stockemann K, Fritzemeier KH, Fuhrmann U. +

+ +

+ J Vasc Surg. 2002 Oct;36(4):833-8. Progesterone inhibits human infragenicular arterial smooth muscle + cell proliferation induced by high glucose and insulin concentrations. Carmody BJ, Arora S, + Wakefield MC, Weber M, Fox CJ, Sidawy AN. +

+

+ J Cell Physiol. 1999 Dec;181(3):385-92. Emerging roles of BRCA1 in transcriptional regulation and + DNA repair. + + Chen Y, Lee WH, Chew HK. +

+

+ Mol Endocrinol. 2005 Aug;19(8):1978-90. Progesterone inhibits the estrogen-induced phosphoinositide + 3-kinase--> AKT--> GSK-3beta--> cyclin D1--> pRB pathway to block uterine epithelial cell + proliferation. Chen B, Pan H, Zhu L, Deng Y, Pollard JW. +

+

+ Endocrinology. 2004 Dec;145(12):5734-44. Regulation of steroidogenesis by p53 in macaque granulosa + cells and H295R human adrenocortical cells. Cherian-Shaw M, Das R, Vandevoort CA, Chaffin CL. +

+

+ Breast Cancer Res Treat. 1994;32(2):153-64. Expression of insulin-like growth factor binding + proteins by T-47D human breast cancer cells: regulation by progestins and antiestrogens. Coutts + A, Murphy LJ, Murphy LC. +

+

+ Progr. Exp. Tumor Res. 1971, vol. 14: 59, Inhibition of tumor induction in chemical carcinogenesis + in the mammary gland, Dao TL. +

+ +

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+

+ Breast Cancer Res Treat. 1998 May;49(2):109-17. Effect of antiprogestins and tamoxifen on growth + inhibition of MCF-7 human breast cancer cells in nude mice. El Etreby MF, Liang Y. +

+

+ Prostate. 2000 Apr 1;43(1):31-42. Induction of apoptosis by mifepristone and tamoxifen in human + LNCaP prostate cancer cells in culture. El Etreby MF, Liang Y, Lewis RW. +

+ +

+ Breast Cancer Res Treat. 1998 Sep;51(2):149-68. Additive effect of mifepristone and tamoxifen on + apoptotic pathways in MCF-7 human breast cancer cells. + El Etreby MF, Liang Y, Wrenn RW, Schoenlein PV. +

+

+ Ann Clin Lab Sci. 1998 Nov-Dec;28(6):360-9. Progesterone inhibits growth and induces apoptosis in + breast cancer cells: inverse effects on Bcl-2 and p53. + Formby B, Wiley TS. +

+

+ Mol Cell Biochem. 1999 Dec;202(1-2):53-61. Bcl-2, survivin and variant CD44 v7-v10 are downregulated + and p53 is upregulated in breast cancer cells by progesterone: inhibition of cell growth and induction + of apoptosis. + + Formby B, Wiley TS. +

+ +

+ Mol Cell Biol. 2006 Oct;26(20):7632-44. TReP-132 is a novel progesterone receptor coactivator + required for the inhibition of breast cancer cell growth and enhancement of differentiation by + progesterone. Gizard F, Robillard R, Gross B, Barbier O, Revillion F, Peyrat JP, Torpier G, Hum + DW, Staels B. +

+

+ FEBS Lett. 2005 Oct 24;579(25):5535-41. Epub 2005 Sep 27. Progesterone inhibits human breast cancer + cell growth through transcriptional upregulation of the cyclin-dependent kinase inhibitor p27Kip1 + gene. Gizard F, Robillard R, Gervois P, Faucompre A, Revillion F, Peyrat JP, Hum WD, Staels B. +

+

+ Mol Cell Biol. 2005 Jun;25(11):4335-48. TReP-132 controls cell proliferation by regulating the + expression of the cyclin-dependent kinase inhibitors p21WAF1/Cip1 and p27Kip1. Gizard F, + Robillard R, Barbier O, Quatannens B, Faucompre A, Revillion F, Peyrat JP, Staels B, Hum DW. +

+ +

+ Mol Endocrinol. 1997 Oct;11(11):1593-607. Biphasic regulation of breast cancer cell growth by + progesterone: role of the cyclin-dependent kinase inhibitors, p21 and p27(Kip1). Groshong SD, + Owen GI, Grimison B, Schauer IE, Todd MC, Langan TA, Sclafani RA, Lange CA, Horwitz KB. +

+

+ Eur J Cancer. 1996 Apr;32A(4):696-701. Androgen-like and anti-androgen-like effects of + antiprogestins in human mammary cancer cells. Hackenberg R, Hannig K, Beck S, Schmidt-Rhode P, + Scholz A, Schulz KD. +

+

+ Cancer Research 1945, vol. 5: 426-430. The Effect of Progesterone and Testosterone Proprionate on + the Incidence of Mammary Cancer in Mice, Heiman, J. +

+ +

+ Proc. Natl. Acad. Sci., USA, 1962, vol.48: 379, + Extinction of experimental mammary cancer, Huggins C, Moon RC and Morii S. +

+

+ Hum Reprod. 1994 Jun;9 Suppl 1:77-81. Non-competitive anti-oestrogenic activity of progesterone + antagonists in primate models. Hodgen GD, van Uem JF, Chillik CF, Danforth DR, Wolf JP, Neulen + J, Williams RF, Chwalisz K. +

+

+ Nat Med. 2004 Oct;10(10):1018-21. From chemical warfare to breast cancer management. + Jensen EV. +

+ +

+ Br. J. Cancer 1962, vol. 16: 209, Jolles B. +

+

+ Vopr Onkol. 2000;46(1):68-73. + [Inhibitory effect of progesterone P1-1 on glutathione-s-transferase and its antiproliferative effect on + human erythroleukemia K562 cells] Kalinina EV, Novichkova MD, Shcherbak NP, Saprin AN. +

+

+ Fertil Steril. 1996 Feb;65(2):323-31. Antiproliferative effects of low-dose micronized + progesterone. Kim S, Korhonen M, Wilborn W, Foldesy R, Snipes W, Hodgen GD, Anderson FD. +

+

+ Clin Cancer Res. 1999 Feb;5(2):395-403. Progestins inhibit the growth of MDA-MB-231 cells + transfected with progesterone receptor complementary DNA. + Lin VC, Ng EH, Aw SE, Tan MG, Ng EH, Chan VS, Ho GH. +

+ +

+ Cancer Res. 2000 Mar 1;60(5):1332-40. + A role for Id-1 in the aggressive phenotype and steroid hormone response of human breast cancer + cells. + Lin CQ, Singh J, Murata K, Itahana Y, Parrinello S, Liang SH, Gillett CE, Campisi J, Desprez PY. "Estrogen + stimulated proliferation and induced Id-1 expression, whereas progesterone inhibited proliferation and + repressed Id-1 expression. Progesterone repressed Id-1 expression, at least in part by repressing + transcription." +

+

+ Endocrinology. 2003 Dec;144(12):5650-7. Epub 2003 Sep 11. Distinct molecular pathways mediate + progesterone-induced growth inhibition and focal adhesion. + Lin VC, Woon CT, Aw SE, Guo C. +

+

+ Clin Cancer Res. 1999 Feb;5(2):395-403. Progestins inhibit the growth of MDA-MB-231 cells + transfected with progesterone receptor complementary DNA. Lin VC, Ng EH, Aw SE, Tan MG, Ng EH, + Chan VS, Ho GH. +

+ +

+ Differentiation. 2006 Dec;74(9-10):481-7. The multiple roles of Id-1 in cancer progression. + + Ling MT, Wang X, Zhang X, Wong YC. +

+

+ Lipschutz, A, Steroid Hormones and Tumors, Williams and Wilkins, Baltimore, 1950. +

+

+ Lancet 1939, vol. 237: 420-421, Anti-tumorigenic action of progesterone, + Lipschutz A, Murillo R, and Vargas, L Jr. +

+ +

+ Lancet 1939, vol 237: 867-869, Antitumorigenic action of testosterone, + Lipschutz A, Vargas L Jr., and Ruz O. +

+

+ J Biol Chem. 1994 Apr 22;269(16):11945-9. RU486 exerts antiestrogenic activities through a novel + progesterone receptor A form-mediated mechanism. + McDonnell DP, Goldman ME. +

+

+ Ital J Biochem. 1981 Jul-Aug;30(4):279-89. Effects of estrogens and progesterone on GABA system in + ovariectomized rat retina. Macaione S, Ientile R, Lentini M, Di Giorgio RM. +

+ +

+ J Cell Physiol. 1995 Apr;163(1):129-36. Phenotypic features of breast cancer cells overexpressing + ornithine-decarboxylase. Manni A, Wechter R, Wei L, Heitjan D, Demers L. +

+

+ Ann Endocrinol (Paris). 1989;50(3):181-8. [Antiestrogens and normal human breast cell proliferation] + Mauvais-Jarvis P, Gompel A, Malet C, +

+ + © Ray Peat Ph.D. 2007. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/salt.html b/raypeat-articles/processed/salt.html new file mode 100644 index 0000000..892a637 --- /dev/null +++ b/raypeat-articles/processed/salt.html @@ -0,0 +1,867 @@ + + + + Salt, energy, metabolic rate, and longevity + + + +

+ Salt, energy, metabolic rate, and longevity +

+ +

+

+ In the 1950s, when the pharmaceutical industry was beginning to promote some new chemicals as diuretics to + replace the traditional mercury compounds, Walter Kempner"s low-salt "rice diet" began to be discussed in + the medical journals and other media. The diuretics were offered for treating high blood pressure, pulmonary + edema, heart failure, "idiopathic edema," orthostatic edema and obesity, and other forms of water retention, + including pregnancy, and since they functioned by causing sodium to be excreted in the urine, their sale was + accompanied by advising the patients to reduce their salt intake to make the diuretic more effective. +

+ +

+ It was clear to some physicians (and to most veterinarians) that salt restriction, especially combined with + salt-losing diuresis, was very harmful during pregnancy, but that combination became standard medical + practice for many years, damaging millions of babies. +

+

+ Despite numerous publications showing that diuretics could cause the edematous problems that they were + supposed to remedy, they have been one of the most profitable types of drug. Dietary salt restriction has + become a cultural cliché, largely as a consequence of the belief that sodium causes edema and hypertension. +

+

+ Salt restriction, according to a review of about 100 studies (Alderman, 2004), lowers the blood pressure a + few points. But that generally doesn"t relate to better health. In one study (3000 people, 4 years), there + was a clear increase in mortality in the individuals who ate less salt. An extra few grams of salt per day + was associated with a 36% reduction in "coronary events" (Alderman, et al., 1995). Another study (more than + 11,000 people, 22 years) also showed an inverse relation between salt intake and mortality (Alderman, et + al., 1997). +

+

+ Tom Brewer, an obstetrician who devoted his career to educating the public about the importance of prenatal + nutrition, emphasizing adequate protein (especially milk), calories, and salt, was largely responsible for + the gradual abandonment of the low-salt plus diuretics treatment for pregnant women. He explained that + sodium, in association with serum albumin, is essential for maintaining blood volume. Without adequate + sodium, the serum albumin is unable to keep water from leaving the blood and entering the tissues. The + tissues swell as the volume of blood is reduced. +

+

+ During pregnancy, the reduced blood volume doesn"t adequately nourish and oxygenate the growing fetus, and + the reduced circulation to the kidneys causes them to release a signal substance (renin) that causes the + blood to circulate faster, under greater pressure. A low salt diet is just one of the things that can reduce + kidney circulation and stimulate renin production. Bacterial endotoxin, and other things that cause + excessive capillary permeability, edema, or shock-like symptoms, will activate renin secretion. +

+

+ The blood volume problem isn"t limited to the hypertension of pregnancy toxemia: "Plasma volume is usually + lower in patients with essential hypertension than in normal subjects" (Tarazi, 1976). +

+ +

+ Several studies of preeclampsia or toxemia of pregnancy showed that supplementing the diet with salt would + lower the women"s blood pressure, and prevent the other complications associated with toxemia (Shanklin and + Hodin, 1979). +

+

+ It has been known for many years that decreasing sodium intake causes the body to respond adaptively, + increasing the renin-angiotensin-aldosterone system (RAAS). The activation of this system is recognized as a + factor in hypertension, kidney disease, heart failure, fibrosis of the heart, and other problems. Sodium + restriction also increases serotonin, activity of the sympathetic nervous system, and plasminogen activator + inhibitor type-1 (PAI-1), which contributes to the accumulation of clots and is associated with breast and + prostate cancer. The sympathetic nervous system becomes hyperactive in preeclampsia (Metsaars, et al., + 2006). +

+

+ Despite the general knowledge of the relation of dietary salt to the RAA system, and its application by + Brewer and others to the prevention of pregnancy toxemia, it isn"t common to see the information applied to + other problems, such as aging and the stress-related degenerative diseases. +

+

+ Many young women periodically crave salt and sugar, especially around ovulation and premenstrually, when + estrogen is high. Physiologically, this is similar to the food cravings of pregnancy. Premenstrual water + retention is a common problem, and physicians commonly offer the same advice to cycling women that was + offered as a standard treatment for pregnant women--the avoidance of salt, sometimes with a diuretic. But + when women premenstrually increase their salt intake according to their craving, the water retention can be + prevented. +

+

+ Blood volume changes during the normal menstrual cycle, and when the blood volume is low, it is usually + because the water has moved into the tissues, causing edema. When estrogen is high, the osmolarity of the + blood is low. (Courtar, et al., 2007; Stachenfeld, et al., 1999). Hypothyroidism (which increases the ratio + of estrogen to progesterone) is a major cause of excessive sodium loss. +

+ +

+ The increase of adrenalin caused by salt restriction has many harmful effects, including insomnia. Many old + people have noticed that a low sodium diet disturbs their sleep, and that eating their usual amount of salt + restores their ability to sleep. The activity of the sympathetic nervous system increases with aging, so + salt restriction is exacerbating one of the basic problems of aging. Chronically increased activity of the + sympathetic (adrenergic) nervous system contributes to capillary leakage, insulin resistance (with increased + free fatty acids in the blood), and degenerative changes in the brain (Griffith and Sutin, 1996). +

+

+ The flexibility of blood vessels (compliance) is decreased by a low-salt diet, and vascular stiffness caused + by over-activity of the sympathetic nervous system is considered to be an important factor in hypertension, + especially with aging. +

+

+ Pregnancy toxemia/preeclampsia involves increased blood pressure and capillary permeability, and an excess + of prolactin. Prolactin secretion is increased by serotonin, which is one of the substances increased by + salt restriction, but prolactin itself can promote the loss of sodium in the urine (Ibarra, et al., 2005), + and contributes to vascular leakage and hypertension. +

+

+ In pregnancy, estrogen excess or progesterone deficiency is an important factor in the harmful effects of + sodium restriction and protein deficiency. A deficiency of protein contributes to hypothyroidism, which is + responsible for the relative estrogen excess. +

+

+ Protein, salt, thyroid, and progesterone happen to be thermogenic, increasing heat production and + stabilizing body temperature at a higher level. Prolactin and estrogen lower the temperature set-point. +

+

+ The downward shift of temperature and energy metabolism in toxemia or salt deprivation tends to slow the use + of oxygen, increasing the glycolytic use of sugar, and contributing to the formation of lactic acid, rather + than carbon dioxide. In preeclampsia, serum lactate is increased, even while free fatty acids are + interfering with the use of glucose. +

+ +

+ One way of looking at those facts is to see that a lack of sodium slows metabolism, lowers carbon dioxide + production, and creates inflammation, stress and degeneration. Rephrasing it, sodium stimulates energy + metabolism, increases carbon dioxide production, and protects against inflammation and other maladaptive + stress reactions. +

+

+ In recent years, Weissman"s "wear-and-tear" theory of aging, and Pearl"s "rate of living" theory have been + clearly refuted by metabolic studies that are showing that intensified mitochondrial respiration decreases + cellular damage, and supports a longer life-span. +

+

+ Many dog owners are aware that small dogs eat much more food in proportion to their size than big dogs do. + And small dogs have a much greater life expectancy than big dogs, in some cases about twice as long + (Speakman, 2003). +

+

+ Organisms as different as yeasts and rodents show a similar association of metabolic intensity and + life-span. A variety of hamster with a 20% higher metabolic rate lived 15% longer than hamsters with an + average metabolic rate (Oklejewicz and Daan, 2002). +

+

+ Individuals within a strain of mice were found to vary considerably in their metabolic rate. The 25% of the + mice with the highest rate used 30% more energy (per gram of body weight) than the 25% with the lowest + metabolic rate, and lived 36% longer (Speakman, et al., 2000). +

+

+ The mitochondria of these animals are "uncoupled," that is, their use of oxygen isn"t directly proportional + to the production of ATP. This means that they are producing more carbon dioxide without necessarily + producing more ATP, and that even at rest they are using a considerable amount of energy. +

+ +

+ One important function of carbon dioxide is to regulate the movement of positively charged alkali metal + ions, such as sodium and calcium. When too much calcium enters a cell it activates many enzymes, prevents + muscle and nerve cells from relaxing, and ultimately kills the cell. The constant formation of acidic carbon + dioxide in the cell allows the cell to remove calcium, along with the small amount of sodium which is + constantly entering the cell. +

+

+ When there is adequate sodium in the extracellular fluid, the continuous inward movement of sodium ions into + the resting cell activates an enzyme, sodium-potassium ATPase, causing ATP to break down into ADP and + phosphate, which stimulates the consumption of fuel and oxygen to maintain an adequate level of ATP. + Increasing the concentration of sodium increases the energy consumption and carbon dioxide production of the + cell. The sodium, by increasing carbon dioxide production, protects against the excitatory, toxic effects of + the intracellular calcium. +

+

+ Hypertonic solutions, containing more than the normal concentration of sodium (from about twice normal to 8 + or 10 times normal) are being used to rescuscitate people and animals after injury. Rather than just + increasing blood volume to restore circulation, the hypertonic sodium restores cellular energy production, + increasing oxygen consumption and heat production while reducing free radical production, improves the + contraction and relaxation of the heart muscle, and reduces inflammation, vascular permeability, and edema. +

+

+ Seawater, which is hypertonic to our tissues, has often been used for treating wounds, and much more + concentrated salt solutions have been found effective for accelerating wound healing (Mangete, et al., + 1993). +

+

+ There have been several publications suggesting that increasing the amount of salt in the diet might cause + stomach cancer, because countries such as Japan with a high salt intake have a high incidence of stomach + cancer. +

+

+ Studies in which animals were fed popular Japanese foods--"salted cuttlefish guts, broiled, salted, dried + sardines, pickled radish, and soy sauce"--besides a chemical carcinogen, showed that the Japanese foods + increased the number of tumors. But another study, adding only soy sauce (with a salt content of about 18%) + to the diet did not increase the incidence of cancer, in another it was protective against stomach cancer + (Benjamin, et al., 1991). Several studies show that dried fish and pickled vegetables are carcinogenic, + probably because of the oxidized fats, and other chemical changes, and fungal contamination, which are + likely to be worse without the salt. Animals fed dried fish were found to have mutagenic urine, apparently + as a result of toxic materials occurring in various preserved foods (Fong, et al., 1979). +

+ +

+ Although preserved foods develop many peculiar toxins, even fresh fish in the diet have been found to be + associated with increased cancer risk (Phukan, et al., 2006). +

+

+ When small animals were given a milliliter of a saturated salt solution with the carcinogen, the number of + tumors was increased with the salt. However, when the salt was given with mucin, it had no cancer promoting + effect. Since the large amount of a saturated salt solution breaks down the stomach"s protective mucus + coating, the stomach cells were not protected from the carcinogen. Rather than showing that salt causes + stomach cancer, the experiments showed that a cup or more of saturated salt solution, or several ounces of + pure salt, shouldn"t be ingested at the same time as a strong carcinogen. +

+

+ Some studies have found pork to be associated with cancer of the esophagous (Nagai, et al., 1982), thyroid + (Markaki, et al., 2003), and other organs, but an experiment with beef, chicken, or bacon diet in rats + provides another perspective on the role of salt in carcinogenesis. After being given a carcinogen, rats + were fed meat diets, containing either 30% or 60% of freeze-dried fried beef, chicken, or bacon. Neither + beef nor chicken changed the incidence of precancerous lesions in the intestine, but the incidence was + reduced by 12% in the animals on the 30% bacon diet, and by 20% in rats getting the diet with 60% bacon. + Salt apparently made the difference. +

+

+ Other protective effects of increased sodium are that it improves immunity (Junger, et al., 1994), reduces + vascular leakiness, and alleviates inflammation (Cara, et al., 1988). All of these effects would tend to + protect against the degenerative diseases, including tumors, atherosclerosis, and Alzheimer"s disease. The + RAA system appears to be crucially involved in all kinds of sickness and degeneration, but the protective + effects of sodium are more basic than just helping to prevent activation of that system. +

+

+ A slight decrease in temperature can promote inflammation (Matsui, et al., 2006). The thermogenic + substances--dietary protein, sodium, sucrose, thyroid and progesterone--are antiinflammatory for many + reasons, but very likely the increased temperature itself is important. +

+ +

+ A poor reaction to stress, with increased cortisol, can raise the body temperature by accelerating the + breakdown and resynthesis of proteins, but adaptive resistance to stress increases the temperature by + increasing the consumption of oxygen and fuel. In the presence of increased cortisol, abdominal fat + increases, along with circulating fatty acids and calcium, as mitochondrial respiration is suppressed. +

+

+ When mice are chilled, they spontaneously prefer slightly salty water, rather than fresh, and it increases + their heat production (Dejima, et al., 1996). When rats are given 0.9 per cent sodium chloride solution with + their regular food, their heat production increases, and their body fat, including abdominal fat, decreases + (Bryant, et al., 1984). These responses to increased dietary sodium are immediate. Part of the effect of + sodium involves regulatory processes in the brain, which are sensitive to the ratio between sodium and + calcium. Decreasing sodium, or increasing calcium, causes the body"s metabolism to shift away from + thermogenesis and accelerated respiration. +

+

+ Regulating intracellular calcium by increasing the production of carbon dioxide is probably a basic + mechanism in sodium"s protection against inflammation and excitatory cell damage and degeneration. +

+

+ Cortisol"s suppression of mitochondrial respiration is closely associated with its ability to increase + intracellular calcium. Cortisol blocks the thermogenic effects of sodium, allowing intracellular calcium to + damage cells. With aging, the tissues are more susceptible to these processes. +

+

+ The thermogenic effects of sodium can be seen in long-term studies, as well as short. A low-sodium diet + accelerates the decrease in heat production that normally occurs with aging, lowering the metabolic rate of + brown fat and body temperature, and increasing the fat content of the body, as well as the activity of the + fat synthesizing enzyme (Xavier, et al., 2003). +

+

+ Activation of heat production and increased body temperature might account for some of the GABA-like + sedative effects of increased sodium. Increasing GABA in the brain increases brown fat heat production + (Horton, et al., 1988). Activation of heat production by brown fat increases slow wave sleep (Dewasmes, et + al., 2003), the loss of which is characteristic of aging. (In adult humans, the skeletal muscles have + heat-producing functions similar to brown fat.) +

+ +

+ Now that inflammation is recognized as having a central role in the degenerative diseases, the fact that + renin, angiotensin, and aldosterone all contribute to inflammation and are increased by a sodium deficiency, + should arouse interest in exploring the therapeutic uses of sodium supplementation, and the integrated use + of all of the factors that normally support respiratory energy production, especially thyroid and + progesterone. Progesterone"s antagonism to aldosterone has been known for many years, and the synthetic + antialdosterone drugs are simply poor imitations of progesterone. +

+

+ But the drug industry is interested in selling new drugs to block the formation and action of each of the + components of the RAAS, rather than an inexpensive method (such as nutrition) to normalize the system. +

+

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+ +

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+ +

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+ +

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+

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+ +

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+

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+

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+

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+

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+ J Hypertens. 1996 Dec;14(12):1461-2. Is salt-sensitivity of blood pressure a reproducible + phenomenon-commentary. Weinberger MH. Hypertension Research Center, Indiana University School + of Medicine, Indianapolis 46202, USA. +

+

+ J Clin Invest. 1983 Apr;71(4):916-25. Stimulation of thermogenesis by carbohydrate overfeeding. + Evidence against sympathetic nervous system mediation. Welle S, Campbell RG. +

+

+ Br Med J (Clin Res Ed). 1986 Jan 18;292(6514):168-70. Treatment of hyponatraemic seizures with + intravenous 29.2% saline. Worthley LI, Thomas PD. "Five patients with severe hyponatraemia and + epileptiform seizures were given 50 ml of 29.2% saline (250 mmol) through a central venous catheter over 10 + minutes to control seizures rapidly, reduce cerebral oedema, and diminish the incidence of permanent + neuronal damage. + + The saline controlled seizures in all patients, increasing the mean serum sodium concentration by 7.4 (SD + 1.14) mmol(mEq)/l and decreasing the mean serum potassium concentration by 0.62 (0.5) mmol(mEq)/l." +

+

+ Metabolism. 2003 Aug;52(8):1072-7. Dietary sodium restriction exacerbates age-related changes in rat + adipose tissue and liver lipogenesis. Xavier AR, Gar"falo MA, Migliorini RH, Kettelhut + IC."Taken together, the data indicate that prolonged dietary sodium restriction exacerbates normal, + age-related changes in white and BAT metabolism." +

+

+ Geriatr Nurs. 1997 Mar-Apr;18(2):87-8. Is salt restriction dangerous for elders? Yen PK. +

+ + Copyright 2007. Raymond Peat, P.O. Box 5764, Eugene OR 97405. All Rights Reserved. www.RayPeat.comNot for + republication without written permission. + + diff --git a/raypeat-articles/processed/serotonin-depression-aggression.html b/raypeat-articles/processed/serotonin-depression-aggression.html new file mode 100644 index 0000000..4ad403d --- /dev/null +++ b/raypeat-articles/processed/serotonin-depression-aggression.html @@ -0,0 +1,552 @@ + + + +

+ +

+ Serotonin, depression, and aggression: The problem of brain energy +

+

+ Extremely serious mistakes about the nature of the solar system didn't matter too much until interplanetary + travel became a possibility. Extremely serious mistakes about brain "transmitters" and "receptors" didn't + matter too much until the drug industry got involved. +

+ +
+ +

+ "Three years before Prozac received approval by the US Food and Drug Administration in late 1987, the German + BGA, that country's FDA equivalent, had such serious reservations about Prozac's safety that it refused to + approve the antidepressant based on Lilly's studies showing that previously nonsuicidal patients who took + the drug had a fivefold higher rate of suicides and suicide attempts than those on older antidepressants, + and a threefold higher rate than those taking placebos." +

+

+ "Using figures on Prozac both from Lilly and independent research, however, Dr. David Healy, an expert on + the brain's serotonin system and director of the North Wales Department of Psychological Medicine at the + University of Wales, estimated that "probably 50,000 people have committed suicide on Prozac since its + launch, over and above the number who would have done so if left untreated." +

+

The Boston Globe, 2000.

+
+ +

+ Anyone who has been reading the mass media and watching television in recent decades is familiar with the + use of tryptophan as an antidepressant. Tryptophan is easily converted to serotonin and melatonin in the + body. The most popular kind of antidepressant, the "serotonin reuptake inhibitor", is said to act by + increasing the action of serotonin in the brain. Many people have read articles in popular science magazines + explaining that a deficiency of serotonin can cause depression, suicide, and aggression. Estrogen is often + said to achieve its "wonderful" effects by increasing the effects of serotonin. +

+

+ Reserpine is an ancient tranquilizer, derived from a plant used in India for centuries. It has a powerful + tranquilizing action, has been used to treat hypertension, and was found to be an antidepressant (Davies and + Shepherd, 1955). It lowers the concentration of serotonin in the brain and other tissues. Isoniazid, an + antidepressant that came into use in the 1950s, is effective, but it probably has no effect on serotonin. + When those drugs were popular, serotonin wasn"t recognized as a "neurotransmitter." It wasn"t until the + 1960s that our present set of doctrines regarding serotonin"s effects on mood and behavior came into being. +

+

+ Serotonin research is relatively new, but it rivals estrogen research for the level of incompetence and + apparent fraudulent intent that can be found in professional publications. +

+

+ This is partly because of the involvement of the drug industry, but the U.S. government also played a role + in setting a pattern of confused and perverse interpretation of serotonin physiology, by its policy of + denigrating and incriminating LSD, a powerful serotonin (approximate) antagonist, by any means possible, for + example claiming that it causes genetic damage and provokes homicidal or suicidal violence. The issue of + genetic damage was already disproved in the 1960s, but this was never publicly acknowledged by the National + Institutes of Mental Health or other government agency. The government"s irresponsible actions helped to + create the drug culture, in which health warnings about drugs were widely disregarded, because the + government had been caught in blatant fraud. In more recent years, government warnings about tryptophan + supplements have been widely dismissed, because the government has so often lied. Even when the public + health agencies try to do something right, they fail, because they have done so much wrong. +

+

+ In animal studies LSD, and other anti-serotonin agents, increase playfulness and accelerate learning, and + cause behavioral impairment only at very high doses. While reserpine was used medically for several decades, + and was eventually found to have harmful side effects, medical research in LSD was stopped before its actual + side effects could be discovered. The misrepresentations about LSD, as a powerful antiserotonin agent, + allowed a set of cultural stereotypes about serotonin to be established. Misconceptions about serotonin and + melatonin and tryptophan, which are metabolically interrelated, have persisted, and it seems that the drug + industry has exploited these mistakes to promote the "new generation" of psychoactive drugs as activators of + serotonin responses. If LSD makes people go berserk, as the government claimed, then a product to amplify + the effects of serotonin should make people sane. +

+

+ The "serotonin reuptake inhibitors" are called the "third generation" of antidepressants. The monoamine + oxidase (MAO) inhibitors, that came into use in the 1950s, are called the "first generation." When their + patents expire on a "generation" of drugs, the drug companies find reasons for claiming that the new drugs + are better. Every doctor in the country seems to know that the old MAO-inhibitors are dangerous because they + can raise blood pressure if you eat certain kinds of cheese while taking them. In fact, statistics + show that they are safer than the new generation of antidepressants. It is hardly possible for + a physician to prescribe the most appropriate drug, because the medical licensing boards are thoroughly + indoctrinated by the drug companies, to believe that the safest and most effective drugs are those whose + patents are still in force. +

+

+ While it is true that the newer antidepressants increase the actions of serotonin, it is not true that this + explains their antidepressant action. This is a culturally conditioned promotional construction. Since + different antidepressants increase, decrease, or don"t affect the actions of serotonin, a radically new kind + of theory of depression and the antidepressants is needed. Theories based on "transmitter" substances and + "receptors" are favored by the drug industry, but that kind of thinking is hardly better than the belief in + demons and their exorcism. If an herbal tea cures depression because the demon doesn"t like its smell, at + least the patient never has to abandon a remedy because a tea patent has expired. +

+

+ In the world of "neurotransmitters" and "receptors," there is ample room for the development of speculative + mechanisms of drug action. Serotonin is regulated by the rate of its synthesis and degradation, by its + uptake, storage, and release, and by its transporters, and its effects are modified by a great variety of + receptors, by the number of these receptors, and by their binding affinities and competitive binders. + "Different receptors" are defined by the effects of chemicals other than serotonin; this means that + serotonin itself hypothetically gains some of the properties of every substance that shows some binding + competition with serotonin. This complexity*note 1 has made it possible to argue that a given condition is + caused by either an excess or a deficiency of serotonin. +

+

+ The drug companies like to call some of their new products SSRI, "selective serotonin reuptake inhibitors," + meaning that they don"t indiscriminately increase all the biogenic amines, the way the old MAO inhibitors + supposedly did. Every drug does many things, each a little differently, so it"s technically true to say that + they "selectively" do this or that. But the term "antidepressant," as distinguished from "tranquilizer," + says that the drug is intended to relieve depression. Injecting serotonin never does that, but sometimes + adrenalin or dopamine does, and these "SSRI" drugs increase the activities of those other amines enough that + those changes could explain the altered mood, if it weren"t for the need to speak of a "new generation of + drugs." Injecting serotonin, or increasing its activity, can cause sedation, helplessness, or apathy, but + these drugs have that effect only some of the time. Therefore, they aren"t called tranquilizers. If they + were really selective for serotonin, they just wouldn"t be antidepressants. And chemicals that antagonize + serotonin do seem to function as antidepressants (Martin, et al., 1992). When an SSRI is used to treat + irritability and aggression, it is appropriate to call it a tranquilizer. When drugs are used empirically, + without really understanding the disease or the drug, classifications, descriptions, and names are + subjective. The serotonin situation reminds me of the history of DES: For almost twenty years, this + synthetic estrogen was marketed for the prevention of abortions; then it came out as the "morning after" + contraception/abortion pill. "If increasing serotonin isn"t the cure, then maybe decreasing serotonin will + be the cure." +

+

+ To begin to understand serotonin, it"s necessary to step back from the culture of neurotransmitters, and to + look at the larger biological picture. +

+

+ Serotonin and estrogen have many systematically interrelated functions, and women are much more likely to + suffer from depression than men are. Serotonin and histamine are increased by estrogen, and their activation + mimics the effects of estrogen. Serotonin is closely involved in mood disorders, but also in a great variety + of other problems that affect women much more frequently than men. These are probably primarily energy + disorders, relating to cellular respiration and thyroid function. Liver disease and brain disease, e.g., + Alzheimer"s disease, are both much more common in women than in men, and serotonin and estrogen strongly + affect the energetic processes in these organs. Liver disease can increase the brain"s exposure to + serotonin, ammonia, and histamine. It isn"t just a coincidence that these three amines occur together and + are neurotoxic; they are all stress-related substances, with natural roles in signaling and regulation. +

+

+ There are good reasons for thinking that serotonin contributes to the nerve damage seen in multiple + sclerosis and Alzheimer"s disease. +

+

+ The high incidence of multiple sclerosis in women, and its onset during their reproductive years, is well + known. The number of brain lesions is associated with the ratio of estrogen to progesterone. Estrogen + activates mast cells to release histamine and serotonin, and activated mast cells can produce brain edema + and demyelination. Blood clots have been microscopically associated with brain lesions like those in + multiple sclerosis, and the platelets in clots release neurotoxic serotonin. +

+

+ In Parkinson"s disease, the benefits seen from increasing the concentration of dopamine could result from + dopamine"s antagonism to serotonin; anti-serotonin drugs can alleviate the symptoms, and 5-hydroxytryptophan + can worsen the symptoms (Chase, et al., 1976). Other movement disorders, including akathisia and chorea, can + be produced by serotonin. In autism, repetitive motions are a common symptom, and serotonin is high in the + blood serum and platelets of autistic children and their relatives. Irritable bowel syndrome, another kind + of "movement disorder," can be treated effectively with anti-serotonin agents. This syndrome is very common + in women, with premenstrual exacerbations, when estrogen is highest. One of the side effects of oral + contraceptives is chorea, uncontrollable dancing movements. Some research has found increased serotonin in + people with Huntington"s chorea (Kish, et al., 1987), and positive results with bromocriptine have been + reported (Agnoli, et al., 1977). +

+

+ The neurosteroid, allopregnanolone, for which progesterone is the precursor, facilitates the inhibitory + action of GABA, which is known to be deficient in some disorders of mood and movement. This suggests that + progesterone will be therapeutic in the movement disorders, as it is in various mood problems. Progesterone + has some specific antiserotonin actions (e.g., Wu, et al., 2000). +

+

+ The "serotonin reuptake inhibitors" "are presumed" to have the same effect on the brain that they have on + blood platelets. They inhibit the ability of platelets to retain and concentrate serotonin, allowing it to + stay in the plasma. This uptake-inhibited condition is a model of the platelet behavior seen in multiple + sclerosis and Alzheimer"s disease. +

+

+ Serotonin and its derivative, melatonin, are both involved in the biology of torpor and hibernation. + Serotonin inhibits mitochondrial respiration. Excitoxic death of nerve cells involves both the limitation of + energy production, and increased cellular activation. Serotonin has both of these actions. +

+

+ In hibernating animals, the stress of a declining food supply causes increased serotonin production. In + humans and animals that don"t hibernate, the stress of winter causes very similar changes. Serotonin lowers + temperature by decreasing the metabolic rate. Tryptophan and melatonin are also hypothermic. In the winter, + more thyroid is needed to maintain a normal rate of metabolism. +

+

+ Increased serotonin interferes with the consolidation of learning. Hypothermia has a similar effect. Since + estrogen increases serotonergia, and decreases body temperature, these effects help to explain the + long-observed interference of estrogen with learning. +

+

+ Although ammonia, produced by fatigue or liver inefficiency, creates torpor, it can also cause convulsions. + It synergizes with serotonin, and both of these promote excitotoxicity. +

+

+ Serotonin"s other names include thrombotonin, thrombocytin, enteramine, and 5-HT, its chemical name + (5-hydroxytryptamine). These historical names derive from its role in the intestine and in blood vessels. In + 1951, it was discovered that enteramine and thrombotonin were a single substance, and its involvement in + circulatory disease, especially hypertension and vascular spasms, was the focus of research. (The increase + in the number of "cardiovascular events" recently seen in the study of women using estrogen is what might be + expected from something which increases serotonin dominance.) It causes vasoconstriction and vasospasm, and + promotes clotting, when it"s released from platelets. Especially when it is released from mast cells, it is + considered to be an inflammatory mediator, along with histamine. Edema, bronchoconstriction, + immunosuppression, and joint swelling are produced by the release of serotonin from platelets or other + cells. As inflammatory mediators, serotonin and histamine are directly involved in asthma, hives, + gastrointestinal damage from alcohol, nerve cell damage, edema, and shock. +

+

+ The broadly protective effects of antihistamine drugs have been energetically exploited by the drug industry + for fifty years. Why haven"t antiserotonin drugs been similarly emphasized? +

+

+ Research on LSD and its derivatives led to drugs such as bromocriptine, which oppose the effects of + histamine and estrogen. Some of bromocriptine"s effects are clearly antagonistic to serotonin, though + bromocriptine is usually called a "dopamine agonist"; dopamine is pretty generally a serotonin antagonist. + Methysergide, a related drug with antiserotonin activity, is effective in protecting the brain from the + effects of strokes. But there is a general disinclination to understand the broad biological meaning of + these effects. +

+

+ I think the corrupt campaign against LSD played a large role in this: If the therapeutic value of LSD and + related drugs (e.g., methysergide) with expired patents,*note2 used as antiserotonin agents, became widely + known, the existing system of power and profit would be threatened. The war on drugs has always had its + ulterior motives,including justifying domestic and foreign interventions in issues that have nothing to do + with drugs. And in the case of the serotonin/antiserotonin mythology, this "war" has been rewarding to the + drug industry--Lilly makes over $2 billion annually on Prozac. Each suicide caused by Prozac would appear to + be balanced by several hundred thousand dollars earned by the corporation. If the war on drugs were serious, + this would be a good place to start. And in weighing what corporate punishments might be appropriate, this + corporation"s financial support for universal capital punishment should be taken into account. Many + experiments have shown that estrogen is very important for aggressive behavior in animals, and estrogen + promotes serotonin"s actions. Some research shows that increased serotonin is associated with certain types + of increased aggressiveness, and antiserotonin agents decrease aggresiveness (Ieni, et al., 1985; McMillen, + et al., 1987) but the clearest research has to do with the crucial role of serotonin in learned + helplessness. Learned helplessness is a biological condition that is created by inescapable stress. In this + state, animals that would normally swim for hours will stop swimming after a few minutes and allow + themselves to drown. They simply don"t have enough mental or physical energy to overcome challenges. +

+

+ In learned helplessness, the level of serotonin is high, and an excess of serotonin helps to create the + state of learned helplessness. +

+

+ Serotonin activates glycolysis, forming lactic acid. Excess lactic acid tends to decrease efficient energy + production by interfering with mitochondrial respiration. +

+

+ Heart failure, hypertension, muscle hyperalgesia (Babenko, et al., 2000), some panic reactions, and other + maladaptive biological events associated with problems of energy metabolism, are promoted by excessive + serotonin. +

+

+ Autistic children and their relatives have high concentrations of serotonin in their serum and platelets. + Members of a family tend to eat the same foods and to share other environmental conditions. Prenatal + hypothyroidism and various kinds of imprinting, including hyperestrogenism, could account for this. Some + studies have reported that thyroid supplements help autistic children, and anti-serotonin drugs have caused + improvement in both children and adults. +

+

+ Serotonin tends to cause hypoglycemia, and hypoglycemia inhibits the conversion of thyroxine into the active + T3 hormone. Hypoglycemia and hypothyroidism increase noradrenaline, and autistic people have been found to + have more noradrenaline than normal. These changes, along with the general hypometabolism caused by excess + serotonin, seem to justify the use of a thyroid supplement in autism and other serotonin-excess syndromes. +

+

+ Overdose with the serotonin reuptake inhibitors, or with 5-hydroxytryptophan, which has effects similar to + serotonin, can cause the sometimes fatal "serotonin syndrome." Symptoms can include tremors, altered + consciousness, poor coordination, cardiovascular disturbances, and seizures. Treatment with anti-serotonin + drugs can alleviate the symptoms and usually can prevent death. +

+

+ The serotonin syndrome has been reported in users of St. John"s wort as an antidepressant. Since the other + large neutral amino acids compete with tryptophan for entry into cells, the branched chain amino acids have + some anti-serotonin activity, and this could be a justification for their use by athletes, since tryptophan + and serotonin decrease glycogen stores and reduce endurance. +

+

+ The only amino acid that has ever been found to be carcinogenic is tryptophan. Its ability to mimic estrogen + in promoting the release of prolactin is probably responsible. +

+

+ A large carbohydrate meal increases the ratio of tryptophan to the competing amino acids, and it has been + proposed that this can shift the body"s balance toward increased serotonin. In an animal study, + bromocriptine, which shifts the balance away from serotonin, reduced obesity and insulin and free fatty + acids, and improved glucose tolerance. +

+

+ All of these observations are easiest to understand in terms of the suppression of cellular energy. + Serotonin, like estrogen, lowers cellular ATP and interferes with oxidative metabolism. +

+

+ Serotonin, like histamine, has its proper physiological functions, but it is a mediator of stress that has + to be systematically balanced by the systems that support high energy respiratory metabolism. The use of + supplements of tryptophan, hydroxytryptophan, or of the serotonin promoting antidepressant drugs, seems to + be biologically inappropriate. +

+

+ Many of the symptoms produced by excess serotonin are also the symptoms of hypothyroidism. Thyroid, + progesterone, and high quality protein nutrition are central to protection against the serotonin syndromes. + (Progesterone, like LSD, can inhibit the firing of serotonergic nerves, but an overdose, unlike LSD, never + produces hallucinations.) +

+

+ One of the many actions of the "SSRI" (such as fluoxetine, Prozac), which aren"t related to their effect on + serotonin, is to increase the concentration of allopregnanolone in the brain, imitating the action of + increased progesterone. Following this discovery, Lilly got Prozac approved as a treatment for premenstrual + syndrome. Since the production of allopregnanolone and progesterone depends on the availability of + pregnenolone and cholesterol, a low cholesterol level would be one of the factors making this an + inappropriate way to treat PMS. +

+

+ If we think biologically, starting with the role of serotonin as a damage-induced inflammatory mediator, we + can speculate that an infinite number of irritating substances will be "serotonin reuptake inhibitors." The + particular history of the "third generation antidepressants" is one that should disturb our tranquility. +

+ +

SOME NOTES AND SOURCES

*Note 1: I don"t want to imply that the receptor theory is wrong + just because it allows for the introduction of innumerable experimental artifacts; it is primarily wrong because + it is tied to the profoundly irrelevant "membrane theory" of cell regulation.*Note 2: Preparation for Lysergic + Acid Amides: United States Patent Office 2,736,728 Patented February 28, 1956 Richard P. Pioch, Indianapolis, + Indiana, assignor, to Eli Lilly and Co., Indianapolis, Indiana, a corporation of Indiana. No drawing. + Application December 6, 1954, Serial No. 473,443. 10 claims. (Cl. 260-285.5)From the PDR on Prozac: "Pharmacodynamics: The antidepressant and antiobsessive-compulsive action of fluoxetine is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically + relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin + into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake + inhibitor of serotonin than of norepinephrine."The Lancet 269 (1955): 117"20. "Reserpine in the + Treatment of Anxious and Depressed Patients," Davies DL and Shepherd M.Gen Pharmacol 1994 + Oct;25(6):1257-1262. + Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of plasma + hemoglobin; the protective action of calmodulin antagonists. Koren-Schwartzer N, Chen-Zion M, + Ben-Porat H, Beitner R Department of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. 1. Injection + of serotonin (5-hydroxytryptamine) to rats, induced a dramatic fall in brain ATP level, accompanied by an + increase in P(i). Concomitant to these changes, the activity of cytosolic phosphofructokinase, the + rate-limiting enzyme of glycolysis, was significantly enhanced. Stimulation of anaerobic glycolysis was also + reflected by a marked increase in lactate content in brain. 2. Brain glucose 1,6-bisphosphate level + was decreased, whereas fructose 2,6-bisphosphate was unaffected by serotonin. 3. All these serotonin-induced + changes in brain, which are characteristic for cerebral ischemia, were prevented by treatment with the + calmodulin (CaM) antagonists, trifluoperazine or thioridazine. 4. Injection of serotonin also induced a marked + elevation of plasma hemoglobin, reflecting lysed erythrocytes, which was also prevented by treatment with the + CaM antagonists. 5. The present results suggest that CaM antagonists may be effective drugs in treatment of many + pathological conditions and diseases in which plasma serotonin levels are known to increase.J Neural Transm + 1998;105(8-9):975-86. Role of tryptophan in the elevated serotonin-turnover in hepatic + encephalopathy. Herneth AM, Steindl P, Ferenci P, Roth E, Hortnagl H Department of Internal + Medicine IV, Gastroenterology and Hepatology, University of Vienna, Austria. The increase of the brain levels of + 5-hydroxyindoleacetic acid (5-HIAA) in hepatic encephalopathy (HE) suggests an increased turnover of serotonin + (5-HT). To study the role of tryptophan on the increased brain 5-HT metabolism in HE, we attempted to monitor + brain levels of tryptophan in rats with thioacetamide-induced acute liver failure by intravenous infusion of + branched-chain amino acids (BCAA). The effect of this treatment on 5-HT synthesis and metabolism was + investigated in five brain areas. BCAA-infusions (1 and 2 gm/kg/24 h) increased the ratio BCAA/aromatic amino + acids in plasma two- and fourfold, respectively, and lowered both plasma and brain levels of tryptophan. At the + higher BCAA-dose all parameters suggesting an altered brain 5-HT metabolism (increased brain levels of 5-HT and + 5-HIAA, increased 5-HIAA/5-HT ratio) were almost completely normalized. These results provide further evidence + for the role of tryptophan in the elevation of brain 5-HT metabolism and for a potential role of BCAA in the + treatment of HE.Tugai VA; Kurs'kii MD; Fedoriv OM. [Effect of serotonin on Ca2+ transport in + mitochondria conjugated with the respiratory chain]. Ukrainskii Biokhimicheskii Zhurnal, 1973 + Jul-Aug, 45(4):408-12.Kurskii MD; Tugai VA; Fedoriv AN. + [Effect of serotonin and calcium on separate components of respiratory chain of mitochondria in some rabbit + tissues]. Ukrainskii Biokhimicheskii Zhurnal, 1970, 42(5):584-8.Watanabe Y; Shibata S; Kobayashi B. + Serotonin-induced swelling of rat liver mitochondria. Endocrinologia Japonica, 1969 Feb, + 16(1):133-47.Mahler DJ; Humoller FL. The influence of serotonin on oxidative metabolism of brain + mitochondria. Proceedings of the Society for Experimental Biology and Medicine, 1968 Apr, + 127(4):1074-9.Eur J Pharmacol 1994 Aug 11;261(1-2):25-32. The effect of alpha 2-adrenoceptor antagonists + in isolated globally ischemic rat hearts. Sargent CA, Dzwonczyk S, Grover G.J. "The alpha + 2-adrenoceptor antagonist, yohimbine, has been reported to protect hypoxic myocardium. Yohimbine has several + other activities, including 5-HT receptor antagonism, at the concentrations at which protection was found." + "Pretreatment with yohimbine (1-10 microM) caused a concentration-dependent increase in reperfusion left + ventricular developed pressure and a reduction in end diastolic pressure and lactate dehydrogenase release. The + structurally similar compound rauwolscine (10 microM) also protected the ischemic myocardium. In contrast, + idozoxan (0.3-10 microM) or tolazoline (10 microM) had no protective effects. The + cardioprotective effects of yohimbine were partially reversed by 30 microM 5-HT. These results indicate that + the mechanism for the cardioprotective activity of yohimbine may involve 5-HT receptor antagonistic + activity." + Zubovskaia AM. [Effect of serotonin on some pathways of oxidative metabolism in the + mitochondria of rabbit heart muscle]. Voprosy Meditsinskoi Khimii, 1968 Mar-Apr, + 14(2):152-7.Warashina Y. [On the effect of serotonin on phosphorylation of rat liver + mitochondria]. Hoppe-Seylers Zeitschrift fur Physiologische Chemie, 1967 Feb, 348(2):139-48.Eur + Neuropsychopharmacol 1997 Oct;7 Suppl 3:S323-S328. Prevention of stress-induced morphological and + cognitive consequences. McEwen BS, Conrad CD, Kuroda Y, Frankfurt M, Magarinos AM, McKittrick C, + Laboratory of Neuroendocrinology, Rockefeller University, New York, NY 10021, USA. Atrophy and dysfunction of + the human hippocampus is a feature of aging in some individuals, and this dysfunction predicts later dementia. + There is reason to believe that adrenal glucocorticoids may contribute to these changes, since the elevations of + glucocorticoids in Cushing's syndrome and during normal aging are associated with atrophy of the entire + hippocampal formation in humans and are linked to deficits in short-term verbal memory. We have developed a + model of stress-induced atrophy of the hippocampus of rats at the cellular level, and we have been investigating + underlying mechanisms in search of agents that will block the atrophy. Repeated restraint stress in rats for 3 + weeks causes changes in the hippocampal formation that include suppression of 5-HT1A receptor binding and + atrophy of dendrites of CA3 pyramidal neurons, as well as impairment of initial learning of a radial arm maze + task. Because serotonin is released by stressors and may play a role in the actions of stress on nerve + cells, we investigated the actions of agents that facilitate or inhibit serotonin reuptake. + Tianeptine is known to enhance serotonin uptake, and we compared it with fluoxetine, an inhibitor of 5-HT + reuptake, as well as with desipramine. Tianeptine treatment (10 mg/kg/day) prevented the stress-induced atrophy + of dendrites of CA3 pycamidal neurons, whereas neither fluoxetine (10 mg/kg/day) nor desipramine (10 mg/kg/day) + had any effect. Tianeptine treatment also prevented the stress-induced impairment of radial maze learning. + Because corticosterone- and stress-induced atrophy of CA3 dendrites is also blocked by phenytoin, an + inhibitor of excitatory amino acid release and actions, these results suggest that serotonin released by + stress or corticosterone may interact pre- or post-synaptically with glutamate released by stress or + corticosterone, and that the final common path may involve interactive effects between serotonin and + glutamate receptors on the dendrites of CA3 neurons innervated by mossy fibers from the dentate gyrus. We + discuss the implications of these findings for treating cognitive impairments and the risk for dementia in + the elderly.J Mol Cell Cardiol 1985 Nov;17(11):1055-63. Digitoxin therapy partially + restores cardiac catecholamine and brain serotonin metabolism in congestive heart failure. Sole MJ, + Benedict CR, Versteeg DH, de Kloet ER. The effect of therapeutic doses of digitalis in modifying neural activity + has been the subject of considerable controversy. In earlier studies we reported an increase both in + serotonergic activity in the posterior hypothalamus and pons-medulla and in cardiac sympathetic tone in the + failing cardiomyopathic hamster. In this study we examine the effects of doses of digitoxin, known + to be therapeutic for hamster heart failure, on monoamine neurotransmitter metabolism in the brain and heart + during the cardiomyopathy. Both digitoxin and ASI-222, a polar amino-glycoside which does not cross the + blood-brain barrier, given either acutely (6 mg/kg ip) or chronically (2 mg/kg/day ip for 10 days), + normalized the failure-induced increase in serotonin turnover in the pons-medulla but had no effect on the + changes in the posterior hypothalamus. Digitoxin therapy also reduced cardiac and adrenal sympathetic activity + partially restoring cardiac catecholamine stores. In order to more clearly define the pathways involved we + measured serotonin (microgram/g protein) in 18 brain nuclei after 10 days of digitoxin or vehicle treatment. + Heart failure was associated with an increase in serotonin in five nuclei: the mammillary bodies, + ventromedial, periventricular and paraventricular nuclei of the hypothalamus, and the centralis superior + nucleus of the raphe. Digitoxin therapy completely normalized the changes in the centralis superior + and ventromedialis nuclei; neither congestive heart failure nor digitoxin affected serotonin levels in other + nuclei. We conclude that there is an increase in activity in specific brain serotonergic nuclei in congestive + heart failure. Digitalis reduces cardiac sympathetic tone and restores the changes in two of these nuclei: the + ventromedial and the centralis superior.+2Brain Res 2000 Jan 24;853(2):275-81. Duration and distribution + of experimental muscle hyperalgesia in humans following combined infusions of serotonin and + bradykinin. Babenko V, Svensson P, Graven-Nielsen T, Drewes AM, Jensen TS, Arendt-Nielsen L.Eur J + Pharmacol 1992 Feb 25;212(1):73-8. 5-HT3 receptor antagonists reverse helpless behaviour in + rats. Martin P, Gozlan H, Puech AJ Departement de Pharmacologie, Faculte de Medecine + Pitie-Salpetriere, Paris, France. The effects of the 5-HT3 receptor antagonists, zacopride, ondansetron and ICS + 205-930, were investigated in an animal model of depression, the learned helplessness test. Rats previously + subjected to a session of 60 inescapable foot-shocks exhibited a deficit of escape performance in three + subsequent shuttle-box sessions. The 5-HT3 receptor antagonists administered i.p. twice daily on a chronic + schedule (zacopride 0.03-2 mg/kg per day; ondansetron and ICS 205-930: 0.125-2 mg/kg per day) reduced the number + of escape failures at low to moderate daily doses. This effect was not observed with the highest dose(s) of + zacopride, ondansetron and ICS 205-930 tested. These results indicate that 5-HT3 antagonists may have effects + like those of conventional antidepressants in rats.Neuropharmacology 1992 Apr;31(4):323-30. Presynaptic + serotonin mechanisms in rats subjected to inescapable shock. Edwards E, Kornrich W, Houtten PV, + Henn FA. "After exposure to uncontrollable shock training, two distinct groups of rats can be defined in terms + of their performance in learning to escape from a controllable stress. Learned helpless rats do not learn to + terminate the controllable stress, whereas non-learned helpless rats learn this response as readily as naive + control rats do." "These results implicate presynaptic serotonin mechanisms in the behavioral deficit caused by + uncontrollable shock. In addition, a limbic-hypothalamic pathway may serve as a control center for the + behavioral response to stress."Neurochem Int 1992 Jul;21(1):29-35. + In vitro neurotransmitter release in an animal model of depression. Edwards E, Kornrich W, van + Houtten P, Henn FA. "Sprague-Dawley rats exposed to uncontrollable shock can be separated by a subsequent shock + escape test into two groups: a "helpless" (LH) group which demonstrates a deficit in escape behavior, and a + "nonlearned helpless" (NLH) group which shows no escape deficit and acquires the escape response as readily as + naive control rats (NC) do." "The major finding concerned a significant increase in endogenous and + K(+)-stimulated serotonin (5-HT) release in the hippocampal slices of LH rats. There were no apparent + differences in acetylcholine, dopamine and noradrenaline release in the hippocampus of LH rats as compared to + NLH and NC rats. These results add further support to previous studies in our laboratory which implicate + presynaptic 5-HT mechanisms in the behavioral deficit caused by uncontrollable shock."Psychiatry Res 1994 + Jun;52(3):285-93. In vivo serotonin release and learned helplessness. Petty F, Kramer G, Wilson + L, Jordan S Mental Health Clinic, Dallas Veterans Affairs Medical Center, TX. Learned helplessness, a behavioral + depression caused by exposure to inescapable stress, is considered to be an animal model of human depressive + disorder. Like human depression, learned helplessness has been associated with a defect in serotonergic + function, but the nature of this relationship is not entirely clear. We have used in vivo microdialysis brain + perfusion to measure serotonin (5-hydroxytryptamine, 5HT) in extracellular space of medial frontal cortex in + conscious, freely moving rats. Basal 5HT levels in rats perfused before exposure to tail-shock stress did not + themselves correlate with subsequent learned helplessness behavior. However, 5HT release after stress showed a + significant increase with helpless behavior. These data support the hypothesis that a cortical + serotonergic excess is causally related to the development of learned helplessness.Pharmacol + Biochem Behav 1994 Jul;48(3):671-6. Does learned helplessness induction by haloperidol involve serotonin + mediation? Petty F, Kramer G, Moeller M Veterans Affairs Medical Center, Dallas 75216. Learned + helplessness (LH) is a behavioral depression following inescapable stress. Helpless behavior was induced in + naive rats by the dopamine D2 receptor blocker haloperidol (HDL) in a dose-dependent manner, with the greatest + effects seen at 20 mg/kg (IP). Rats were tested 24 h after injection. Haloperidol (IP) increased release of + serotonin (5-HT) in medial prefrontal cortex (MPC) as measured by in vivo microdialysis. Perfusion of HDL + through the probe in MPC caused increased cortical 5-HT release, as did perfusion of both dopamine and the + dopamine agonist apomorphine. Our previous work found that increased 5-HT release in MPC correlates with the + development of LH. The present work suggests that increased DA release in MPC, known to occur with both + inescapable stress and with HDL, may play a necessary but not sufficient role in the development of LH. Also, + this suggests that increased DA activity in MPC leads to increased 5-HT release in MPC and to subsequent + behavioral depression.Stroke 1991 Nov;22(11):1448-51. Platelet secretory products may contribute to + neuronal injury. Joseph R, Tsering C, Grunfeld S, Welch KM Department of Neurology, Henry Ford + Hospital and Health Sciences Center, Detroit, MI 48202. BACKGROUND: We do not fully understand the mechanisms + for neuronal damage following cerebral arterial occlusion by a thrombus that consists mainly of platelets. The + view that certain endogenous substances, such as glutamate, may also contribute to neuronal injury is now + reasonably well established. Blood platelets are known to contain and secrete a number of substances that have + been associated with neuronal dysfunction. Therefore, we hypothesize that a high concentration (approximately + several thousand-fold higher than in plasma, in our estimation) of locally released platelet secretory products + derived from the causative thrombus may contribute to neuronal injury and promote reactive gliosis. SUMMARY OF + COMMENT: We have recently been able to report some direct support for this concept. When organotypic spinal cord + cultures were exposed to platelet and platelet products, a significant reduction in the number and the size of + the surviving neurons occurred in comparison with those in controls. We further observed that serotonin, a major + platelet product, has neurotoxic properties. There may be other platelet components with similar effect. + CONCLUSIONS: The hypothesis of platelet-mediated neurotoxicity gains some support from these recent in vitro + findings. The concept could provide a new area of research in stroke, both at the clinical and basic + levels.J. Clin Psychopharmacol 1991 Aug; 11(4):277-9. + Disseminated intravascular coagulation and acute myoglobinuric renal failure: a consequence of the + serotonergic syndrome. Miller F, Friedman R, Tanenbaum J, Griffin A. LetterChronobiol Int 2000 + Mar;17(2):155-72. Association of the antidiabetic effects of bromocriptine with a shift in the daily + rhythm of monoamine metabolism within the suprachiasmatic nuclei of the Syrian hamster. Luo S, Luo + J, Cincotta AH. + "Bromocriptine, a dopamine D2 agonist, inhibits seasonal fattening and improves seasonal insulin resistance + in Syrian hamsters." + "Compared with control values, bromocriptine treatment significantly reduced weight gain (14.9 vs. -2.9 + g, p < .01) and the areas under the GTT glucose and insulin curves by 29% and 48%, respectively (p < .05). + Basal plasma insulin concentration was markedly reduced throughout the day in bromocriptine-treated animals + without influencing plasma glucose levels. Bromocriptine reduced the daily peak in FFA by 26% during the late + light span (p < .05)." "Thus, bromocriptine-induced resetting of daily patterns of SCN neurotransmitter + metabolism is associated with the effects of bromocriptine on attenuation of the obese insulin-resistant and + glucose-intolerant condition. A large body of corroborating evidence suggests that such bromocriptine-induced + changes in SCN monoamine metabolism may be functional in its effects on metabolism."Eur J Pharmacol 1982 Jul + 30;81(4):569-76. Actions of serotonin antagonists on dog coronary artery. Brazenor RM, Angus + JA. Serotonin released from platelets may initiate coronary vasospasm in patients with variant angina. If this + hypothesis is correct, serotonin antagonists without constrictor activity may be useful in this form of angina. + We have investigated drugs classified as serotonin antagonists on dog circumflex coronary artery ring segments + in vitro. Ergotamine, dihydroergotamine, + bromocriptine, lisuride, ergometrine, ketanserin, trazodone, cyproheptadine and pizotifen caused + non-competitive antagonism of serotonin concentration-response curves. In addition, ketanserin, + trazodone, bromocriptine and pizotifen inhibited noradrenaline responses in concentrations similar to those + required for serotonin antagonism. All drugs with the exception of ketanserin, cyproheptadine and pizotifen + showed some degree of intrinsic constrictor activity. Methysergide antagonized responses to serotonin + competitively but also constricted the coronary artery. The lack of a silent competitive serotonin antagonist + precludes a definite characterization of coronary serotonin receptors at this time. However, the profile of + activity observed for the antagonist drugs in the coronary artery differs from that seen in other vascular + tissues. Of the drugs tested, ketanserin may be the most useful in variant angina since it is a potent 5HT + antagonist, lacks agonist activity and has alpha-adrenoceptor blocking activity.Eur J Pharmacol 1985 May + 8;111(2):211-20. Maternal aggression in mice: effects of treatments with PCPA, 5-HTP and 5-HT receptor + antagonists. Ieni JR, Thurmond JB. Drug treatments which influence brain serotonergic systems were + administered to lactating female mice during the early postpartum period, and their effects on aggressive + behavior, locomotor activity and brain monoamines were examined. P-chlorophenylalanine (200 and 400 mg/kg) and + 5-hydroxytryptophan (100 mg/kg) inhibited fighting behavior of postpartum mice toward unfamiliar male intruder + mice. These drug-treated postpartum females showed increased latencies to attack male intruders and also reduced + frequencies of attack. In addition, postpartum mice treated with the serotonin receptor antagonists, + mianserin (2 and 4 mg/kg), methysergide (4 mg/kg) and methiothepin (0.25 and 0.5 mg/kg), displayed + significantly less aggressive behavior than control mice, as measured by reduced number of attacks. + Whole brain monoamine and monoamine metabolite levels were measured after drug treatments. The behavioral + results are discussed in terms of drug-induced changes in brain chemistry and indicate a + possible role for serotonin in the mediation of maternal aggressive behavior of mice. + Naunyn Schmiedebergs Arch Pharmacol 1987 Apr;335(4):454-64. + Effects of gepirone, an aryl-piperazine anxiolytic drug, on aggressive behavior and brain monoaminergic + neurotransmission. McMillen BA, Scott SM, Williams HL, Sanghera MK. + +
+ In support of this conclusion was the observed potentiation of antiaggressive effects by blocking 5HT + receptors wit small doses of methiothepin or methysergide, which would exacerbate the decreased + release of 5HT caused by gepirone. These results are in harmony with reports that decreased serotonergic + activity has anxiolytic-like effects in animal models of anxiety.Farmakol Toksikol 1975 Mar-Apr;38(2):148-51. + [Participation of the serotonin-reactive brain structure in certain forms of behavior in golden + hamsters]. + Popova NK, Bertogaeva VD. + A viviacious play of young hamsters is shown to be accompanied by a drop of the serotonin level in the brain + stem and the subsequent slumber - by its rise, while the corticosteroids content of the peripheral + blood with the playful behavior experiences no changes. Iprazid and 5-oxytryptophan inhibit the playful + activity, while dioxyphenylalanina (DOPA) does not influence it. A similar depression of the + serotonin level in the brain stem was also noted in an aggressive behavior and stress conditions arising when + adult male-hamsters are grouped together. A conclusion is drawn to the effect that changes in the content of + serotonin in the brain stem are not associated with the emotional colouration of the condition, but + rather reflect the transition from the somnolence to a highly active behavior.Biol Psychiatry 1985 + Sep;20(9):1023-5 Triiodothyronine-induced reversal of learned helplessness in rats. Martin P, + Brochet D, Soubrie P, Simon P.

+ © Ray Peat Ph.D. 2012. All Rights Reserved. www.RayPeat.com +

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Serotonin: Effects in disease, aging and inflammation

+

+ Interpreting medical publications requires some skills that aren't needed for understanding more strictly + scientific reports, because medical writing often takes into account the fact that physicians spend most of + their time interacting with the public, rather than studying. The public's understanding of medicine is + shaped by "public relations," by the introduction of words and concepts that frame the argument. (The + linguist George Lakoff summarized the essence of public relations by observing that people reject facts that + are outside their view of reality, their mental framework.) Television and public schools now frame the + worldview of the affluent cultures, according to the needs of the ruling powers. Long before specific + prescription drugs could be advertised directly to consumers, the medical and pharmaceutical industries were + creating a favorable frame for their products.Many years ago, public relations experts used expensive + opinion polls to judge the effectiveness of their efforts, but now there is a convenient way to see how the + general public is thinking: Wikipedia, the internet encyclopedia. The success of corporate advertising can + be seen in their recent article on serotonin, which says "It is a well-known contributor to feelings of + well-being; therefore it is also known as a 'happiness hormone' despite not being a hormone."The culture + that has happy and unhappy hormones was a culture in which each hormone had a receptor, a substance in a + cell which, when its ligand was bound to it, made the cell do something. Although that culture still has + influence in the 21st century, discoveries made between 1940 and 1970 showed that those mechanical ideas of + receptors didn't reflect biological reality. Albert Szent-Gyorgi and the Pullmans showed that the electronic + qualities of molecules determined their functions, and Szent-Gyorgyi showed that the state of the cell, + tissue, and organism governed the effect of hormones and drugs. In the 1960s, substances with very different + biological effects, such as acetylcholine and adrenaline, were shown to be selectively bound to the same + cellular site in some cells. It was primarily the drug industry that created and sustained the specific + receptor doctrine. That doctrine suited the recognition of their public relations- marketing experts, that + successful advertising had to be directed at the sixth-grade educational level. The ideas of bioelectronics + and context-sensitive molecules, like morphogenetic fields, were just too complicated to sell well.Although + metaphorical thinking can be creative and productive, metaphors mustn't be taken literally. The + identification of multiple types of receptor for a given natural substance involves the use of different + substances as metaphors or similes for the natural substance. That type of pharmacology is slowly being + replaced by an attempt to understand state-dependent sensitivities. The energetic state of a cell, and of + the whole organism, determines the meaning of events and conditions, such as the presence of the "regulatory + substances."The receptor culture can be tentatively disregarded when thinking about the history of + serotonin. In the 1930s Vittorio Erspamer identified an amine in the intestine, that caused the intestine to + contract. Then a group in England extracted an amine from serum that caused blood vessels to contract, and + identified its chemical nature. Later, Erspamer showed that the intestinal amine and the vascular amine were + chemically the same. The English group who had identified the substance by extracting tons of beef blood, + wanted to find sensitive ways to assay it for further studies, and in 1951 they gave a sample to a + pharmacologist, John Gaddum, who tested its effects on tissues including blood vessels and rat + uteruses.Gaddum tested the serotonin in combination with a variety of other drugs, including ergot + derivatives, that he knew acted on smooth muscles, and very soon observed that LSD blocked the effects of + serotonin. Since he knew that LSD produced mental effects (Sandoz had distributed samples of it to + researchers in 1947), he reasoned that the brain might also contain serotonin, and by 1952 was able to + demonstrate that it does contain small amounts of it. A couple of years later he suggested "that the mental + effects of lysergic acid diethylamide are due to interference with the normal action of this HT [5- + hydroxytryptamine, serotonin]." At the Rockefeller Institute in New York, Woolley and Shaw also saw the + antagonistic effects on smooth muscle, and drew similar conclusions about the brain. Erspamer (Renic. sc. + farmital. 1, 1, 1954) showed that LSD was a highly effective antagonist against the antidiuresis caused by + serotonin (enteramine).Around the same time, in the early 1950s, several people recognized that the symptoms + produced by administering an excess of serotonin were similar to those experienced by people with intestinal + tumors called argentaffinomas or carcinoid tumors, which are usually in the small intestine or appendix. The + normal intestine contains about 95% of the serotonin in the body (and the brain normally contains only about + 1%), and in the normal person only about 1% of the dietary tryptophan is converted to serotonin. But in an + advanced case of carcinoid, 60% of the tryptophan can be turned into serotonin. Especially if the tumor has + invaded the liver, the serotonin won't be destroyed by the liver in the usual way, and will circulate in the + bloodstream at high levels, producing symptoms of flushing, sweating (sometimes dark-colored), diarrhea + (serotonin stimulates small intestine smooth muscle, but inhibits the large [Bennett & Whitney, 1966]), + nausea, anxiety, reduced urination, muscle and joint pains, and, in late stages, very often cardiovascular + disease (especially inflammation, fibroma and calcification of the valves in the right side of the heart) + and aggressive behavior (Russo, et al., 2004) and psychosis.Testing Gaddum's idea of antagonism between LSD + and serotonin in humans, Montanari and Tonini found that intramuscular injections of serotonin antagonized + the psychological effects of LSD. Other drugs, especially other ergot derivatives, were more successful than + LSD in blocking the effects of serotonin (Dubach and Gsell, 1962). There have been suggestions that + pregnancy hormones could control serotonin excess (McCullough and Myers, 1965). Since estrogen promotes + serotonin, progesterone is likely to be the protective factor (Donner & Handa, 2009; Hiroi, et al., + 2006; Berman, et al., 2006; Bethea, et al., 2000).More recently (Spigset, et al., 2004), it was found that + LSD binding to a presumed serotonin receptor was low in carcinoid patients, supporting the idea of + antagonism between the substances, but in the older studies symptoms, rather than competition for binding to + certain proteins, were the focus of attention. The effects produced by injections and oral doses of + synthetic serotonin, and of substances that block the synthesis of serotonin, were studied in both animals + and humans. When a symptom such as clotting, flushing, or diarrhea is produced by serotonin itself, or + prevented by a blocker of serotonin synthesis, "receptors" aren't an issue.Aldous Huxley was one of the + first people to think about the general biological meaning of drugs such as LSD. Referring to the ideas of + Henri Bergson and William Blake, he suggested that the brain usually acts as a filter, or "reducing valve," + to make us disregard most of the information we are receiving through our senses, and that the psychedelic + drugs temporarily remove the filter, or open the sensory reducing valve. Bergson had suggested that the + filter was a practical measure needed to allow us to focus on practical survival needs; Blake had suggested + that the doors of perception were kept closed for cultural reasons.Some recent reviews have discussed the + evidence supporting the serotonin system as primarily inhibitory and protective (Anne Frederickson, 1998, + Neil Goodman, 2002). Goodman describes the serotonergic system as one of our "diffuse neuroregulatory + systems," and suggests that drugs such as LSD weaken its inhibitory, filtering effect. (Jacobs, 1983, 1987: + by changes in the effects of serotonin in the brain, produced by things that affect its synthesis, release, + catabolism, or receptor action.) LSD depresses the rate of firing of serotonergic nerves in the raphe nuclei + (Trulson and Jacobs, 1979) causing arousal similar to stimulation of the reticular formation, as if by + facilitating sensory input into the reticular formation (Bowman and Rand, 1980).In European culture, some + people--e.g., Plato, Descarte, Locke, Eccles, probably even B.F. Skinner--have believed that mind and body + are essentially different things (analogous to computer hardware and its programs), while another + tradition--Blake, Lamarck, Darwin, C.L. Morgan, Pavlov, Reich, C.R. Cloninger, for example--has emphasized + the continuity of consciousness and character with the body.Understanding the authoritarian personality has + been an important issue in the 20th century. Wilhelm Reich used some old ideas about the nervous system that + were current near the beginning of the century, and Cloninger (1995) and others (Netter, et al., 1996, + Ruegg, et al., 1997, Gerra, 2000), toward the end of the century, were able to incorporate the newer + information about the serotonergic-dopaminergic antagonisms. In this newer view, high serotonin production + causes behavioral inhibition and harm avoidance, which are traits of the authoritarian personality, while + anti-authorians tend to have "novelty seeking" personalities, with high dopamine and low serotonin + functions.In the 1960s, experimenters put electrodes into a chicken's optic nerve, and when the chicken saw + a checkerboard pattern, they could measure a patterned electrical activity in the nerve. Without the light + stimulating the retina, the nerve was quiet. But when they gave the chicken LSD or similar chemicals, they + recorded patterned electrical activity in the nerve, in the absence of external stimulation. Around the same + time, other experimenters showed that retinal fatigue quickly desensitized the retina, preventing the + transmission of impulses to the brain, except when the light pattern corresponded to something familiar, + showing that impulses from the brain are always involved in renewing, in patterned ways, the sensitivity of + the retina.The latter experiment shows that everyone's perception involves an outward-directed activity of + the brain, and the experiments using the chemical stimulants suggested that the intensity of the outward- + directed action can vary.The inhibitory serotonergic "harm avoidance" system, and the opposing excitatory + activating "novelty seeking" systems are constantly being influenced by many factors, including nutrition, + hormones, environmental challenges and opportunities, social interactions, seasons, and the rhythm of night + and day alternation.Several kinds of research are now showing that the effects of the environment on the + serotonergic system and its antagonists can influence every aspect of health, not just the personality.For + example, there have been suggestions that early life isolation of an animal can affect its serotonergic + activity and increase its anxiety, aggression, or susceptibility to stress (Malick and Barnett, 1976, + Malick, 1979, dos Santos, et al, 2010), and these effects are associated with increased risk of becoming + depressed, and developing organic problems. Animals kept in darkness (or with blurring lenses) become + nearsighted, as the eyeball grows longer under the influence of increased serotonin, and the eyes are + protected against myopia by serotonin antagonists (George, et al., 2005). The incidence of myopia is + increasing, at least in countries with industrialized economies, and is more common in females.Migraine + headaches are also increasing in incidence. By the end of the 1950s, it was widely accepted that migraine + headaches and associated symptoms including nausea and visual disturbances were caused by an excess of + serotonin, and antiserotonin drugs of various types were being used for treatment. In one of the early + studies of the use of LSD in psychotherapy, some of the patients noticed that their chronic headaches had + stopped. Cluster headaches have also responded well to LSD and similar drugs (Sewell, et al., 2006).Women + have migraines more often than men do, and they tend to occur in association with ovulation or menstruation. + Estrogen inhibits monoamino oxidase, MAO, especially the A form that is most active in detoxifying + serotonin, and it increases the enzymes that control the rate of serotonin synthesis. During serotonin + excess, the veins and capillaries of the pia mater are engorged with blood, while circulation to the brain + generally is depressed. Visual symptoms are probably produced by contriction of arterioles, while the pain + is associated with engorged veins. Progesterone activates the MAO-A, and has other antiserotonin effects on + blood vessels and nerves.Recently (Shansky, et al., 2010; Figueiredo, et al., 2007), females have been found + to be more susceptible to stress, and to have reduced uptake of serotonin (prolonging its effects), which + increases glucocorticoids and ACTH. Kendler, et al. (2005) have found that people with reduced serotonin + uptake are more susceptible to stress-induced depression.The increase of inhibitory serotonin with stress + and depression is probably biologically related to the role of serotonin in hibernation, which is an extreme + example of "harm avoidance" by withdrawal. A diet high in polyunsaturated fat increases the tendency to go + into hibernation, probably by increasing the brain's uptake of tryptophan. When this is combined with an + increasingly cold environment, the form of MAO that removes serotonin decreases its activity, while the form + that removes norepinephrine increases its activity. The metabolite of serotonin, 5-HIAA, decreases, as the + effect of serotonin increases.In experiments to investigate the mechanism of hibernation, animals were + injected with serotonin, at different environmental temperatures. In a cool environment, the serotonin + caused their temperature to fall, by decreasing their heat production, and increasing their loss of heat (by + causing vasodilation in the skin, "flushing"). In a hot environment, serotonin can cause the animal's + temperature to rise.Serotonin can reduce the production of energy by inhibiting mitochondrial respiratory + enzymes (Medvedev, 1990, 1991), and by reduction of oxygen delivery to tissues by vasoconstriction. It also + appears to interfere with the use of glucose (de Leiva, et al., 1978, Moore, et al., 2004).The brains of + people with Alzheimer's disease have a decreased ability to metabolize glucose, and high cortisol + contributes to the altered glucose metabolism, and to the destruction of nerve cells. People with + Cloninger's "harm avoidance" personality trait, which is closely associated with serotonin (Hansenne, et + al., 1999), are more likely to develop dementia (Clément, et al., 2010). These observations are consistent + with the stress-susceptibility of people with high serotonin exposure, and to the effects of cortisol on + nerves and glucose-derived energy production.Researchers in Brasil have suggested that the serotonergic + system facilitates conditioned fear, while inhibiting the fight or flight reaction, and that this can + protectively limit the stress response (Graeff, et al., 1996). "5HT systems reduce the impact of impending + or actual aversive events. Anticipation of an aversive event is associated with anxiety and this motivates + avoidance behaviour" (Deakin, 1990). In a stressful situation, the serotonergic nerves can prevent ulcers. + In other contexts, though, increased serotonin can cause ulcers.The protective, defensive reactions + involving serotonin's blocking of certain types of reaction to ordinary stresses, are similar to the effects + of serotonin in hibernation and in Alzheimer's disease (Mamelak, 1997; Heininger, 2000; Perry, et al., + 2002). In those extreme conditions, serotonin reduces energy expenditure, eliminating all brain functions + except those needed for simple survival. These parallels suggest that improving energy production, for + example by providing ketones as an alternative energy source, while reducing the stress hormones, might be + able to replace the defensive reactions with restorative adaptive nerve processes, preventing or reversing + Alzheimer's disease.One of the factors promoting excess cortisol production is intestinal irritation, + causing absorption of endotoxin and serotonin. Fermentable fibers (including pectins and + fructooligosaccharides) support the formation of bacterial toxins, and can cause animals to become anxious + and aggressive. Fed to horses, some types of fiber increase the amount of serotonin circulating in the + blood. Grains, beans, and other seeds contain fermentable fibers that can promote intestinal irritation.The + liver has several ways to detoxify endotoxin and serotonin, but these can fail as a result of poor nutrition + and hypothyroidism.The lung can bind and destroy any excess serotonin that reaches it. A lack of carbon + dioxide makes platelets release their stored serotonin, and it probably has the same effect in the lung + endothelial cells. Without being able to bind the serotonin, the enzyme (indoleamine 2,3-dioxygenase) would + be unable to destroy it.An excess of tryptophan in the diet, especially with deficiencies of other + nutrients, can combine with inflammation to increase serotonin. Polyunsaturated fatty acids promote the + absorption of tryptophan by the brain, and its conversion to serotonin. (A "deficiency" of polyunsaturated + fat decreases the expression of the enzyme that synthesizes serotonin [McNamara, et al., 2009).Some fruits, + including bananas, pineapples, and tomatoes, contain enough serotonin to produce physiological effects in + susceptible people.Besides avoiding foods containing fermentable fibers and starches that resist quick + digestion, eating fibrous foods that contain antibacterial chemicals, such as bamboo shoots or raw carrots, + helps to reduce endotoxin and serotonin. Activated charcoal can absorb many toxins, including bacterial + endotoxin, so it is likely to reduce serotonin absorption from the intestine. Since it can also bind or + destroy vitamins, it should be used only intermittently. Frolkis, et al. (1989, 1984) found that it extended + median and average lifespan of rats, beginning in old age (28 months) by 43% and 34%, respectively, when + given in large quantities (equivalent to about a cup per day for humans) for ten days of each month.The + amino acid theanine, found in tea, has been reported to decrease the amount of serotonin in the brain, + probably by decreasing its synthesis and increasing its degradation. This seems to be the opposite of + the processes in hibernation. Progesterone, thyroid, and niacinamide (not nicotinic acid or inositol + hexanicotinate) are other safe substances that help to reduce serotonin formation, and/or accelerate its + elimination. (Niacinamide seems to increase serotonin uptake.)To provide usable energy to the over-stressed + brain (and heart), R.L. Veech has advocated the use of ketones, but the pure chemicals are expensive to + make. An easily available and inexpensive source of ketones (in the form of ketoacids, which can be + converted to amino acids if they aren't needed for energy) is the juice extracted (with a centrifugal + juicer) from raw potatoes, which also contains proteins and other nutrients. The juice can be scrambled like + eggs, and is usually tolerated even by very debilitated people.Hypothyroidism is a very common cause of + increased serotonin (e.g., Henley, et al., 1998), and if the thyroid hormone is supplemented until symptoms + are resolved, it's likely that the serotonin will have been normalized.

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+ + © Ray Peat Ph.D. 2015. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/stemcells.html b/raypeat-articles/processed/stemcells.html new file mode 100644 index 0000000..0e92430 --- /dev/null +++ b/raypeat-articles/processed/stemcells.html @@ -0,0 +1,2433 @@ + + Stem cells, cell culture, and culture: Issues in regeneration + +

+ Stem cells, cell culture, and culture: Issues in regeneration +

+ +

+ Cell renewal is a factor in all aspects of health and disease, not just in aging and the degenerative + diseases. Many people are doing valid research relating to cell renewal and regeneration, but its usefulness + is seriously limited by cultural and commercial constraints. By recovering some of our suppressed + traditional culture, I think regenerative therapies can be developed quickly, by identifying and eliminating + as far as possible the main factors that interfere with tissue renewal. +

+ +

+ Science grew up in the highly authoritarian cultures of western Europe, and even as it contributed to + cultural change, it kept an authoritarian mystique. Any culture functions as a system of definitions of + reality and the limits of possibility, and to a great extent the "laws of nature" are decreed so that they + will harmonize with the recognized laws of society. +

+

+ The practical success of Newton's "laws" of motion when they were applied to ballistics and "rocket science" + has led many people to value calculation, based on those laws, over evidence. In biology, the idea that an + organism is "the information it contains in its DNA blueprint" is an extention of this. The organism is + turned into something like a deductive expression of the law of DNA. This attitude has been disastrous. +

+ +

+ The old feudal idea of a divine and stable social organization was applied by some people to their idea of + biological organization, in which each cell (ruled by its nucleus) had its ordained place in the organism, + with the brain and the "master gland," the pituitary, ruling the subordinate organs, tissues, and cells. + "Anatomy" was taught from dead specimens, microscope slides, and illustrations in books. Most biologists' + thoughts about cells in organisms reflect the static imagery of their instruction. ("The histological + image of these tissues actually reflects an instantaneous picture of cells in a continuous flux." + Zajicek, 1981.) +

+

+ When a person has playful and observant interactions with natural things, both regularities and + irregularities will be noticed, and in trying to understand those events, the richness of the experience + will suggest an expansive range of possibilities. Perception and experimentation lead to understandings that + are independent of culture and tradition. +

+ +

+ But the mystique of science easily imposes itself, and distracts our attention from direct interactions with + things. As we learn to operate lab instruments, we are taught the kinds of results that can be expected, and + the concepts that will explain and predict the results of our operations. Science, as we learn about it in + schools and the mass media, is mostly a set of catechisms. +

+

+ Our theories about organisms inform our experiments with cells or tissues that have been isolated from those + organisms. The conditions for growing cells in dishes are thought of as "physiological," in relation to the + solution's "physiological osmolarity," "physiological pH," nutrients, oxygenation, temperature, pressure, + etc. But these concepts of what is physiological derive from the monolithic ideology of the doctrinaire, and + often fraudulent, mainstream of biological science. +

+

+ The catechismic nature of science has led people to expect some "break-throughs" to occur in certain areas, + and as authoritarian science has grown into "big science" managed by corporations and governments, those + break-throughs are generally expected to be produced by the newest and most expensive developments of "high + technology." +

+

+ But looking closely at the real events and processes in the sciences in the last couple of centuries, it + turns out that useful advances have been produced mainly by breaking away from authoritarian doctrines, to + return to common sense and relatively simple direct observations. +

+

+ Although people were cloning animals in the 1960s, it was still widely taught that it was impossible. The + students of the professors who taught that it was impossible are now saying that it requires high technology + and new research. +

+

+ For the last 100 years the most authoritative view in biology has been that there are no stem cells in + adults, that brains, hearts, pancreases and oocytes are absolutely incapable of regeneration. But now, + people seem to be finding stem cells wherever they look, but there is a mystique of high technology involved + in finding and using them. +

+

+ Whether it's deliberate or not, the emphasis on stem cell technology has the function of directing attention + away from traditional knowledge, the way allopathic medicine has de-emphasized the intrinsic ability of + people to recover from disease. +

+ +

+ This resembles the way that the Mendel-Morgan gene doctrine was used to suppress the knowledge gained from + centuries of experience of plant and animal breeders, and to belittle the discoveries of Luther Burbank, + Paul Kammerer, Trofim Lysenko, and Barbara McClintock. The same type of biochemical process that caused the + hereditary changes those researchers studied are involved in the differentiation and dedifferentiation of + stem cells that regulate healing and regeneration. +

+

+ In the 1940s, even children discussed the biological discoveries of the 1920s and 1930s, the work in + regeneration and adaptation, parthenogenesis, and immortalization. The ideas of J. Loeb, T. Boveri, A. + Gurwitsch, J. Needham, C.M. Child, A. Carrel, et al., had become part of the general culture. +

+

+ But that real biology was killed by a consortium of industry and government that began a little before the + second world war. In 1940, the government was supporting research in chemical and biological warfare, and + with the Manhattan Project the role of government became so large that all of the major research + universities were affected. Shortly after the war, many researchers from the Manhattan Project were + redeployed into "molecular genetics," where the engineering attitude was applied to organisms. +

+

+ The simplistic genetic dogmas were compatible with the reductionist engineering approach to the organism. + The role of the government assured that the universities would subscribe to the basic scientific agenda. The + atmosphere of that time was described by Carl Lindegren as "The Cold War in Biology" (1966). +

+ +

+ The disappearance of the field concept in developmental biology was one of the strangest events in the + history of science. It didn't just fade away, it was "disappeared," in a massive undertaking of social + engineering. In its absence, stem cells will seem to be a profitable technological marvel, rather than a + universal life function, with a central role in everything we are and everything we do and can become. +

+

+ Many people have tried to explain aging as a loss of cells, resulting from an intrinsic inability of any + cell other than a germ cell to multiply more than a certain number of times. More than 40 years ago Leonard + Hayflick popularized this doctrine in its most extreme form, saying that no cell can divide more than 50 + times unless it is converted into a cancer cell. He and his followers claimed that they had explained why + organisms must age and die. At the moment the ovum is fertilized, the clock starts ticking for the + essentially mortal somatic cells. +

+

+ In 1970, it was being seriously proposed that memory was produced by the death of brain cells, in a manner + analogous to the holes punched in cards to enter data into computers. The cultural dogma made it impossible + to consider that learning could be associated with the birth of new cells in the adult brain. +

+

+ With the announcement in 1997 of the cloning of the sheep Dolly from a somatic cell taken from a 6 year old + sheep, there was renewed interest in the idea made famous by Alexis Carrel that all cells are potentially + immortal, and in the possibility of preserving the vitality of human cells. Within a few months, Hayflick + began reminding the public that "In the early 1960's we overthrew this dogma after finding that normal cells + do have a finite replicative capacity." ("During the first half of this century it was believed that because + cultured normal cells were immortal, aging must be caused by extra-cellular events.") The way Hayflick + "overthrew" more than 35 years of work at the Rockefeller Institute was by growing one type of cell, a lung + fibroblast, in culture dishes, and finding that the cultures deteriorated quickly. +

+ +

+ To draw global conclusions about an organism's development and aging from the degenerative processes seen in + a single type of cell, grown in isolation from all normal stimuli, would have been treated as nothing but + wild speculation, except that it occurred within a culture that needed it. No aspect of Hayflick's cell + culture system could properly be called physiological. +

+

+ Other researchers, simply by changing a single factor, caused great increases in the longevity of the + cultured cells. Simply using a lower, more natural oxygen concentration, the cells were able to undergo 20 + more divisions. Just by adding niacin, 30 more divisions; vitamin E, 70 more divisions. Excess oxygen is a + poison requiring constant adaptation. +

+

+ Hayflick also published the observation that, while the cells kept in dishes at approximately body + temperature deteriorated, cells kept frozen in liquid nitrogen didn't deteriorate, and he concluded that + "time" wasn't the cause of aging. When I read his comments about the frozen cells, I wondered how anyone of + normal intelligence could make such stupid statements. Since then, facts that came out because of the + Freedom of Information Act, cause me to believe that a financial motive guided his thoughts about his + cultured fibroblasts. +

+

+ Hayflick and his followers have been attacking the idea of anti-aging medicine as quackery. But he is + closely involved with the Geron corporation, which proposes that genetic alterations relating to telomeres + may be able to cure cancer and prevent aging. Their claims were reported by CNN as "Scientists discover + cellular 'fountain of youth'." +

+ +

+ The "wear and tear" doctrine of aging that derived from the ideology of the gene was reinforced and renewed + by Hayflick's cell culture observations, and it continued to rule the universities and popular culture. +

+

+ But detailed investigation of skin cell growth showed that cells in the lower layer of the skin divide at + least 10,000 times in a normal lifetime, and similar processes occur in the lining of the intestine. The + endometrium and other highly renewable tissues just as obviously violated Hayflick's limit. Transplantation + experiments showed that pieces of mammary tissue or skin tissue could survive through ten normal lifetimes + of experimental animals without suffering the effects of aging. +

+

+ Even the liver and adrenal gland are now known to be continuously renewed by "cell streaming," though at a + slower rate than the skin, conjunctiva, and intestine. Neurogenesis in the brain is now not only widely + accepted, it is even proposed as a mechanism to explain the therapeutic effects of antidepressants + (Santarelli, et al., 2003). +

+ +

+ August Weismann's most influential doctrine said that "somatic cells are mortal, only the germline cells are + immortal," but he based the doctrine on his mistaken belief that only the "germline" cells contained all the + genes of the organism. In 1885, to "refute" Darwin's belief that acquired traits could be inherited, he + promulgated an absolute "barrier" between "germline" and "soma," and invented facts to show that hereditary + information can flow only from the germline to the somatic cells, and not the other direction. Shortly after + DNA became popular in the 1950s as "the genetic material," Weismann's barrier was restated as the Central + Dogma of molecular genetics, that information flows only from DNA to RNA to protein, and never the other + direction. +

+

+ It was only in 2003, after the reality of cloning was widely recognized, that a few experimenters began to + investigate the origin of "germline" cells in the ovary, and to discover that they derive from somatic cells + (Johnson, et al., 2004). With this discovery, the ancient knowledge that a twig (klon, in Greek) + cut from a tree could grow into a whole tree, bearing fruit and viable seeds, was readmitted to general + biology, and the Weismann barrier was seen to be an illusion. +

+

+ Millions of people have "explained" female reproductive aging as the consequence of the ovary "running out + of eggs." Innumerable publications purported to show the exact ways in which that process occurs, following + the Weismann doctrine. But now that it is clear that adult ovaries can give birth to new oocytes, a new + explanation for female reproductive aging is needed. It is likely that the same factors that cause female + reproductive aging also cause aging of other systems and organs and tissues, and that those factors are + extrinsic to the cells themselves, as Alexis Carrel and others demonstrated long ago. This is a way of + saying that all cells are potential stem cells. The "niche" in which new cells are born in the streaming + organism, and the processes by which damaged cells are removed, are physiological issues that can be + illuminated by the idea of a morphogenetic field. +

+

+ When the post-war genetic engineers took over biological research, the idea of a biophysical field was + totally abandoned, but after about 15 years, it became necessary to think of problems beyond those existing + within a single bacterium, namely, the problem of how an ovum becomes and embryo. Francis Crick, of DNA + fame, who was educated as a physicist, revived (without a meaningful historical context) the idea of a + diffusion gradient as a simple integrating factor that wouldn't be too offensive to the reductionists. But + for events far beyond the scale of the egg's internal structure, for example to explain how a nerve axon can + travel a very long distance to innervate exactly the right kind of cell, the diffusion of molecules loses + its simplicity and plausibility. (Early in the history of experimental embryology, it was observed that + electrical fields affect the direction of growth of nerve fibers.) +

+

+ C. M. Child saw a gradient of metabolic activity as an essential component of the morphogenetic field. This + kind of gradient doesn't deny the existence of diffusion gradients, or other physical components of a field. + Electrical and osmotic (and electro-osmotic) events are generated by metabolism, and affect other factors, + including pH, oxidation and reduction, cell motility and cell shape, ionic selectivity and other types of + cellular selectivity and specificity. Gradients of DNA methylation exist, and affect the expression of + inherited information. +

+

+ Methylation decreases the expression of particular genes, and during the differention of cells in the + development of an embryo, genes are methylated and demethylated as the cell adapts to produce the proteins + that are involved in the structure and function of a particular tissue. Methylation (which increases a + molecule's affinity for fats) is a widespread process in cells, and for example regulates cellular + excitability. It is affected by diet and a variety of stresses. +

+

+ DNA methylation patterns are normally fairly stable, and can help to account for the transgenerational + transmission of acquired adaptations, and for neonatal imprinting that can last a lifetime. But with injury, + stress, and aging, the methylation patterns of differentiated tissues can be changed, contributing to the + development of tumors, or to the loss of cellular functions. Even learning can change the methylation of + specific genes. During in vitro culture, the enzymes of gene methylation are known to be increased, + relative to their normal activity (Wang, et al., 2005). +

+ +

+ The phenomenon of "gene" methylation in response to environmental and metabolic conditions may eventually + lead to the extinction of the doctrine that "cells are controlled by their genes." +

+

+ During successful adaptation to stress, cells make adjustments to their metabolic systems (for example with + a holistic change of the degree of phosphorylation, which increases molecules' affinity for water), and + their metabolic processes can contribute to changes in their state of differentiation. Some changes may lead + to successful adaptation (for example by producing biogenic stimulators that stimulate cell functioning and + regeneration), others to failed adaptation. Even the decomposition of cells can release substances that + contribute to the adaptation of surrounding cells, for example when sphingosines stimulate the production of + stem cells. +

+

+ DNA methylation is just one relatively stable event that occurs in relation to a metabolic field. + Modifications of histones (regulatory proteins in chromosomes, which are acetylated as well as methylated) + and structural-contractile filaments also contribute to the differentiation of cells, but the pattern of DNA + methylation seems to guide the methylation of histones and the structure of the chromosomes (Nan, et al., + 1998). +

+

+ Steroids and phospholipids, neurotransmitters and endorphins, ATP, GTP, other phosphates, retinoids, NO and + CO2--many materials and processes participate in the coherence of the living state, the living substance. + Carbon dioxide, for example, by binding to lysine amino groups in the histones, will influence their + methylation. Carbon dioxide is likely to affect other amino groups in the chromosomes. +

+ +

+ The number and arrangement of mitochondria is an important factor in producing and maintaining the metabolic + gradients. Things that decrease mitochondrial energy production--nitric oxide, histamine, cytokines, + cortisol--increase DNA methylation. Decreased gene expression is associated with reduced respiratory energy. + It seems reasonable to guess that increased gene expression would demand increased availability of energy. +

+

+ As an ovum differentiates into an organism, cells become progressively more specialized, inhibiting the + expression of many genes. Less energy is needed by stably functioning cells, than by actively adapting + cells. A.I. Zotin described the process of maturing and differentiating as a decrease of entropy, an + increase of order accompanying a decreased energy expenditure. The entropic egg develops into a less + entropic embryo with a great expenditure of energy. +

+

+ The partially differentiated stem cell doesn't go through all the stages of development, but it does expend + energy intensely as it matures. +

+

+ The restoration of energy is one requirement for the activation of regeneration. When a hormone such as + noradrenaline or insulin causes a stem cell to differentiate in vitro, it causes new mitochondria to form. + This is somewhat analogous to the insertion of mitochondria into the ripening oocyte, by the nurse cells + that surround it. The conditionally decreased entropy of maturation is reversed, and when sufficient + respiratory energy is available, the renewed and refreshed cell will be able to renew an appropriate degree + of differentiation. +

+

+ When simple organisms, such as bacteria, fungi, or protozoa are stressed, for example by the absence of + nutrients or the presence of toxins, they slow their metabolism, and suppress the expression of genes, + increasing the methylation of DNA, to form resistant and quiescent spores. Our differentiated state doesn't + go to the metabolic extreme seen in sporulation, but it's useful to look at maturity and aging in this + context, because it suggests that the wrong kind of stress decreases the ability of the organism to adapt, + by processes resembling those in the spore-forming organisms. +

+ +

+ Charles Vacanti, who has grown cartilage from cells taken from 100 year old human cartilage, believes our + tissues contain "spore cells," very small cells with slow metabolism and extreme resistance to heat, cold, + and starvation. +

+

+ If the slowed metabolism of aging, like that of sporulating cells, is produced by a certain kind of stress + that lowers cellular energy and functions, it might be useful to think of the other stages of the stress + reaction in relation to the production of stem cells. Selye divided stress into a first stage of shock, + followed by a prolonged adaptation, which could sometimes end in exhaustion. If the maturity of + differentiated functioning is equivalent to the adaptation phase, and cellular decline and disintegration is + the exhaustion phase, then the shock-like reaction would correspond to the birth of new stem cells. +

+

+ Selye described estrogen's effects as equivalent to the shock-phase of stress. Estrogen's basic action is to + make oxygen unavailable, lowering the oxygen tension of the tissues, locally and temporarily. Like nitric + oxide, which is produced by estrogenic stimulation, estrogen interferes with energy production, so if its + stimulation is prolonged, cells are damaged or killed, rather than being stimulated to regenerate. +

+

+ Extrinsic factors elicit renewal, the way stress can elicit adaptation. While aging cells can't use the + oxygen that is present, a scarcity of oxygen can serve as a stimulus to maximize the respiratory systems. + Brief oxygen deprivation excites a cell, causes it to swell, and to begin to divide. +

+ +

+ Oxygen deprivation, as in the normally hypoxic bone marrow, stimulates the formation of stem cells, as well + as the biogenesis of mitochondria. As the newly formed cells, with abundant mitochondria, get adequate + oxygen, they begin differentiation. +

+

+ Form, based on cellular differentiation, follows function--a vein transplanted into an artery develops + anatomically into an artery, a colon attached directly to the anus becomes a new rectum with its appropriate + innervation, a broken bone restructures to form a normal bone. If the bladder is forced to function more + than normal, by artificially keeping it filled, its thin wall of smooth muscle develops into a thick wall of + striated muscle that rhythmically contracts, like the heart. If a tadpole is given a vegetarian diet, the + absorptive surface of its digestive system will develop to be twice the size of those that are fed meat. + Pressure, stretching, and pulsation are among the signals that guide cells' differentiation. +

+

+ Very early in the study of embryology it was noticed that the presence of one tissue sometimes induced the + differentiation of another kind, and also that there were factors in embryonic tissues that would stimulate + cell division generally, and others that could inhibit the growth of a particular tissue type. Diffusable + substances and light were among the factors identified as growth regulators. +

+

+ Extracts of particular tissues were found to suppress the multiplication of cells in that type of tissue, in + adult animals as well as in embryos. In the 1960s, the tissue-specific inhibitors were called chalones. +

+

+ The brain's development is governed by the presence in the organism of the body part to which it + corresponds, such as the eyes or legs. The number of cells in a particular part of the nervous system is + governed by the quantity of nervous input, sensory or motor, that it receives. An enriched environment + causes a bigger brain to grow. Sensory nerve stimulation of a particular region of the brain causes nerve + cells to migrate to that area (a process called neurobiotaxis; deBeers, 1927), but nerve stimulation also + causes mitochondria to accumulate in stimulated areas. Nerve activity has a trophic, sustaining influence on + other organs, as well as on the brain. Nerve stimulation, like mechanical pressure or stretching, is an + important signal for cellular differentiation. +

+ +

+ When stem cells or progenitor cells are called on to replace cells in an organ, they are said to be + "recruited" by that organ, or to "home" to that organ, if they are coming from elsewhere. Traditionally, the + bone marrow has been considered to be the source of circulating stem cells, but it now appears that a + variety of other less differentiated cells can be recruited when needed. Cells from the blood can repair the + endothelium of blood vessels, and endothelial cells can become mesenchymal cells, in the heart, for example. +

+

+ The standard doctrine about cancer is that a tumor derives from a single mutant cell, but it has been known + for a long time that different types of cell, such as phagocytes and mast cells, usually reside in tumors, + and it is now becoming clear that tumors recruit cells, including apparently normal cells, from other parts + of the same organ. For example, a brain tumor of glial cells, a glioma, recruits glial cells from + surrounding areas of the brain, in a process that's analogous to the embryological movement of nerve cells + to a center of excitation. Each tumor, in a sense, seems to be a center of excitation, and its fate seems to + depend on the nature of the cells that respond to its signals. +

+

+ To accommodate some of the newer facts about tumors, the cancer establishment has begun speaking of "the + cancer stem cell" as the real villain, the origin of the tumor, while the bulk of the tumor is seen to be + made up of defective cells that have a short life-span. But if we recognize that tumors are recruiting cells + from beyond their boundaries, this process would account for the growth and survival of a tumor even while + most of its cells are inert and dying, without invoking the invisible cancer stem cell. And this view, that + it is the field which is defective rather than the cell, is consistent with the evidence which has been + accumulating for 35 years that tumor cells, given the right environment, can differentiate into healthy + cells. (Hendrix, et al., 2007) +

+ +

+ Simply stretching an organ (Woo, et al., 2007) is stimulus enough to cause it to recruit cells from the + bloodstream, and will probably stimulate multiplication in its local resident cells, too. Every "cancer + field" probably begins as a healing process, and generally the healing and regeneration are at least + partially successful. +

+

+ When an organ--the brain, heart, liver, or a blood vessel--is inflamed or suffering from an insufficient + blood supply, stem cells introduced into the blood will migrate specifically to that organ. +

+

+ Organ specific materials (chalones) are known to circulate in the blood, inhibiting cell division in cells + typical to that organ, but it also seems that organ specific materials are secreted by a damaged organ, that + help to prepare stem cells for their migration into that organ. When undifferentiated cells are cultured + with serum from a person with liver failure, they begin to differentiate into liver cells. +

+

+ It is still common to speak of each organ as having a "clonal origin" in the differentiating embryo, as a + simple expansion of a certain embryonic anlage. The implication of this way of thinking is that + differentiation is determination in an irreversible sense. This is another case of medical ideas + being based on images of fixed histological material. Normal cells, including nerve and muscle cells, can + change type, with connective tissue cells becoming nerve cells, nerve cells becoming muscle and fiber cells, + fat, fiber, and muscle cells redifferentiating, for example. +

+ +

+ Cell movements in solid tissues aren't limited to the short distances between capillaries and the tissues + nourished by those capillaries, rather, cells can migrate much greater distances, without entering the + bloodstream. The speed of a single cell moving by ameboid motion can be measured by watching cells on a + glass slide as they move toward food, or by watching cells of the slime mold Dictyostelium when they are + aggregating, or by watching the pigment cells in and around moles or melanomas, under the influence of + hormones. At body temperature, a single cell can crawl about an inch per day. Waves or spots of brown + pigment can be seen migrating through the skin away from a mole, preceding the disintegration of the mole + under the influence of progesterone or DHEA. Under ordinary conditions, pigment cells can sometimes be seen + migrating into depigmented areas of skin, during the recovery of an area affected by vitiligo. These + organized movements of masses of cells happen to be easy to see, but there is evidence that other types of + cell can reconstruct tissues by their ameboid movements, when circumstances are right. Tumors or tissue + abnormalities can appear or disappear with a suddenness that seems impossible to people who have studied + only fixed tissue preparations. +

+

+ Stimulation is anabolic, building tissue, when the organism is adapting to the stimulation. Unused + structures in cells and tissues are always being recycled by metabolic processes. When tissues are injured + and become unable to function, some of their substances stimulate the growth of replacement cells. +

+

+ Some types of injury or irritation can activate regenerative processes. A dermatology journal described the + case of an old man who had been bald for many years who fell head-first into his fireplace. As his burned + scalp healed, new hair grew. In the U.S., experimenters (Ito, et al., 2007) have found that injuring the + skin of mice stimulates the formation of stem cells that are able to become hair follicle cells, supporting + the regeneration of cells that had been absent. A brief exposure to estrogen, and other stress related + signals (nitric oxide, endorphin, prostaglandins) can initiate stem cell proliferation. +

+

+ In the years after the first world war, Vladimir Filatov, who developed techniques of reconstructive + surgery, including corneal transplants, found that cold storage of tissues (for example, corneas from + cadavers) caused them to function better than fresh tissues, and he found that these stressed tissues would + often spread a healing influence out into the surrounding tissues. Extracts of stressed tissues produced + similar effects. +

+

+ L.V. Polezhaev began studying the regenerative capacities of mammals in the late 1940s, and his work showed + that processes similar to embryonic induction are involved in the organism's responses to damaged tissues. + For example, when a piece of killed muscle tissue is enclosed in a capsule ("diffusion chamber") that + permits molecules, but no cells, to diffuse through it, and implanted subcutaneously, it had no inductive + effect on surrounding cells. But when the pores of the capsule allowed cells to enter, skeletal muscle + formed where the dead tissue had been, and tissue resembling heart muscle formed outside the capsule. + Phagocytosis had been essential for the induction to occur. +

+ +

+ Macrophages are ordinarily thought of as "antigen-presenting cells" that help to activate the specific + immune responses. But apparently phagocytosis is involved in the replacement of damaged tissues, by + recruiting or inducing the differentiation of replacement cells. The phagocytosis function isn't limited to + the blood cells commonly called phagocytes; even nerve cells can ingest particles and fragments of damaged + tissues. +

+

+ Many factors regulate the process of phagocytosis. Stress and lipid peroxidation decrease phagocytosis + (Izg"t-Uysal, et al., 2004), and also damage mitochondria and inhibit cell renewal. +

+

+ Unsaturated fatty acids inhibit phagocytosis (Guimaraes, et al., 1991, 1992; Costa Rosa, et al., 1996; + Virella, et al., 1989; Akamatsu, et al., 1990), and suppress mitochondrial function (Gomes, et al., 2006). + Dietary restriction activates phagocytosis (Moriguchi, et al., 1989), suggesting that normal diets contain + suppressive materials. +

+

+ Subnormal temperatures cause a shift from phagocytosis to inflammation. Light, especially the red light + which penetrates easily into tissues, activates the formation of new cells as well as their differentiation. + It affects energy production, increasing the formation of mitochondria, and the activity of the DNA + methyltransferase enzymes. Red light accelerates wound healing, and improves the quality of the scar, + reducing the amount of fibrosis. The daily cycling between darkness and light is probably an important + factor in regulating the birth and differentiation of cells. +

+

+ Darkness suppresses mitochondrial function, and light activates it. Prolonged darkness increases cortisol, + and cortisol (which makes cells more susceptible to excitotoxic death) inhibits stem cell proliferation (Li, + et al., 2006; Liu, et al., 2003). Neurogenesis is suppressed by stress, and increased by spontaneous + activity, and has a circadian rhythm. Aging and depression both involve a diminished ability to rhythmically + lower the production of cortisol. Cell renewal requires a rhythmic decrease in the exposure to cortisol.. +

+ +

+ In the spring, with increased day length, the brains of song-birds grow, with an increased proliferation of + cells in the part of the brain involved in singing. The production of progesterone increases in most animals + in the spring, and it is the main hormone responsible for the birds' brain growth. +

+

+ Progesterone and its metabolites protect brain cells against injury, and improve the brain's ability to + recover after traumatic injury (Brinton and Wang, 2006). In the 1960s, Marion Diamond's group showed that + environmental enrichment, or progesterone, caused brains to grow larger, and that these changes were passed + on to descendants in a cumulative, increasing way. This suggests that the factors that promote neurogenesis + also cause changes in the apparatus of reproduction and inheritance, that support the development of the + brain--probably including the methylation system, which is involved in regulating genes, and also mood and + behavior. +

+

+ Women's monthly cycles, in which a brief estrogen dominance is followed by sustained exposure to + progesterone, are probably an important factor in the renewal of the cells of the brain and other organs, as + well as those of the reproductive organs. The daily rhythms of hormones and metabolism are known to be + involved in the regulation of cell renewal. +

+

+ Environmental enrichment, learning, high altitude, and thyroid hormone promote the formation of new + mitochondria, and stimulate stem cell proliferation. At least in some laboratories, 20% oxygen, + approximately the amount as in the atmosphere, suppresses the proliferation of stem cells (He, et al., + 2007). This was the unphysiologically high concentration of oxygen used in Hayflick's cell cultures. At high + altitudes, where tissues are exposed to less oxygen, and more carbon dioxide, there is a lower incidence of + all the degenerative diseases, including cancer, heart disease, and dementia. Improved cellular energy + production and more active renewal of cells would probably account for those differences. +

+ +

+ For Crick, the idea of a diffusion gradient to explain embryonic development was simply an extension of his + reductionist orientation, in which diffusing molecules induced or inhibited bacterial genes, and in which + genes controlled cells. For people with that orientation, the adaptive mutations described by Carl + Lindegren, and later by John Cairns, or even the stress-induced variability described by Lysenko, Strong, + and McClintock, were heretical. Polezhaev's demonstration that cells could do something that molecular + diffusion didn't do, threatened to take biology away from the reductionists. If the organism's adaptation to + the environment involves changing its own genes, Crick's paradigm fails. +

+

+ Crick's Central Dogma, derived from the ideology that produced Weismann's Barrier, has been invoked by + generations of professors who wanted to deny the possibility of adaptive tissue renewal and regeneration. + Without the dogma, new ideas about aging and disease will be needed. If somatic cells can adjust their + genes, and if they can also differentiate into new eggs and sperms, new ideas about inheritance of acquired + traits will be needed. +

+

+ The replacement of injured cells means that mutations need not accumulate. Cell renewal with elimination of + mutant cells has been observed in sun-damaged skin simply by stopping the damage, and mitochondria with + damaged DNA can be replaced by healthy mitochondria simply by doing the right kind of exercise. +

+

+ The regulation of cell renewal probably involves all of the processes of life, but there are a few simple, + interacting factors that suppress renewal. The accumulation of polyunsaturated fats, interacting with a high + concentration of oxygen, damages mitochondria, and causes a chronic excessive exposure to cortisol. With + mitochondrial damage, cells are unable to produce the progesterone needed to oppose cortisol and to protect + cells. +

+ +

+ Choosing the right foods, the right atmosphere, the right mental and physical activities, and finding the + optimal rhythms of light, darkness, and activity, can begin to alter the streaming renewal of cells in all + the organs. Designing a more perfect environment is going to be much simpler than the schemes of the genetic + engineers. +

+

REFERENCES

+

+ Growth 43, 58-61, 1979. The effect of progesterone on brain and body growth of chick + embryos. G. Ahmad and S. Zamenhof. [This showed that progesterone, added during the time of + active neuronal proliferation, increased the chicks' brain weight, while the stress hormone, corticosterone, + reduced the weight.] +

+ +

+ J Invest Dermatol. 1990 Sep;95(3):271-4. Suppressive effects of linoleic acid on neutrophil oxygen + metabolism and phagocytosis. Akamatsu H, Komura J, Miyachi Y, Asada Y, Niwa Y. +

+

+ Curr Alzheimer Res. 2006 Feb;3(1):11-7. Preclinical analyses of the therapeutic potential of + allopregnanolone to promote neurogenesis in vitro and in vivo in transgenic mouse model of Alzheimer's + disease. Brinton RD, Wang JM. "Herein, we present data to support a preclinical proof of + concept for the therapeutic potential of allopregnanolone to promote neurogenesis. Our recent work has + demonstrated that the neuroactive progesterone metabolite, allopregnanolone + (3alpha-hydroxy-5alpha-pregnan-20-one), (APalpha) induced, in a dose dependent manner, a significant + increase in proliferation of neuroprogenitor cells (NPCs) derived from the rat hippocampus and human neural + stem cells (hNSM) derived from the cerebral cortex [1]." "The in vitro and in vivo neurogenic properties of + APalpha coupled with a low molecular weight, easy penetration of the blood brain barrier and lack of + toxicity, are key elements required for developing APalpha as a neurogenic / regenerative therapeutic for + restoration of neurons in victims of Alzheimer's disease." +

+ +

+ Arch Biochem Biophys. 1996 Jan 1;325(1):107-12. + Thyromimetic action of the peroxisome proliferators clofibrate, perfluorooctanoic acid, and + acetylsalicylic acid includes changes in mRNA levels for certain genes + + involved in mitochondrial biogenesis. Cai Y, Nelson BD, Li R, Luciakova K, dePierre JW. +

+

+ Biochem Mol Biol Int. 1996 Nov;40(4):833-42. The effect of N-3 PUFA rich diet upon macrophage and + lymphocyte metabolism and function. Costa Rosa LF, Safi DA, Guimar"es AR. +

+

+ G. R. de Beer, An Introducton to Experimental Embryology, + + Oxford, 1926. +

+

+ Biol. Rev. 1927;2:137-197, The mechanics of verterate development. + de Beer GR. +

+

+ Vrach delp. 1937, 20: 803-820. Summary of 20 years' achievements in ophthalmology. + Filatov VP. +

+

+ Vestnik oftal. 1938, 12: 107-159. + Tissue transplantation in intra-ocular diseases. Filatov VP. +

+ +

+ Med zhur 1937, 9: 847-853. + Intramuscular injections of cod liver oil in therapy of pigmented retinitis. Filatov VP, + Verbitska E A. +

+

+ Am Rev Soviet Med. 1946, 3: 388-395. + The treatment of retinitis pigmentosa with intramuscular injection of cod liver oil. + Filatov VP, Verbitska EA. +

+

+ Am Rev Soviet Med 1946, 3: 395-397. Retinitis pigmentosa. Filatov VP. +

+ +

+ Am Rev Soviet Med 1946, 3: 397-398. + The implantation of preserved placenta in retinitis pigmentosa. Filatov VP Verbitska EA. +

+

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+ Nature. 2007 May 17;447(7142):316-20. Wnt-dependent de novo hair follicle regeneration in adult + mouse skin after wounding. + + Ito M, Yang Z, Andl T, Cui C, Kim N, Millar SE, Cotsarelis G. +

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+ J Cereb Blood Flow Metab. 2007 Mar 28; + Regeneration and plasticity in the brain and spinal cord. Johansson BB. +

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+ Nature, 428, 145 - 150, (2004). Johnson, J., Canning, J., Kaneko, T., Pru, J.K. & Tilly, J.L. +

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+ Nature. 1998 May 28;393(6683):386-9. Transcriptional repression by the methyl-CpG-binding protein + MeCP2 involves a histone deacetylase complex. Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, + Eisenman RN, Bird A. +

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+ Doklady AN SSSR 150, 430-433, 1963., "Stimulation of nerve cell reproduction of cerebral cortex in + mammals," L. V. Polezhaev and E. N. Karnaukhove +

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+ L. V. Polezhaev, Loss and Restoration of Regenerative Capacity in Tissues and Organs of + Animals, page 219, 1972. +

+ +

+ J Hirnforsch 1991;32(5):659-664. Normalization of protein synthesis and the structure of brain + dystrophic neurons after the action of hypoxia, 10% NaCl and organ-specific RNA. Polezhaev LV, + Cherkasova LV, Vitvitsky VN, Timonin AV "Transplantation of embryonic nervous tissue (ENT) in one of + the hemispheres normalizes all the above abnormalities observed in some neurologic and mental diseases + in humans." + + "At the beginning 10% NaCl increased the destruction of brain cortical neurons and then stimulated + protein synthesis in them. RNA injections stimulated the synthesis in cortical neurons and + normalized their structure. Thus, we propose a safe and simple method for normalization of dystrophic + neurons which can be used after certain improvement for curing neurodegenerative and neuropsychic diseases + in humans." +

+

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+ +

+ J Urol. 2007 Apr;177(4):1568-72. Over expression of stem cell homing cytokines in urogenital organs + following vaginal distention. Woo LL, Hijaz A, Kuang M, Penn MS, Damaser MS, Rackley RR. +

+

+ Med Hypotheses. 1981 Oct;7(10):1241-51. The histogenesis of glandular neoplasia. Zajicek G. +

+

+ Stem cells, cell culture, and culture: Issues in regeneration + +

+

+ Cell renewal is a factor in all aspects of health and disease, not just in aging and the degenerative + diseases. Many people are doing valid research relating to cell renewal and regeneration, but its usefulness + is seriously limited by cultural and commercial constraints. By recovering some of our suppressed + traditional culture, I think regenerative therapies can be developed quickly, by identifying and eliminating + as far as possible the main factors that interfere with tissue renewal. +

+ +

+ Science grew up in the highly authoritarian cultures of western Europe, and even as it contributed to + cultural change, it kept an authoritarian mystique. Any culture functions as a system of definitions of + reality and the limits of possibility, and to a great extent the "laws of nature" are decreed so that they + will harmonize with the recognized laws of society. +

+

+ The practical success of Newton's "laws" of motion when they were applied to ballistics and "rocket science" + has led many people to value calculation, based on those laws, over evidence. In biology, the idea that an + organism is "the information it contains in its DNA blueprint" is an extention of this. The organism is + turned into something like a deductive expression of the law of DNA. This attitude has been disastrous. +

+ +

+ The old feudal idea of a divine and stable social organization was applied by some people to their idea of + biological organization, in which each cell (ruled by its nucleus) had its ordained place in the organism, + with the brain and the "master gland," the pituitary, ruling the subordinate organs, tissues, and cells. + "Anatomy" was taught from dead specimens, microscope slides, and illustrations in books. Most biologists' + thoughts about cells in organisms reflect the static imagery of their instruction. ("The histological + image of these tissues actually reflects an instantaneous picture of cells in a continuous flux." + Zajicek, 1981.) +

+

+ When a person has playful and observant interactions with natural things, both regularities and + irregularities will be noticed, and in trying to understand those events, the richness of the experience + will suggest an expansive range of possibilities. Perception and experimentation lead to understandings that + are independent of culture and tradition. +

+ +

+ But the mystique of science easily imposes itself, and distracts our attention from direct interactions with + things. As we learn to operate lab instruments, we are taught the kinds of results that can be expected, and + the concepts that will explain and predict the results of our operations. Science, as we learn about it in + schools and the mass media, is mostly a set of catechisms. +

+

+ Our theories about organisms inform our experiments with cells or tissues that have been isolated from those + organisms. The conditions for growing cells in dishes are thought of as "physiological," in relation to the + solution's "physiological osmolarity," "physiological pH," nutrients, oxygenation, temperature, pressure, + etc. But these concepts of what is physiological derive from the monolithic ideology of the doctrinaire, and + often fraudulent, mainstream of biological science. +

+

+ The catechismic nature of science has led people to expect some "break-throughs" to occur in certain areas, + and as authoritarian science has grown into "big science" managed by corporations and governments, those + break-throughs are generally expected to be produced by the newest and most expensive developments of "high + technology." +

+

+ But looking closely at the real events and processes in the sciences in the last couple of centuries, it + turns out that useful advances have been produced mainly by breaking away from authoritarian doctrines, to + return to common sense and relatively simple direct observations. +

+

+ Although people were cloning animals in the 1960s, it was still widely taught that it was impossible. The + students of the professors who taught that it was impossible are now saying that it requires high technology + and new research. +

+

+ For the last 100 years the most authoritative view in biology has been that there are no stem cells in + adults, that brains, hearts, pancreases and oocytes are absolutely incapable of regeneration. But now, + people seem to be finding stem cells wherever they look, but there is a mystique of high technology involved + in finding and using them. +

+

+ Whether it's deliberate or not, the emphasis on stem cell technology has the function of directing attention + away from traditional knowledge, the way allopathic medicine has de-emphasized the intrinsic ability of + people to recover from disease. +

+ +

+ This resembles the way that the Mendel-Morgan gene doctrine was used to suppress the knowledge gained from + centuries of experience of plant and animal breeders, and to belittle the discoveries of Luther Burbank, + Paul Kammerer, Trofim Lysenko, and Barbara McClintock. The same type of biochemical process that caused the + hereditary changes those researchers studied are involved in the differentiation and dedifferentiation of + stem cells that regulate healing and regeneration. +

+

+ In the 1940s, even children discussed the biological discoveries of the 1920s and 1930s, the work in + regeneration and adaptation, parthenogenesis, and immortalization. The ideas of J. Loeb, T. Boveri, A. + Gurwitsch, J. Needham, C.M. Child, A. Carrel, et al., had become part of the general culture. +

+

+ But that real biology was killed by a consortium of industry and government that began a little before the + second world war. In 1940, the government was supporting research in chemical and biological warfare, and + with the Manhattan Project the role of government became so large that all of the major research + universities were affected. Shortly after the war, many researchers from the Manhattan Project were + redeployed into "molecular genetics," where the engineering attitude was applied to organisms. +

+

+ The simplistic genetic dogmas were compatible with the reductionist engineering approach to the organism. + The role of the government assured that the universities would subscribe to the basic scientific agenda. The + atmosphere of that time was described by Carl Lindegren as "The Cold War in Biology" (1966). +

+ +

+ The disappearance of the field concept in developmental biology was one of the strangest events in the + history of science. It didn't just fade away, it was "disappeared," in a massive undertaking of social + engineering. In its absence, stem cells will seem to be a profitable technological marvel, rather than a + universal life function, with a central role in everything we are and everything we do and can become. +

+

+ Many people have tried to explain aging as a loss of cells, resulting from an intrinsic inability of any + cell other than a germ cell to multiply more than a certain number of times. More than 40 years ago Leonard + Hayflick popularized this doctrine in its most extreme form, saying that no cell can divide more than 50 + times unless it is converted into a cancer cell. He and his followers claimed that they had explained why + organisms must age and die. At the moment the ovum is fertilized, the clock starts ticking for the + essentially mortal somatic cells. +

+

+ In 1970, it was being seriously proposed that memory was produced by the death of brain cells, in a manner + analogous to the holes punched in cards to enter data into computers. The cultural dogma made it impossible + to consider that learning could be associated with the birth of new cells in the adult brain. +

+

+ With the announcement in 1997 of the cloning of the sheep Dolly from a somatic cell taken from a 6 year old + sheep, there was renewed interest in the idea made famous by Alexis Carrel that all cells are potentially + immortal, and in the possibility of preserving the vitality of human cells. Within a few months, Hayflick + began reminding the public that "In the early 1960's we overthrew this dogma after finding that normal cells + do have a finite replicative capacity." ("During the first half of this century it was believed that because + cultured normal cells were immortal, aging must be caused by extra-cellular events.") The way Hayflick + "overthrew" more than 35 years of work at the Rockefeller Institute was by growing one type of cell, a lung + fibroblast, in culture dishes, and finding that the cultures deteriorated quickly. +

+ +

+ To draw global conclusions about an organism's development and aging from the degenerative processes seen in + a single type of cell, grown in isolation from all normal stimuli, would have been treated as nothing but + wild speculation, except that it occurred within a culture that needed it. No aspect of Hayflick's cell + culture system could properly be called physiological. +

+

+ Other researchers, simply by changing a single factor, caused great increases in the longevity of the + cultured cells. Simply using a lower, more natural oxygen concentration, the cells were able to undergo 20 + more divisions. Just by adding niacin, 30 more divisions; vitamin E, 70 more divisions. Excess oxygen is a + poison requiring constant adaptation. +

+

+ Hayflick also published the observation that, while the cells kept in dishes at approximately body + temperature deteriorated, cells kept frozen in liquid nitrogen didn't deteriorate, and he concluded that + "time" wasn't the cause of aging. When I read his comments about the frozen cells, I wondered how anyone of + normal intelligence could make such stupid statements. Since then, facts that came out because of the + Freedom of Information Act, cause me to believe that a financial motive guided his thoughts about his + cultured fibroblasts. +

+

+ Hayflick and his followers have been attacking the idea of anti-aging medicine as quackery. But he is + closely involved with the Geron corporation, which proposes that genetic alterations relating to telomeres + may be able to cure cancer and prevent aging. Their claims were reported by CNN as "Scientists discover + cellular 'fountain of youth'." +

+ +

+ The "wear and tear" doctrine of aging that derived from the ideology of the gene was reinforced and renewed + by Hayflick's cell culture observations, and it continued to rule the universities and popular culture. +

+

+ But detailed investigation of skin cell growth showed that cells in the lower layer of the skin divide at + least 10,000 times in a normal lifetime, and similar processes occur in the lining of the intestine. The + endometrium and other highly renewable tissues just as obviously violated Hayflick's limit. Transplantation + experiments showed that pieces of mammary tissue or skin tissue could survive through ten normal lifetimes + of experimental animals without suffering the effects of aging. +

+

+ Even the liver and adrenal gland are now known to be continuously renewed by "cell streaming," though at a + slower rate than the skin, conjunctiva, and intestine. Neurogenesis in the brain is now not only widely + accepted, it is even proposed as a mechanism to explain the therapeutic effects of antidepressants + (Santarelli, et al., 2003). +

+ +

+ August Weismann's most influential doctrine said that "somatic cells are mortal, only the germline cells are + immortal," but he based the doctrine on his mistaken belief that only the "germline" cells contained all the + genes of the organism. In 1885, to "refute" Darwin's belief that acquired traits could be inherited, he + promulgated an absolute "barrier" between "germline" and "soma," and invented facts to show that hereditary + information can flow only from the germline to the somatic cells, and not the other direction. Shortly after + DNA became popular in the 1950s as "the genetic material," Weismann's barrier was restated as the Central + Dogma of molecular genetics, that information flows only from DNA to RNA to protein, and never the other + direction. +

+

+ It was only in 2003, after the reality of cloning was widely recognized, that a few experimenters began to + investigate the origin of "germline" cells in the ovary, and to discover that they derive from somatic cells + (Johnson, et al., 2004). With this discovery, the ancient knowledge that a twig (klon, in Greek) + cut from a tree could grow into a whole tree, bearing fruit and viable seeds, was readmitted to general + biology, and the Weismann barrier was seen to be an illusion. +

+

+ Millions of people have "explained" female reproductive aging as the consequence of the ovary "running out + of eggs." Innumerable publications purported to show the exact ways in which that process occurs, following + the Weismann doctrine. But now that it is clear that adult ovaries can give birth to new oocytes, a new + explanation for female reproductive aging is needed. It is likely that the same factors that cause female + reproductive aging also cause aging of other systems and organs and tissues, and that those factors are + extrinsic to the cells themselves, as Alexis Carrel and others demonstrated long ago. This is a way of + saying that all cells are potential stem cells. The "niche" in which new cells are born in the streaming + organism, and the processes by which damaged cells are removed, are physiological issues that can be + illuminated by the idea of a morphogenetic field. +

+

+ When the post-war genetic engineers took over biological research, the idea of a biophysical field was + totally abandoned, but after about 15 years, it became necessary to think of problems beyond those existing + within a single bacterium, namely, the problem of how an ovum becomes and embryo. Francis Crick, of DNA + fame, who was educated as a physicist, revived (without a meaningful historical context) the idea of a + diffusion gradient as a simple integrating factor that wouldn't be too offensive to the reductionists. But + for events far beyond the scale of the egg's internal structure, for example to explain how a nerve axon can + travel a very long distance to innervate exactly the right kind of cell, the diffusion of molecules loses + its simplicity and plausibility. (Early in the history of experimental embryology, it was observed that + electrical fields affect the direction of growth of nerve fibers.) +

+

+ C. M. Child saw a gradient of metabolic activity as an essential component of the morphogenetic field. This + kind of gradient doesn't deny the existence of diffusion gradients, or other physical components of a field. + Electrical and osmotic (and electro-osmotic) events are generated by metabolism, and affect other factors, + including pH, oxidation and reduction, cell motility and cell shape, ionic selectivity and other types of + cellular selectivity and specificity. Gradients of DNA methylation exist, and affect the expression of + inherited information. +

+

+ Methylation decreases the expression of particular genes, and during the differention of cells in the + development of an embryo, genes are methylated and demethylated as the cell adapts to produce the proteins + that are involved in the structure and function of a particular tissue. Methylation (which increases a + molecule's affinity for fats) is a widespread process in cells, and for example regulates cellular + excitability. It is affected by diet and a variety of stresses. +

+

+ DNA methylation patterns are normally fairly stable, and can help to account for the transgenerational + transmission of acquired adaptations, and for neonatal imprinting that can last a lifetime. But with injury, + stress, and aging, the methylation patterns of differentiated tissues can be changed, contributing to the + development of tumors, or to the loss of cellular functions. Even learning can change the methylation of + specific genes. During in vitro culture, the enzymes of gene methylation are known to be increased, + relative to their normal activity (Wang, et al., 2005). +

+ +

+ The phenomenon of "gene" methylation in response to environmental and metabolic conditions may eventually + lead to the extinction of the doctrine that "cells are controlled by their genes." +

+

+ During successful adaptation to stress, cells make adjustments to their metabolic systems (for example with + a holistic change of the degree of phosphorylation, which increases molecules' affinity for water), and + their metabolic processes can contribute to changes in their state of differentiation. Some changes may lead + to successful adaptation (for example by producing biogenic stimulators that stimulate cell functioning and + regeneration), others to failed adaptation. Even the decomposition of cells can release substances that + contribute to the adaptation of surrounding cells, for example when sphingosines stimulate the production of + stem cells. +

+

+ DNA methylation is just one relatively stable event that occurs in relation to a metabolic field. + Modifications of histones (regulatory proteins in chromosomes, which are acetylated as well as methylated) + and structural-contractile filaments also contribute to the differentiation of cells, but the pattern of DNA + methylation seems to guide the methylation of histones and the structure of the chromosomes (Nan, et al., + 1998). +

+

+ Steroids and phospholipids, neurotransmitters and endorphins, ATP, GTP, other phosphates, retinoids, NO and + CO2--many materials and processes participate in the coherence of the living state, the living substance. + Carbon dioxide, for example, by binding to lysine amino groups in the histones, will influence their + methylation. Carbon dioxide is likely to affect other amino groups in the chromosomes. +

+ +

+ The number and arrangement of mitochondria is an important factor in producing and maintaining the metabolic + gradients. Things that decrease mitochondrial energy production--nitric oxide, histamine, cytokines, + cortisol--increase DNA methylation. Decreased gene expression is associated with reduced respiratory energy. + It seems reasonable to guess that increased gene expression would demand increased availability of energy. +

+

+ As an ovum differentiates into an organism, cells become progressively more specialized, inhibiting the + expression of many genes. Less energy is needed by stably functioning cells, than by actively adapting + cells. A.I. Zotin described the process of maturing and differentiating as a decrease of entropy, an + increase of order accompanying a decreased energy expenditure. The entropic egg develops into a less + entropic embryo with a great expenditure of energy. +

+

+ The partially differentiated stem cell doesn't go through all the stages of development, but it does expend + energy intensely as it matures. +

+

+ The restoration of energy is one requirement for the activation of regeneration. When a hormone such as + noradrenaline or insulin causes a stem cell to differentiate in vitro, it causes new mitochondria to form. + This is somewhat analogous to the insertion of mitochondria into the ripening oocyte, by the nurse cells + that surround it. The conditionally decreased entropy of maturation is reversed, and when sufficient + respiratory energy is available, the renewed and refreshed cell will be able to renew an appropriate degree + of differentiation. +

+

+ When simple organisms, such as bacteria, fungi, or protozoa are stressed, for example by the absence of + nutrients or the presence of toxins, they slow their metabolism, and suppress the expression of genes, + increasing the methylation of DNA, to form resistant and quiescent spores. Our differentiated state doesn't + go to the metabolic extreme seen in sporulation, but it's useful to look at maturity and aging in this + context, because it suggests that the wrong kind of stress decreases the ability of the organism to adapt, + by processes resembling those in the spore-forming organisms. +

+ +

+ Charles Vacanti, who has grown cartilage from cells taken from 100 year old human cartilage, believes our + tissues contain "spore cells," very small cells with slow metabolism and extreme resistance to heat, cold, + and starvation. +

+

+ If the slowed metabolism of aging, like that of sporulating cells, is produced by a certain kind of stress + that lowers cellular energy and functions, it might be useful to think of the other stages of the stress + reaction in relation to the production of stem cells. Selye divided stress into a first stage of shock, + followed by a prolonged adaptation, which could sometimes end in exhaustion. If the maturity of + differentiated functioning is equivalent to the adaptation phase, and cellular decline and disintegration is + the exhaustion phase, then the shock-like reaction would correspond to the birth of new stem cells. +

+

+ Selye described estrogen's effects as equivalent to the shock-phase of stress. Estrogen's basic action is to + make oxygen unavailable, lowering the oxygen tension of the tissues, locally and temporarily. Like nitric + oxide, which is produced by estrogenic stimulation, estrogen interferes with energy production, so if its + stimulation is prolonged, cells are damaged or killed, rather than being stimulated to regenerate. +

+

+ Extrinsic factors elicit renewal, the way stress can elicit adaptation. While aging cells can't use the + oxygen that is present, a scarcity of oxygen can serve as a stimulus to maximize the respiratory systems. + Brief oxygen deprivation excites a cell, causes it to swell, and to begin to divide. +

+ +

+ Oxygen deprivation, as in the normally hypoxic bone marrow, stimulates the formation of stem cells, as well + as the biogenesis of mitochondria. As the newly formed cells, with abundant mitochondria, get adequate + oxygen, they begin differentiation. +

+

+ Form, based on cellular differentiation, follows function--a vein transplanted into an artery develops + anatomically into an artery, a colon attached directly to the anus becomes a new rectum with its appropriate + innervation, a broken bone restructures to form a normal bone. If the bladder is forced to function more + than normal, by artificially keeping it filled, its thin wall of smooth muscle develops into a thick wall of + striated muscle that rhythmically contracts, like the heart. If a tadpole is given a vegetarian diet, the + absorptive surface of its digestive system will develop to be twice the size of those that are fed meat. + Pressure, stretching, and pulsation are among the signals that guide cells' differentiation. +

+

+ Very early in the study of embryology it was noticed that the presence of one tissue sometimes induced the + differentiation of another kind, and also that there were factors in embryonic tissues that would stimulate + cell division generally, and others that could inhibit the growth of a particular tissue type. Diffusable + substances and light were among the factors identified as growth regulators. +

+

+ Extracts of particular tissues were found to suppress the multiplication of cells in that type of tissue, in + adult animals as well as in embryos. In the 1960s, the tissue-specific inhibitors were called chalones. +

+

+ The brain's development is governed by the presence in the organism of the body part to which it + corresponds, such as the eyes or legs. The number of cells in a particular part of the nervous system is + governed by the quantity of nervous input, sensory or motor, that it receives. An enriched environment + causes a bigger brain to grow. Sensory nerve stimulation of a particular region of the brain causes nerve + cells to migrate to that area (a process called neurobiotaxis; deBeers, 1927), but nerve stimulation also + causes mitochondria to accumulate in stimulated areas. Nerve activity has a trophic, sustaining influence on + other organs, as well as on the brain. Nerve stimulation, like mechanical pressure or stretching, is an + important signal for cellular differentiation. +

+ +

+ When stem cells or progenitor cells are called on to replace cells in an organ, they are said to be + "recruited" by that organ, or to "home" to that organ, if they are coming from elsewhere. Traditionally, the + bone marrow has been considered to be the source of circulating stem cells, but it now appears that a + variety of other less differentiated cells can be recruited when needed. Cells from the blood can repair the + endothelium of blood vessels, and endothelial cells can become mesenchymal cells, in the heart, for example. +

+

+ The standard doctrine about cancer is that a tumor derives from a single mutant cell, but it has been known + for a long time that different types of cell, such as phagocytes and mast cells, usually reside in tumors, + and it is now becoming clear that tumors recruit cells, including apparently normal cells, from other parts + of the same organ. For example, a brain tumor of glial cells, a glioma, recruits glial cells from + surrounding areas of the brain, in a process that's analogous to the embryological movement of nerve cells + to a center of excitation. Each tumor, in a sense, seems to be a center of excitation, and its fate seems to + depend on the nature of the cells that respond to its signals. +

+

+ To accommodate some of the newer facts about tumors, the cancer establishment has begun speaking of "the + cancer stem cell" as the real villain, the origin of the tumor, while the bulk of the tumor is seen to be + made up of defective cells that have a short life-span. But if we recognize that tumors are recruiting cells + from beyond their boundaries, this process would account for the growth and survival of a tumor even while + most of its cells are inert and dying, without invoking the invisible cancer stem cell. And this view, that + it is the field which is defective rather than the cell, is consistent with the evidence which has been + accumulating for 35 years that tumor cells, given the right environment, can differentiate into healthy + cells. (Hendrix, et al., 2007) +

+ +

+ Simply stretching an organ (Woo, et al., 2007) is stimulus enough to cause it to recruit cells from the + bloodstream, and will probably stimulate multiplication in its local resident cells, too. Every "cancer + field" probably begins as a healing process, and generally the healing and regeneration are at least + partially successful. +

+

+ When an organ--the brain, heart, liver, or a blood vessel--is inflamed or suffering from an insufficient + blood supply, stem cells introduced into the blood will migrate specifically to that organ. +

+

+ Organ specific materials (chalones) are known to circulate in the blood, inhibiting cell division in cells + typical to that organ, but it also seems that organ specific materials are secreted by a damaged organ, that + help to prepare stem cells for their migration into that organ. When undifferentiated cells are cultured + with serum from a person with liver failure, they begin to differentiate into liver cells. +

+

+ It is still common to speak of each organ as having a "clonal origin" in the differentiating embryo, as a + simple expansion of a certain embryonic anlage. The implication of this way of thinking is that + differentiation is determination in an irreversible sense. This is another case of medical ideas + being based on images of fixed histological material. Normal cells, including nerve and muscle cells, can + change type, with connective tissue cells becoming nerve cells, nerve cells becoming muscle and fiber cells, + fat, fiber, and muscle cells redifferentiating, for example. +

+ +

+ Cell movements in solid tissues aren't limited to the short distances between capillaries and the tissues + nourished by those capillaries, rather, cells can migrate much greater distances, without entering the + bloodstream. The speed of a single cell moving by ameboid motion can be measured by watching cells on a + glass slide as they move toward food, or by watching cells of the slime mold Dictyostelium when they are + aggregating, or by watching the pigment cells in and around moles or melanomas, under the influence of + hormones. At body temperature, a single cell can crawl about an inch per day. Waves or spots of brown + pigment can be seen migrating through the skin away from a mole, preceding the disintegration of the mole + under the influence of progesterone or DHEA. Under ordinary conditions, pigment cells can sometimes be seen + migrating into depigmented areas of skin, during the recovery of an area affected by vitiligo. These + organized movements of masses of cells happen to be easy to see, but there is evidence that other types of + cell can reconstruct tissues by their ameboid movements, when circumstances are right. Tumors or tissue + abnormalities can appear or disappear with a suddenness that seems impossible to people who have studied + only fixed tissue preparations. +

+

+ Stimulation is anabolic, building tissue, when the organism is adapting to the stimulation. Unused + structures in cells and tissues are always being recycled by metabolic processes. When tissues are injured + and become unable to function, some of their substances stimulate the growth of replacement cells. +

+

+ Some types of injury or irritation can activate regenerative processes. A dermatology journal described the + case of an old man who had been bald for many years who fell head-first into his fireplace. As his burned + scalp healed, new hair grew. In the U.S., experimenters (Ito, et al., 2007) have found that injuring the + skin of mice stimulates the formation of stem cells that are able to become hair follicle cells, supporting + the regeneration of cells that had been absent. A brief exposure to estrogen, and other stress related + signals (nitric oxide, endorphin, prostaglandins) can initiate stem cell proliferation. +

+

+ In the years after the first world war, Vladimir Filatov, who developed techniques of reconstructive + surgery, including corneal transplants, found that cold storage of tissues (for example, corneas from + cadavers) caused them to function better than fresh tissues, and he found that these stressed tissues would + often spread a healing influence out into the surrounding tissues. Extracts of stressed tissues produced + similar effects. +

+

+ L.V. Polezhaev began studying the regenerative capacities of mammals in the late 1940s, and his work showed + that processes similar to embryonic induction are involved in the organism's responses to damaged tissues. + For example, when a piece of killed muscle tissue is enclosed in a capsule ("diffusion chamber") that + permits molecules, but no cells, to diffuse through it, and implanted subcutaneously, it had no inductive + effect on surrounding cells. But when the pores of the capsule allowed cells to enter, skeletal muscle + formed where the dead tissue had been, and tissue resembling heart muscle formed outside the capsule. + Phagocytosis had been essential for the induction to occur. +

+ +

+ Macrophages are ordinarily thought of as "antigen-presenting cells" that help to activate the specific + immune responses. But apparently phagocytosis is involved in the replacement of damaged tissues, by + recruiting or inducing the differentiation of replacement cells. The phagocytosis function isn't limited to + the blood cells commonly called phagocytes; even nerve cells can ingest particles and fragments of damaged + tissues. +

+

+ Many factors regulate the process of phagocytosis. Stress and lipid peroxidation decrease phagocytosis + (Izg"t-Uysal, et al., 2004), and also damage mitochondria and inhibit cell renewal. +

+

+ Unsaturated fatty acids inhibit phagocytosis (Guimaraes, et al., 1991, 1992; Costa Rosa, et al., 1996; + Virella, et al., 1989; Akamatsu, et al., 1990), and suppress mitochondrial function (Gomes, et al., 2006). + Dietary restriction activates phagocytosis (Moriguchi, et al., 1989), suggesting that normal diets contain + suppressive materials. +

+

+ Subnormal temperatures cause a shift from phagocytosis to inflammation. Light, especially the red light + which penetrates easily into tissues, activates the formation of new cells as well as their differentiation. + It affects energy production, increasing the formation of mitochondria, and the activity of the DNA + methyltransferase enzymes. Red light accelerates wound healing, and improves the quality of the scar, + reducing the amount of fibrosis. The daily cycling between darkness and light is probably an important + factor in regulating the birth and differentiation of cells. +

+

+ Darkness suppresses mitochondrial function, and light activates it. Prolonged darkness increases cortisol, + and cortisol (which makes cells more susceptible to excitotoxic death) inhibits stem cell proliferation (Li, + et al., 2006; Liu, et al., 2003). Neurogenesis is suppressed by stress, and increased by spontaneous + activity, and has a circadian rhythm. Aging and depression both involve a diminished ability to rhythmically + lower the production of cortisol. Cell renewal requires a rhythmic decrease in the exposure to cortisol.. +

+ +

+ In the spring, with increased day length, the brains of song-birds grow, with an increased proliferation of + cells in the part of the brain involved in singing. The production of progesterone increases in most animals + in the spring, and it is the main hormone responsible for the birds' brain growth. +

+

+ Progesterone and its metabolites protect brain cells against injury, and improve the brain's ability to + recover after traumatic injury (Brinton and Wang, 2006). In the 1960s, Marion Diamond's group showed that + environmental enrichment, or progesterone, caused brains to grow larger, and that these changes were passed + on to descendants in a cumulative, increasing way. This suggests that the factors that promote neurogenesis + also cause changes in the apparatus of reproduction and inheritance, that support the development of the + brain--probably including the methylation system, which is involved in regulating genes, and also mood and + behavior. +

+

+ Women's monthly cycles, in which a brief estrogen dominance is followed by sustained exposure to + progesterone, are probably an important factor in the renewal of the cells of the brain and other organs, as + well as those of the reproductive organs. The daily rhythms of hormones and metabolism are known to be + involved in the regulation of cell renewal. +

+

+ Environmental enrichment, learning, high altitude, and thyroid hormone promote the formation of new + mitochondria, and stimulate stem cell proliferation. At least in some laboratories, 20% oxygen, + approximately the amount as in the atmosphere, suppresses the proliferation of stem cells (He, et al., + 2007). This was the unphysiologically high concentration of oxygen used in Hayflick's cell cultures. At high + altitudes, where tissues are exposed to less oxygen, and more carbon dioxide, there is a lower incidence of + all the degenerative diseases, including cancer, heart disease, and dementia. Improved cellular energy + production and more active renewal of cells would probably account for those differences. +

+ +

+ For Crick, the idea of a diffusion gradient to explain embryonic development was simply an extension of his + reductionist orientation, in which diffusing molecules induced or inhibited bacterial genes, and in which + genes controlled cells. For people with that orientation, the adaptive mutations described by Carl + Lindegren, and later by John Cairns, or even the stress-induced variability described by Lysenko, Strong, + and McClintock, were heretical. Polezhaev's demonstration that cells could do something that molecular + diffusion didn't do, threatened to take biology away from the reductionists. If the organism's adaptation to + the environment involves changing its own genes, Crick's paradigm fails. +

+

+ Crick's Central Dogma, derived from the ideology that produced Weismann's Barrier, has been invoked by + generations of professors who wanted to deny the possibility of adaptive tissue renewal and regeneration. + Without the dogma, new ideas about aging and disease will be needed. If somatic cells can adjust their + genes, and if they can also differentiate into new eggs and sperms, new ideas about inheritance of acquired + traits will be needed. +

+

+ The replacement of injured cells means that mutations need not accumulate. Cell renewal with elimination of + mutant cells has been observed in sun-damaged skin simply by stopping the damage, and mitochondria with + damaged DNA can be replaced by healthy mitochondria simply by doing the right kind of exercise. +

+

+ The regulation of cell renewal probably involves all of the processes of life, but there are a few simple, + interacting factors that suppress renewal. The accumulation of polyunsaturated fats, interacting with a high + concentration of oxygen, damages mitochondria, and causes a chronic excessive exposure to cortisol. With + mitochondrial damage, cells are unable to produce the progesterone needed to oppose cortisol and to protect + cells. +

+ +

+ Choosing the right foods, the right atmosphere, the right mental and physical activities, and finding the + optimal rhythms of light, darkness, and activity, can begin to alter the streaming renewal of cells in all + the organs. Designing a more perfect environment is going to be much simpler than the schemes of the genetic + engineers. +

+

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+

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+ +

+ Nature. 1998 May 28;393(6683):386-9. Transcriptional repression by the methyl-CpG-binding protein + MeCP2 involves a histone deacetylase complex. Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, + Eisenman RN, Bird A. +

+

+ L. V. Polezhaev and E. N. Karnaukhova, "Stimulation of physiologic regeneration of nervous tissue of + the cerebral cortex and its significance for biogenic therapy of neuro-mental diseases," pages 86-116 in + + Sbornik: Klinicheskie eksperimentalnye osnovy biogennoi terapii psikhozov, + 1962. +

+ +

+ Doklady AN SSSR 150, 430-433, 1963., "Stimulation of nerve cell reproduction of cerebral cortex in + mammals," L. V. Polezhaev and E. N. Karnaukhove +

+

+ L. V. Polezhaev, Loss and Restoration of Regenerative Capacity in Tissues and Organs of + Animals, page 219, 1972. +

+

+ J Hirnforsch 1991;32(5):659-664. Normalization of protein synthesis and the structure of brain + dystrophic neurons after the action of hypoxia, 10% NaCl and organ-specific RNA. Polezhaev LV, + Cherkasova LV, Vitvitsky VN, Timonin AV "Transplantation of embryonic nervous tissue (ENT) in one of + the hemispheres normalizes all the above abnormalities observed in some neurologic and mental diseases + in humans." + + "At the beginning 10% NaCl increased the destruction of brain cortical neurons and then stimulated + protein synthesis in them. RNA injections stimulated the synthesis in cortical neurons and + normalized their structure. Thus, we propose a safe and simple method for normalization of dystrophic + neurons which can be used after certain improvement for curing neurodegenerative and neuropsychic diseases + in humans." +

+

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+ +

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+

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+ +

+ Reprod Biomed Online. 2005 May;10(5):607-16. + Gene expression in the preimplantation embryo: in-vitro developmental changes. + + Wang S, Cowan CA, Chipperfield H, Powers RD. +

+

+ Tissue Eng. 2006 Oct 1; [Epub ahead of print] + Effects of Glutamine, Glucose, and Oxygen Concentration on the Metabolism and Proliferation of Rabbit + Adipose-Derived Stem Cells. Follmar KE, Decroos FC, Prichard HL, Wang HT, Erdmann D, Olbrich + KC. +

+

+ J Urol. 2007 Apr;177(4):1568-72. Over expression of stem cell homing cytokines in urogenital organs + following vaginal distention. Woo LL, Hijaz A, Kuang M, Penn MS, Damaser MS, Rackley RR. +

+ +

+ Med Hypotheses. 1981 Oct;7(10):1241-51. The histogenesis of glandular neoplasia. Zajicek G. +

+

+ Stem cells, cell culture, and culture: Issues in regeneration + +

+

+ Cell renewal is a factor in all aspects of health and disease, not just in aging and the degenerative + diseases. Many people are doing valid research relating to cell renewal and regeneration, but its usefulness + is seriously limited by cultural and commercial constraints. By recovering some of our suppressed + traditional culture, I think regenerative therapies can be developed quickly, by identifying and eliminating + as far as possible the main factors that interfere with tissue renewal. +

+

+ Science grew up in the highly authoritarian cultures of western Europe, and even as it contributed to + cultural change, it kept an authoritarian mystique. Any culture functions as a system of definitions of + reality and the limits of possibility, and to a great extent the "laws of nature" are decreed so that they + will harmonize with the recognized laws of society. +

+ +

+ The practical success of Newton's "laws" of motion when they were applied to ballistics and "rocket science" + has led many people to value calculation, based on those laws, over evidence. In biology, the idea that an + organism is "the information it contains in its DNA blueprint" is an extention of this. The organism is + turned into something like a deductive expression of the law of DNA. This attitude has been disastrous. +

+

+ The old feudal idea of a divine and stable social organization was applied by some people to their idea of + biological organization, in which each cell (ruled by its nucleus) had its ordained place in the organism, + with the brain and the "master gland," the pituitary, ruling the subordinate organs, tissues, and cells. + "Anatomy" was taught from dead specimens, microscope slides, and illustrations in books. Most biologists' + thoughts about cells in organisms reflect the static imagery of their instruction. ("The histological + image of these tissues actually reflects an instantaneous picture of cells in a continuous flux." + Zajicek, 1981.) +

+ +

+ When a person has playful and observant interactions with natural things, both regularities and + irregularities will be noticed, and in trying to understand those events, the richness of the experience + will suggest an expansive range of possibilities. Perception and experimentation lead to understandings that + are independent of culture and tradition. +

+

+ But the mystique of science easily imposes itself, and distracts our attention from direct interactions with + things. As we learn to operate lab instruments, we are taught the kinds of results that can be expected, and + the concepts that will explain and predict the results of our operations. Science, as we learn about it in + schools and the mass media, is mostly a set of catechisms. +

+

+ Our theories about organisms inform our experiments with cells or tissues that have been isolated from those + organisms. The conditions for growing cells in dishes are thought of as "physiological," in relation to the + solution's "physiological osmolarity," "physiological pH," nutrients, oxygenation, temperature, pressure, + etc. But these concepts of what is physiological derive from the monolithic ideology of the doctrinaire, and + often fraudulent, mainstream of biological science. +

+ +

+ The catechismic nature of science has led people to expect some "break-throughs" to occur in certain areas, + and as authoritarian science has grown into "big science" managed by corporations and governments, those + break-throughs are generally expected to be produced by the newest and most expensive developments of "high + technology." +

+

+ But looking closely at the real events and processes in the sciences in the last couple of centuries, it + turns out that useful advances have been produced mainly by breaking away from authoritarian doctrines, to + return to common sense and relatively simple direct observations. +

+

+ Although people were cloning animals in the 1960s, it was still widely taught that it was impossible. The + students of the professors who taught that it was impossible are now saying that it requires high technology + and new research. +

+ +

+ For the last 100 years the most authoritative view in biology has been that there are no stem cells in + adults, that brains, hearts, pancreases and oocytes are absolutely incapable of regeneration. But now, + people seem to be finding stem cells wherever they look, but there is a mystique of high technology involved + in finding and using them. +

+

+ Whether it's deliberate or not, the emphasis on stem cell technology has the function of directing attention + away from traditional knowledge, the way allopathic medicine has de-emphasized the intrinsic ability of + people to recover from disease. +

+

+ This resembles the way that the Mendel-Morgan gene doctrine was used to suppress the knowledge gained from + centuries of experience of plant and animal breeders, and to belittle the discoveries of Luther Burbank, + Paul Kammerer, Trofim Lysenko, and Barbara McClintock. The same type of biochemical process that caused the + hereditary changes those researchers studied are involved in the differentiation and dedifferentiation of + stem cells that regulate healing and regeneration. +

+

+ In the 1940s, even children discussed the biological discoveries of the 1920s and 1930s, the work in + regeneration and adaptation, parthenogenesis, and immortalization. The ideas of J. Loeb, T. Boveri, A. + Gurwitsch, J. Needham, C.M. Child, A. Carrel, et al., had become part of the general culture. +

+

+ But that real biology was killed by a consortium of industry and government that began a little before the + second world war. In 1940, the government was supporting research in chemical and biological warfare, and + with the Manhattan Project the role of government became so large that all of the major research + universities were affected. Shortly after the war, many researchers from the Manhattan Project were + redeployed into "molecular genetics," where the engineering attitude was applied to organisms. +

+ +

+ The simplistic genetic dogmas were compatible with the reductionist engineering approach to the organism. + The role of the government assured that the universities would subscribe to the basic scientific agenda. The + atmosphere of that time was described by Carl Lindegren as "The Cold War in Biology" (1966). +

+

+ The disappearance of the field concept in developmental biology was one of the strangest events in the + history of science. It didn't just fade away, it was "disappeared," in a massive undertaking of social + engineering. In its absence, stem cells will seem to be a profitable technological marvel, rather than a + universal life function, with a central role in everything we are and everything we do and can become. +

+

+ Many people have tried to explain aging as a loss of cells, resulting from an intrinsic inability of any + cell other than a germ cell to multiply more than a certain number of times. More than 40 years ago Leonard + Hayflick popularized this doctrine in its most extreme form, saying that no cell can divide more than 50 + times unless it is converted into a cancer cell. He and his followers claimed that they had explained why + organisms must age and die. At the moment the ovum is fertilized, the clock starts ticking for the + essentially mortal somatic cells. +

+

+ In 1970, it was being seriously proposed that memory was produced by the death of brain cells, in a manner + analogous to the holes punched in cards to enter data into computers. The cultural dogma made it impossible + to consider that learning could be associated with the birth of new cells in the adult brain. +

+ +

+ With the announcement in 1997 of the cloning of the sheep Dolly from a somatic cell taken from a 6 year old + sheep, there was renewed interest in the idea made famous by Alexis Carrel that all cells are potentially + immortal, and in the possibility of preserving the vitality of human cells. Within a few months, Hayflick + began reminding the public that "In the early 1960's we overthrew this dogma after finding that normal cells + do have a finite replicative capacity." ("During the first half of this century it was believed that because + cultured normal cells were immortal, aging must be caused by extra-cellular events.") The way Hayflick + "overthrew" more than 35 years of work at the Rockefeller Institute was by growing one type of cell, a lung + fibroblast, in culture dishes, and finding that the cultures deteriorated quickly. +

+

+ To draw global conclusions about an organism's development and aging from the degenerative processes seen in + a single type of cell, grown in isolation from all normal stimuli, would have been treated as nothing but + wild speculation, except that it occurred within a culture that needed it. No aspect of Hayflick's cell + culture system could properly be called physiological. +

+ +

+ Other researchers, simply by changing a single factor, caused great increases in the longevity of the + cultured cells. Simply using a lower, more natural oxygen concentration, the cells were able to undergo 20 + more divisions. Just by adding niacin, 30 more divisions; vitamin E, 70 more divisions. Excess oxygen is a + poison requiring constant adaptation. +

+

+ Hayflick also published the observation that, while the cells kept in dishes at approximately body + temperature deteriorated, cells kept frozen in liquid nitrogen didn't deteriorate, and he concluded that + "time" wasn't the cause of aging. When I read his comments about the frozen cells, I wondered how anyone of + normal intelligence could make such stupid statements. Since then, facts that came out because of the + Freedom of Information Act, cause me to believe that a financial motive guided his thoughts about his + cultured fibroblasts. +

+

+ Hayflick and his followers have been attacking the idea of anti-aging medicine as quackery. But he is + closely involved with the Geron corporation, which proposes that genetic alterations relating to telomeres + may be able to cure cancer and prevent aging. Their claims were reported by CNN as "Scientists discover + cellular 'fountain of youth'." +

+ +

+ The "wear and tear" doctrine of aging that derived from the ideology of the gene was reinforced and renewed + by Hayflick's cell culture observations, and it continued to rule the universities and popular culture. +

+

+ But detailed investigation of skin cell growth showed that cells in the lower layer of the skin divide at + least 10,000 times in a normal lifetime, and similar processes occur in the lining of the intestine. The + endometrium and other highly renewable tissues just as obviously violated Hayflick's limit. Transplantation + experiments showed that pieces of mammary tissue or skin tissue could survive through ten normal lifetimes + of experimental animals without suffering the effects of aging. +

+

+ Even the liver and adrenal gland are now known to be continuously renewed by "cell streaming," though at a + slower rate than the skin, conjunctiva, and intestine. Neurogenesis in the brain is now not only widely + accepted, it is even proposed as a mechanism to explain the therapeutic effects of antidepressants + (Santarelli, et al., 2003). +

+ +

+ August Weismann's most influential doctrine said that "somatic cells are mortal, only the germline cells are + immortal," but he based the doctrine on his mistaken belief that only the "germline" cells contained all the + genes of the organism. In 1885, to "refute" Darwin's belief that acquired traits could be inherited, he + promulgated an absolute "barrier" between "germline" and "soma," and invented facts to show that hereditary + information can flow only from the germline to the somatic cells, and not the other direction. Shortly after + DNA became popular in the 1950s as "the genetic material," Weismann's barrier was restated as the Central + Dogma of molecular genetics, that information flows only from DNA to RNA to protein, and never the other + direction. +

+

+ It was only in 2003, after the reality of cloning was widely recognized, that a few experimenters began to + investigate the origin of "germline" cells in the ovary, and to discover that they derive from somatic cells + (Johnson, et al., 2004). With this discovery, the ancient knowledge that a twig (klon, in Greek) + cut from a tree could grow into a whole tree, bearing fruit and viable seeds, was readmitted to general + biology, and the Weismann barrier was seen to be an illusion. +

+

+ Millions of people have "explained" female reproductive aging as the consequence of the ovary "running out + of eggs." Innumerable publications purported to show the exact ways in which that process occurs, following + the Weismann doctrine. But now that it is clear that adult ovaries can give birth to new oocytes, a new + explanation for female reproductive aging is needed. It is likely that the same factors that cause female + reproductive aging also cause aging of other systems and organs and tissues, and that those factors are + extrinsic to the cells themselves, as Alexis Carrel and others demonstrated long ago. This is a way of + saying that all cells are potential stem cells. The "niche" in which new cells are born in the streaming + organism, and the processes by which damaged cells are removed, are physiological issues that can be + illuminated by the idea of a morphogenetic field. +

+

+ When the post-war genetic engineers took over biological research, the idea of a biophysical field was + totally abandoned, but after about 15 years, it became necessary to think of problems beyond those existing + within a single bacterium, namely, the problem of how an ovum becomes and embryo. Francis Crick, of DNA + fame, who was educated as a physicist, revived (without a meaningful historical context) the idea of a + diffusion gradient as a simple integrating factor that wouldn't be too offensive to the reductionists. But + for events far beyond the scale of the egg's internal structure, for example to explain how a nerve axon can + travel a very long distance to innervate exactly the right kind of cell, the diffusion of molecules loses + its simplicity and plausibility. (Early in the history of experimental embryology, it was observed that + electrical fields affect the direction of growth of nerve fibers.) +

+

+ C. M. Child saw a gradient of metabolic activity as an essential component of the morphogenetic field. This + kind of gradient doesn't deny the existence of diffusion gradients, or other physical components of a field. + Electrical and osmotic (and electro-osmotic) events are generated by metabolism, and affect other factors, + including pH, oxidation and reduction, cell motility and cell shape, ionic selectivity and other types of + cellular selectivity and specificity. Gradients of DNA methylation exist, and affect the expression of + inherited information. +

+

+ Methylation decreases the expression of particular genes, and during the differention of cells in the + development of an embryo, genes are methylated and demethylated as the cell adapts to produce the proteins + that are involved in the structure and function of a particular tissue. Methylation (which increases a + molecule's affinity for fats) is a widespread process in cells, and for example regulates cellular + excitability. It is affected by diet and a variety of stresses. +

+

+ DNA methylation patterns are normally fairly stable, and can help to account for the transgenerational + transmission of acquired adaptations, and for neonatal imprinting that can last a lifetime. But with injury, + stress, and aging, the methylation patterns of differentiated tissues can be changed, contributing to the + development of tumors, or to the loss of cellular functions. Even learning can change the methylation of + specific genes. During in vitro culture, the enzymes of gene methylation are known to be increased, + relative to their normal activity (Wang, et al., 2005). +

+ +

+ The phenomenon of "gene" methylation in response to environmental and metabolic conditions may eventually + lead to the extinction of the doctrine that "cells are controlled by their genes." +

+

+ During successful adaptation to stress, cells make adjustments to their metabolic systems (for example with + a holistic change of the degree of phosphorylation, which increases molecules' affinity for water), and + their metabolic processes can contribute to changes in their state of differentiation. Some changes may lead + to successful adaptation (for example by producing biogenic stimulators that stimulate cell functioning and + regeneration), others to failed adaptation. Even the decomposition of cells can release substances that + contribute to the adaptation of surrounding cells, for example when sphingosines stimulate the production of + stem cells. +

+

+ DNA methylation is just one relatively stable event that occurs in relation to a metabolic field. + Modifications of histones (regulatory proteins in chromosomes, which are acetylated as well as methylated) + and structural-contractile filaments also contribute to the differentiation of cells, but the pattern of DNA + methylation seems to guide the methylation of histones and the structure of the chromosomes (Nan, et al., + 1998). +

+

+ Steroids and phospholipids, neurotransmitters and endorphins, ATP, GTP, other phosphates, retinoids, NO and + CO2--many materials and processes participate in the coherence of the living state, the living substance. + Carbon dioxide, for example, by binding to lysine amino groups in the histones, will influence their + methylation. Carbon dioxide is likely to affect other amino groups in the chromosomes. +

+ +

+ The number and arrangement of mitochondria is an important factor in producing and maintaining the metabolic + gradients. Things that decrease mitochondrial energy production--nitric oxide, histamine, cytokines, + cortisol--increase DNA methylation. Decreased gene expression is associated with reduced respiratory energy. + It seems reasonable to guess that increased gene expression would demand increased availability of energy. +

+

+ As an ovum differentiates into an organism, cells become progressively more specialized, inhibiting the + expression of many genes. Less energy is needed by stably functioning cells, than by actively adapting + cells. A.I. Zotin described the process of maturing and differentiating as a decrease of entropy, an + increase of order accompanying a decreased energy expenditure. The entropic egg develops into a less + entropic embryo with a great expenditure of energy. +

+

+ The partially differentiated stem cell doesn't go through all the stages of development, but it does expend + energy intensely as it matures. +

+

+ The restoration of energy is one requirement for the activation of regeneration. When a hormone such as + noradrenaline or insulin causes a stem cell to differentiate in vitro, it causes new mitochondria to form. + This is somewhat analogous to the insertion of mitochondria into the ripening oocyte, by the nurse cells + that surround it. The conditionally decreased entropy of maturation is reversed, and when sufficient + respiratory energy is available, the renewed and refreshed cell will be able to renew an appropriate degree + of differentiation. +

+

+ When simple organisms, such as bacteria, fungi, or protozoa are stressed, for example by the absence of + nutrients or the presence of toxins, they slow their metabolism, and suppress the expression of genes, + increasing the methylation of DNA, to form resistant and quiescent spores. Our differentiated state doesn't + go to the metabolic extreme seen in sporulation, but it's useful to look at maturity and aging in this + context, because it suggests that the wrong kind of stress decreases the ability of the organism to adapt, + by processes resembling those in the spore-forming organisms. +

+ +

+ Charles Vacanti, who has grown cartilage from cells taken from 100 year old human cartilage, believes our + tissues contain "spore cells," very small cells with slow metabolism and extreme resistance to heat, cold, + and starvation. +

+

+ If the slowed metabolism of aging, like that of sporulating cells, is produced by a certain kind of stress + that lowers cellular energy and functions, it might be useful to think of the other stages of the stress + reaction in relation to the production of stem cells. Selye divided stress into a first stage of shock, + followed by a prolonged adaptation, which could sometimes end in exhaustion. If the maturity of + differentiated functioning is equivalent to the adaptation phase, and cellular decline and disintegration is + the exhaustion phase, then the shock-like reaction would correspond to the birth of new stem cells. +

+

+ Selye described estrogen's effects as equivalent to the shock-phase of stress. Estrogen's basic action is to + make oxygen unavailable, lowering the oxygen tension of the tissues, locally and temporarily. Like nitric + oxide, which is produced by estrogenic stimulation, estrogen interferes with energy production, so if its + stimulation is prolonged, cells are damaged or killed, rather than being stimulated to regenerate. +

+

+ Extrinsic factors elicit renewal, the way stress can elicit adaptation. While aging cells can't use the + oxygen that is present, a scarcity of oxygen can serve as a stimulus to maximize the respiratory systems. + Brief oxygen deprivation excites a cell, causes it to swell, and to begin to divide. +

+ +

+ Oxygen deprivation, as in the normally hypoxic bone marrow, stimulates the formation of stem cells, as well + as the biogenesis of mitochondria. As the newly formed cells, with abundant mitochondria, get adequate + oxygen, they begin differentiation. +

+

+ Form, based on cellular differentiation, follows function--a vein transplanted into an artery develops + anatomically into an artery, a colon attached directly to the anus becomes a new rectum with its appropriate + innervation, a broken bone restructures to form a normal bone. If the bladder is forced to function more + than normal, by artificially keeping it filled, its thin wall of smooth muscle develops into a thick wall of + striated muscle that rhythmically contracts, like the heart. If a tadpole is given a vegetarian diet, the + absorptive surface of its digestive system will develop to be twice the size of those that are fed meat. + Pressure, stretching, and pulsation are among the signals that guide cells' differentiation. +

+

+ Very early in the study of embryology it was noticed that the presence of one tissue sometimes induced the + differentiation of another kind, and also that there were factors in embryonic tissues that would stimulate + cell division generally, and others that could inhibit the growth of a particular tissue type. Diffusable + substances and light were among the factors identified as growth regulators. +

+

+ Extracts of particular tissues were found to suppress the multiplication of cells in that type of tissue, in + adult animals as well as in embryos. In the 1960s, the tissue-specific inhibitors were called chalones. +

+

+ The brain's development is governed by the presence in the organism of the body part to which it + corresponds, such as the eyes or legs. The number of cells in a particular part of the nervous system is + governed by the quantity of nervous input, sensory or motor, that it receives. An enriched environment + causes a bigger brain to grow. Sensory nerve stimulation of a particular region of the brain causes nerve + cells to migrate to that area (a process called neurobiotaxis; deBeers, 1927), but nerve stimulation also + causes mitochondria to accumulate in stimulated areas. Nerve activity has a trophic, sustaining influence on + other organs, as well as on the brain. Nerve stimulation, like mechanical pressure or stretching, is an + important signal for cellular differentiation. +

+ +

+ When stem cells or progenitor cells are called on to replace cells in an organ, they are said to be + "recruited" by that organ, or to "home" to that organ, if they are coming from elsewhere. Traditionally, the + bone marrow has been considered to be the source of circulating stem cells, but it now appears that a + variety of other less differentiated cells can be recruited when needed. Cells from the blood can repair the + endothelium of blood vessels, and endothelial cells can become mesenchymal cells, in the heart, for example. +

+

+ The standard doctrine about cancer is that a tumor derives from a single mutant cell, but it has been known + for a long time that different types of cell, such as phagocytes and mast cells, usually reside in tumors, + and it is now becoming clear that tumors recruit cells, including apparently normal cells, from other parts + of the same organ. For example, a brain tumor of glial cells, a glioma, recruits glial cells from + surrounding areas of the brain, in a process that's analogous to the embryological movement of nerve cells + to a center of excitation. Each tumor, in a sense, seems to be a center of excitation, and its fate seems to + depend on the nature of the cells that respond to its signals. +

+

+ To accommodate some of the newer facts about tumors, the cancer establishment has begun speaking of "the + cancer stem cell" as the real villain, the origin of the tumor, while the bulk of the tumor is seen to be + made up of defective cells that have a short life-span. But if we recognize that tumors are recruiting cells + from beyond their boundaries, this process would account for the growth and survival of a tumor even while + most of its cells are inert and dying, without invoking the invisible cancer stem cell. And this view, that + it is the field which is defective rather than the cell, is consistent with the evidence which has been + accumulating for 35 years that tumor cells, given the right environment, can differentiate into healthy + cells. (Hendrix, et al., 2007) +

+ +

+ Simply stretching an organ (Woo, et al., 2007) is stimulus enough to cause it to recruit cells from the + bloodstream, and will probably stimulate multiplication in its local resident cells, too. Every "cancer + field" probably begins as a healing process, and generally the healing and regeneration are at least + partially successful. +

+

+ When an organ--the brain, heart, liver, or a blood vessel--is inflamed or suffering from an insufficient + blood supply, stem cells introduced into the blood will migrate specifically to that organ. +

+

+ Organ specific materials (chalones) are known to circulate in the blood, inhibiting cell division in cells + typical to that organ, but it also seems that organ specific materials are secreted by a damaged organ, that + help to prepare stem cells for their migration into that organ. When undifferentiated cells are cultured + with serum from a person with liver failure, they begin to differentiate into liver cells. +

+

+ It is still common to speak of each organ as having a "clonal origin" in the differentiating embryo, as a + simple expansion of a certain embryonic anlage. The implication of this way of thinking is that + differentiation is determination in an irreversible sense. This is another case of medical ideas + being based on images of fixed histological material. Normal cells, including nerve and muscle cells, can + change type, with connective tissue cells becoming nerve cells, nerve cells becoming muscle and fiber cells, + fat, fiber, and muscle cells redifferentiating, for example. +

+ +

+ Cell movements in solid tissues aren't limited to the short distances between capillaries and the tissues + nourished by those capillaries, rather, cells can migrate much greater distances, without entering the + bloodstream. The speed of a single cell moving by ameboid motion can be measured by watching cells on a + glass slide as they move toward food, or by watching cells of the slime mold Dictyostelium when they are + aggregating, or by watching the pigment cells in and around moles or melanomas, under the influence of + hormones. At body temperature, a single cell can crawl about an inch per day. Waves or spots of brown + pigment can be seen migrating through the skin away from a mole, preceding the disintegration of the mole + under the influence of progesterone or DHEA. Under ordinary conditions, pigment cells can sometimes be seen + migrating into depigmented areas of skin, during the recovery of an area affected by vitiligo. These + organized movements of masses of cells happen to be easy to see, but there is evidence that other types of + cell can reconstruct tissues by their ameboid movements, when circumstances are right. Tumors or tissue + abnormalities can appear or disappear with a suddenness that seems impossible to people who have studied + only fixed tissue preparations. +

+

+ Stimulation is anabolic, building tissue, when the organism is adapting to the stimulation. Unused + structures in cells and tissues are always being recycled by metabolic processes. When tissues are injured + and become unable to function, some of their substances stimulate the growth of replacement cells. +

+

+ Some types of injury or irritation can activate regenerative processes. A dermatology journal described the + case of an old man who had been bald for many years who fell head-first into his fireplace. As his burned + scalp healed, new hair grew. In the U.S., experimenters (Ito, et al., 2007) have found that injuring the + skin of mice stimulates the formation of stem cells that are able to become hair follicle cells, supporting + the regeneration of cells that had been absent. A brief exposure to estrogen, and other stress related + signals (nitric oxide, endorphin, prostaglandins) can initiate stem cell proliferation. +

+

+ In the years after the first world war, Vladimir Filatov, who developed techniques of reconstructive + surgery, including corneal transplants, found that cold storage of tissues (for example, corneas from + cadavers) caused them to function better than fresh tissues, and he found that these stressed tissues would + often spread a healing influence out into the surrounding tissues. Extracts of stressed tissues produced + similar effects. +

+

+ L.V. Polezhaev began studying the regenerative capacities of mammals in the late 1940s, and his work showed + that processes similar to embryonic induction are involved in the organism's responses to damaged tissues. + For example, when a piece of killed muscle tissue is enclosed in a capsule ("diffusion chamber") that + permits molecules, but no cells, to diffuse through it, and implanted subcutaneously, it had no inductive + effect on surrounding cells. But when the pores of the capsule allowed cells to enter, skeletal muscle + formed where the dead tissue had been, and tissue resembling heart muscle formed outside the capsule. + Phagocytosis had been essential for the induction to occur. +

+ +

+ Macrophages are ordinarily thought of as "antigen-presenting cells" that help to activate the specific + immune responses. But apparently phagocytosis is involved in the replacement of damaged tissues, by + recruiting or inducing the differentiation of replacement cells. The phagocytosis function isn't limited to + the blood cells commonly called phagocytes; even nerve cells can ingest particles and fragments of damaged + tissues. +

+

+ Many factors regulate the process of phagocytosis. Stress and lipid peroxidation decrease phagocytosis + (Izg"t-Uysal, et al., 2004), and also damage mitochondria and inhibit cell renewal. +

+

+ Unsaturated fatty acids inhibit phagocytosis (Guimaraes, et al., 1991, 1992; Costa Rosa, et al., 1996; + Virella, et al., 1989; Akamatsu, et al., 1990), and suppress mitochondrial function (Gomes, et al., 2006). + Dietary restriction activates phagocytosis (Moriguchi, et al., 1989), suggesting that normal diets contain + suppressive materials. +

+

+ Subnormal temperatures cause a shift from phagocytosis to inflammation. Light, especially the red light + which penetrates easily into tissues, activates the formation of new cells as well as their differentiation. + It affects energy production, increasing the formation of mitochondria, and the activity of the DNA + methyltransferase enzymes. Red light accelerates wound healing, and improves the quality of the scar, + reducing the amount of fibrosis. The daily cycling between darkness and light is probably an important + factor in regulating the birth and differentiation of cells.. +

+

+ Darkness suppresses mitochondrial function, and light activates it. Prolonged darkness increases cortisol, + and cortisol (which makes cells more susceptible to excitotoxic death) inhibits stem cell proliferation (Li, + et al., 2006; Liu, et al., 2003). Neurogenesis is suppressed by stress, and increased by spontaneous + activity, and has a circadian rhythm. Aging and depression both involve a diminished ability to rhythmically + lower the production of cortisol. Cell renewal requires a rhythmic decrease in the exposure to cortisol.. +

+ +

+ In the spring, with increased day length, the brains of song-birds grow, with an increased proliferation of + cells in the part of the brain involved in singing. The production of progesterone increases in most animals + in the spring, and it is the main hormone responsible for the birds' brain growth. +

+

+ Progesterone and its metabolites protect brain cells against injury, and improve the brain's ability to + recover after traumatic injury (Brinton and Wang, 2006). In the 1960s, Marion Diamond's group showed that + environmental enrichment, or progesterone, caused brains to grow larger, and that these changes were passed + on to descendants in a cumulative, increasing way. This suggests that the factors that promote neurogenesis + also cause changes in the apparatus of reproduction and inheritance, that support the development of the + brain--probably including the methylation system, which is involved in regulating genes, and also mood and + behavior. +

+

+ Women's monthly cycles, in which a brief estrogen dominance is followed by sustained exposure to + progesterone, are probably an important factor in the renewal of the cells of the brain and other organs, as + well as those of the reproductive organs. The daily rhythms of hormones and metabolism are known to be + involved in the regulation of cell renewal. +

+

+ Environmental enrichment, learning, high altitude, and thyroid hormone promote the formation of new + mitochondria, and stimulate stem cell proliferation. At least in some laboratories, 20% oxygen, + approximately the amount as in the atmosphere, suppresses the proliferation of stem cells (He, et al., + 2007). This was the unphysiologically high concentration of oxygen used in Hayflick's cell cultures. At high + altitudes, where tissues are exposed to less oxygen, and more carbon dioxide, there is a lower incidence of + all the degenerative diseases, including cancer, heart disease, and dementia. Improved cellular energy + production and more active renewal of cells would probably account for those differences. +

+ +

+ For Crick, the idea of a diffusion gradient to explain embryonic development was simply an extension of his + reductionist orientation, in which diffusing molecules induced or inhibited bacterial genes, and in which + genes controlled cells. For people with that orientation, the adaptive mutations described by Carl + Lindegren, and later by John Cairns, or even the stress-induced variability described by Lysenko, Strong, + and McClintock, were heretical. Polezhaev's demonstration that cells could do something that molecular + diffusion didn't do, threatened to take biology away from the reductionists. If the organism's adaptation to + the environment involves changing its own genes, Crick's paradigm fails. +

+

+ Crick's Central Dogma, derived from the ideology that produced Weismann's Barrier, has been invoked by + generations of professors who wanted to deny the possibility of adaptive tissue renewal and regeneration. + Without the dogma, new ideas about aging and disease will be needed. If somatic cells can adjust their + genes, and if they can also differentiate into new eggs and sperms, new ideas about inheritance of acquired + traits will be needed. +

+

+ The replacement of injured cells means that mutations need not accumulate. Cell renewal with elimination of + mutant cells has been observed in sun-damaged skin simply by stopping the damage, and mitochondria with + damaged DNA can be replaced by healthy mitochondria simply by doing the right kind of exercise. +

+

+ The regulation of cell renewal probably involves all of the processes of life, but there are a few simple, + interacting factors that suppress renewal. The accumulation of polyunsaturated fats, interacting with a high + concentration of oxygen, damages mitochondria, and causes a chronic excessive exposure to cortisol. With + mitochondrial damage, cells are unable to produce the progesterone needed to oppose cortisol and to protect + cells. +

+ +

+ Choosing the right foods, the right atmosphere, the right mental and physical activities, and finding the + optimal rhythms of light, darkness, and activity, can begin to alter the streaming renewal of cells in all + the organs. Designing a more perfect environment is going to be much simpler than the schemes of the genetic + engineers. +

+

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+

+ Reprod Biomed Online. 2005 May;10(5):607-16. + Gene expression in the preimplantation embryo: in-vitro developmental changes. + + Wang S, Cowan CA, Chipperfield H, Powers RD. +

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+ Tissue Eng. 2006 Oct 1; [Epub ahead of print] + Effects of Glutamine, Glucose, and Oxygen Concentration on the Metabolism and Proliferation of Rabbit + Adipose-Derived Stem Cells. Follmar KE, Decroos FC, Prichard HL, Wang HT, Erdmann D, Olbrich + KC. +

+ +

+ J Urol. 2007 Apr;177(4):1568-72. Over expression of stem cell homing cytokines in urogenital organs + following vaginal distention. Woo LL, Hijaz A, Kuang M, Penn MS, Damaser MS, Rackley RR. +

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+ Med Hypotheses. 1981 Oct;7(10):1241-51. The histogenesis of glandular neoplasia. Zajicek G. +

+ + © Ray Peat Ph.D. 2007. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/sugar-issues.html b/raypeat-articles/processed/sugar-issues.html new file mode 100644 index 0000000..f83511a --- /dev/null +++ b/raypeat-articles/processed/sugar-issues.html @@ -0,0 +1,495 @@ + + + +

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+ + Sugar issues +

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Since the first doctor noticed, hundreds of years ago, that the urine of a diabetic patient tasted sweet, + it has been common to call the condition the sugar disease, or sugar diabetes, and since nothing was known about + physiological chemistry, it was commonly believed that eating too much sugar had to be the cause, since the + ability of the body to convert the protein in tissues into sugar wasn"t discovered until 1848, by Claude Bernard + (who realized that diabetics lost more sugar than they took in). Even though patients continued to pass sugar in + their urine until they died, despite the elimination of sugar from their diet, medical policy required that they + be restrained to keep them from eating sugar. That prescientific medical belief, that eating sugar causes + diabetes, is still held by a very large number, probably the majority, of physicians. Originally, diabetes was + understood to be a wasting disease, but as it became common for doctors to measure glucose, obese people were + often found to have hyperglycemia, so the name diabetes has been extended to them, as type 2 diabetes. High + blood sugar is often seen along with high blood pressure and obesity in Cushing's syndrome, with excess + cortisol, and these features are also used to define the newer metabolic syndrome. Following the old reasoning + about the sugar disease, the newer kind of obese diabetes is commonly blamed on eating too much sugar. Obesity, + especially a fat waist, and all its associated health problems, are said by some doctors to be the result of + eating too much sugar, especially fructose. (Starch is the only common carbohydrate that contains no fructose.) + Obesity is associated not only with diabetes or insulin resistance, but also with atheroslcerosis and heart + disease, high blood pressure, generalized inflammation, arthritis, depression, risk of dementia, and cancer. + There is general agreement about the problems commonly associated with obesity, but not about the causes or the + way to prevent or cure obesity and the associated conditions. In an earlier newsletter, I wrote about P. A. + Piorry in Paris, in 1864, and Dr. William Budd in England, in 1867, who treated diabetes by adding a large + amount of ordinary sugar, sucrose, to the patient's diet. Glucose was known to be the sugar appearing in the + diabetics' urine, but sucrose consists of half glucose, and half fructose. In 1874, E. Kulz in Germany reported + that diabetics could assimilate fructose better than glucose. In the next decades there were several more + reports on the benefits of feeding fructose, including the reduction of glucose in the urine. With the discovery + of insulin in 1922, fructose therapy was practically forgotten, until the 1950s when new manufacturing + techniques began to make it economical to use. Its use in diabetic diets became so popular that it became + available in health food stores, and was also used in hospitals for intravenous feeding. However, while fructose + was becoming popular, the cholesterol theory of heart disease was being promoted. This was the theory that + eating foods containing saturated fat and cholesterol caused heart disease. (My newsletter, Cholesterol, + longevity, intelligence, and health, discussed the development of that theory.) A Swedish physician and + researcher, Uffe Ravnskov, has reviewed the medical arguments for the theory that lipids in the blood are the + cause of atherosclerosis and heart disease, and shows that there has never been evidence of causality, something + which some people, such as Broda Barnes, understood from the beginning. In the 1950s, an English professor, John + Yudkin, didn't accept the idea that eating saturated fat was the cause of high blood levels of triglycerides and + cholesterol, but he didn"t question the theory that lipids in the blood caused the circulatory disease. He + argued that it was sugar, especially the fructose component of sucrose, rather than dietary fat, that caused the + high blood lipids seen in the affluent countries, and consequently the diseases. He was sure it was a specific + chemical effect of the fructose, because he argued that the nutrients that were removed in refining white flour + and white sugar were insignificant, in the whole diet. Following the publication of Yudkin's books, and + coinciding with increasing promotion of the health benefits of unsaturated vegetable oils, many people were + converted to Yudkin's version of the lipid theory of heart disease, i.e., that the "bad lipids" in the blood are + the result of eating sugar. This has grown into essentially a cult, in which sugar is believed to act like an + intoxicant, forcing people to eat until they become obese, and develop the "metabolic syndrome," and "diabetes," + and the many problems that derive from that. The publicity campaign against "saturated fat" as an ally of + cholesterol derived its support from the commercial promotion of the polyunsaturated seed oils as food for + humans. Although the early investigators of vitamin E knew that the polyunsaturated oils could cause sterility, + and others later found that their use in commercial animal foods could cause brain degeneration, there were a + few biologists (mostly associated with George Burr) who believed that this type of fatty acid is an essential + nutrient. George and Mildred Burr had created what they claimed to be a disease in rats caused by the absence of + linoleic or linolenic acid in their food. Although well known researchers had previously published evidence that + animals on a fat free diet were healthy--even healthier than on a normal diet--Burr and his wife published their + contradictory claim without bothering to discuss the conflicting evidence. I haven't seen any instance in which + Burr or his followers ever mentioned the conflicting evidence. Although other biologists didn't accept Burr's + claims, and several researchers subsequently published contrary results, he later became famous when the seed + oil industry wanted scientific-seeming reasons for selling their product as an "essential" food. The fact that + eating the polyunsaturated fats could cause the blood cholesterol level to decrease slightly was advertised as a + health benefit. Later, when human trials showed that more people on the "heart healthy" diet died of heart + disease and cancer, more conventional means of advertising were used instead of human tests. Burr's experimental + diet consisted of purified casein (milk protein) and purified sucrose, supplemented with a vitamin concentrate + and some minerals. Several of the B vitamins weren't known at the time, and the mineral mixture lacked zinc, + copper, manganese, molybdenum, and selenium. More of the essential nutrients were unknown in his time than in + Yudkin's, so his failure to consider the possibility of other nutritional deficiencies affecting health is more + understandable. In 1933, Burr observed that his fat-deficient rats consumed oxygen at an extremely high rate, + and even then, the thought didn't occur to him that other nutritional deficiencies might have been involved in + the condition he described. Ordinarily, the need for vitamins and minerals corresponds to the rate at which + calories are being burned, the metabolic rate. Burr recalled that the rats on the fat free diet drank more + water, and he reasoned that the absence of linoleic or linolenic acid in their skin was allowing water vapor to + escape at a high rate. He didn't explain why the saturated fats the rats were synthesizing from sugar didn't + serve at least as well as a "vapor barrier"; they are more effective at water-proofing than unsaturated fats, + because of their greater hydrophobicity. The condensed and cross-linked keratin protein in skin cells is the + main reason for the skin's relatively low permeability. When an animal is burning calories at a higher rate, its + sweat glands are more actively maintaining a normal body temperature, cooling by evaporation; the amount of + water evaporated is an approximate measure of metabolic rate, and of thyroid function. In 1936, a man in Burr's + lab, William Brown, agreed to eat a similar diet for six months, to see whether the "essential fatty acid + deficiency" affected humans as it did rats. The diet was very similar to the rats', with a large part of the + daily 2500 calories being provided at hourly intervals during the day by sugar syrup (flavored with citric acid + and anise oil), protein from 4 quarts of special fat-free skimmed milk, a quart of which was made into cottage + cheese, the juice of half an orange, and a "biscuit" made with potato starch, baking powder, mineral oil, and + salt, with iron, viosterol (vitamin D), and carotene supplemented. Brown had suffered from weekly migraine + headaches since childhood, and his blood pressure was a little high when he began the diet. After six weeks on + the diet, his migraines stopped, and never returned. His plasma inorganic phosphorus declined slightly during + the experiment (3.43 mg./100 cc. of plasma and 2.64 on the diet, and after six months on a normal diet 4.2 + mg.%), and his total serum proteins increased from 6.98 gm.% to 8.06 gm.% on the experimental diet. His + leucocyte count was lower on the high sugar diet, but he didn't experience colds or other sickness. On a normal + diet, his systolic blood pressure varied from 140 to 150 mm. of mercury, the diastolic, 95 to 100. After a few + months on the sugar and milk diet, his blood pressure had lowered to about 130 over 85 to 88. Several months + after he returned to a normal diet, his blood pressure rose to the previous level. On a normal diet, his weight + was 152 pounds, and his metabolic rate was from 9% to 12% below normal, but after six months on the diet it had + increased to 2% below normal. After three months on the sugar and milk diet, his weight leveled off at 138 + pounds. After being on the diet, when he ate 2000 calories of sugar and milk within two hours, his respiratory + quotient would exceed 1.0, but on his normal diet his maximum respiratory quotient following those foods was + less than 1.0. The effect of diabetes is to keep the respiratory quotient low, since a respiratory quotient of + one corresponds to the oxidation of pure carbohydrate, and extreme diabetics oxidize fat in preference to + carbohydrate, and may have a quotient just a little above 0.7. The results of Brown's and Burr's experiments + could be interpreted to mean that the polyunsaturated fats not only lower the metabolic rate, but especially + interfere with the metabolism of sugars. In other words, they suggest that the normal diet is diabetogenic. + During the six months of the experiment, the unsaturation of Brown's serum lipids decreased. The authors + reported that "There was no essential change in the serum cholesterol as a result of the change in diet." + However, in November and December, two months before the experiment began, it had been 252 mg.% in two + measurements. At the beginning of the test, it was 298, two weeks later, 228, and four months later, 206 mg%. + The total quantity of lipids in his blood didn't seem to change much, since the triglycerides increased as the + cholesterol decreased. By the time of Brown's experiment, other researchers had demonstrated that the + cholesterol level was increased in hypothyroidism, and decreased as thyroid function, and oxygen consumption, + increased. If Burr's team had been reading the medical literature, they would have understood the relation + between Brown's increased metabolic rate and decreased cholesterol level. But they did record the facts, which + is valuable. The authors wrote that "The most interesting subjective effect of the 'fat-free' regimen was the + definite disappearance of a feeling of fatigue at the end of the day's work." A lowered metabolic rate and + energy production is a common feature of aging and most degenerative diseases. From the beginning of an animal's + life, sugars are the primary source of energy, and with maturation and aging there is a shift toward replacing + sugar oxidation with fat oxidation. Old people are able to metabolize fat at the same rate as younger people, + but their overall metabolic rate is lower, because they are unable to oxidize sugar at the same high rate as + young people. Fat people have a similar selectively reduced ability to oxidize sugar. Stress and starvation lead + to a relative reliance on the fats stored in the tissues, and the mobilization of these as circulating free + fatty acids contributes to a slowing of metabolism and a shift away from the use of glucose for energy. This is + adaptive in the short term, since relatively little glucose is stored in the tissues (as glycogen), and the + proteins making up the body would be rapidly consumed for energy, if it were not for the reduced energy demands + resulting from the effects of the free fatty acids. One of the points at which fatty acids suppress the use of + glucose is at the point at which it is converted into fructose, in the process of glycolysis. When fructose is + available, it can by-pass this barrier to the use of glucose, and continue to provide pyruvic acid for + continuing oxidative metabolism, and if the mitochondria themselves aren't providing sufficient energy, it can + leave the cell as lactate, allowing continuing glycolytic energy production. In the brain, this can sustain life + in an emergency. Many people lately have been told, as part of a campaign to explain the high incidence of fatty + liver degeneration in the US, supposedly resulting from eating too much sugar, that fructose can be metabolized + only by the liver. The liver does have the highest capacity for metabolizing fructose, but the other organs do + metabolize it. If fructose can by-pass the fatty acids' inhibition of glucose metabolism, to be oxidized when + glucose can't, and if the metabolism of diabetes involves the oxidation of fatty acids instead of glucose, then + we would expect there to be less than the normal amount of fructose in the serum of diabetics, although their + defining trait is the presence of an increased amount of glucose. According to Osuagwu and Madumere (2008), that + is the case. If a fructose deficiency exists in diabetes, then it is appropriate to supplement it in the diet. + Besides being one of the forms of sugar involved in ordinary energy production, interchangeable with glucose, + fructose has some special functions, that aren't as well performed by glucose. It is the main sugar involved in + reproduction, in the seminal fluid and intrauterine fluid, and in the developing fetus. After these crucial + stages of life are past, glucose becomes the primary molecular source of energy, except when the system is under + stress. It has been suggested (Jauniaux, et al., 2005) that the predominance of fructose rather than glucose in + the embryo's environment helps to maintain ATP and the oxidative state (cellular redox potential) during + development in the low-oxygen environment. The placenta turns glucose from the mother's blood into fructose, and + the fructose in the mother's blood can pass through into the fetus, and although glucose can move back from the + fetus into the mother's blood, fructose is unable to move in that direction, so a high concentration is + maintained in the fluids around the fetus. The control of the redox potential is sometimes called the "redox + signalling system," since it coherently affects all processes and conditions in the cell, including pH and + hydrophobicity. For example, when a cell prepares to divide, the balance shifts strongly away from the oxidative + condition, with increases in the ratios of NADH to NAD+, of GSH to GSSG, and of lactate to pyruvate. These same + shifts occur during most kinds of stress. In natural stress, decreased availability of oxygen or nutrients is + often the key problem, and many poisons can produce similar interference with energy production, for example + cyanide or carbon monoxide, which block the use of oxygen, or ethanol, which inhibits the oxidation of sugars, + fats, and amino acids (Shelmet, et al., 1988). When oxygen isn't constantly removing electrons from cells (being + chemically reduced by them) those electrons will react elsewhere, creating free radicals (including activated + oxygen) and reduced iron, that will create inappropriate chemical reactions (Niknahad, et al., 1995; + MacAllister, et al., 2011). Stresses and poisons of many different types, interfering with the normal flow of + electrons to oxygen, produce large amounts of free radicals, which can spread structural and chemical damage, + involving all systems of the cell. Ethyl alcohol is a common potentially toxic substance that can have this + effect, causing oxidative damage by allowing an excess of electrons to accumulate in the cell, shifting the + cells' balance away from the stable oxidized state. Fructose has been known for many years to accelerate the + oxidation of ethanol (by about 80%). Oxygen consumption in the presence of ethanol is increased by fructose more + than by glucose (Thieden and Lundquist, 1967). Besides removing the alcohol from the body more quickly, it + prevents the oxidative damage, by maintaining or restoring the cell's redox balance, the relatively oxidized + state of the NADH/NAD+, lactate/pyruvate, and GSH/GSSH systems. Although glucose has this stabilizing, + pro-oxidative function in many situations, this is a general feature of fructose, sometimes allowing it to have + the opposite effect of glucose on the cell's redox state. It seems to be largely this generalized shift of the + cell's redox state towards oxidation that is behind the ability of a small amount of fructose to catalyze the + more rapid oxidation of a large amount of glucose. Besides protecting against the reductive stresses, fructose + can also protect against the oxidative stress of increased hydrogen peroxide (Spasojevic, et al., 2009). Its + metabolite, fructose 1,6-bisphosphate, is even more effective as an antioxidant. Keeping the metabolic rate high + has many benefits, including the rapid renewal of cells and their components, such as cholesterol and other + lipids, and proteins, which are always susceptible to damage from oxidants, but the high metabolic rate also + tends to keep the redox system in the proper balance, reducing the rate of oxidative damage. Endotoxin absorbed + from the intestine is one of the ubiquitous stresses that tends to cause free radical damage. Fructose, probably + more than glucose, is protective against damage from endotoxin. Many stressors cause capillary leakage, allowing + albumin and other blood components to enter extracellular spaces or to be lost in the urine, and this is a + feature of diabetes, obesity, and a variety of inflammatory and degenerative diseases including Alzheimer's + disease (Szekanecz and Koch, 2008; Ujiie, et al., 2003). Although the mechanism isn't understood, fructose + supports capillary integrity; fructose feeding for 4 and 8 weeks caused a 56% and 51% reduction in capillary + leakage, respectively (Chakir, et al., 1998; Plante, et al., 2003). The ability of the mitochondria to oxidize + pyruvic acid and glucose is characteristically lost to some degree in cancer. When this oxidation fails, the + disturbed redox balance of the cell will usually lead to the cell's death, but if it can survive, this balance + favors growth and cell division, rather than differentiated function. This was Otto Warburg's discovery, that + was rejected by official medicine for 75 years. Cancer researchers have become interested in this enzyme system + that controls the oxidation of pyruvic acid (and thus sugar) by the mitochondria, since these enzymes are + crucially defective in cancer cells (and also in diabetes). The chemical DCA, dichloroacetate, is effective + against a variety of cancers, and it acts by reactivating the enzymes that oxidize pyruvic acid. Thyroid + hormone, insulin, and fructose also activate these enzymes. These are the enzymes that are inactivated by + excessive exposure to fatty acids, and that are involved in the progressive replacement of sugar oxidation by + fat oxidation, during stress and aging, and in degenerative diseases; for example, a process that inactivates + the energy-producing pyruvate dehydrogenase in Alzheimer's disease has been identified (Ishiguro, 1998). + Niacinamide, by lowering free fatty acids and regulating the redox system, supporting sugar oxidation, is useful + in the whole spectrum of metabolic degenerative diseases. A few times in the last 80 years, people (starting + with Nasonov) have recognized that the hydrophobicity of a cell changes with its degree of excitation, and with + its energy level. Recently, even in non-living physical-chemical systems, hydrophobicity and redox potential + have been seen to vary together and to influence each other. Recent work shows how the oxidation of fatty acids + contributes to the dissolution of mitochondria (Macchioni, et al., 2010). At first glance it might seem odd that + the presence of fatty material could reduce the "fat loving" (lipophilic, equivalent to hydrophobic) property of + a cell, but the fat used as fuel is in the form of fatty acids, which are soap-like, and spontaneously introduce + "wetness" into the relatively water-resistant cell substance. The presence of fatty acids, impairing the last + oxidative stage of respiration, increases the tendency of the mitochondrion to release its cytochrome c into the + cell in a reduced form, leading to the apoptotic death of the cell. The oxidized form of the cytochrome is more + hydrophobic, and stable. Burr didn't understand that it was his rats' high sugar diet, freed of the + anti-oxidative unsaturated fatty acids, that caused their extremely high metabolic rate, but since that time + many experiments have made it clear that it is specifically the fructose component of sucrose that is protective + against the antimetabolic fats. Although Brown, et al., weren't focusing on the biological effects of sugar, + their results are important in the history of sugar research because their work was done before the culture had + been influenced by the development of the lipid theory of heart disease, and the later idea that fructose is + responsible for increasing the blood lipids. In 1963 and 1964, experiments (Carroll, 1964) showed that the + effects of glucose and fructose were radically affected by the type of fat in the diet. Although 0.6% of + calories as polyunsaturated fat prevents the appearance of the Mead acid (which is considered to indicate a + deficiency of essential fats) the "high fructose" diets consistently add 10% or more corn oil or other highly + unsaturated fat to the diet. These large quantities of PUFA aren't necessary to prevent a deficiency, but they + are needed to obscure the beneficial effects of fructose. Many studies have found that sucrose is less fattening + than starch or glucose, that is, that more calories can be consumed without gaining weight. During exercise, the + addition of fructose to glucose increases the oxidation of carbohydrate by about 50% (Jentjens and Jeukendrup, + 2005). In another experiment, rats were fed either sucrose or Coca-Cola and Purina chow, and were allowed to eat + as much as they wanted (Bukowiecki, et al, 1983). They consumed 50% more calories without gaining extra weight, + relative to the standard diet. Ruzzin, et al. (2005) observed rats given a 10.5% or 35% sucrose solution, or + water, and observed that the sucrose increased their energy consumption by about 15% without increasing weight + gain. Macor, et al. (1990) found that glucose caused a smaller increase in metabolic rate in obese people than + in normal weight people, but that fructose increased their metabolic rate as much as it did that of the normal + weight people. Tappy, et al. (1993) saw a similar increase in heat production in obese people, relative to the + effect of glucose. Brundin, et al. (1993) compared the effects of glucose and fructose in healthy people, and + saw a greater oxygen consumption with fructose, and also an increase in the temperature of the blood, and a + greater increase in carbon dioxide production. These metabolic effects have led several groups to recommend the + use of fructose for treating shock, the stress of surgery, or infection (e.g., Adolph, et al., 1995). The + commonly recommended alternative to sugar in the diet is starch, but many studies show that it produces all of + the effects that are commonly ascribed to sucrose and fructose, for example hyperglycemia (Villaume, et al., + 1984) and increased weight gain. The addition of fructose to glucose "can markedly reduce hyperglycemia during + intraportal glucose infusion by increasing net hepatic glucose uptake even when insulin secretion is + compromised" (Shiota, et al., 2005). "Fructose appears most effective in those normal individuals who have the + poorest glucose tolerance" (Moore, et al., 2000). Lipid peroxidation is involved in the degenerative diseases, + and many publications argue that fructose increases it, despite the fact that it can increase the production of + uric acid, which is a major component of our endogenous antioxidant system (e.g., Waring, et al., 2003). When + rats were fed for 8 weeks on a diet with 18% fructose and 11% saturated fatty acids, the content of + polyunsatured fats in the blood decreased, as they had in the Brown, et al., experiment, and their total + antioxidant status was increased (Girard, et al., 2005). When stroke-prone spontaneously hypertensive rats were + given 60% fructose, superoxide dismutase in their liver was increased, and the authors suggest that this "may + constitute an early protective mechanism" (Brosnan and Carkner, 2008). When people were given a 300 calorie + drink containing glucose, or fructose, or orange juice, those receiving the glucose had a large increase in + oxidative and inflammatory stress (reactive oxygen species, and NF-kappaB binding), and those changes were + absent in those receiving the fructose or orange juice (Ghanim, et al., 2007). One of the observations in Brown, + et al., was that the level of phosphate in the serum decreased during the experimental diet. Several later + studies show that fructose increases the excretion of phosphate in the urine, while decreasing the level in the + serum. However, a common opinion is that it's only the phosphorylation of fructose, increasing the amount in + cells, that causes the decrease in the serum; that could account for the momentary drop in serum phosphate + during a fructose load, but--since there is only so much phosphate that can be bound to intracellular + fructose--it can't account for the chronic depression of the serum phosphate on a continuing diet of fructose or + sucrose. There are many reasons to think that a slight reduction of serum phosphate would be beneficial. It has + been suggested that eating fruit is protective against prostate cancer, by lowering serum phosphate (Kapur, + 2000). The aging suppressing gene discovered in 1997, named after the Greek life-promoting goddess Klotho, + suppresses the reabsorption of phosphate by the kidney (which is also a function of the parathyroid hormone), + and inhibits the formation of the activated form of vitamin D, opposing the effect of the parathyroid hormone. + In the absence of the gene, serum phosphate is high, and the animal ages and dies prematurely. In humans, in + recent years a very close association has been has been documented between increased phosphate levels, within + the normal range, and increased risk of cardiovascular disease. Serum phosphate is increased in people with + osteoporosis (Gallagher, et al., 1980), and various treatments that lower serum phosphate improve bone + mineralization, with the retention of calcium phosphate (Ma and Fu, 2010; Batista, et al., 2010; Kelly, et al., + 1967; Parfitt, 1965; Kim, et al., 2003). At high altitude, or when taking a carbonic anhydrase inhibitor, there + is more carbon dioxide in the blood, and the serum phosphate is lower; sucrose and fructose increase the + respiratory quotient and carbon dioxide production, and this is probably a factor in lowering the serum + phosphate. Fructose affects the body's ability to retain other nutrients, including magnesium, copper, calcium, + and other minerals. Comparing diets with 20% of the calories from fructose or from cornstarch, Holbrook, et al. + (1989) concluded "The results indicate that dietary fructose enhances mineral balance." Ordinarily, things (such + as thyroid and vitamin D) which improve the retention of magnesium and other nutrients are considered good, but + the fructose mythology allows researchers to conclude, after finding an increased magnesium balance, with either + 4% or 20% of energy from fructose (compared to cornstarch, bread, and rice), "that dietary fructose adversely + affects macromineral homeostasis in humans." (Milne and Nielsen, 2000). Another study compared the effects of a + diet with plain water, or water containing 13% glucose, or sucrose, or fructose, or high fructose corn syrup on + the properties of rats' bones: Bone mineral density and mineral content, and bone strength, and mineral balance. + The largest differences were between animals drinking the glucose and the fructose solutions. The rats getting + the glucose had reduced phosphorus in their bones, and more calcium in their urine, than the rats that got + fructose. "The results suggested that glucose rather than fructose exerted more deleterious effects on mineral + balance and bone" (Tsanzi, et al., 2008). An older experiment compared two groups with an otherwise well + balanced diet, lacking vitamin D, containing either 68% starch or 68% sucrose. A third group got the starch + diet, but with added vitamin D. The rats on the vitamin D deficient starch diet had very low levels of calcium + in their blood, and the calcium content of their bones was low, exactly what is expected with the vitamin D + deficiency. However, the rats on the sucrose diet, also vitamin D deficient, had normal levels of calcium in + their blood. The sucrose, unlike the starch, maintained claim homeostasis. A radioactive calcium tracer showed + normal uptake by the bone, and also apparently normal bone development, although their bones were lighter than + those receiving vitamin D. People have told me that when they looked for articles on fructose in PubMed they + couldn't find anything except articles about its bad effects. There are two reasons for that. PubMed, like the + earlier Index Medicus, represents the material in the National Library of Medicine, and is a medical, rather + than a scientific, database, and there is a large amount of important research that it ignores. And because of + the authoritarian and conformist nature of the medical profession, when a researcher observes something that is + contrary to majority opinion, the title of the publication is unlikely to focus on that. In too many articles in + medical journals, the title and conclusions positively misrepresent the data reported in the article. When the + idea of "glycemic index" was being popularized by dietitians, it was already known that starch, consisting of + chains of glucose molecules, had a much higher index than fructose and sucrose. The more rapid appearance of + glucose in the blood stimulates more insulin, and insulin stimulates fat synthesis, when there is more glucose + than can be oxidized immediately. If starch or glucose is eaten at the same time as polyunsaturated fats, which + inhibit its oxidation, it will produce more fat. Many animal experiments show this, even when they are intending + to show the dangers of fructose and sucrose. For example (Thresher, et al., 2000), rats were fed diets with 68% + carbohydrate, 12% fat (corn oil), and 20% protein. In one group the carbohydrate was starch (cornstarch and + maltodextrin, with a glucose equivalence of 10%), and in other groups it was either 68% sucrose, or 34% fructose + and 34% glucose, or 34% fructose and 34% starch. (An interesting oddity, fasting triglycerides were highest in + the fructose+starch group.) The weight of their fat pads (epididymal, retroperitoneal, and mesenteric) was + greatest in the fructose+starch group, and least in the sucrose group. The starch group's fat was intermediate + in weight between those of the sucrose and the fructose+glucose groups. At the beginning of the experimental + diet, the average weight of the animals was 213.1 grams. After five weeks, the animals in the fructose+glucose + group gained 164 grams, those in the sucrose group gained 177 grams, and those in the starch group gained 199.2 + grams. The animals ate as much of the diet as they wanted, and those in the sucrose group ate the least. The + purpose of their study was to see whether fructose causes "glucose intolerance" and "insulin resistance." Since + insulin stimulates appetite (Chance, et al, 1986; Dulloo and Girardier, 1989; Czech, 1988; DiBattista, 1983; + Sonoda, 1983; Godbole and York, 1978), and fat synthesis, the reduced food consumption and reduced weight gain + show that fructose was protecting against these potentially harmful effects of insulin. Much of the current + concern about the dangers of fructose is focussed on the cornstarch-derived high fructose corn syrup, HFCS. Many + studies assume that its composition is nearly all fructose and glucose. However, Wahjudi, et al. (2010) analyzed + samples of it before and after hydrolyzing it in acid, to break down other carbohydrates present in it. They + found that the carbohydrate content was several times higher than the listed values. "The underestimation of + carbohydrate content in beverages may be a contributing factor in the development of obesity in children," and + it's especially interesting that so much of it is present in the form of starch-like materials. Many people are + claiming that fructose consumption has increased greatly in the last 30 or 40 years, and that this is + responsible for the epidemic of obesity and diabetes. According to the USDA Economic Research Service, the 2007 + calorie consumption as flour and cereal products increased 3% from 1970, while added sugar calories decreased + 1%. Calories from meats, eggs, and nuts decreased 4%, from dairy foods decreased 3%, and calories from added + fats increased 7%. The percentage of calories from fruits and vegetables stayed the same. The average person + consumed 603 calories per day more in 2007 than in 1970. If changes in the national diet are responsible for the + increase of obesity, diabetes, and the diseases associated with them, then it would seem that the increased + consumption of fat and starch is responsible, and that would be consistent with the known effects of starches + and polyunsaturated fats. In monkeys living in the wild, when their diet is mainly fruit, their cortisol is low, + and it rises when they eat a diet with less sugar (Behie, et al., 2010). Sucrose consumption lowers ACTH, the + main pituitary stress hormone (Klement, et al., 2009; Ulrich-Lai, et al., 2007), and stress promotes increased + sugar and fat consumption (Pecoraro, et al., 2004). If animals' adrenal glands are removed, so that they lack + the adrenal steroids, they choose to consume more sucrose (Laugero, et al., 2001). Stress seems to be perceived + as a need for sugar. In the absence of sucrose, satisfying this need with starch and fat is more likely to lead + to obesity. The glucocorticoid hormones inhibit the metabolism of sugar. Sugar is essential for brain + development and maintenance. The effects of environmental stimulation and deprivation-stress can be detected in + the thickness of the brain cortex in as little as 4 days in growing rats (Diamond, et al., 1976). These effects + can persist through a lifetime, and are even passed on transgenerationally. Experimental evidence shows that + polyunsaturated (omega-3) fats retard fetal brain development, and that sugar promotes it. These facts argue + against some of the currently popular ideas of the evolution of the human brain based on ancestral diets of fish + or meat, which only matters as far as those anthropological theories are used to argue against fruits and other + sugars in the present diet. Honey has been used therapeutically for thousands of years, and recently there has + been some research documenting a variety of uses, including treatment of ulcers and colitis, and other + inflammatory conditions. Obesity increases mediators of inflammation, including the C-reactive protein (CRP) and + homocysteine. Honey, which contains free fructose and free glucose, lowers CRP and homocysteine, as well as + triglycerides, glucose, and cholesterol, while it increased insulin more than sucrose did (Al-Waili, 2004). + Hypoglycemia intensifies inflammatory reactions, and insulin can reduce inflammation if sugar is available. + Obesity, like diabetes, seems to involve a cellular energy deficiency, resulting from the inability to + metabolize sugar. Sucrose (and sometimes honey) is increasingly being used to reduce pain in newborns, for minor + things such as injections (Guala, et al., 2001; Okan, et al., 2007; Anand, et al., 2005; Schoen and Fischell, + 1991). It's also effective in adults. It acts by influencing a variety of nerve systems, and also reduces + stress. Insulin is probably involved in sugar analgesia, as it is in inflammation, since it promotes entry of + endorphins into the brain (Witt, et al., 2000). An extracellular phosphorylated fructose metabolite, + diphosphoglycerate, has an essential regulatory effect in the blood; another fructose metabolite, fructose + diphosphate, can reduce mast cell histamine release and protect against oxidative and hypoxic injury and + endotoxic shock, and it reduces the expression of the inflammation mediators TNF-alpha, IL-6, nitric oxide + synthase, and the activation of NF-kappaB, among other protective effects, and its therapeutic value is known, + but its relation to dietary sugars hasn't been investigated. A daily diet that includes two quarts of milk and a + quart of orange juice provides enough fructose and other sugars for general resistance to stress, but larger + amounts of fruit juice, honey, or other sugars can protect against increased stress, and can reverse some of the + established degenerative conditions. Refined granulated sugar is extremely pure, but it lacks all of the + essential nutrients, so it should be considered as a temporary therapeutic material, or as an occasional + substitute when good fruit isn't available, or when available honey is allergenic.

+ REFERENCES +

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Batista DG, Neves KR, Graciolli FG, dos Reis LM, Graciolli RG, Dominguez WV, Neves CL, Magalhães + AO, Custódio MR, Moysés RM, Jorgetti V. Am J Primatol. 2010 Jun;72(7):600-6. Sources of variation in fecal + cortisol levels in howler monkeys in Belize. Behie AM, Pavelka MS, Chapman CA. Am J Hypertens. 2008 + Jun;21(6):708-14. Hepatic effects of a fructose diet in the stroke-prone spontaneously hypertensive rat. Brosnan + MJ, Carkner RD.Am J Physiol. 1993 Apr;264(4 Pt 1):E504-13. Whole body and splanchnic oxygen consumption and + blood flow after oral ingestion of fructose or glucose. Brundin T, Wahren J. "Compared with glucose, fructose + ingestion is accompanied by a more marked rise in CO2 production, possibly reflecting an increased + extrasplanchnic oxidation of lactate and an accumulation of heat in the body."Arkansas Academy of Science + Proceedings, Vol. 19, 1965, 59- . 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Changes in lipid metabolism and antioxidant defense status in + spontaneously hypertensive rats and Wistar rats fed a diet enriched with fructose and saturated fatty acids. + Girard A, Madani S, El Boustani ES, Belleville J, Prost J. "The FS diet resulted in hypertriglyceridemia but + increased the total antioxidant status, which may prevent lipid peroxidation in these rats."Diabetologia. 1978 + Mar;14(3):191-7. Lipogenesis in situ in the genetically obese Zucker fatty rat (fa/fa): role of hyperphagia and + hyperinsulinaemia. Godbole V, York DA.Minerva Pediatr. 2001 Aug;53(4):271-4. Glucose or sucrose as an analgesic + for newborns: a randomised controlled blind trial. Guala A, Pastore G, Liverani ME, Giroletti G, Gulino E, + Meriggi AL, Licardi G, Garipoli V.Am J Clin Nutr. 1989 Jun;49(6):1290-4. Dietary fructose or starch: effects on + copper, zinc, iron, manganese, calcium, and magnesium balances in humans.Holbrook JT, Smith JC Jr, Reiser + S.Rinsho Byori 1998;46(10):1003-7. Involvement of tau protein kinase in amyloid-beta-induced neurodegeneration. + Ishiguro K.J Clin Endocrinol Metab 2005; 90(2):1171-5. Polyol concentrations in the fluid compartments of the + human conceptus during the first trimester of pregnancy: maintenance of redox potential in a low oxygen + environment. Jauniaux E, Hempstock J, Teng C, Battaglia FC, Burton GJ.Br J Nutr. 2005 Apr;93(4):485-92. High + rates of exogenous carbohydrate oxidation from a mixture of glucose and fructose ingested during prolonged + cycling exercise. Jentjens RL, Jeukendrup AE. "Furthermore, exogenous CHO oxidation rates during the last 90 min + of exercise were approximately 50% higher (P<0.05) in GLU+FRUC compared with GLU (1.49 (SE 0.08) and 0.99 (SE + 0.06) g/min, respectively)."Cancer Invest. 2000;18(7):664-9. A medical hypothesis: phosphorus balance and + prostate cancer. Kapur S.J Lab Clin Med. 1967 Jan;69(1):110-5. Relationship between serum phosphate + concentration and bone resorption in osteoporosis. Kelly PJ, Jowsey J, Riggs BL, Elveback LR.J Vet Sci. 2003 + Aug;4(2):151-4. Studies on the effects of biomedicinal agents on serum concentration of Ca2+, P and ALP activity + in osteoporosis-induced rats. Kim SK, Lee MH, Rhee MH.Metabolism. 2009 Dec;58(12):1825-31. Effects of glucose + infusion on neuroendocrine and cognitive parameters in Addison disease. Klement J, Hubold C, Hallschmid M, Loeck + C, Oltmanns KM, Lehnert H, Born J, Peters A.Endocrinology. 2001 Jul;142(7):2796-804. Sucrose ingestion + normalizes central expression of corticotropin-releasing-factor messenger ribonucleic acid and energy balance in + adrenalectomized rats: a glucocorticoid-metabolic-brain axis? Laugero KD, Bell ME, Bhatnagar S, Soriano L, + Dallman MF.Chem Biol Interact. 2011 May 30;191(1-3):308-14. Metabolic mechanisms of methanol/formaldehyde in + isolated rat hepatocytes: carbonyl-metabolizing enzymes versus oxidative stress. MacAllister SL, Choi J, Dedina + L, O'Brien PJ.Mol Cell Biuochem 2010;341(1-2):149-57. Cytochrome c redox state influences the binding and + release of cytochrome c in model membranes and in brain mitochondria. Macchioni L, Corazz I, Davidescu M, + Francescangeli E, Roberti R, Corazzi L. Minerva Endocrinol 1990 Oct-Dec; 15(4):273-7. [Postprandial + thermogenesis and obesity: effects of glucose and fructose]. Macor C, De Palo C, Vettor R, Sicolo N, De Palo E, + Federspil G. J Am Coll Nutr. 2000 Feb;19(1):31-7. The interaction between dietary fructose and magnesium + adversely affects macromineral homeostasis in men. Milne DB, Nielsen FH.J Clin Endocrinol Metab 2000 + Dec;85(12):4515-9. Acute fructose administration decreases the glycemic response to an oral glucose tolerance + test in normal adults. Moore MC, Cherrington AD, Mann SL, Davis SN. J Rheumatol. 2003 Apr;30(4):849-50. Acute + gout precipitated by total parenteral nutrition. Moyer RA, John DS.Chem Biol Interact. 1995 Oct 20;98(1):27-44. + Hepatocyte injury resulting from the inhibition of mitochondrial respiration at low oxygen concentrations + involves reductive stress and oxygen activation. Niknahad H, Khan S, O'Brien PJ. "Furthermore, increasing the + hepatocyte NADH/NAD+ ratio with NADH generating compounds such as ethanol, glycerol, or beta-hydroxybutyrate + markedly increased cytotoxicity (prevented by desferoxamine) and further increased the intracellular release of + non-heme iron. Cytotoxicity could be prevented by glycolytic substrates (eg. fructose, dihydroxyacetone, + glyceraldehyde) or the NADH utilising substrates acetoacetate or acetaldehyde which decreased the reductive + stress and prevented intracellular iron release."Eur J Pediatr. 2007 Oct;166(10):1017-24. Analgesia in preterm + newborns: the comparative effects of sucrose and glucose. Okan F, Coban A, Ince Z, Yapici Z, Can G.Nigerian J. + Biochem. Mol Biology 23(1): 12-14, 2008. Depleted blood fructose in diabetes. Osuagwu CG and Madumere + HEO.Menopause. 2011 Sep 15. Improvement in immediate memory after 16 weeks of tualang honey (Agro Mas) + supplement in healthy postmenopausal women.Othman Z, Shafin N, Zakaria R, Hussain NH, Mohammad WM.J Bone Joint + Surg Br. 1965 Feb;47:137-9. CHANGES IN SERUM CALCIUM AND PHOSPHORUS DURING STILBOESTROL TREATMENT OF + OSTEOPOROSIS. PARFITT AM.Endocrinology. 2004 Aug;145(8):3754-62. Chronic stress promotes palatable feeding, + which reduces signs of stress: feedforward and feedback effects of chronic stress. Pecoraro N, Reyes F, Gomez F, + Bhargava A, Dallman MF. Physiol Behav. 2009 Mar 23;96(4-5):651-61. An unexpected reduction in sucrose + concentration activates the HPA axis on successive post shift days without attenuation by discriminative + contextual stimuli. Pecoraro N, de Jong H, Dallman MF.Cardiovasc Res 2003;59(4):963-70. Reduction of endothelial + NOS and bradykinin-induced extravastion of macromolecules in skeletal muscle of the fructose-fed rat model. + Plante GE, Perreault M, Lanthier A, Marette A, Maheux P.Diabetes Metab. 2005 Apr;31(2):178-88. Consumption of + carbohydrate solutions enhances energy intake without increased body weight and impaired insulin action in rat + skeletal muscles. Ruzzin J, Lai YC, Jensen J. "Fructose and sucrose solutions enhanced energy intake but did not + increase body weight."Clin Pediatr (Phila). 1991 Jul;30(7):429-32. Pain in neonatal circumcision. Schoen EJ, + Fischell AA. J. Clin Invest. 1988; 81:1137-1145. Ethanol causes acute inhibition of carbohydrate, fat, and + protein oxidation and insulin resistance, Shelmet JJ, Reichard GA, Skutches CL, Hoeldtke RD, Owen OE, and Boden + G. J Appl Physiol. 1987 Aug;63(2):465-70. Regulatory alterations of daily energy expenditure induced by fasting + or overfeeding in unrestrained rats. Shibata H, Bukowiecki LJ."O2 consumption decreased by 15% on the 1st day of + fasting and then by an additional 15% on the 2nd day. On the 3rd day, when rats were fed again, energy intake + increased by 30% above control (prefasting) values, whereas energy expenditure rapidly increased but no more + than control values. On the other hand, when ad libitum fed animals were offered a sucrose solution (32%) for 2 + days, energy intake increased by 30% and energy expenditure by 9-12%. On the 3rd day, when the rats were fed + with their normal diet, energy intake significantly decreased under control (preoverfeeding) values during one + day, but energy expenditure rapidly returned to normal values. The results show that fasting decreases, whereas + hyperphagia increases 24-h energy expenditure during the treatments."Am J Physiol Endocrinol Metab. 2005 + Jun;288(6):E1160-7. Inclusion of low amounts of fructose with an intraportal glucose load increases net hepatic + glucose uptake in the presence of relative insulin deficiency in dog. Shiota M, Galassetti P, Igawa K, Neal DW, + Cherrington AD. Physiol Behav. 1983 Mar;30(3):325-9. Hyperinsulinemia and its role in maintaining the + hypothalamic hyperphagia in chickens. Sonoda T.Carbohydr Res. 2009 Sep 8;344(13):1676-81. Protective role of + fructose in the metabolism of astroglial C6 cells exposed to hydrogen peroxide. Spasojević I, Bajić A, Jovanović + K, Spasić M, Andjus P. Arthritis Res Ther 2008; 10(5);224. Vascular involvement in rheumatic diseases: 'vascular + rheumatology.' Szekanecz Z, Koch AE.Am J Clin Nutr 1993 Nov;58(5 Suppl):766S-770S. Fructose and dietary + thermogenesis. Tappy L, Jequier E. Biochem J 1967;102(1):177-80. The influence of fructose and its metabolites + on ethanol metabolism in vitro. Thieden HI and Lundquist F. "without ethanol... fructose strongly increased the + pyruvate concentrtion, which resulted in a decrease of the lactate/pyruvate concentration Am J Physiol Regul + Integr Comp Physiol. 2000 Oct;279(4):R1334-40. Comparison of the effects of sucrose and fructose on insulin + action and glucose tolerance.Thresher JS, Podolin DA, Wei Y, Mazzeo RS, Pagliassotti MJ. Bone. 2008 + May;42(5):960-8. The effect of feeding different sugar-sweetened beverages to growing female Sprague-Dawley rats + on bone mass and strength. Tsanzi E, Light HR, Tou JC. Microcirculation 2003;10(6);463-70. Blood-brain barrier + permeability precedes senile plaque formation in an Alzheimer disease model. Ujiie M, Dickstein DL, Carlow DA, + Jefferies WA.Physiol Behav. 2011 Apr 18;103(1):104-10. HPA axis dampening by limited sucrose intake: reward + frequency vs. caloric consumption. Ulrich-Lai YM, Ostrander MM, Herman JP.Am J Physiol. 1986 Jun;250(6 Pt + 1):E607-14. Synergistic improvement of glucose tolerance by sucrose feeding and exercise training. Vallerand AL, + Lupien J, Bukowiecki LJ. Diabete Metab. 1984 Sep;10(3):206-10. [Plasma glucose and C-peptide after ingestion of + sucrose and starch in controlled insulin-dependent diabetics. Importance of glucose availability]. Villaume C, + Rousselle D, Mejean L, Beck B, Drouin P, Debry G.Journal of the American Medical Association November 10, 2010; + Carbohydrate Analysis of High Fructose Corn Syrup (HFCS) Containing Commercial Beverages. Wahjudi PN, Hsieh E, + Mary E Patterson ME, Catherine S Mao CS, Lee WNP.Clin Sci (Lond). 2003 Jun 12. Uric acid reduces + exercise-induced oxidative stress in healthy adults. Waring WS, Convery AA, Mishra V, Shenkin A, Webb DJ, + Maxwell SR.J Pharmacol Exp Ther. 2000 Dec;295(3):972-8. Insulin enhancement of opioid peptide transport across + the blood-brain barrier and assessment of analgesic effect.Witt KA, Huber JD, Egleton RD, Davis TP. Life Sci. + 1983 Jul 4;33(1):75-82. Serum lipids and cholesterol distribution in lipoproteins of exercise-trained female + rats fed sucrose. Deshaies Y, Vallerand AL, Bukowiecki LJ. Am J Physiol. 1983 Apr;244(4):R500-7. Effects of + sucrose, caffeine, and cola beverages on obesity, cold resistance, and adipose tissue cellularity. Bukowiecki + LJ, Lupien J, Folléa N, Jahjah L. Am J Physiol 1987 Sep;253(3 Pt 1):G390-6. Fructose prevents hypoxic cell death + in liver. Anundi I, King J, Owen DA, Schneider H, Lemasters JJ, Thurman RG.

+ © Ray Peat Ph.D. 2012. All Rights Reserved. www.RayPeat.com +

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+ The Cancer Matrix     It isn't hard to understand that + in heart failure the heart is undergoing changes in a unitary way, with all parts of the organ + affected, and that parallel changes are happening in the rest of the body, interacting with and contributing + to the changes in the heart, so that heart failure is now considered to be a systemic disease. (Most doctors + see the systemic nature of heart disease, at least to the extent of warning their patients to lower + cholesterol and avoid thyroid hormone.) But if someone tells a cancer patient or an oncologist that cancer + is a systemic disease, the thought will be flatly rejected as untrue. They have been taught that cancer is a + disease of bad, mutated, cells, which have to be completely eradicated, and that the patient's general + health is a separate issue. +

+

+    The US government (NIH, CDC) provides a cancer curriculum to schools. For high school, + grades 9-12, they explain that a series of gene mutations causes it. In grade school, the basic idea of + the cancer curriculum is just to teach them to fear cancer and the sunlight which, according to the + curriculum, seems to be a very important mutagen. +    The gene mutation theory of cancer is sustained by a broader mystique of "genetics" in + our culture. Over 100 years ago, an ideology of chance and random changes in organisms was superimposed + onto the theory of evolution. After 1944, when Avery, MacLeod and McCarty showed that strands of DNA + carry hereditary information, the doctrine of random change took on a specific chemical meaning--changes + in the sequence of bases in the DNA molecule. This made it easier to disregard the evidence of the + inheritance of acquired changes, since chemical, even biochemical, reactions are usually interpreted + statistically, with an assumption of randomness. If the changes in the DNA code are random, and not + influenced by the organism's physiology and biochemistry, then the four nucleotides that make up DNA + (abbreviated G, C, A, and T) should show a random composition, but in fact the ratio of GC pairs to AT + pairs varies in different types of organism, and in mitochondrial DNA, the GC (guanine-cytosine) content + corresponds closely to the rate of oxidative metabolism and longevity (Lehmann, et al., + 2008).  +    The official (government and American Cancer Society) view of cancer is that a tumor + consists of the descendants of a single mutated cell. A current "proof" of this is that in a given + tumor, all of the X chromosomes which are active have the same genetic composition, while in the rest of + the organism, the X chromosome which remains active is a matter of chance. That shows, they argue, that + the tumor must have developed from a cell in which that chromosome was active, not from a group of + cells. However, non-random inactivation of X chromosomes is now known to occur, and that it involves + epigenetic imprinting processes, such as methylation (Falconer, et al., 1982; Heard, 2004). Mary Lyon, + the person who discovered that females inactivate one of their X chromosomes, has recognized the + complexity of the process (Lyon, 2004). In arguing against the idea that the development of cancer is an + epigenetic process, the cancer-gene people have invoked a process that responds to epigenetic + influences. +    The assumption of randomness, and the assertions of the cancer doctors who subscribe + to the doctrine, have had terrible effects on biology and medicine. Following the doctrine, their + treatments must concentrate on eliminating every single cell of the cancer clone. Since surgery can't + eliminate defective cells that have entered the blood stream, radiation and chemical toxins are logical + necessities. Since mutations are random events, the person's general health is of little importance to + the oncologist. Typically, they will tell the patient that their diet doesn't matter, except that they + should avoid antioxidants if they are going to have radiation therapy.  +     For centuries, the definition of a malignant tumor has been that it's one which + will return after it has been cut out. In recent years, the definition has been extended to those that + return after the original tumor has been eliminated by radiation or chemotherapy. The idea of a "cancer + stem cell," an especially tough type of cell from the mutated clone, has been invoked to explain the + reason for the regrowth of a tumor in an area that was treated with intense radiation. However, it's now + clear that normal cells are attracted to an irradiated area (Klopp, et al., 2007; Kidd, et al., 2009). + The recognition of a "bystander effect," in which radiation (or other--Mothersill and Seymour, 2009) + injury to one cell injures near-by cells by signals from the injured cell, has led to the recognition + that ordinary stem cells or repair cells entering an area where a tumor has been destroyed will be + modified by the residual damage of cells in the area. The ability to recruit normal cells into a damaged + area, the "cancer field," the way normal organs do, shows that tumors can be thought of as organ-like + structures, and that knowledge of the organizing principles of normal organs might improve our knowledge + of tumors. The idea that cancer is primarily a problem of organization isn't new: Johannes Muller, in + the 19th century, and J.W. Orr, and D.W. Smithers, in the 1940s and 1950s, and many others, have + suggested that something outside of the individual cell could cause the + disorganization.   +     Once it is accepted that cancer is a systemic disease, and that a tumor, or the + place in the body where a tumor has been removed, is something more than a collection of defective + cells, very different therapeutic approaches can be considered. Looking at the events in a failing + heart, we can see that the potential repair cells recruited by the stressed heart are diverted by the + conditions that they encounter there, and either die or become connective tissue cells, secreting + collagen, rather than becoming new muscle cells.  +     Something that everyone knows about tumors is that they are harder than the normal + tissues in which they appear--they can be identified as lumps. Like the failing heart, they become + harder than normal, and like the failing heart, the hardening can proceed to calcification. There has + been general recognition that inflammation has a role in both heart disease and cancer, but the fact + that chronic inflammation leads to fibrosis, and that fibrosis often leads to calcification, is still + usually considered not to be relevant to understanding and treating cancer. The tissue hardness that + allows oncologists to diagnose cancer (Huang and Ingber, 2005) is ignored when choosing treatments, + which isn't surprising, since treatments that destroy cancer cells increase the production of + collagen. +    Aspirin is commonly recommended for preventing heart attacks, because it helps to + prevent abnormal blood clots, but it has other effects that are beneficial in heart disease, for example + reducing the generalized fibrosis of the heart that develops after a heart attack (Kalkman, et al., + 1995; Wu, et al., 2012). It also protects against fibrosis in other organs, by a variety of mechanisms, + and this effect on the extracellular matrix seems to be one of ways in which it protects against cancer. + DCA, dichloroacetate, the drug that has been in the news in recent years because it can stop cancer + growth, by restoring the oxidation of glucose and stopping the aerobic production of lactic acid, has + been found to reduce the fibrosis of a failing heart, by the same mechanism, restoring glucose + oxidation. In general, substances that increase collagen production are promoters of cancer and + contribute to the progression of heart failure, and other degenerative changes. +    The incidence of cancer increases exponentially with age, but when random mutations + are seen as the cause of cancer, aging as an essential cause of cancer is disregarded. The total + collagen content of the body increases with aging, and the stiffness of that collagen also increases. + The total collagen content in cancer patients is higher than in people without cancer (Zimin, et al., + 2010). This suggests that the processes in the body that produce aging are acting more intensely in + those who develop cancer. As the collagen accumulates in the extracellular matrix, the whole body + becomes more favorable for the appearance of cancer.  +    Plastic surgeons have promoted the idea of injecting collagen into tissues with the + argument that they are "replacing collagen lost with aging," but in fact collagen accumulates with + aging. It is the greater compactness and stiffness of collagen in old skin that produces noticeable + changes such as wrinkling. The difference between calf skin leather, used for soft gloves and purses, + and cow hide, used for shoe soles and boots, illustrates the changes that occur with aging. Supermarkets + used to categorize chickens as fryers and stewers, or stewing hens. The difference was the age and + toughness, very young chickens could be cooked quickly, old laying hens had accumulated more collagen, + and especially the cross-linked hardened collagen, and required long cooking to reduce the toughness. + Old beef animals are usually sold as cheaper stew meat or hamburger, because the age-hardened collagen + can make a steak too rubbery to chew if it's quickly cooked.  +    In a healthy young organism, tissue injuries are repaired by processes reminiscent + of Metchnikov's experiment in which he put a thorn into a jelly fish, and found that wandering cells, + phagocytes, converged on the foreign object, surrounding it. If they couldn't eat it, they caused it to + be expelled. The importance of that experiment was that it showed that injured tissues emit signals that + attract certain types of cell. The process of removing damaged tissues by phagocytosis guides the + formation of new tissue, starting with the secretion of collagen, which guides the maturation of the new + cells.  +    Around the middle of the last century, Hans Selye experimented with the antiseptic + implantation of a short piece of a narrow glass tube under the skin of rats. The irritation from the + glass object caused a collagenous capsule to be formed around it, in the well known "foreign body + reaction." He found that a filament of tissue formed in the center of the tube, connecting the two ends + of the capsule. The isolated tissue of the filament quickly underwent the degenerative changes seen in + aged connective tissues, but if he periodically removed the fluid around it, and allowed fresh lymph + fluid to fill the capsule, the filament retained a youthful elasticity, even as the rat aged. Isolation + from the organism caused age-like degeneration to develop rapidly. When the organism can't remove a + foreign object, the collagenous capsule that encloses it has a high probability of forming a cancer. + This "foreign body carcinogenesis" has been studied for many years.     +        +    Foreign body carcinogenesis is closely related to chemical carcinogenesis, radiation + carcinogenesis, and hormonal carcinogenesis. Chemical carcinogens such as methylcholanthrene are + irritating when injected, and stimulate collagen production. Neither type of carcinogenesis is always + effective, because this collagen reaction can be protective, by isolating the irritant toxin (Zhang, et + al., 2013). Radiation stimulates the secretion of collagen, and causes cross-linking that makes it + stiffer, and slows its removal, leading to its accumulation (Sassi, et al., 2001). Some types of + cross-linking block the ability of macrophages to remove it, creating something like a diffuse foreign + body reaction. Estrogen, for example in the process of causing breast cancer, causes increased collagen + synthesis. This is widely recognized, in the association of "breast density" (a high collagen content) + with the risk of cancer. Estrogen also causes the formation of the enzymes that cross-link and stiffen + the collagen, lysyl oxidase and transglutaminase(Sanada, et al., 1978; Campisi, et al., 2008; + Balestrieri, et al., 2012). +    Although ultraviolet and ionizing radiation can act directly on collagen, to stiffen + it, the greatest effect of the radiation is probably by reaction with relatively unstable components of + tissues, such as polyunsaturated fatty acids, which then react with the collagen, cross-linking it + (Igarashi, et al., 1989). Even in the absence of radiation, a deficiency of vitamin E accelerates the + spontaneous decomposition of the unsaturated fats, accelerating the aging of collagen (Sundholm and + Visapää, 1978 ). Many observations suggest that all of the collagen-aging carcinogenic factors interact + synergistically. +    When cells are placed on a glass slide coated with collagen, they move to parts of + the collagen that have been cross-linked, and they move from slightly cross-linked collagen to stiffer, + more thoroughly cross-linked areas (Vincent, et al., 2013). When they are on stiffer collagen, they pull + themselves more tightly toward it, continuously expending energy in the process. The muscle-like + contraction of the cell causes it to become more rigid (Huang and Ingber, 2005). The increased hardness + of even small tumors makes it possible to identify lymph node metastases from a breast cancer by touch, + without removing them (Miyaji, et al., 1997). +    The increased energy cost of this "isotonic contraction" of the cell filaments + requires more energy to sustain, and will tend to create lactic acid, the way intense muscle contraction + does, while consuming oxygen at a higher rate. The increased lactic acid and decreased oxygen + availability stimulate the synthesis of more collagen, the growth of new blood vessels, expression of + enzymes for increasing the stiffness of the collagen, and other processes associated with inflammation, + aging, and cancer. Blocking even one of these processes, the lysyl oxidase cross-linking enzyme, can + reduce the invasiveness of a cancer (Lee, et al., 2011). Some observations (Tan, et al., 2010) show that + the circulating cells of metastatic cancer are more rigid than other cells, which would increase the + likelihood that they will block capillaries, creating oxygen-deprived nests of collagen-secreting + cells. +   One of the substances produced by stressed cells that's involved in tumor induction, + growth, and metastasis (Tanaka, et al., 2003; Datta, et al., 2010; Was, et al., 2010) is the enzyme heme + oxygenase, which breaks down the essential component of respiratory enzymes, heme, producing carbon + monoxide as a product, which inhibits cell respiration, increasing reliance on the glycolysis which + produces lactic acid. If metastatic cells continue to produce this enzyme, this is likely to contribute + to reconstituting the "cancer field," with increased HIF, hypoxia inducible factor, and a variety of + other regulatory agents, each of which has its protective functions elsewhere, but which in combination + can worsen the tumor. +    Substances that inhibit inflammation are likely to also inhibit excessive collagen + synthesis, serotonin secretion, and the formation of estrogen. Besides aspirin, some effective + substances are apigenin and naringenin, found in oranges and guavas. These flavonoids also inhibit the + formation of nitric oxide and prostaglandins, which are important for inflammation and carcinogenesis + (Liang, et al., 1999). Increased CO2, which has a variety of anti-inflammatory effects, can decrease + collagen formation and tissue collagen content significantly (Ryu, et al., 2010). +    Deprivation of glucose and oxygen, which can be the local result of a cellular + environment of condensed, stiffened collagen and the cellular tension and activation produced in + response, combined with systemic stress that causes free fatty acids to interfere with the oxidation of + sugar, activates enzymes that can dissolve collagen (MMP-2 and MMP-9). These enzymes are involved in + metastasis, allowing cells to escape from the condensed collagen, but although they are normally thought + of as enzymes that act outside of cells, they can also enter the cell's nucleus, where they degrade the + DNA, causing the mutations and chromosomal abnormalities that are so characteristic of cancer (Hill, et + al., 2012). Like glucose deprivation, exposure to 2-deoxyglucose, often used in tumor imaging, promotes + metastasis (Schlappack, et al., 1991). +    The fact that cancer cells are stressed and damaged, and accumulate DNA damage, + means that in a typical tumor there is a high rate of cell death. The number of apoptotic + (disintegrating) cells in a tumor corresponds to the aggressiveness of the tumor (Vakkala, et al, 1999). + In the 1940s and 1950s, Polezhaev demonstrated that dying cells stimulate cell renewal, and this is true + in young and healthy organs, as well as in tumors.  +    In 36% of women who had had a breast removed, from 7 to 22 years previously, + identifiable (by the same tests used to diagnose breast cancer) cancer cells could be found circulating + in their blood stream (Meng, et al., 2004). Tissue biopsies would be able to find the sources of those + circulating cells, nests of similar cells throughout the body, which were dying about as fast as they + were replicating. In 1969, Harry Rubin described an autopsy study which found that everyone over the age + of 50 had at least one diagnosable cancer in some tissue. "Occult microscopic cancers are exceedingly + common in the general population and are held in a dormant state by a balance between cell proliferation + and cell death and also an intact host immune surveillance"(Goldstein and Mascitelli, 2011). These + authors observed that the stress of surgery stimulates tumor growth, by various mechanisms, and that + surgery increases the risk of developing cancer in apparently cancer-free patients. +    In 1956, Hardin Jones wrote "If one has cancer and opts to do nothing at all, he + will live longer and feel better than if he undergoes radiation, chemotherapy or surgery, other than + when used in immediate life-threatening situations." In the 1990s, a group of cancer specialists were + asked what they would do if they were diagnosed with prostate cancer, and most of them said they would + do nothing.  +    The radical mastectomy, which removed massive amounts of apparently normal tissue as + well as the breast tumor, was practiced for hundreds of years, and was the standard treatment for breast + cancer until the 1980s, after G.W. Crile, Jr., had publicized the evidence showing that simply removing + the tumor lump itself didn't cause a higher mortality rate, and that the surgery produced much less + disability.  +    Although the lumpectomy was eventually accepted by the profession, the evidence that + the long term survival rate was higher when the surgery was done during the luteal phase in + premenopausal women has been generally ignored, because the cancer ideology maintains that the fate of + the cancer is in the cells, rather than in the patient's hormone balance.  +    Because of the continual indoctrination about the importance of "early diagnosis to + increase the chance of a cure," and the widely publicized "cure rates," it's easy for doctors to rush + people into treatment, before they have time to study the issue. Dean Burk, who was a collaborator of + Otto Warburg's for many years, was quoted in regard to the claims of the American Cancer Society that + "They lie like scoundrels." +     In the 1970s, I noticed that the definitions of the features of uterine cancer had + been changed recently, including as "cancer" things that had previously been classified as merely + abnormal or precancerous.  Reading more about the grading of cancer, I saw that other cancers + had been defined more inclusively since the 1940s. Things that had previously not been called cancer + were now being counted among the cancers that were cured by the various treatments, so, necessarily, the + rate of cure had increased. The true situation could be seen by the age-specific mortality rate for each + type of cancer. During the period when the "cure rates" were increasing, the age-specific death rates + had increased. I think that's the sort of thing that Dean Burk had in mind.  +     Nearly all of the studies of "cure rates" are comparisons of one + ideologically-based and lucrative treatment against another ideologically-based and more or less + lucrative treatment. When the cure rate, for example for breast cancer surgery, varies with the amount + of progesterone in the body, there is very little interest in investigating the processes involved, + because lucrative products aren't involved. +    When abnormal "metastatic" cells circulate in the blood or lymph, most of them die + spontaneously when they stick in a place that doesn't support their growth. Many of the nests of cells + that have started to grow probably regress spontaneously when conditions in the body change. Even large, + clearly diagnosed tumors occasionally regress spontaneously. Aging and sickness tend to support the + vicious cycles that lead to the progressive deterioration of the collagenous matrix. Stress (even + anxiety-induced hyperventilation) produces alkalosis, and alkalosis favors increased collagen synthesis, + while lower pH inhibits it (Frick, et al., 1997). For example, within a minute or two of + hyperventilating, platelets release serotonin, and serotonin is a major promoter of collagen synthesis + and fibrosis.  +    The vicious cycles that promote cancer can be interrupted to some extent simply by + reducing exposure to things that promote stress and inflammation--endotoxin, polyunsaturated fats, amino + acid imbalance, nutritional deficiencies, ionizing radiation, estrogens--and maintaining optimal levels + of things that protect against those--carbon dioxide, vitamin E, progesterone, light, aspirin, sugars, + and thyroid hormone, for example. +      +

REFERENCES

+ J Cell Physiol. 2012 Apr;227(4):1577-82. Interplay between membrane lipid peroxidation, + transglutaminase activity, and cyclooxygenase 2 expression in the tissue adjoining to breast + cancer. + Balestrieri ML, Dicitore A, Benevento R, Di Maio M, Santoriello A, Canonico S, Giordano A, Stiuso + P. + J Neurosci Res. 2008 May 1;86(6):1297-305. Effect of growth factors and steroids on + transglutaminase activity and expression in primary astroglial cell cultures. Campisi A, Bramanti + V, Caccamo D, Li Volti G, Cannavò G, Currò M, Raciti G, Galvano F, Amenta F, Vanella A, Ientile R, Avola + R. + J Biol Chem. 2010 Nov 19;285(47):36842-8.  CXCR3-B can mediate growth-inhibitory signals in + human renal cancer cells by down-regulating the expression of heme oxygenase-1. Datta D, Banerjee + P, Gasser M, Waaga-Gasser AM, Pal S. +  Genet Res. 1982 Jun;39(3):237-59. Non-random X-chromosome inactivation in the mouse: + difference of reaction to imprinting. Falconer DS, Isaacson JH, Gauld IK. + Am J Physiol. 1997 May;272(5 Pt 1):C1450-6. Acute metabolic acidosis inhibits the induction of + osteoblastic egr-1 and type 1 collagen. Frick KK, Jiang L, Bushinsky DA. + QJM (2011) 104 (9): 811-815. Surgery and cancer promotion: are we trading beauty for + cancer? + Goldstein MR and Mascitelli L. + Biochim Biophys Acta. 2005 Sep 25;1756(1):1-24. The role of pH dynamics and the Na+/H+ antiporter + in the etiopathogenesis and treatment of cancer. Two faces of the same coin--one single + nature. Harguindey S, Orive G, Luis Pedraz J, Paradiso A, Reshkin SJ. + Curr Opin Cell Biol. 2004 Jun;16(3):247-55. Recent advances in X-chromosome inactivation. Heard + E.  + Neuroscience. 2012 Sep 18;220:277-90. Intranuclear matrix metalloproteinases promote DNA damage + and apoptosis induced by oxygen-glucose deprivation in neurons. Hill JW, Poddar R, Thompson JF, + Rosenberg GA, Yang Y. + Cancer Cell. 2005 Sep;8(3):175-6. Cell tension, matrix mechanics, and cancer development. Huang + S, Ingber DE. + Br J Dermatol. 1989 Jul;121(1):43-9.The effects of vitamin E deficiency on rat skin. + Igarashi A, Uzuka M, Nakajima K. + J Mol Cell Cardiol. 1995 Nov;27(11):2483-94. Chronic aspirin treatment affects collagen + deposition in non-infarcted myocardium during remodeling after coronary artery ligation in the rat. + Kalkman EA, van Suylen RJ, van Dijk JP, Saxena PR, Schoemaker RG. + Stem Cells. 2009 Oct;27(10):2614-23. Direct evidence of mesenchymal stem cell tropism for tumor + and wounding microenvironments using in vivo bioluminescent imaging. Kidd S, Spaeth E, Dembinski + JL, Dietrich M, Watson K, Klopp A, Battula VL, Weil M, Andreeff M, Marini FC. + Cancer Res. 2007 Dec 15;67(24):11687-95. Tumor irradiation increases the recruitment of + circulating mesenchymal stem cells into the tumor microenvironment. Klopp AH, Spaeth EL, Dembinski + JL, Woodward WA, Munshi A, Meyn RE, Cox JD, Andreeff M, Marini FC. +  PLoS One. 2012;7(2):e32572. Cellular traction stresses increase with increasing metastatic + potential. Kraning-Rush CM, Califano JP, Reinhart-King CA. + Oncol Lett. 2011 Sep 1;2(5):831-838. Lysyl oxidase-like-1 enhances lung metastasis when lactate + accumulation and monocarboxylate transporter expression are involved. Lee GH, Kim DS, Chung MJ, + Chae SW, Kim HR, Chae HJ. + REJUVENATION RESEARCH 11(2), 2008. Do Mitochondrial DNA and Metabolic Rate Complement Each Other + in Determination of the Mammalian Maximum Longevity? Lehmann G, Segal E, Muradian KK, Fraifeld + VE. + Carcinogenesis 1999 Oct;20(10):1945-52.  + Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related + flavonoids in mouse macrophages. Liang YC, Huang YT, Tsai SH, Lin-Shiau SY, Chen CF, Lin JK + European Journal of Human Genetics (2005) 13, 796–797. X Chromosome Inactivation: No longer + 'all-or-none'. Lyon MF. + Clin Cancer Res Dec, 2004 10; 8152. Circulating Tumor Cells in Patients with Breast Cancer + Dormancy. Meng S, Tripathy D, Frenkel EP, Shete S, Naftalin EZ, Huth JF, Beitsch PD, Leitch M, Hoover S, + Euhus D, Haley B, Morrison L, et al. + Cancer. 1997 Nov 15;80(10):1920-5. The stiffness of lymph nodes containing lung carcinoma + metastases: a new diagnostic parameter measured by a tactile sensor. Miyaji K, Furuse A, Nakajima + J, Kohno T, Ohtsuka T, Yagyu K, Oka T, Omata S. + J Radiol Prot. 2009 Jun;29(2A):A21-8. Implications for environmental health of multiple stressors. + Mothersill C, Seymour C. + J Cell Physiol. 2011 Feb;226(2):299-308. pH control mechanisms of tumor survival and growth. + Parks SK, Chiche J, Pouyssegur J. + J Appl Physiol. 2010 Jul;109(1):203-10. Chronic hypercapnia alters lung matrix composition in + mouse pups. Ryu J, Heldt GP, Nguyen M, Gavrialov O, Haddad GG. + Biochim Biophys Acta. 1978 Jul 3;541(3):408-13. Changes in collagen cross-linking and lysyl + oxidase by estrogen. Sanada H, Shikata J, Hamamoto H, Ueba Y, Yamamuro T, Takeda T. + Radiother Oncol. 2001 Mar;58(3):317-23. Type I collagen turnover and cross-linking are increased + in irradiated skin of breast cancer patients. Sassi M, Jukkola A, Riekki R, Höyhtyä M, Risteli L, + Oikarinen A, Risteli J. + Br J Cancer. 1991 Oct;64(4):663-70. Glucose starvation and acidosis: effect on experimental + metastatic potential, DNA content and MTX resistance of murine tumour cells. Schlappack OK, + Zimmermann A, Hill RP. + Lipids. 1978 Nov;13(11):755-7. Cross linking of collagen in the presence of oxidizing lipid. + Sundholm F, Visapää A. + Biosens Bioelectron. 2010 Dec 15;26(4):1701-5. Versatile label free biochip for the detection of + circulating tumor cells from peripheral blood in cancer patients. Tan SJ, Lakshmi RL, Chen P, Lim + WT, Yobas L, Lim CT. + Br J Cancer. 2003 Mar 24;88(6):902-9. Antiapoptotic effect of haem oxygenase-1 induced by nitric + oxide in experimental solid tumour. Tanaka S, Akaike T, Fang J, Beppu T, Ogawa M, Tamura F, + Miyamoto Y, Maeda H. + Vakkala M., Lähteenmäki K., Raunio H., Pääkkö P., Soini Y. Apoptosis during breast carcinoma + progression. Clin. Cancer Res., 5: 319-324, 1999. + Biotechnol J. 2013 Apr;8(4):472-84. Mesenchymal stem cell durotaxis depends on substrate + stiffness gradient strength. Vincent LG, Choi YS, Alonso-Latorre B, Del Álamo JC, Engler AJ. + Curr Drug Targets. 2010 Dec;11(12):1551-70. Heme oxygenase-1 in tumor biology and therapy. Was H, + Dulak J, Jozkowicz A.  + Oxid Med Cell Longev. 2012;2012:761710. Protective effects of aspirin from cardiac hypertrophy + and oxidative stress in cardiomyopathic hamsters. Wu R, Yin D, Sadekova N, Deschepper CF, de + Champlain J, Girouard H. + Cancer Res. 2013 May 1;73(9):2770-81. Fibroblast- + Specific Protein 1/S100A4-Positive Cells Prevent Carcinoma through Collagen Production and + Encapsulation of Carcinogens. Zhang J, Chen L, Liu X, Kammertoens T, Blankenstein T, Qin Z. + Bull Exp Biol Med. 2010 Oct;149(5):663-5. Impact of the content of collagens I and III and their + ratio in cancer patients for the formation of postoperative ventral hernia. Zimin JI, Chichevatov + DA, Ponomareva EE. +

+ + © Ray Peat Ph.D. 2015. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/three-hormones.html b/raypeat-articles/processed/three-hormones.html new file mode 100644 index 0000000..a8b900a --- /dev/null +++ b/raypeat-articles/processed/three-hormones.html @@ -0,0 +1,203 @@ + + Progesterone Pregnenolone & DHEA - Three Youth-Associated Hormones + +

+ Progesterone Pregnenolone & DHEA - Three Youth-Associated Hormones +

+ +

+ PROGESTERONE INFORMATION +

+

+ Raymond Peat, MA, PhD (Univ. of Oregon) +

+

+ Endocrine Physiologist, specializing in hormonal changes in stress and aging +

+

+ Sixty years ago, progesterone was found to be the main hormone produced by the ovaries. Since it was + necessary for fertility and for maintaining a healthy pregnancy, it was called the "pro-gestational + hormone," and its name sometimes leads people to think that it isn't needed when you don't want to get + pregnant. In fact, it is the most protective hormone the body produces, and the large amounts that are + produced during pregnancy result from the developing baby's need for protection from the stressful + environment. Normally, the brain contains a very high concentration of progesterone, reflecting its + protective function for that most important organ. The thymus gland, the key organ of our immune system, is + also profoundly dependent on progesterone. +

+

+ In experiments, progesterone was found to be the basic hormone of adaptation and of resistance to stress. + The adrenal glands use it to produce their anti-stress hormones, and when there is enough progesterone, they + don't have to produce the potentially harmful cortisone. In a progesterone deficiency, we produce too much + cortisone, and excessive cortisone causes osteoporosis, aging of the skin, damage to brain cells, and the + accumulation of fat, especially on the back and abdomen. +

+

+ Experiments have shown that progesterone relieves anxiety, improves memory, protects brain cells, and even + prevents epileptic seizures. It promotes respiration, and has been used to correct emphysema. In the + circulatory system, it prevents bulging veins by increasing the tone of blood vessels, and improves the + efficiency of the heart. It reverses many of the signs of aging in the skin, and promotes healthy bone + growth. It can relieve many types of arthritis, and helps a variety of immunological problems. +

+

+ If progesterone is taken dissolved in vitamin E, it is absorbed very efficiently, and distributed quickly to + all of the tissues. If a woman has ovaries, progesterone helps them to produce both progesterone and + estrogen as needed, and also helps to restore normal functioning of the thyroid and other glands. If her + ovaries have been removed, progesterone should be taken consistently to replace the lost supply. A + progesterone deficiency has often been associated with increased susceptibility to cancer, and progesterone + has been used to treat some types of cancer. +

+

+ It is important to emphasize that progesterone is not just the hormone of pregnancy. To use it only "to + protect the uterus" would be like telling a man he doesn't need testosterone if he doesn't plan to father + children, except that progesterone is of far greater and more basic significance than testosterone. While + men do naturally produce progesterone, and can sometimes benefit from using it, it is not a male hormone. + Some people get that impression, because some physicians recommend combining estrogen with either + testosterone or progesterone, to protect against some of estrogen's side effects, but progesterone is the + body's natural complement to estrogen. Used alone, progesterone often makes it unnecessary to use estrogen + for hot flashes or insomnia, or other symptoms of menopause. +

+

+ When dissolved in vitamin E, progesterone begins entering the blood stream almost as soon as it contacts any + membrane, such as the lips, tongue, gums, or palate, but when it is swallowed, it continues to be absorbed + as part of the digestive process. When taken with food, its absorption occurs at the same rate as the + digestion and absorption of the food. +

+

+ PREGNENOLONE +

+

+ Pregnenolone, which is the raw material for producing many of the hormones of stress and adaptation, was + known as early as 1934, but for several years it was considered to be an "inert" substance. A reason for + this belief is that it was first tested on healthy young animals. Since these animals were already producing + large amounts of pregnenolone (in the brain, adrenal glands, and gonads), additional pregnenolone had no + effect. +

+ +

+ In the 1940s, pregnenolone was tested in people who were sick or under stress, and it was found to have a + wide range of beneficial actions, but the drug industry never had much interest in it. Its very generality + made it seem unlike a drug, and its natural occurrence made it impossible to patent. Thus, many synthetic + variants, each with a more specialized action and some serious side effects, came to be patented and + promoted for use in treating specific conditions. The drug companies created an atmosphere in which many + people felt that each disease should have a drug, and each drug, a disease. The side effects of some of + those synthetic hormones were so awful that many people came to fear them. For example, synthetic varieties + of "cortisone" can destroy immunity, and can cause osteoporosis, diabetes, and rapid aging, with loss of + pigment in the skin and hair, and extreme thinning of the skin. +

+

+ Natural pregnenolone is present in young people of both sexes at a very high concentration, and one reason + for the large amount produced in youth is that it is one of our basic defenses against the harmful side + effects that an imbalance of even our natural hormones can produce. In excess, natural cortisone or estrogen + can be dangerous, but when there is an abundance of pregnenolone, their side effects are prevented or + minimized. +

+

+ In a healthy young person or animal, taking even a large dose of pregnenolone has no hormone-like or + drug-like action at all. It is unique in this way. But if the animal or person is under stress, and + producing more cortisone than usual, taking pregnenolone causes the cortisone to come down to the normal + level. After the age of 40 or 45, it seems that everyone lives in a state of continuous "stress," just as a + normal part of aging. This coincides with the body's decreased ability to produce an abundance of + pregnenolone. +

+

+ When aging rats are given a supplement of pregnenolone, it immediately improves their memory and general + performance. Human studies, as early as the 1940s, have also demonstrated improved performance of ordinary + tasks. It is now known that pregnenolone is one of the major hormones in the brain. It is produced by + certain brain cells, as well as being absorbed into the brain from the blood. It protects brain cells from + injury caused by fatigue, and an adequate amount has a calming effect on the emotions, which is part of the + reason that it protects us from the stress response that leads to an excessive production of cortisone. + People feel a mood of resilience and an ability to confront challenges. +

+

+ Many people have noticed that pregnenolone has a "face-lifting" action. This effect seems to be produced by + improved circulation to the skin, and by an actual contraction of some muscle-like cells in the skin. A + similar effect can improve joint mobility in arthritis, tissue elasticity in the lungs, and even eyesight. + Many studies have shown it to be protective of "fibrous tissues" in general, and in this connection it was + proven to prevent the tumors that can be caused by estrogen. +

+

+ Pregnenolone is largely converted into two other "youth-associated" protective hormones, progesterone and + DHEA. At the age of 30, both men and women produce roughly 30 to 50 mg. of pregnenolone daily. When taken + orally, even in the powdered form, it is absorbed fairly well. One dose of approximately 300 mg (the size of + an aspirin tablet) keeps acting for about a week, as absorption continues along the intestine, and as it is + "recycled" in the body. Part of this long lasting effect is because it improves the body's ability to + produce its own pregnenolone. It tends to improve function of the thyroid and other glands, and this + "normalizing" effect on the other glands helps to account for its wide range of beneficial effects. +

+

DHEA: ANOTHER YOUTH-ASSOCIATED HORMONE

+

+ Raymond Peat, MA, PhD (Univ. of Oregon) +

+

+ Endocrine Physiologist +

+

+ DHEA (dehydroepiandrosterone) has a technical-sounding name because it has never been identified with a + single dominant function, in spite of its abundance in the body. Many researchers still think of it as a + substance produced by the adrenal glands, but experiments show that animals without adrenals are able to + produce it in normal amounts. Much of it is formed in the brain (from pregnenolone), but it is probably + produced in other organs, including the skin. The brain contains a much higher concentration of DHEA than + the blood does. +

+

+ In old age, we produce only about 5% as much as we do in youth. This is about the same decrease that occurs + with progesterone and pregnenolone. The other hormones (for example, cortisone) do not decrease so much; as + a result, our balance shifts continually during aging toward dominance by hormones such as cortisone, which + use up more and more body substance, without rebuilding it. Protection against the toxic actions of these + specialized hormones is a major function of DHEA and the other youth-associated hormones. +

+ +

+ For example, starvation, aging, and stress cause the skin to become thin and fragile. An excess of + cortisone--whether it is from medical treatment, or from stress, aging, or malnutrition--does the same + thing. Material from the skin is dissolved to provide nutrition for the more essential organs. Other organs, + such as the muscles and bones, dissolve more slowly, but just as destructively, under the continued + influence of cortisone. DHEA blocks these destructive effects of cortisone, and actively restores the normal + growth and repair processes to those organs, strengthening the skin and bones and other organs. Stimulation + of bone-growth by DHEA has been demonstrated in vitro (in laboratory tests), and it has been used to relieve + many symptoms caused by osteoporosis and arthritis, even when applied topically in an oily solution. +

+

+ Estrogen is known to produce a great variety of immunological defects, and DHEA, apparently by its balancing + and restorative actions, is able to correct some of those immunological defects, including some "autoimmune" + diseases. +

+

+ It is established that DHEA protects against cancer, but it isn't yet understood how it does this. It + appears to protect against the toxic cancer-producing effects of excess estrogen, but its anti-cancer + properties probably involve many other functions. +

+

+ Diabetes can be produced experimentally by certain poisons which kill the insulin-producing cells in the + pancreas. Rabbits were experimentally made diabetic, and when treated with DHEA their diabetes was cured. It + was found that the insulin-producing cells had regenerated. Many people with diabetes have used brewer's + yeast and DHEA to improve their sugar metabolism. In diabetes, very little sugar enters the cells, so + fatigue is a problem. DHEA stimulates cells to absorb sugar and to burn it, so it increases our general + energy level and helps to prevent obesity. +

+

+ Young people produce about 12 to 15 milligrams of DHEA per day, and that amount decreases by about 2 mg. per + day for every decade after the age of 30. This is one of the reasons that young people eat more without + getting fat, and tolerate cold weather better: DHEA, like the thyroid hormone, increases our heat production + and ability to burn calories. At the age of 50, about 4 mg. of DHEA per day will usually restore the level + of DHEA in the blood to a youthful level. It is important to avoid taking more than needed, since some + people (especially if they are deficient in progesterone, pregnenolone, or thyroid) can turn the excess into + estrogen or testosterone, and large amounts of those sex hormones can disturb the function of the thymus + gland and the liver. +

+ +

+ People who have taken an excess of DHEA have been found to have abnormally high estrogen levels, and this + can cause the liver to enlarge, and the thymus to shrink. +

+

+ One study has found that the only hormone abnormality in a groupt of Alzheimers patients' brains was an + excess of DHEA. In cell culture, DHEA can cause changes in glial cells resembling those seen in the aging + brain. These observations suggest that DHEA should be used with caution. Supplements of pregnenolone and + thyroid seem to be the safest way to optimize DHEA production. +

+

+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com +

+ + diff --git a/raypeat-articles/processed/thyroid-insanities.html b/raypeat-articles/processed/thyroid-insanities.html new file mode 100644 index 0000000..14e10dd --- /dev/null +++ b/raypeat-articles/processed/thyroid-insanities.html @@ -0,0 +1,1601 @@ + + Thyroid, insomnia, and the insanities: Commonalities in disease + +

+ Thyroid, insomnia, and the insanities: Commonalities in disease +

+ +

+

SOME FACTORS IN STRESS, INSOMNIA AND THE BRAIN SYNDROMES:

+ +

+ Serotonin, an important mediator of stress, shock, and inflammation, is a vasoconstrictor that impairs + circulation in a great variety of circumstances. +

+

+ Stress impairs metabolism, and serotonin suppresses mitochondrial energy production. +

+

+ Stress and shock tend to increase our absorption of bacterial endotoxin from the intestine, and endotoxin + causes the release of serotonin from platelets in the blood. +

+

+ Schizophrenia is one outcome of stress, both cumulative and acute. Prenatal stress commonly predisposes a + person to develop schizophrenia at a later age. +

+

+ Serotonin"s restriction of circulation to the uterus is a major factor in toxemia of pregnancy and related + complications of pregnancy. +

+

+ Hypothyroidism increases serotonin activity in the body, as it increases estrogen dominance. +

+

+ Estrogen inhibits the enzyme monoamino oxidase (MAO), and is highly associated with increased serotonin + activity. Progesterone has the opposite effect on MAO. +

+

+ The frontal lobes of the brain are hypometabolic in schizophrenia. Serotonin can cause vasoconstriction in + the brain. +

+

Serotonin release causes lipid peroxidation.

+

Schizophrenics have high levels of lipid peroxidation.

+

+ Antioxidants, including uric acid, are deficient in schizophrenics. +

+

+ Therapies which improve mitochondrial respiration alleviate the symptoms of schizophrenia. +

+

+ Energy depletion leads to brain atrophy, but with normal stimulation and nutrition even adult brains can + grow. +

+

+ Schizophrenics and depressed people have defective sleep. +

+

+ Increasing the body"s energy level and temperature improves the quality of sleep. +

+

+

+ Everyone is familiar with the problem of defining insanity, in the case of people who plead innocent by + reason of insanity. The official definition of insanity in criminal law is "the inability to tell right from + wrong." Obviously, that can"t be generalized to everyday life, because any sane person realizes that + certainty is impossible, and that most situations, including elections, offer you at best the choice of "the + lesser of two evils," or the opportunity to "do the right thing," and to "throw your vote away." People who + persist in doing what they know is really right are "eccentric," in the sense that they don"t adapt to + society"s norms. In a society that chooses to destroy ecosystems, rather than adapting to them, the question + of sanity should be an everyday political issue. +

+

+ The use of medical terms tends to give authority to the people who are in charge of defining the terms, and + it can give the impression of objectivity when there really isn"t any scientific validity behind the terms. + In their historical senses, "crazy" (flawed) and "insane" (unsound) are probably more objective terms than + the medically-invented terms, dementia praecox (premature idiocy) or schizophrenia (divided mind). +

+

+ "Odd Speech" is one of the dimensions used in the diagnosis of insanity. I am reminded of William + Wordsworth"s dismissal of William Blake as insane after failing to understand some of Blake"s + poems--Wordsworth was conventional enough to become England"s Poet Laureate, and to his limited perspective, + Blake"s clear verses were incomprehensibly odd. +

+

+ Whenever a trusted government employee decides to blow the whistle on criminal activities, his agency + invariably puts out the information that this now discharged employee is psychologically unbalanced. + Dissent, in other words, is easy to dispose of by psychiatric tainting. +

+

+ If we are going to speak of mental impairment, then we should have objective measures of what we are talking + about. Blake unquestionably could do anything better than Wordsworth, because he was neither stupid nor + dishonest, and it"s almost a rule that ordinary employees are more competent than the administrators who + evaluate their work. Objective standards of mental impairment would be more popular among patients than + among diagnosticians, judges, and lawmakers. +

+

+ In a famous test of the objectivity of diagnosis, a filmed interview with a patient was shown to British and + U.S. psychiatrists. 69% of the Americans diagnosed the patient as schizophrenic, but only 2% of the British + psychiatrists did. +

+

+ The strictly medical/psychological definition of insanity is still, despite the existence of the + International Classification of Diseases, and in the U.S. the Diagnostic and Statistical Manual, which + enumerate a large number of "mental disorders," a crazily indefinite grouping of symptoms, and hasn"t made + diagnosis more objective.. For example, in the last 30 years autism has been separated from childhood + schizophrenia, but now the tendency is for both of them to be called developmental brain disorders. Both + schizophrenia and autism are now often described in terms of a "spectrum of conditions," which hardly + matters, since they are not understood in terms of cause, prevention, or cure. +

+

+ The problem is in the history of psychosis as a medical idea. About 100 years ago, attempts were made to + classify psychoses by their symptoms, unifying a great variety of old diagnostic categories into two groups, + manic-depressive mood disorders, and "dementia praecox," or schizophrenia, which (as indicated by its name, + premature dementia) was considered to be progressive and incurable. Several kinds of mental disorder were + found to have clear causes, including vitamin deficiencies and various poisons and infections, but the idea + of a certain thing called schizophrenia still persists. +

+

+ The unitary concept of psychosis grew up in a culture in which "endogenous insanity" was a "hereditary + taint," that for a time was "treated" by imprisonment, and that more recently has been treated with + sterilization or euthanasia to eliminate the "insanity genes." +

+

+ The idea that the disease is "in the genes" now serves the drug industry well, since they offer chemicals + that will correct the specific "chemical error." +

+

+ Not all psychiatrists and psychologists subscribed to the idea of a unitary psychosis, defined by a variety + of symptoms. A positive contribution of Freudian psychoanalysis (and its congeners and competitors) was that + it made people think in terms of causes and the possibility of cures, instead of hopelessness, + stigmatization, isolation and eradication. Although Freud expressed the thought that biological causes and + cures would eventually be found, the profession he founded was not sympathetic to the idea of physiological + therapies. +

+

+ Looking for general physiological problems behind the various symptoms is very different from the practice + of classifying the insanities according to their symptoms and the hypothetical "brain chemicals" that are + believed to "cause the symptoms." The fact that some patients hallucinate caused many psychiatrists to + believe that hallucinogenic chemicals, interfering with nerve transmitter substances such as dopamine or + serotonin, were going to provide insight into psychotic states. The dopamine excess (or serotonin + deficiency) theories developed at a time when only a few "transmitter substances" were known, and when they + were thought to act as very specific on/off nerve switches, rather than as links in metabolic networks. The + drug industry helps to keep those ideas alive. +

+

+ The idea that the brain is like a computer, and that the nerves are like wires and switches, is behind all + of the theories about transmitter substances and synapses. If this metaphor about the nature of the brain + and the organism is fundamentally wrong, then the theories of schizophrenia based on nerve transmitter + substances can hardly be right. Another theory of schizophrenia based on the computer metaphor has to do + with the idea that nerve cells" wire-like and switch-like functions depend on their membranes, and, in the + most popular version, that these all-important membranes are made of fish oil. The supporting evidence is + supposed to be that the fish-oil-like fatty acids are depleted from the tissues of schizophrenics. Just + looking at that point, the "evidence" is more likely to be the result of stress, which depletes unsaturated + fatty acids, especially of the specified type, in producing lipid peroxides and other toxic molecules. +

+

+ In one of its variations, the "essential fatty acid deficiency" doctrine suggests that a certain + prostaglandin deficiency is the cause of schizophrenia, but experiments have shown that an excess + of that prostaglandin mimics the symptoms of psychosis. +

+

+ The drug industry"s effect on the way the organism is commonly understood + has been pervasively pathological. For example, the dogma about "cell surface receptors" has sometimes + explicitly led people to say that the "brain chemicals" are active + + only + at the surface of cells, and not inside the cells. +

+

+ The consequences of this mistake have been catastrophic. For example, + serotonin"s precursor, tryptophan, and the drugs called "serotonin reuptake inhibitors," and other + serotonergic drugs, and serotonin itself, are carcinogenic and/or tumor promoters. Excessive serotonin + is a major factor in kidney and heart failure, liver and lung disease, stroke, pituitary abnormalities, + inflammatory diseases, practically every kind of sickness, at the beginning, middle, and end of life. In + the brain, serotonin regulates circulation and mitochondrial function, temperature, respiration and + appetite, alertness and learning, secretion of prolactin, growth hormones and stress hormones, and + participates in the most complex biochemical webs. But the pharmaceutical industry"s myth has led people + to believe that serotonin is the chemical of happiness, and that tryptophan is its benign nutritional + precursor, and that they are going to harmlessly influence the "receptors on nerve membranes." + +

+

+ A particular drug has many effects other than those that are commonly recognized as its "mechanism of + action," but when an "antidepressant" or a "tranquilizer" or a "serotonin reuptake inhibitor" alleviates + a particular condition, some people argue that the condition must have been caused by the "specific + chemistry" that the drug is thought to affect. Because of the computer metaphor for the brain, these + effects are commonly thought to be primarily in the synapses, the membranes, and the transmitter + chemicals. +

+

+ The argument for a "genetic" cause of schizophrenia relies heavily on twin studies in which the frequency + of both twins being schizophrenic is contrasted to the normal incidence of schizophrenia in the + population, which is usually about 1%. There is a concordance of 30% to 40% between monozygotic + (identical) twins, and a 5% to 10% concordance between fraternal twins, and both of these rates are + higher than that of other siblings in the same family. That argument neglects the closer similarity of + the intrauterine conditions experienced by twins, for example the sharing of the same placenta, and + experiencing more concordant biochemical interactions between fetus and mother. +

+

+ Defects of the brain, head, face, and even hands and fingerprints are seen more frequently in the + genetically identical twin who later develops schizophrenia than the twin who doesn"t develop + schizophrenia. Of the twins, it is the baby with the lower birth weight and head size that is at a + greater risk of developing schizophrenia. +

+

+ Oliver Gillie (in his book, + Who Do You Think You Are?) + + discussed some of the fraud that has occurred in twin studies, but no additional fraud is needed when + the non-genetic explanation is simply ignored and excluded from discussion. The editors of most medical + and scientific journals are so convinced of the reality of genetic determination that they won"t allow + their readers to see criticisms of it. +

+

+ Prenatal malnutriton or hormonal stress or other stresses are known to damage the brain, and especially its + most highly evolved and metabolically active frontal lobes, and to reduce its growth, relative to the + rest of the body. +

+

+ The standard medical explanation for the association of pregnancy toxemia + and eclampsia with birth defects has been, until recently, that both mother and child were genetically + inferior, and that the defective child created the pregnancy sickness. The same "reasoning" has been + invoked to explain the association of birth complications with later disease: + The defective baby was the + + cause + + of a difficult birth. That argument has recently been discredited (McNeil and Cantor-Graae, 1999). +

+

+ Schizophrenics are known to have had a higher rate of obstetrical complications, including oxygen + deprivation and Cesarian deliveries, than normal people. Like people with Alzheimer"s disease, the + circumference of their heads at birth was small, in proportion to their body weight and gestational + age. +

+

+ Animal studies show that perinatal brain problems tend to persist, influencing the brain"s metabolism and + function in adulthood. +

+

+ Like the other major brain diseases, shizophrenia involves a low metabolic rate in crucial parts of the + brain. In schizophrenics, "hypofrontality," low metabolism of the frontal lobes, is characteristic, + along with abnormal balance between the hemispheres, and other regional imbalances. +

+

+ A very important form of prenatal stress occurs in toxemia and preeclampsia, in which estrogen is dominant, + and endotoxin and serotonin create a stress reaction with hypertension and impaired blood circulation to + the uterus and placenta. +

+

+ The brain, just like any organ or tissue, is an energy-producing metabolic system, and its oxidative + metabolism is extremely intense, and it is more dependent on oxygen for continuous normal functioning + than any other organ. Without oxygen, its characteristic functioning (consciousness) stops instantly + (when blood flow stops, blindness begins in about three seconds, and other responses stop after a few + more seconds). The concentration of ATP, which is called the cellular energy molecule, doesn"t decrease + immediately. Nothing detectable happens to the "neurotransmitters, synapses, or membrane structures" in + this short period + ; + + consciousness is a metabolic process that, in the computer metaphor, would be the flow of electrons + itself, under the influence of an electromotive force, a complex but continuous sort of electromagnetic + field. The computer metaphor would seem to have little to offer for understanding the brain. +

+

+ In this context, I think it"s necessary, for the + present, to ignore the diagnostic details, the endless variety of qualifications of the idea of + "schizophrenia," that fill the literature. Those diagnostic concepts seem to tempt people to look for + "the precise cause of this particular subcategory" of schizophrenia, and to believe that a specific drug + or combination of drugs will be found to treat it, while encouraging them to ignore the patient"s + physiology and history. + +

+

+ If we use the standard medical terms at all, it should be with the recognition that they are, in their + present and historical form, not scientifically meaningful. +

+

+ The idea that schizophrenia is a disease in itself tends to distract attention from the things it has in + common with Alzheimer"s disease, autism, depression, mania, the manic-depressive syndrome, the + hyperactivity-attention deficit syndrome, and many other physical and mental problems. When brain + abnormalities are found in "schizophrenics" but not in their normal siblings, it could be tempting to + see the abnormalities as the "cause of schizophrenia," unless we see similar abnormalities in a variety + of sicknesses. +

+

+ For the present, it"s best to think first in the most general terms possible, such as a "brain stress + syndrome," which will include brain aging, stroke, altitude sickness, seizures, malnutrition, poisoning, + the despair brought on by inescapable stress, and insomnia, which are relatively free of culturally + arbitrary definitions. Difficulty in learning, remembering, and analyzing are objective enough that it + could be useful to see what they have to do with a "brain stress syndrome." +

+

+ Stress damages the energy producing systems of cells, especially the aerobic mitochondria, in many ways, + and this damage can often be repaired. The insanities that are most often called schizophrenia tend to + occur in late adolescence, or around menopause, or in old age, which are times of stress, especially + hormonal stress. Post-partum psychosis often has features that resemble schizophrenia. +

+

+ Although the prenatal factors that predispose a person toward the brain stress syndrome, and those that + trigger specific symptoms later in life, might seem to be utterly different, the hormonal and + biochemical reactions are probably closely related, involving the adaptive responses of various + functional systems to the problem of insufficient adaptive ability and inadequate energy. +

+

+ By considering cellular energy production, local blood flow, and the systemic support system, we can get + insight into some of the biochemical events that are involved in therapies that are sometimes + successful. A unified concept of health and disease will help to understand both the origins and the + appropriate treatments for a great variety of brain stress syndromes. +

+

+

+ The simple availability of oxygen, and the ability to use it, are regulated by carbon dioxide and + serotonin, which act in opposite directions. Carbon dioxide inhibits the release of serotonin. Carbon + dioxide and serotonin are regulated most importantly by thyroid function. Hypothyroidism is + characterized by increased levels of both noradrenalin and serotonin, and of other stress-related + hormones, including cortisol and estrogen. Estrogen shifts the balance of the "neurotransmitters" in the + same direction, toward increased serotonin and adrenalin, for example by inhibiting enzymes that degrade + the monoamine "neurotransmitters." +

+

+ When an animal such as a squirrel approaches + hibernation and is producing less carbon dioxide, the decrease in carbon dioxide releases serotonin, + which slows respiration, lowers temperature, suppresses appetite, and produces torpor. + +

+

+ But in energy-deprived humans, increases of adrenalin oppose the hibernation reaction, alter energy + production and the ability to relax, and to sleep deeply and with restorative effect. +

+

+ In several ways, torpor is the opposite of sleep. + Rapid eye movement (REM), that occurs at intervals during sleep and in association with increased + respiration, disappears when the brain of a hibernating animal falls below a certain temperature. But + torpor isn"t like "non-REM" deep sleep, and in fact seems to be + + like wakefulness, + in the sense that a sleep-debt is incurred + : + + Hibernating animals periodically come out of torpor so they can sleep, and in those periods, when their + temperature rises sharply, they have a very high percentage of deep "slow wave sleep." +

+

+ Although it is common to speak of sleep and hibernation as variations on the theme of economizing on energy + expenditure, I suspect that nocturnal sleep has the special function of minimizing the stress of + darkness itself, and that it has subsidiary functions, including its now well confirmed role in the + consolidation and organization of memory. This view of sleep is consistent with observations that + disturbed sleep is associated with obesity, and that the torpor-hibernation chemical, serotonin, + powerfully interferes with learning. +

+

+ Babies spend most of their time sleeping, and during life the amount of time spent sleeping decreases, with + nightly sleeping time decreasing by about half an hour per decade after middle age. Babies have an + extremely high metabolic rate and a stable temperature. With age the metabolic rate progressively + declines, and as a result the ability to maintain an adequate body temperature tends to decrease with + aging. +

+

+ (The simple fact that body temperature regulates all organic functions, including brain waves, is + habitually overlooked. The actions of a drug on brain waves, for example, may be mediated by its effects + on body temperature, but this wouldn"t be very interesting to pharmacologists looking for + "transmitter-specific" drugs.) +

+

+ Torpor is the opposite of restful sleep, and with aging, depression, hypothyroidism, and a variety of brain + syndromes, sleep tends toward the hypothermic torpor. +

+

+ An individual cell behaves analogously to the whole person. A baby"s "high energy resting state" is + paralleled by the stable condition of a cell that is abundantly charged with energy + ; + + ATP and carbon dioxide are at high levels in these cells. Progesterone"s effects on nerve cells include + favoring the high energy resting state, and this is closely involved in progesterone"s "thermogenic" + effect, in which it raises the temperature set-point. +

+

+ The basal metabolic rate, which is mainly governed by thyroid, roughly corresponds to the average body + temperature. However, in hypothyroidism, there is an adaptive increase in the activity of the + sympathetic nervous system, producing more adrenalin, which helps to maintain body temperature by + causing vasoconstriction in the skin. In aging, menopause, and various stressful conditions, the + increased adrenalin (and the increased cortisol production which is produced by excess adrenalin) causes + a tendency to wake more easily, and to have less restful sleep. +

+

+ While the early morning body temperature will sometimes be low in hypothyroidism, I have found many + exceptions to this. In protein deficiency, sodium deficiency, in menopause with flushing symptoms, and + in both phases of the manic depression cycle, and in some schizophrenics, the morning temperature is + high, corresponding to very high levels of adrenalin and cortisol. Taking the temperature before and + after breakfast will show a reduction of temperature, the opposite of what occurs in simple + hypothyroidism, because raising the blood sugar permits the adrenalin and cortisol to fall. +

+

+ The characteristic sleep pattern of hypothyroidism and old age is similar to the pattern seen in + schizophrenia and depression, a decrease of deep slow wave sleep. Serotonin, like torpor, produces a + similar effect. In other words, a torpor-like state can be seen in all of these brain-stress states. + Several studies have found that anti-serotonin drugs improve sleep, and also reduce symptoms of + schizophrenia and depression. It is common for the "neuroleptic" drugs to raise body temperature, even + pathologically as in the "neuroleptic malignant syndrome." +

+

+ In old people, who lose heat easily during the day, their extreme increase in the compensatory nervous and + hormonal adrenalin activity causes their night-time heat regulation (vasoconstriction in the + extremities) to rise to normal. +

+

+ Increased body temperature improves sleep, especially the deep slow wave sleep. A hot bath, or even warming + the feet, has the same effect as thyroid in improving sleep. Salty and sugary foods taken at bedtime, or + during the night, help to improve the quality and duration of sleep. Both salt and sugar lower the + adrenalin level, and both tend to raise the body temperature. +

+

+ Hypothyroidism tends to cause the blood and other body fluids to be deficient in both sodium and glucose. + Consuming salty carbohydrate foods momentarily makes up to some extent for the thyroid deficiency. +

+

+ In the peiodic table of the elements, lithium is immediately above sodium, meaning that it has the chemical + properties of sodium, but with a smaller atomic radius, which makes its electrical charge more intense. + Its physiological effects are so close to sodium"s that we can get clues to sodium"s actions by watching + what lithium does. +

+

+ Chronic consumption of lithium blocks the release of adrenalin from the adrenal glands, and it also has + extensive antiserotonin effects, inhibiting its release from some sites, and blocking its actions at + others. +

+

+ Lithium forms a complex with the ammonia molecule, and since the ammonia molecule mimics the effects of + serotonin, especially in fatigue, this could be involved in lithium"s antiserotonergic effects. Ammonia, + like serotonin, impairs mitochondrial energy production (at a minimum, it uses energy in being converted + to urea), so anti-ammonia, anti-serotonin agents make more energy available for adaptation. Lithium has + been demonstrated to restore the energy metabolism of mitochondria (Gulidova, 1977). +

+

+ Therapies that have been successful in treating "schizophrenia" include penicillin, sleep therapy, + hyperbaric oxygen, carbon dioxide therapy, thyroid, acetazolamide, lithium and vitamins. These all make + fundamental contributions to the restoration of biological energy. Antibiotics, for example, lower + endotoxin formation in the intestine, protect against the induction by endotoxin of serotonin, + histamine, estrogen, and cortisol. Acetazolamide causes the tissues to retain carbon dioxide, and + increased carbon dioxide acidifies cells, preventing serotonin secretion. +

+

+

+

REFERENCES

+

+

+ Gen Pharmacol 1994 Oct;25(6):1257-1262. + + Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of + plasma hemoglobin; the protective action of calmodulin antagonists. + + Koren-Schwartzer N, Chen-Zion M, Ben-Porat H, Beitner R Department of Life Sciences, Bar-Ilan + University, Ramat Gan, Israel. + + 1. Injection of serotonin (5-hydroxytryptamine) to rats, induced a dramatic fall in brain ATP level, + accompanied by an increase in P(i). Concomitant to these changes, the activity of cytosolic + phosphofructokinase, the rate-limiting enzyme of glycolysis, was significantly enhanced. Stimulation of + anaerobic glycolysis was also reflected by a marked increase in lactate content in brain. 2. Brain + glucose + + 1,6-bisphosphate level was decreased, whereas fructose 2,6-bisphosphate was unaffected by serotonin. 3. + All these serotonin-induced changes in brain, which are characteristic for cerebral ischemia, were + prevented by treatment with the calmodulin (CaM) antagonists, trifluoperazine or thioridazine. 4 + . Injection of serotonin also induced a marked elevation of plasma hemoglobin, reflecting lysed + erythrocytes, + which was also prevented by treatment with the CaM antagonists. 5. + + The present results suggest that CaM antagonists may be effective drugs in treatment of many + pathological conditions and diseases in which plasma serotonin levels are known to increase. +

+

+ WMJ 1990 Nov-Dec;62(6):93-7. + + [Effect of inflammatory mediators on respiration in rat liver mitochondria]. + Semenov VL. +

+

+ Vopr Med Khim 1990 Sep-Oct;36(5):18-21 [Regulation by biogenic amines of energy functions of + mitochondria]. + + Medvedev A.E. Biogenic amines (phenylethylamine, tyramine, dopamine, tryptamine, + + serotonin and spermine) decreased activities of the rotenone-insensitive NADH-cytochrome c reductase, the + succinate cytochrome c reductase and the succinate dehydrogenase + . +

+

+ Vopr Med Khim 1991 Sep-Oct;37(5):2-6. + + [The role of monoamine oxidase in the regulation of mitochondrial energy functions]. + Medvedev AE, Gorkin VZ. +

+

+ Lik Sprava 1997 Jan-Feb;(1):61-5. + + [Microhemodynamics and energy metabolism in schizophrenia patients]. +

+ + showed lowering of ATP level and rise in the content of cathodic LDG4-LDG5 fractions, accumulation in + blood of lactic and pyruvic acids. +

+

+ Schizophr Res 1996 Oct 18;22(1):41-7. + Are reduced head circumference at birth and increased obstetric complications associated only with + schizophrenic psychosis? A comparison with schizo-affective and unspecified functional psychoses. + + McNeil TF, Cantor-Graae E, Nordstrom LG, Rosenlund T. +

+

+ Schizophr Res 1993 Jun;10(1):7-14. + Puberty and the onset of psychosis. + + Galdos PM, van Os JJ, Murray RM Department of Child and Adolescent Psychiatry, Bethlem Royal Hospital, + London, UK. According to the neurodevelopmental hypothesis of schizophrenia, maturational events in the + brain at puberty interact with congenital defects to produce psychotic symptoms. As girls reach puberty + at a younger age than boys, we predicted that (i) females would show earlier onset of psychotic illness + arising around puberty, and (ii) + + onset of psychosis in females would be related to menarche. + + Analysis of epidemiological data regarding admission to psychiatric units in (a) England over the period + 1973-1986, (b) France over the period 1975`-1980, as well as examination of 97 psychotic adolescents + referred to an adolescent unit over a 14 year period, supported both these propositions. + +

+

+ Int J Psychophysiol 1999 Dec;34(3):237-47. + + Timing of puberty and syndromes of schizotypy: a replication. + + Kaiser J, Gruzelier JH. "Active syndrome findings were confined to the male subsample with late maturing + males showing higher scores on the + + Cognitive Failures and Odd Speech + subscales than early maturers. As in the previous study, there was no relationship between a global + psychosis proneness scale and maturational rate. These findings support a neurodevelopmental model of + psychosis-proneness and show the importance of adopting a syndromal view." +

+

+ Am J Physiol 1978 Mar;234(3):H300-4. + Potentiation of the cerebrovascular response to intra-arterial 5-hydroxytryptamine. + + Eidelman BH, Mendelow AD, McCalden TA, Bloom DS. Infusion of 5-hydroxytryptamine (5HT) into the internal + carotid artery of normal baboons was not accompanied by alteration of gray matter cerebral blood flow. + + In animals pretreated with depot estrogen and progesterone (dosage equivalent to oral contraceptive + preparations), infusion of 5HT produced a marked decrease in gray matter blood flow. + + A similar decrease in flow was obtained when the 5HT was infused with a concentrate of beta-lipoprotein. + Steroid substances appear to enhance the cerebrovascular constrictor responses to 5HT. A further series + of six experiments has shown that the monoamine oxidase inhibitor tranylcypromine similarly produced + constrictor responses to 5HT. It is possible that the steroids, the beta-lipoprotein, and the + tranylcypromine produced constrictor responses to 5HT by the same mechanism (inhibition of + cerebrovascular monoamine oxidase). +

+

+ FASEB J 1989 Apr;3(6):1753-9. + Steroid regulation of monoamine oxidase activity in the adrenal medulla. + + Youdim MB, Banerjee DK, Kelner K, Offutt L, Pollard HB. "Administration of different steroid hormones in + vivo has distinct and specific effects on the MAO activity of the adrenal medulla." "As in the intact + animal, we found that + + endothelial cell MAO activity was stimulated 1.5- 2.5-fold by 10 microM progesterone, hydrocortisone, + and dexamethasone, inhibited by ca. 50% by 17-alpha-estradiol, + + but unaffected by testosterone." ". . . steroid-induced changes in total cell division ([14C]thymidine + incorporation) and total protein synthesis ([14C]leucine incorporation) were seen after changes in MAO + A." +

+

+ J Pharmacol Exp Ther 1984 Apr;229(1):244-9 + Mechanisms of specific change by estradiol in sensitivity of rat uterus to serotonin. + Ichida S, Oda Y, Tokunaga H, Hayashi T, Murakami T, Kita T. +

+

+ Neuroendocrinology 1983;36 (3): 235-41. + Gonadal hormone regulation of MAO and other enzymes in hypothalamic areas. + + Luine VN, Rhodes JC. "Activities of type A monoamine oxidase (MAO), acetylcholine esterase (AChE), and + glucose-6-phosphate dehydrogenase (G6PDH) were differentially altered in hormone-sensitive areas of the + preoptic-hypothalamic continuum after administration of estrogen and progesterone." + + "Estrogen decreased activity of MAO in the PVE of the anterior hypothalamus, + pars lateralis of the ventromedial nucleus and in the Ar-ME. Acute administration of progesterone (1 h) + to estrogen-treated females did not further alter estrogen-dependent changes in AChE or G6PDH; however, + MAO activity in the ventromedial nucleus and Ar-ME was rapidly increased after progesterone." + + "Administration of the protein synthesis inhibitor anisomycin prior to + progesterone + + did not antagonize progesterone-dependent increases in MAO. Progesterone added in vitro to homogenates from + estrogen-treated but not from untreated females increased MAO activity." + +

+

+ J Neurochem 1981 Sep;37(3):640-8. + Gonadal influences on the sexual differentiation of monoamine oxidase type A and B activities in the rat + brain. + + Vaccari A, Caviglia A, Sparatore A, Biassoni R + + "When masculinization was prevented by neonatal administration of estradiol (E) + + to males, hypothalamic MAO-A and MAO-B activities increased in both control and MAO-inhibited rats." ". + . . single, high doses of steroids to adult, but not to newborn rats, did acutely affect the kinetics of + MAO-A. + + The activity of MAO-A was also decreased by high concentrations of E or TS in vitro. The imprinting for + patterns + + of hypothalamic MAO-A and MAO-B in the two sexes results, probably, from genetic predetermination." + +

+

+ Gynecol Obstet Invest 2000;49(3):150-5. + + Transport and metabolism of serotonin in the human placenta from normal and severely pre-eclamptic + pregnancies. + + Carrasco G, Cruz MA, Gallardo V, Miguel P, Dominguez A, Gonzalez C. "These findings suggest that the + higher plasma-free serotonin levels observed in severe pre-eclampsia + + are mainly due to a reduction in MAO-A activity + and not limited by the rate of serotonin uptake into the cells." +

+

+ Psychiatry Res 1989 Jun;28(3):279-88. + + Acetazolamide and thiamine: an ancillary therapy for chronic mental illness. + + Sacks W, Esser AH, Feitel B, Abbott K Cerebral Metabolism Laboratory, Nathan S. Kline Institute for + Psychiatric Research, Orangeburg, NY 10962. Twenty-four chronic schizophrenic patients were treated + successfully with the addition of acetazolamide and thiamine (A + T) to their unchanged existing + therapies in a double-blind, placebo-controlled crossover study. Therapeutic effects were measured by + the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms. + + Overall, 50% of the patients showed improvement on all assessment scales. + + No untoward effects occurred in these patients or in patients in previous studies who have been treated + continuously with A + T therapy for as long as 3 years. +

+

+ J Neural Transm 1998;105(8-9):975-86. + Role of tryptophan in the elevated serotonin-turnover in hepatic encephalopathy. + + Herneth AM, Steindl P, Ferenci P, Roth E, Hortnagl H. "The increase of the brain levels of + 5-hydroxyindoleacetic acid (5-HIAA) in hepatic encephalopathy (HE) suggests an increased turnover of + serotonin (5-HT)." +

+

+ J Neurosci Res 1981;6(2):225-36 + A difference in the in vivo cerebral production of [1-14C] lactate from D-[3-14C] glucose in chronic mental + patients. + + Sacks W, Schechter DC, Sacks S. "Previously unpublished whole-blood lactate determinations in these + experiments indicated a cerebral production of much higher specific activity of [1-14C]-lactate from the + D-[3-14C] glucose by mental patients." + +

+

+ Ther Umsch 2000 Feb;57(2):76-80. + [Antidepressive therapy by modifying sleep]. + Haug HJ, Fahndrich E. +

+

+ Schizophr Res 1998 Jun 22;32(1):1-8. + Reduced status of plasma total antioxidant capacity in schizophrenia. + Yao JK, Reddy R, McElhinny LG, van Kammen DP. +

+

+ FASEB J 1998 Dec;12(15):1777-83. + Increased F2-isoprostanes in Alzheimer's disease: evidence for enhanced lipid peroxidation in vivo. + + Pratico D, MY Lee V, Trojanowski JQ, Rokach J, Fitzgerald GA. +

+

+ Dis Nerv Syst 1976 Feb;37(2):98-103. + Glucose-insulin metabolism in chronic schizophrenia. + + Brambilla F, Guastalla A, Guerrini A, Riggi F, Rovere C, Zanoboni A, Zanoboni-Muciaccia W. + +

+

+ Psychiatr Clin (Basel) 1975;8(6):304-13. + Blood flow and oxidative metabolism of the brain in patients with schizophrenia. + Hoyer S, Oesterreich K. +

+

+ Zh Nevropatol Psikhiatr Im S S Korsakova 1977;77(8):1179-86 + [Effect of lithium on the energy metabolism of nervous tissue]. + Gulidova GP, Khzardzhian VG, Mikhailova NM + . + "Lithium (0.5--4 mM) either significantly increase, either completely normalizers the intensity of the + oxidative and energy metabolism of the brain mitochondria, decreased by the influence of the blood serum + of patients with manic-depressive psychosis and attack like schizophrenia." "Processes of + phosphorilation become normalized in a joint action on the mitochondria by lithium and antioxidants." + "It is assumed that an increase in the intensity of the energy metabolism is one of the mechanisms of + therapeutical and prophylactic action of lithium." +

+

+ Ateneo Parmense Acta Biomed 1975 Jan-Apr;46(1-2):5-19. + + [Clinical significance of changes in tryptophan metabolism]. + + Ambanelli U, Manganelli P. "The oxidative pathway is most important of the metabolic pathway of the + amino acid; the degredation of tryptophan is + + particularly influenced by steroid hormones and vitamins' want. The + metabolic anomalies are demonstrable both in malignant tumors (mostly in bladder cancer and Hodgkin's + disease), both during psychiatric diseases (such as depression and schizophrenia) and in the diseases of + connective tissue in addition to congenital errors of the degradation of tryptophan (such as Hartnup's + disease, tryptophanuria and 3-hydroxychinureninuria)." + +

+

+ Acta Neurol Scand Suppl 1977;64:534-5. + + Blood flow and oxidative metabolism of the brain in the course of acute schizophrenia. + Hoyer S, Oesterreich K. +

+

+ Med Hypotheses 1994 Dec;43(6):420-35 + + Schizophrenia is a diabetic brain state: an elucidation of impaired neurometabolism. + Holden RJ, Mooney PA. +

+

+ Neuropsychobiology 1990-91;24(1):1-7. + Frontality, laterality, and cortical-subcortical gradient of cerebral blood flow in schizophrenia: + relationship to symptoms and neuropsychological functions. + Sagawa K, Kawakatsu S, Komatani A, Totsuka S. +

+

+ Schizophr Res 1989 Nov-Dec;2(6):439-48. + + Effect of attention on frontal distribution of delta activity and cerebral metabolic rate in + schizophrenia. + + Guich SM, Buchsbaum MS, Burgwald L, Wu J, Haier R, Asarnow R, Nuechterlein K, Potkin S. "Analysis + confirmed increased delta activity in the frontal region of patients with schizophrenia in comparison to + normal controls, and a significant correlation between increased frontal delta and relative reduction in + frontal + + lobe metabolism among patients with schizophrenia. This finding of increased delta is consistent with + PET, blood flow and topographic EEG studies of schizophrenia, suggesting reduced frontal + activity." +

+

+ Br J Psychiatry 1990 Feb;156:216-27. + + Glucose metabolic rate in normals and schizophrenics during the Continuous Performance Test assessed by + positron emission tomography. + + Buchsbaum MS, Nuechterlein KH, Haier RJ, Wu J, Sicotte N, Hazlett E, Asarnow R, Potkin S, Guich S "When + the group of schizophrenic patients was divided into deficit and nondeficit types, a preliminary + exploratory analysis suggested + + thalamic, frontal, and parietal cortical hypometabolism in the deficit subgroup, with normal metabolism + in the nondeficit patient group in those areas; in contrast, hippocampal and anterior cingulate cortical + metabolism was reduced in both deficit and nondeficit subtypes. These results suggest that the limbic + system, especially the hippocampus, is functionally involved in schizophrenic psychosis and that + different manifestations of schizophrenia may involve different neuronal circuits." +

+

+ Psychol Med 1994 Nov;24(4):947-55. + + Patterns of cortical activity in schizophrenia. + + Schroeder J, Buchsbaum MS, Siegel BV, Geider FJ, Haier RJ, Lohr J, Wu J, Potkin SG. + + "Schizophrenics were significantly more hypofrontal than the controls, + + with higher values on the 'parietal cortex and motor strip' factor and a trend towards higher values in + the temporal cortex. + + A canonical discriminant analysis confirmed that the 'hypofrontality' and + 'parietal cortex and motor strip' factors accurately separated the schizophrenic group from the healthy + controls." + +

+

+ Schizophr Res 1996 Mar;19(1):41-53 + . Cerebral metabolic activity correlates of subsyndromes in chronic schizophrenia. + + Schroder J, Buchsbaum MS, Siegel BV, Geider FJ, Lohr J, Tang C, Wu J, Potkin SG. "The delusional + + cluster showed a significantly reduced hippocampal activity, while the + negative symptoms cluster presented with a prominent hypofrontality and significantly increased left + temporal cortex values." + +

+

+ Psychiatry Res 1997 Oct 31;75(3):131-44. + + Cerebral glucose metabolism in childhood onset schizophrenia. + + Jacobsen LK, Hamburger SD, Van Horn JD, Vaituzis AC, McKenna K, Frazier JA, Gordon CT, Lenane MC, + Rapoport JL, Zametkin AJ. "Decreased frontal cortical glucose metabolism has been demonstrated in adult + schizophrenics both at rest and while engaging in tasks that normally increase frontal metabolism, such + as the Continuous Performance Test (CPT).". "These findings suggest that childhood onset schizophrenia + may be associated with a similar, but not more severe, degree of hypofrontality relative to that seen in + adult onset schizophrenia." +

+

+ Pharmacol Biochem Behav 1990 Apr; 35(4):955-62. + The effects of ondansetron, a 5-HT3 receptor antagonist, on cognition in rodents and primates. + + Barnes JM, Costall B, Coughlan J, Domeney AM, Gerrard PA, Kelly ME, Naylor RJ, Onaivi ES, Tomkins DM, + Tyers MB. "The selective 5-HT3 receptor antagonist, onansetron, has been assessed in three tests of + cognition in the mouse, rat and marmoset. In a habituation test in the mouse, ondansetron facilitated + performance in young adult and aged animals, and inhibited an impairment in habituation induced by + scopolamine, electrolesions or ibotenic acid lesions of the nucleus basalis magnocellularis." "In an + object discrimination and reversal learning task in the marmoset, assessed using a Wisconsin General + Test Apparatus, ondansetron improved performance in a reversal learning task. We + + conclude that ondansetron potently improves basal performance in rodent and primate tests of cognition + and inhibits the impairments in performance caused by cholinergic deficits." +

+

+ Pharmacol Biochem Behav 1992 May;42(1):75-83. Ondansetron and arecoline prevent scopolamine-induced + cognitive deficits in the marmoset. + + Carey GJ, Costall B, Domeney AM, Gerrard PA, Jones DN, Naylor RJ, Tyers MB + + School of Pharmacy, University of Bradford, UK. + The cognitive-enhancing potential of the 5-hydroxytryptamine (5-HT) + selective 5-HT3 receptor antagonist, ondansetron, was investigated in a model of cognitive impairment + induced by the muscarinic receptor antagonist, scopolamine. + +

+

+ J Comp Physiol Psychol 1977 Jun;91(3): 642-8. + Tryptophan and tonic immobility in chickens: effects of dietary and systemic manipulations. + + Gallup GG Jr, Wallnau LB, Boren JL, Gagliardi GJ, Maser JD, Edson PH. + + "Systemic injections of tryptophan, the dietary precursor to serotonin, led + to a dose-dependent increase in immobility, with optimal effects being observed within 30 min after + injection. Dietary depletion of endogenous tryptophan served to attenuate the duration of immobility, + and a diet completely free of tryptophan, but supplemented with niacin, practically abolished the + reaction. + + Dietary replacement served to reinstate the response." + "The data are discussed in light of evidence showing serotonergic involvement in tonic immobility." +

+

+ J Neurosci Res 1995 Feb 15;40(3):407-413. + Endotoxin administration stimulates cerebral catecholamine release in freely moving rats as assessed by + microdialysis. + Lavicky J, Dunn AJ. +

+

+ J Neurosci Res 1998 Feb 15;51(4):517-525. + Lipopolysaccharide regulates both serotonin- and thrombin-induced + intracellular calcium mobilization in rat C6 glioma cells: possible involvement of nitric oxide + synthase-mediated pathway. + + Tawara Y, Kagaya A, Uchitomi Y, Horiguchi J, Yamawaki S. + +

+

+ Infect Immun 1996 Dec;64(12):5290-5294..Biphasic, organ-specific, and strain-specific accumulation of platelets induced in mice by a + lipopolysaccharide from Escherichia coli and its possible involvement in shock. + Shibazaki M, Nakamura M, Endo Y. "Platelets contain a large amount of 5-hydroxytryptamine (5HT, + serotonin). Intravenous injection into BALB/c mice of a Boivin's preparation of lipopolysaccharide + (LPS) from Escherichia coli induced rapid 5HT accumulation in the lung (within 5 min) and slow 5HT + accumulation in the liver (2 to 5 h later)." "A shock, which was + manifested by crawling, convulsion, or prostration, followed + shortly after the rapid accumulation of 5HT in the lung. On the other hand, the slow accumulation of + 5HT in the liver could be induced by much lower doses of LPS (1 microg/kg or less), even when given + by intraperitoneal injection." + +

+

+ Life Sci 1997;61(18):1819-1827. + Serotonin 5HT2A receptor activation inhibits inducible nitric oxide synthase activity in C6 glioma + cells. + Miller KJ, Mariano CL, Cruz WR. +

+

+ Harefuah 2000 May 15;138(10):809-12, 910. + + [Jet lag causing or exacerbating psychiatric disorders]. + + Katz G, Durst R, Zislin J, Knobler H, Knobler HY. We presume, relying on the literature and our + accumulated experience, that in predisposed individuals jet lag may play a role in triggering + exacerbation of, or de novo affective disorders, as well as, though less convincing, schizophreniform + psychosis or even schizophrenia. An illustrative case vignette exemplifies the possible relationship + between jet lag following eastbound flight and psychotic manifestations. +

+

+ Life Sci 1987 May 18;40(20):2031-9. + + Dysfunction in a prefrontal substrate of sustained attention in schizophrenia. + + Cohen RM, Semple WE, Gross M, Nordahl TE, DeLisi LE, Holcomb HH, King AC, Morihisa JM, Pickar D. + Regional brain metabolism was measured in normal subjects and patients with schizophrenia while they + performed an auditory discrimination task designed to emphasize sustained attention. A direct + relationship was found in the normal + + subjects between metabolic rate in the middle prefrontal cortex and accuracy of performance. The metabolic + rate in the middle prefrontal cortex of patients with schizophrenia, even those who performed as well as + normals, was found to be significantly lower than normal and unrelated to performance. The findings + point to a role of the mid-prefrontal region in sustained attention and to dysfunction of this region in + schizophrenia. +

+

+ Acta Psychiatr Scand 1987 Dec;76(6):628-41. + Regional brain glucose metabolism in drug free schizophrenic patients and clinical correlates. + + Wiesel FA, Wik G, Sjogren I, Blomqvist G, Greitz T, Stone-Elander S. "Thus, the lower the metabolic rate + was, the more autistic the patient. Metabolic rates were not correlated to atrophic changes of the + brain. No basis for a specific alteration in frontal cortical metabolism of schizophrenics was obtained. + Changes in regional metabolic rates in schizophrenia are suggested to reflect disturbances in more + general mechanisms which are of importance in neuronal function." +

+

+ Chung Hua Shen Ching Ching Shen Ko Tsa Chih 1991 Oct;24(5):268-71, 316-7. + + [Developments observation of serum thyrohormone level in schizophrenics. + + Wang X. "The authors reported that abnormal levels of T4, FT4I in 16 cases patients relate to disease + course and severe symptoms and suggested that the change of serum T4, FT4I in some cases was related to + the disease in itself." +

+

+ Biol Psychiatry 1991 Mar 1;29(5):457-66. + Multidimensional hormonal discrimination of paranoid schizophrenic from bipolar manic + patients. Mason JW, Kosten TR, Giller EL. +

+

+ Zh Nevropatol Psikhiatr Im S S Korsakova 1991;91(1):122-3 + [Status of the thyroid gland in patients with schizophrenia]. + + Turianitsa IM, Lavkai IIu, Mishanich II, Margitich VM, Razhov KF. "The rise of TTH concentration + represents one of the mechanisms of correction, aimed at the attainment of the physiological content of + T4 at the expense of its additional output for its level in the blood serum is appreciably + reduced." +

+

+ Can J Psychiatry 1990 May;35(4):342-3. + Increased detection of elevated TSH using immunoradiometric assay. + + Little KY, Kearfott KS, Castellanos X, Rinker A, Whitley R. Using a highly sensitive immunoradiometric + assay, the authors detected an increased rate of elevated thyrotropin in 2,099 patients vs 1,789 + patients examined with radioimmunoassay. Closer scrutiny of mood disorder patients with elevations found + confirmatory evidence of thyroid dysfunction in most. +

+

+ Metabolism 1990 May;39(5):538-43. + + Serum thyrotropin in hospitalized psychiatric patients: evidence for hyperthyrotropinemia as measured by + an ultrasensitive thyrotropin assay. + Chopra IJ, Solomon DH, Huang TS. +

+

+ J Nerv Ment Dis 1989 Jun;177(6):351-8. + + Serum thyroxine levels in schizophrenic and affective disorder diagnostic subgroups. + Mason JW, Kennedy JL, Kosten TR, Giller EL Jr + . "For TT4, 75% of the PS group showed a rise during recovery in contrast to 4% of the remaining groups; + for FT4, 50% of the PS group showed a rise compared with 14% of the other groups." "This study + emphasizes the importance of exploring more fully the psychiatric significance of thyroxine levels + within the endocrinological normal range and of doing longitudinal assessments of thyroxine and symptom + changes during clinical recovery in psychiatric disorders." +

+

+ Biol Psychiatry 1989 Jan;25(1):67-74. + Serum thyroxine change and clinical recovery in psychiatric inpatients. + + Southwick S, Mason JW, Giller EL, Kosten TR. "A strong correlation between the range values for BPRS + [Brief Psychiatric Rating Scale] sum and for FT4 (p less than 0.005) and TT4 (p less than 0.001) levels + indicated that change in overall symptom severity was linked to change in thyroxine levels during + clinical recovery." "These findings suggest that a "normalizing" principle underlies the relationship + between clinical recovery and thyroxine levels and that both FT4 and TT4 levels within the normal range + appear to have clinical significance in either reflecting or contributing to the course of a variety of + psychiatric disorders and possibly having a role in pathogenesis." +

+

+ J Clin Psychiatry 1980 Sep;41(9):316-8. + Myxedema psychosis--insanity defense in homicide. + Easson WM. +

+

+ Int J Psychiatry Med 1988;18(3):263-70. + + The diagnostic dilemma of myxedema and madness, axis I and axis II: a longitudinal case report. + + Darko DF, Krull A, Dickinson M, Gillin JC, Risch SC. "A patient with presumed chronic paranoid + schizophrenia had chronic thyroiditis and Grade I hypothyroidism. Psychosis cleared following treatment + with thyroid replacement." "The differential diagnosis among hypothyroidism and primary axis I psychotic + and depressive psychopathology has always been problematic." +

+

+ P R Health Sci J 1993 Jun;12(2):85-7. + [Alzheimer's disease: the untold story]. + Pico-Santiago G. After considering the potential relationship between amyloid deposits and + myxedematous infiltrations, the hypothesis is formulated that Alzheimer's disease may be due to + functional hypothyroidism and may thus respond to thyroid therapy. +

+

+ Psychiatry Res 1998 Jul 27;80(1):29-39. + + Reduced level of plasma antioxidant uric acid in schizophrenia. +

+ + and inversely correlated with psychosis. There was a trend for lower uric acid levels in relapsed + patients relative to clinically stable patients. Smoking, which can modify plasma antioxidant capacity, + was not found to have prominent effects on uric acid levels. The present finding of a significant + decrease of a + + selective antioxidant provides additional support to the hypothesis that oxidative stress in + schizophrenia may be due to a defect in the antioxidant defense system." +

+

+ Zh Nevropatol Psikhiatr Im S S Korsakova 1989; 89(5):108-10. + [Lipid peroxidation processes in patients with schizophrenia]. + Kovaleva ES, Orlov ON, Tsutsu'lkovskaia MIa, Vladimirova TV, Beliaev BS. + +

+

+ Zh Nevropatol Psikhiatr Im S S Korsakova 1991;91(7):121-4. + [Significance of disorders of the processes of lipid peroxidation in patients with persistent paranoid + schizophrenia resistant to the treatment]. + + Govorin NV, Govorin AV, Skazhutin SA. +

+

+ Patol Fiziol Eksp Ter 1999 Jul-Sep;(3):19-22. + [The biogenic amine content of rat tissues in the postresuscitation period following hemorrhagic shock and + the effect of the preparation semax]. + + Bastrikova NA, Shestakova SV, Antonova SV, Krushinskaia IaV, Goncharenko EN, Kudriashova NIu, + Novoderzhkina IS, Sokolova NA, Kozhura VL. "Early after resuscitation the trend was noted to higher LPO + products concentration in plasma and serotonin in the brain stem." "It is suggested that biogenic + amines, especially serotonin system, are involved in mechanisms of postresuscitation disorders, in + cerebral defects in particular, through prolongation of secondary hypoxia early after hemorrhagic shock + and activation of hypothalamo-hypophyso-adrenal system late after the shock." +

+

+ Prostaglandins Leukot Essent Fatty Acids 1996 Aug;55(1-2):33-43. + + Free radical pathology in schizophrenia: a review. + + Reddy RD, Yao JK. + +

+

+ Schizophr Res 1996 Mar;19(1):19-26. + Impaired antioxidant defense at the onset of psychosis. + + Mukerjee S, Mahadik SP, Scheffer R, Correnti EE, Kelkar H. +

+

+ Biol Psychiatry 1998 May 1;43(9):674-9. + Elevated plasma lipid peroxides at the onset of nonaffective psychosis. + + Mahadik SP, Mukherjee S, Scheffer R, Correnti EE, Mahadik JS. +

+

+ Brain Res 1999 Aug 21;839(1):74-84. + + Psychological stress-induced enhancement of brain lipid peroxidation via nitric oxide systems and its + modulation by anxiolytic and anxiogenic drugs in mice. + + Matsumoto K, Yobimoto K, Huong NT, Abdel-Fattah M, Van Hien T, Watanabe H. "The effects of diazepam and + FG7142 were abolished by the BZD receptor antagonist flumazenil (10 mg/kg, i.p.). These results indicate + that psychological stress causes oxidative damage to the brain lipid via enhancing constitutive + NOS-mediated production of NO, and that drugs with a BZD or 5-HT(1A) receptor agonist profile have a + protective effect on oxidative brain membrane damage induced by psychological stress." +

+

+ Anesteziol Reanimatol 1998 Nov-Dec; (6):20-5. + [Role of hyperbaric oxygenation in the treatment of posthypoxic encephalopathy of toxic etiology]. + + Ermolov AS, Epifanova NM, Romasenko MV, Luzhnikov EA, Ishmukhametov AI, Golikov PP, Khvatov VB, Kukshina + AA, Davydov BV, Kuksova NS, et al. Hyperbaric oxygenation (HBO) was used in the treatment of 475 + patients with toxic encephalopathy (TE) developing as a result of exo- and endotoxicosis. HBO promoted + correction of all components of homeostasis, + + decreased endotoxicosis, reduced psychopathological and neurological disorders, and promoted social + adaptation. +

+

+ J Neurochem 2000 Jan; 74(1): 114-24. + Metabolic impairment elicits brain cell type-selective changes in oxidative stress and cell death in + culture. + + Park LC, Calingasan NY, Uchida K, Zhang H, Gibson GE. "Abnormalities in oxidative metabolism and + inflammation accompany many neurodegenerative diseases. Thiamine deficiency (TD) is an animal model in + which chronic oxidative stress and inflammation lead to selective neuronal death, whereas other cell + types show an inflammatory response." "Among the cell types tested, only in neurons did TD induce + apoptosis and cause the accumulation of 4-hydroxy-2-nonenal, a lipid peroxidation product. On the other + hand, chronic lipopolysaccharide-induced inflammation significantly inhibited cellular dehydrogenase and + KGDHC activities in microglia and astrocytes but not in neurons or endothelial cells. The results + demonstrate that the selective cell changes during TD in vivo reflect inherent properties of the + different brain cell types." +

+

+ Psychol Med 1976 Aug;6(3):359-69. + + Possible association of schizophrenia with a disturbance in prostaglandin metabolism: a physiological + hypothesis. + + Feldberg W. Schizophrenia may be associated with increased prostaglandin synthesis in certain parts of + the brain. This hypothesis is based on the following findings: (1) Catalepsy, which is the nearest + equivalent in animals to human catatonia, + + develops in cats when prostaglandin E1 is injected into the cerebral ventricles and when during endotoxin + or lipid A fever the prostaglandin E2 level in cisternal c.s.f. rises to high levels; however, when + fever and prostaglandin level are brought down by non-steroid anti-pyretics which inhibit prostaglandin + synthesis, catalepsy disappears as well. (2) Febrile episodes are a genuine syndrome of + schizophrenia. +

+

+ Zh Nevropatol Psikhiatr Im S S Korsakova 1966;66(6):912-7. + [Treatment of acute schizophrenia with antibiotics, gamma-globulin and vitamins]. + + Neikoya M. +

+

+ Prostaglandins Med 1979 Jan;2(1):77-80. + Penicillin and essential fatty acid supplementation in schizophrenia. + + Vaddadi KS. + +

+

+ Psychiatr Dev 1989 Spring;7(1):19-47. + + Positron emission tomography in psychiatry. + + Wiesel FA. "Schizophrenia is the most extensively studied psychiatric disorder. Most studies have + demonstrated decreased metabolic rates in wide areas of the brain. It is proposed that the metabolic + changes observed in the brains of schizophrenic patients are due to a fundamental change in neuronal + function." "Bipolar depressed patients probably have a decreased brain metabolism." "Alcohol dependent + subjects with a long duration of abuse may have a decreased brain metabolism." +

+

+ Arch Gen Psychiatry 1976 Nov;33(11):1377-81. + Platelet monamine oxidase in chronic schizophrenia. Some enzyme characteristics relevant to reduced + activity. + + Murphy DL, Donnelly CH, Miller L, Wyatt RJ. "These findings suggest that the reduced MAO activity found + in chronic schizophrenic patients is apparently not accounted for by nonspecific changes in platelets or + platelet mitochondria." +

+

+ Exp Neurol 1997 May;145(1):118-29. + + Long-term reciprocal changes in dopamine levels in prefrontal cortex versus nucleus accumbens in rats + born by Caesarean section compared to vaginal birth. + + El-Khodor BF, Boksa P. "Epidemiological evidence indicates a higher incidence of pregnancy and birth + complications among individuals who later develop schizophrenia, a disorder linked to alterations in + mesolimbic dopamine (DA) function. Two birth + + complications usually included in these epidemiological studies, and still frequently encountered in the + general population, are birth by Caesarean section (C-section) and fetal asphyxia." "At 2 months of age, + in animals born by rapid C-section, steady state levels of DA were decreased by 53% in the prefrontal + cortex and increased by 40% in both the nucleus accumbens and striatum, in comparison to the vaginally + born + + group. DA turnover increased in the prefrontal cortex, decreased in the nucleus accumbens, and showed no + significant change in the striatum, in the C-section group. Thus, birth by a Caesarean procedure + produces long-term reciprocal changes in DA levels and metabolism in the nucleus accumbens and + prefrontal cortex." "Although appearing robust at birth on gross observation, more subtle measurements + revealed that rat pups born by C-section show altered respiratory rates and activity levels and + increased levels of whole brain lactate, suggestive of low grade brain hypoxia, during the first 24 h of + life, in comparison to vaginally born controls." "It is concluded that C-section birth is sufficient + perturbation to produce long-lasting effects on DA levels and metabolism + + in the central nervous system of the rat." +

+

+ Rehabilitation (Stuttg) 1983 May;22(2):81-5 + [Physical capacity of schizophrenic patients]. + Deimel H, Lohmann S. + + "Reduced physical capacity in schizophrenic illness has been described in + medical literature, but so far not been substantiated empirically. The findings of progressive bicycle + ergometry confirm the assertion, with the following main results having been obtained: 1. As opposed to + a matched comparison group of untrained healthy clients, the schizophrenically ill patients demonstrated + significantly lower endurance levels + + in respect of the aerobic-anaerobic threshold. + 2. Relative to the load maximum attainable highly significant differences + existed between the groups. Particularly noteworthy had been early exercise termination already at + submaximal loads by the schizophrenic patients. 3. The patients under study obtained values one third + below standard compared to the maximum load target for untrained persons, with age and weight being + taken into account." + +

+

+ Folia Psychiatr Neurol Jpn 1984;38(4):425-36 + Antipsychotic and prophylactic effects of acetazolamide (Diamox) on atypical psychosis. + + Inoue H, Hazama H, Hamazoe K, Ichikawa M, Omura F, Fukuma E, Inoue K, Umezawa Y We investigated the + antipsychotic and prophylactic effects of acetazolamide (Diamox) on atypical psychosis. Acetazolamide + was given to 30 patients: Type I, puberal periodic psychosis, a psychosis whose onset occurs during the + period of puberty and which appears repetitively with psychosis-like condition at about the same + interval as the menstrual cycle (6 cases); Type II, a) presenile atypical psychosis which initially + appears in patients in their 20s or 30s accompanied by manic-depressive cycles and shows acute + confusional and dreamy states in the presenile period, incurable cases (7), b) atypical psychosis, in + the narrow sense, cases which show acute hallucination, delusion, confusional and dreamy states + accompanied by affective symptoms (8 cases); Type III, repetitively the atypical manic and depressive + states, and atypical manic-depressive psychosis, and transient changes in consciousness, refractory + cases (2); Type IV, atypical schizophrenia, which is considered to be schizophrenia but shows the + abnormalities in electroencephalogram and emotional disorders (7 cases). Among these cases, + + some extent of the therapeutic effects of acetazolamide (500-1,000 mg/day) was obtained in about 70%. + The high therapeutic effects were particularly observed in Types I, II and III. It was less effective + against atypical schizophrenia. Acetazolamide showed the effectiveness in 10 cases out of 13 cases to + which lithium carbonate and carbamazepine were ineffective. + + The high therapeutic effects of acetazolamide were shown in the cases whose + + symptoms were aggravated at the interval of the menstrual cycle. + + No correlation was observed between the electroencephalographic abnormalities and the therapeutic + effects. In addition, the prophylactic effects of acetazolamide on the periodic crisis were observed in + 9 cases. From these results, acetazolamide was considered to have the antipsychotic and prophylactic + effects on atypical psychosis. + + Since side effects due to acetazolamide were rarely observed, the present drug was considered to have a + high safety margin. +

+

+ Am J Psychiatry 1999 Apr;156(4):617-23 + Minor physical anomalies, dermatoglyphic asymmetries, and cortisol levels in adolescents with schizotypal + personality disorder. + + Weinstein DD, Diforio D, Schiffman J, Walker E, Bonsall R. "The schizotypal personality disorder group + showed more minor physical anomalies and dermatoglyphic asymmetries than the normal comparison group and + higher cortisol levels than both of the other groups." + +

+

+ Am J Psychiatry 1992 Jan;149(1):57-61 + Congenital malformations and structural developmental anomalies in groups at high risk for psychosis. + McNeil TF, Blennow G, Lundberg L. "The inferred genetic risk for + + psychosis does not appear to be associated with greater rates of early somatic developmental anomalies, + suggesting that early developmental anomalies do not represent an expression of genetic influence toward + psychosis." +

+

+ Schizophr Bull 1984;10(2):204-32. + + Psychophysiological dysfunctions in the developmental course of schizophrenic disorders. + + Dawson ME, Nuechterlein KH. "Two electrodermal anomalies are identified in different subgroups of + symptomatic + + patients: (1) an abnormally high sympathetic arousal and (2) an abnormal + absence of skin conductance orienting responses to innocuous environmental stimuli." + +

+

+ Behav Brain Res 2000 Jan;107(1-2):71-83. + Changes in adult brain and behavior caused by neonatal limbic damage: implications for the etiology of + schizophrenia. + + Hanlon FM, Sutherland RJ. ."This study contributes to our understanding of the pathogenesis of + schizophrenia by showing that early damage to limbic structures produced behavioral, morphological, and + neuropharmacological abnormalities related to pathology in adult schizophrenics." +

+

+ Neurochem Res 1996 Sep; 21(9):995-1004. + Mitochondrial involvement in schizophrenia and other functional psychoses. + + Whatley SA, Curti D, Marchbanks RM. "Gene expression has been studied in post-mortem frontal cortex + samples from patients who had suffered from schizophrenia and depressive illness." "We conclude that + changes in mitochondrial gene expression are involved in schizophrenia and probably other functional + psychoses." +

+

+ Eur J Pharmacol 1994 Aug 11;261(1-2):25-32. + The effect of alpha 2-adrenoceptor antagonists in isolated globally ischemic rat hearts. + Sargent CA, Dzwonczyk S, Grover GJ. "The alpha 2-adrenoceptor antagonist, yohimbine, has been + reported to protect hypoxic myocardium. Yohimbine has + several other activities, including 5-HT receptor antagonism, at the concentrations at which protection + was found." + "The + cardioprotective effects of yohimbine were partially reversed by 30 microM 5-HT. These results + indicate that the mechanism for the cardioprotective activity of yohimbine may involve 5-HT receptor + antagonistic activity." + +

+

+ J Cardiovasc Pharmacol 1993 Oct;22(4):664-672. + Protective effect of serotonin (5-HT2) receptor antagonists in ischemic rat hearts. + + Grover GJ, Sargent CA, Dzwonczyk S, Normandin DE, Antonaccio MJ. +

+

+ J Appl Physiol 1994 Jul;77(1):277-284. + + Aerobic muscle contraction impaired by serotonin-mediated vasoconstriction. + + Dora KA, Rattigan S, Colquhoun EQ, Clark MG. +

+

+ J Cereb Blood Flow Metab 1995 Jul;15(4):706-13. + Enhanced cerebrovascular responsiveness to hypercapnia following depletion of central serotonergic + terminals. + + Kelly PA, Ritchie IM, McBean DE, Sharkey J, Olverman HJ. +

+

+ Arch Gen Psychiatry 1984 Mar;41(3): 293-300. + Regional brain glucose metabolism in chronic schizophrenia. A positron emission transaxial tomographic + study. + + Farkas T, Wolf AP, Jaeger J, Brodie JD, Christman DR, Fowler JS. + + ". . . schizophrenics had significantly lower activity in the frontal lobes, + relative to posterior regions." + +

+

+ Semin Nucl Med 1986 Jan;16(1):2-34. + Positron emission tomography imaging of regional cerebral glucose metabolism. + + Alavi A, Dann R, Chawluk J, Alavi J, Kushner M, Reivich M. "In patients with Alzheimer's disease . . . + parietal, temporal, and to some degree, frontal glucose metabolism is significantly diminished even in + the early stages of the disease. Patients with Huntington's disease and those at risk of developing this + disorder have a typical pattern of diminished CMRglu in the caudate nuclei and putamen. In patients with + stroke, PET images with FDG have demonstrated abnormal findings earlier than either XCT or MRI and with + a wider topographic distribution. FDG scans have revealed interictal zones of decreased LCMRglu in + approximately 70% of patients with partial epilepsy. The location of the area of hypometabolism + corresponds to the site of the epileptic focus as determined by electroencephalography and microscopic + examination of the resected tissue." +

+

+ Schizophr Bull 1988; 14(2): 169-76. + + From syndrome to illness: delineating the pathophysiology of schizophrenia with PET. + + Cohen RM, Semple WE, Gross M, Nordahl TE. "In normal controls, the metabolic rate in the middle + prefrontal cortex, measured during the ongoing performance of auditory discrimination, is associated + with their accuracy of performance. In unmedicated patients with + + schizophrenia, even those who performed as well as normals, the metabolic + rate in the mid-prefrontal cortex was found to be significantly lower than normal. Further, this + decreased metabolic rate was unrelated to performance." "The mid-prefrontal cortex and its dopamine + neurotransmitter pathway input are important biological determinants of sustained attention." + +

+

+ Biol Psychiatry 1989 Apr 1;25(7):835-51. + Increased temporal lobe glucose use in chronic schizophrenic patients. + + DeLisi LE, Buchsbaum MS, Holcomb HH, Langston KC, King AC, Kessler R, Pickar D, Carpenter WT Jr, + Morihisa JM, Margolin R, et al. Temporal lobe glucose metabolic rate was assessed in 21 off-medication + patients with schizophrenia and 19 normal controls by positron emission tomography with + 18F-deoxyglucose. Patients with schizophrenia had significantly greater + + metabolic activity in the left than the right anterior temporal lobe, and the extent of this + lateralization was in proportion to the severity of + psychopathology. +

+

+ Am J Obstet Gynecol 1999 Dec;181(6):1479-84. + + Stimulated nitric oxide release and nitric oxide sensitivity in forearm arterial vasculature during + normotensive and preeclamptic pregnancy. + + Anumba DO, Ford GA, Boys RJ, Robson SC. "Alterations in serotonin receptor coupling to nitric oxide + synthase, or a limitation of availability of the substrate for nitric oxide synthase (L-arginine) during + pregnancy, could account for the reduction in stimulated nitric oxide release." +

+

+ J Hypertens 1999 Mar;17(3):389-96. + + U46619-mediated vasoconstriction of the fetal placental vasculature in vitro in normal and hypertensive + pregnancies. + + Read MA, Leitch IM, Giles WB, Bisits AM, Boura AL, Walters WA. + +

+

+ Am J Obstet Gynecol 1999 Feb;180(2 Pt 1):371-7. + Ketanserin versus dihydralazine in the management of severe early-onset preeclampsia: maternal + outcome. + + Bolte AC, van Eyck J, Kanhai HH, Bruinse HW, van Geijn HP, Dekker GA. "Ketanserin [a selective serotonin + 2 receptor blocker] is an attractive alternative in the management of severe early-onset + preeclampsia." +

+

+ Am J Obstet Gynecol 1996 Dec;175(6):1543-50 + . Novel appearance of placental nuclear monoamine oxidase: biochemical and histochemical evidence for + hyperserotonomic state in preeclampsia-eclampsia. + + Gujrati VR, Shanker K, Vrat S, Chandravati, Parmar SS. "Placental serotonin increases with severity + (rsystolic 0.84, rdiastolic 0.83) and monoamine oxidase decreases (rsystolic 0.86, rdiastolic 0.79). + Placental monoamine oxidase showed marked changes in preeclampsia-eclampsia." ."A severity-dependent + decrease was present in the nuclei of placentas with preeclampsia-eclampsia." "The study delineates an + impaired catabolism of placental serotonin in preeclampsia-eclampsia." "The novel appearance of + monoamine oxidase in nuclei in proximity to its normal site and low activity resulting in a + hyperserotonomic state may lead to preeclampsia-eclampsia." +

+

+ Chung Hua Fu Chan Ko Tsa Chih 1996 Nov;31(11):670-2 + [Changes of plasma levels of monoamines in normal pregnancy and pregnancy-induced hypertension women and + their significance]. + + Lin B, Zhu S, Shao B. "Compared with NP [normal pregnant], the contents of DA in moderate and severe PIH + [pregnancy-induced hypertension] were markedly and very markedly decreased respectively (P < 0.05 and + P < 0.01), while the levels of 5-HT in PIH increased significantly (P < 0.05)." "The changes of + monoamines may be one of the causes of small artery spasm in PIH." +

+

+ Lancet 1997 Nov 1;350(9087):1267-71. + Randomised controlled trial of ketanserin and aspirin in prevention of pre-eclampsia. +

+

+

+ Osaka City Med J 1989 Jun;35(1):1-11. + + Serotonin and tryptamine metabolism in the acute hepatic failure model: changes in tryptophan and its + metabolites in the liver, brain and kidney. + + Kodama C, Mizoguchi Y, Kawada N, Sakagami Y, Seki S, Kobayashi K, Morisawa S. + +

+

+ Br J Pharmacol 1984 Apr;81(4):645-650. + + Induction of hypoglycaemia and accumulation of 5-hydroxytryptamine in the liver after the injection of + mitogenic substances into mice. + + Endo Y + . +

+

+ Eur J Pharmacol 1983 Aug 5;91(4):493-499. + + A lipopolysaccharide and concanavalin A induce variations of serotonin levels in mouse tissues. + Endo Y. +

+

+ Brain Res 1986 Jul 16;378(1):164-8 + 5-Hydroxytryptamine-2 antagonist increases human slow wave sleep. + + Idzikowski C, Mills FJ, Glennard R Ritanserin, a specific 5-HT2 antagonist, was given to volunteers in a + double-blind placebo controlled sleep study. Slow wave sleep doubled in duration at the expense of stage + 2. The finding that a serotonin antagonist changed the architecture of sleep without producing insomnia + is of fundamental importance and calls for a re-examination of traditional theories of sleep control + which assign a facilitatory role to serotonin. +

+

+ Med Hypotheses 2000 Apr;54(4):645-7 + + Role of the pineal gland in hibernators: a concept proposed to clarify why hibernators have to leave + torpor and sleep. + Kocsard-Varo G + . + +

+

+ Chronobiol Int 2000 Mar;17(2):103-28. + + The temporal organization of daily torpor and hibernation: circadian and circannual rhythms. + Kortner G, Geiser F. +

+

+ Neuroreport 2000 Mar 20;11(4):881-5 + Slow waves in the sleep electroencephalogram after daily torpor are homeostatically regulated. + Deboer T, Tobler I. +

+

+ Neuroendocrinology 1982 Jun; 34(6): 438-443. + Sleep organization in hypo- and hyperthyroid rats. + Carpenter AC, Timiras PS. "The results show an increased number + of awakenings during slow wave sleep (SWS) in hypothyroid animals, whereas total sleep time, levels + of SWS, paradoxical sleep, and diurnal organization were unaffected by thyroid status. + Our findings indicate that adequate levels of thyroid hormone are necessary to sustain extended periods + of SWS in the adult rat while hyperthyroid animals show no disruption of sleep organization. + A corollary finding is that daily sleep quotas are independent of whole body metabolic rates." +

+ + © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/thyroid.html b/raypeat-articles/processed/thyroid.html new file mode 100644 index 0000000..2ce7efb --- /dev/null +++ b/raypeat-articles/processed/thyroid.html @@ -0,0 +1,357 @@ + + Thyroid: Therapies, Confusion, and Fraud + +

+ Thyroid: Therapies, Confusion, and Fraud +

+ + I. Respiratory-metabolic defect II. 50 years of commercially motivated fraud III. Tests and the "free hormone + hypothesis" IV. Events in the tissues V. Therapies VI. Diagnosis + + I. Respiratory defect + + Broda Barnes, more than 60 years ago, summed up the major effects of hypothyroidism on health very neatly when + he pointed out that if hypothyroid people don't die young from infectious diseases, such as tuberculosis, they + die a little later from cancer or heart disease. He did his PhD research at the University of Chicago, just a + few years after Otto Warburg, in Germany, had demonstrated the role of a "respiratory defect" in cancer. At the + time Barnes was doing his research, hypothyroidism was diagnosed on the basis of a low basal metabolic rate, + meaning that only a small amount of oxygen was needed to sustain life. This deficiency of oxygen consumption + involved the same enzyme system that Warburg was studying in cancer cells. Barnes experimented on rabbits, and + found that when their thyroid glands were removed, they developed atherosclerosis, just as hypothyroid people + did. By the mid-1930s, it was generally known that hypothyroidism causes the cholesterol level in the blood to + increase; hypercholesterolemia was a diagnostic sign of hypothyroidism. Administering a thyroid supplement, + blood cholesterol came down to normal exactly as the basal metabolic rate came up to the normal rate. The + biology of atherosclerotic heart disease was basically solved before the second world war. Many other diseases + are now known to be caused by respiratory defects. Inflammation, stress, immunodeficiency, autoimmunity, + developmental and degenerative diseases, and aging, all involve significantly abnormal oxidative processes. Just + brief oxygen deprivation triggers processes that lead to lipid peroxidation, producing a chain of other + oxidative reactions when oxygen is restored. The only effective way to stop lipid peroxidation is to restore + normal respiration. Now that dozens of diseases are known to involve defective respiration, the idea of + thyroid's extremely broad range of actions is becoming easier to accept. + + II. 50 years of fraud + + Until the second world war, hypothyroidism was diagnosed on the basis of BMR (basal metabolic rate) and a large + group of signs and symptoms. In the late 1940s, promotion of the (biologically inappropriate) PBI (protein-bound + iodine) blood test in the U.S. led to the concept that only 5% of the population were hypothyroid, and that the + 40% identified by "obsolete" methods were either normal, or suffered from other problems such as sloth and + gluttony, or "genetic susceptibility" to disease. During the same period, thyroxine became available, and in + healthy young men it acted "like the thyroid hormone." Older practitioners recognized that it was not + metabolically the same as the traditional thyroid substance, especially for women and seriously hypothyroid + patients, but marketing, and its influence on medical education, led to the false idea that the standard Armour + thyroid USP wasn't properly standardized, and that certain thyroxine products were; despite the fact that both + of these were shown to be false. By the 1960s, the PBI test was proven to be irrelevant to the diagnosis of + hypothyroidism, but the doctrine of 5% hypothyroidism in the populaton became the basis for establishing the + norms for biologically meaningful tests when they were introduced. Meanwhile, the practice of measuring serum + iodine, and equating it with "thyroxine the thyroid hormone," led to the practice of examining only the iodine + content of the putative glandular material that was offered for sale as thyroid USP. This led to the + substitution of materials such as iodinated casein for desiccated thyroid in the products sold as thyroid USP. + The US FDA refused to take action, because they held that a material's iodine content was enough to identify it + as "thyroid USP." In this culture of misunderstanding and misrepresentation, the mistaken idea of + hypothyroidism's low incidence in the population led to the acceptance of dangerously high TSH (thyroid + stimulating hormone) activity as "normal." Just as excessive FSH (follicle stimulating hormone) has been shown + to have a role in ovarian cancer, excessive stimulation by TSH produces disorganization in the thyroid gland. + + III. Tests & the "free hormone hypothesis" + + After radioactive iodine became available, many physicians would administer a dose, and then scan the body with + a Geiger counter, to see if it was being concentrated in the thyroid gland. If a person had been eating + iodine-rich food (and iodine was used in bread as a preservative/dough condition, and was present in other foods + as an accidental contaminant), they would already be over saturated with iodine, and the gland would fail to + concentrate the iodine. The test can find some types of metastatic thyroid cancer, but the test generally wasn't + used for that purpose. Another expensive and entertaining test has been the thyrotropin release hormone (TRH) + test, to see if the pituitary responds to it by increasing TSH production. A recent study concluded that "TRH + test gives many misleading results and has an elevated cost/benefit ratio as compared with the characteristic + combination of low thyroxinemia and non-elevated TSH." (Bakiri, Ann. Endocr (Paris) 1999), but the technological + drama, cost, and danger (Dokmetas, et al., J Endocrinol Invest 1999 Oct; 22(9): 698-700) of this test is going + to make it stay popular for a long time. If the special value of the test is to diagnose a pituitary + abnormality, it seems intuitively obvious that overstimulating the pituitary might not be a good idea (e.g., it + could cause a tumor to grow). Everything else being equal, as they say, looking at the amount of thyroxine and + TSH in the blood can be informative. The problem is that it's just a matter of faith that "everything else" is + going to be equal. The exceptions to the "rule" regarding normal ranges for thyroxine and TSH have formed the + basis for some theories about "the genetics of thyroid resistance," but others have pointed out that, when a few + other things are taken into account, abnormal numbers for T4, T3, TSH, can be variously explained. The actual + quantity of T3, the active thyroid hormone, in the blood can be measured with reasonable accuracy (using + radioimmunoassay, RIA), and this single test corresponds better to the metabolic rate and other meaningful + biological responses than other standard tests do. But still, this is only a statistical correspondence, and it + doesn't indicate that any particular number is right for a particular individual. Sometimes, a test called the + RT3U, or resin T3 uptake, is used, along with a measurement of thyroxine. A certain amount of radioactive T3 is + added to a sample of serum, and then an adsorbent material is exposed to the mixture of serum and radioactive + T3. The amount of radioactivity that sticks to the resin is called the T3 uptake. The lab report then gives a + number called T7, or free thyroxine index. The closer this procedure is examined, the sillier it looks, and it + looks pretty silly on its face.. The idea that the added radioactive T3 that sticks to a piece of resin will + correspond to "free thyroxine," is in itself odd, but the really interesting question is, what do they mean by + "free thyroxine"? Thyroxine is a fairly hydrophobic (insoluble in water) substance, that will associate with + proteins, cells, and lipoproteins in the blood, rather than dissolving in the water. Although the Merck Index + describes it as "insoluble in water," it does contain some polar groups that, in the right (industrial or + laboratory) conditions, can make it slightly water soluble. This makes it a little different from progesterone, + which is simply and thoroughly insoluble in water, though the term "free hormone" is often applied to + progesterone, as it is to thyroid. In the case of progesterone, the term "free progesterone" can be traced to + experiments in which serum containing progesterone (bound to proteins) is separated by a (dialysis) membrane + from a solution of similar proteins which contain no progesterone. Progesterone "dissolves in" the substance of + the membrane, and the serum proteins, which also tend to associate with the membrane, are so large that they + don't pass through it. On the other side, proteins coming in contact with the membrane pick up some + progesterone. The progesterone that passes through is called "free progesterone," but from that experiment, + which gives no information on the nature of the interactions between progesterone and the dialysis membrane, or + about its interactions with the proteins, or the proteins' interactions with the membrane, nothing is revealed + about the reasons for the transmission or exchange of a certain amount of progesterone. Nevertheless, that type + of experiment is used to interpret what happens in the body, where there is nothing that corresponds to the + experimental set-up, except that some progesterone is associated with some protein. The idea that the "free + hormone" is the active form has been tested in a few situations, and in the case of the thyroid hormone, it is + clearly not true for the brain, and some other organs. The protein-bound hormone is, in these cases, the active + form; the associations between the "free hormone" and the biological processes and diseases will be completely + false, if they are ignoring the active forms of the hormone in favor of the less active forms. The conclusions + will be false, as they are when T4 is measured, and T3 ignored. Thyroid-dependent processes will appear to be + independent of the level of thyroid hormone; hypothyroidism could be caller hyperthyroidism. Although + progesterone is more fat soluble than cortisol and the thyroid hormones, the behavior of progesterone in the + blood illustrates some of the problems that have to be considered for interpreting thyroid physiology. When red + cells are broken up, they are found to contain progesterone at about twice the concentration of the serum. In + the serum, 40 to 80% of the progesterone is probably carried on albumin. (Albumin easily delivers its + progesterone load into tissues.) Progesterone, like cholesterol, can be carried on/in the lipoproteins, in + moderate quantities. This leaves a very small fraction to be bound to the "steroid binding globulin." Anyone who + has tried to dissolve progesterone in various solvents and mixtures knows that it takes just a tiny amount of + water in a solvent to make progesterone precipitate from solution as crystals; its solubility in water is + essentially zero. "Free" progesterone would seem to mean progesterone not attached to proteins or dissolved in + red blood cells or lipoproteins, and this would be zero. The tests that purport to measure free progesterone are + measuring something, but not the progesterone in the watery fraction of the serum. The thyroid hormones + associate with three types of simple proteins in the serum: Transthyretin (prealbumin), thyroid binding + globulin, and albumin. A very significant amount is also associated with various serum lipoproteins, including + HDL, LDL, and VLDL (very low density lipoproteins). A very large portion of the thyroid in the blood is + associated with the red blood cells. When red cells were incubated in a medium containing serum albumin, with + the cells at roughly the concentration found in the blood, they retained T3 at a concentration 13.5 times higher + than that of the medium. In a larger amount of medium, their concentration of T3 was 50 times higher than the + medium's. When laboratories measure the hormones in the serum only, they have already thrown out about 95% of + the thyroid hormone that the blood contained. The T3 was found to be strongly associated with the cells' + cytoplasmic proteins, but to move rapidly between the proteins inside the cells and other proteins outside the + cells. When people speak of hormones travelling "on" the red blood cells, rather than "in" them, it is a + concession to the doctrine of the impenetrable membrane barrier. Much more T3 bound to albumin is taken up by + the liver than the small amount identified in vitro as free T3 (Terasaki, et al., 1987). The specific binding of + T3 to albumin alters the protein's electrical properties, changing the way the albumin interacts with cells and + other proteins. (Albumin becomes electrically more positive when it binds the hormone; this would make the + albumin enter cells more easily. Giving up its T3 to the cell, it would become more negative, making it tend to + leave the cell.) This active role of albumin in helping cells take up T3 might account for its increased uptake + by the red cells when there were fewer cells in proportion to the albumin medium. This could also account for + the favorable prognosis associated with higher levels of serum albumin in various sicknesses. When T3 is + attached chemically (covalently, permanently) to the outside of red blood cells, apparently preventing its entry + into other cells, the presence of these red cells produces reactions in other cells that are the same as some of + those produced by the supposedly "free hormone." If T3 attached to whole cells can exert its hormonal action, + why should we think of the hormone bound to proteins as being unable to affect cells? The idea of measuring the + "free hormone" is that it supposedly represents the biologically active hormone, but in fact it is easier to + measure the biological effects than it is to measure this hypothetical entity. Who cares how many angels might + be dancing on the head of a pin, if the pin is effective in keeping your shirt closed? + + IV. Events in the tissues + + Besides the effects of commercial deception, confusion about thyroid has resulted from some biological clich"s. + The idea of a "barrier membrane" around cells is an assumption that has affected most people studying cell + physiology, and its effects can be seen in nearly all of the thousands of publications on the functions of + thyroid hormones. According to this idea, people have described a cell as resembling a droplet of a watery + solution, enclosed in an oily bag which separates the internal solution from the external watery solution. The + clich" is sustained only by neglecting the fact that proteins have a great affinity for fats, and fats for + proteins; even soluble proteins, such as serum albumin, often have interiors that are extremely fat-loving. + Since the structural proteins that make up the framework of a cell aren't "dissolved in water" (they used to be + called "the insoluble proteins"), the lipophilic phase isn't limited to an ultramicroscopically thin surface, + but actually constitutes the bulk of the cell. Molecular geneticists like to trace their science from a 1944 + experiment that was done by Avery., et al. Avery's group knew about an earlier experiment, that had demonstrated + that when dead bacteria were added to living bacteria, the traits of the dead bacteria appeared in the living + bacteria. Avery's group extracted DNA from the dead bacteria, and showed that adding it to living bacteria + transferred the traits of the dead organisms to the living. In the 1930s and 1940s, the movement of huge + molecules such as proteins and nucleic acids into cells and out of cells wasn't a big deal; people observed it + happening, and wrote about it. But in the 1940s the idea of the barrier membrane began gaining strength, and by + the 1960s nothing was able to get into cells without authorization. At present, I doubt that any molecular + geneticist would dream of doing a gene transplant without a "vector" to carry it across the membrane barrier. + Since big molecules are supposed to be excluded from cells, it's only the "free hormone" which can find its + specific port of entry into the cell, where another clich" says it must travel into the nucleus, to react with a + specific site to activate the specific genes through which its effects will be expressed. I don't know of any + hormone that acts that way. Thyroid, progesterone, and estrogen have many immediate effects that change the + cell's functions long before genes could be activated. Transthyretin, carrying the thyroid hormone, enters the + cell's mitochondria and nucleus (Azimova, et al., 1984, 1985). In the nucleus, it immediately causes generalized + changes in the structure of chromosomes, as if preparing the cell for major adaptive changes. Respiratory + activation is immediate in the mitochondria, but as respiration is stimulated, everything in the cell responds, + including the genes that support respiratory metabolism. When the membrane people have to talk about the entry + of large molecules into cells, they use terms such as "endocytosis" and "translocases," that incorporate the + assumption of the barrier. But people who actually investigate the problem generally find that "diffusion," + "codiffusion," and absorption describe the situation adequately (e.g., B.A. Luxon, 1997; McLeese and Eales, + 1996). "Active transport" and "membrane pumps" are ideas that seem necessary to people who haven't studied the + complex forces that operate at phase boundaries, such as the boundary between a cell and its environment. + + V. Therapy + + Years ago it was reported that Armour thyroid, U.S.P., released T3 and T4, when digested, in a ratio of 1:3, and + that people who used it had much higher ratios of T3 to T4 in their serum, than people who took only thyroxine. + The argument was made that thyroxine was superior to thyroid U.S.P., without explaining the significance of the + fact that healthy people who weren't taking any thyroid supplement had higher T3:T4 ratios than the people who + took thyroxine, or that our own thyroid gland releases a high ratio of T3 to T4. The fact that the T3 is being + used faster than T4, removing it from the blood more quickly than it enters from the thyroid gland itself, + hasn't been discussed in the journals, possibly because it would support the view that a natural glandular + balance was more appropriate to supplement than pure thyroxine. The serum's high ratio of T4 to T3 is a + pitifully poor argument to justify the use of thyroxine instead of a product that resembles the proportion of + these substances secreted by a healthy thyroid gland, or maintained inside cells. About 30 years ago, when many + people still thought of thyroxine as "the thryoid hormone," someone was making the argument that "the thyroid + hormone" must work exclusively as an activator of genes, since most of the organ slices he tested didn't + increase their oxygen consumption when it was added. In fact, the addition of thyroxine to brain slices + suppressed their respiration by 6% during the experiment. Since most T3 is produced from T4 in the liver, not in + the brain, I think that experiment had great significance, despite the ignorant interpretation of the author. An + excess of thyroxine, in a tissue that doesn't convert it rapidly to T3, has an antithyroid action. (See Goumaz, + et al, 1987.) This happens in many women who are given thyroxine; as their dose is increased, their symptoms get + worse. The brain concentrates T3 from the serum, and may have a concentration 6 times higher than the serum + (Goumaz, et al., 1987), and it can achieve a higher concentration of T3 than T4. It takes up and concentrates + T3, while tending to expel T4. Reverse T3 (rT3) doesn't have much ability to enter the brain, but increased T4 + can cause it to be produced in the brain. These observations suggest to me that the blood's T3:T4 ratio would be + very "brain favorable" if it approached more closely to the ratio formed in the thyroid gland, and secreted into + the blood. Although most synthetic combination thyroid products now use a ratio of four T4 to one T3, many + people feel that their memory and thinking are clearer when they take a ratio of about three to one. More active + metabolism probably keeps the blood ratio of T3 to T4 relatively high, with the liver consuming T4 at about the + same rate that T3 is used. Since T3 has a short half life, it should be taken frequently. If the liver isn't + producing a noticeable amount of T3, it is usually helpful to take a few micorgrams per hour. Since it restores + respiration and metabolic efficiency very quickly, it isn't usually necessary to take it every hour or two, but + until normal temperature and pulse have been achieved and stabilized, sometimes it's necessary to take it four + or more times during the day. T4 acts by being changed to T3, so it tends to accumulate in the body, and on a + given dose, usually reaches a steady concentration after about two weeks. An effective way to use supplements is + to take a combination T4-T3 dose, e.g., 40 mcg of T4 and 10 mcg of T3 once a day, and to use a few mcg of T3 at + other times in the day. Keeping a 14-day chart of pulse rate and temperature allows you to see whether the dose + is producing the desired response. If the figures aren't increasing at all after a few days, the dose can be + increased, until a gradual daily increment can be seen, moving toward the goal at the rate of about 1/14 per day + + VI. Diagnosis + + In the absence of commercial techniques that reflect thyroid physiology realistically, there is no valid + alternative to diagnosis based on the known physiological indicators of hypothyroidism and hyperthyroidism. The + failure to treat sick people because of one or another blood test that indicates "normal thyroid function," or + the destruction of patients' healthy thyroid glands because one of the tests indicates hyperthyroidism, isn't + acceptable just because it's the professional standard, and is enforced by benighted state licensing boards. + Toward the end of the twentieth century, there has been considerable discussion of "evidence-based medicine." + Good judgment requires good information, but there are forces that would over-rule individual judgment as to + whether published information is applicable to certain patients. In an atmosphere that sanctions prescribing + estrogen or insulin without evidence of an estrogen deficiency or insulin deficiency, but that penalizes + practitioners who prescribe thyroid to correct symptoms, the published "evidence" is necessarily heavily biased. + In this context, "meta-analysis" becomes a tool of authoritarianism, replacing the use of judgment with the + improper use of statistical analysis. Unless someone can demonstrate the scientific invalidity of the methods + used to diagnose hypothyroidism up to 1945, then they constitute the best present evidence for evaluating + hypothyroidism, because all of the blood tests that have been used since 1950 have been.shown to be, at best, + very crude and conceptually inappropriate methods. Thomas H. McGavack's 1951 book, The Thyroid, was + representative of the earlier approach to the study of thyroid physiology. Familiarity with the different + effects of abnormal thyroid function under different conditions, at different ages, and the effects of gender, + were standard parts of medical education that had disappeared by the end of the century. Arthritis, + irregularities of growth, wasting, obesity, a variety of abnormalities of the hair and skin, carotenemia, + amenorrhea, tendency to miscarry, infertility in males and females, insomnia or somnolence, emphysema, various + heart diseases, psychosis, dementia, poor memory, anxiety, cold extremities, anemia, and many other problems + were known reasons to suspect hypothyroidism. If the physician didn't have a device for measuring oxygen + consumption, estimated calorie intake could provide supporting evidence. The Achilles' tendon reflex was another + simple objective measurement with a very strong correlation to the basal metabolic rate. Skin electrical + resistance, or whole body impedance wasn't widely accepted, though it had considerable scientific validity. A + therapeutic trial was the final test of the validity of the diagnosis: If the patient's symptoms disappeared as + his temperature and pulse rate and food intake were normalized, the diagnostic hypothesis was confirmed. It was + common to begin therapy with one or two grains of thyroid, and to adjust the dose according to the patient's + response. Whatever objective indicator was used, whether it was basal metabolic rate, or serum cholesterol. or + core temperature, or reflex relaxation rate, a simple chart would graphically indicate the rate of recovery + toward normal health. + +

REFERENCES

 + + McGavack, Thomas Hodge.: The thyroid,: St. Louis, Mosby, 1951. 646 p. ill.Several chapters contributed by + various authors.Call Numbers WK200 M145t 1951 (Rare Book). Endocrinology 1979 Sep; 105(3): 605-12. + Carrier-mediated transport of thyroid hormones through the rat blood-brain barrier: primary role of + albumin-bound hormone. Pardridge WM. Endocrinology 1987 Apr;120(4):1590-6. Brain cortex reverse triiodothyronine + (rT3) and triiodothyronine concentrations under steady state infusions of thyroxine and rT3. Goumaz MO, Kaiser + CA, Burger A.G. J Clin Invest 1984 Sep;74(3):745-52. Tracer kinetic model of blood-brain barrier transport of + plasma protein-bound ligands. Empiric testing of the free hormone hypothesis. Pardridge WM, Landaw EM. Previous + studies have shown that the fraction of hormone or drug that is plasma protein bound is readily available for + transport through the brain endothelial wall, i.e., the blood-brain barrier (BBB). To test whether these + observations are reconcilable with the free-hormone hypothesis, a tracer-kinetic model is used Endocrinology + 113(1), 391-8, 1983, Stimulation of sugar transport in cultured heart cells by triiodothyronine (T2) covalently + bound to red blood cells and by T3 in the presence of serum, Dickstein Y, Schwartz H, Gross J, Gordon A. + Endocrinology 1987 Sep; 121(3): 1185-91. Stereospecificity of triiodothyronine transport into brain, liver, and + salivary gland: role of carrier- and plasma protein-mediated transport. Terasaki T, Pardridge WM. J. + Neurophysiol 1994 Jul;72(1):380-91. Film autoradiography identifies unique features of [125I]3,3'5'-(reverse) + triiodothyronine transport from blood to brain. Cheng LY, Outterbridge LV, Covatta ND, Martens DA, Gordon JT, + Dratman MB Brain Res 1991 Jul 19;554(1-2):229-36. Transport of iodothyronines from bloodstream to brain: + contributions by blood:brain and choroid plexus:cerebrospinal fluid barriers. Dratman MB, Crutchfield FL, + Schoenhoff MB.. Mech Ageing Dev 1990 Mar 15;52(2-3):141-7. Blood-brain transport of triiodothyronine is reduced + in aged rats. Mooradian AD Geriatrics Section, Tucson VA Medical Center, AZ. Endocrinology 1987 + Sep;121(3):1185-91. Stereospecificity of triiodothyronine transport into brain, liver, and salivary gland: role + of carrier- and plasma protein-mediated transport. Terasaki T, Pardridge WM. J Clin Invest 1984 + Sep;74(3):745-52. Tracer kinetic model of blood-brain barrier transport of plasma protein-bound ligands. Empiric + testing of the free hormone hypothesis. Pardridge WM, Landaw EM. Endocrinology 1980 Dec;107(6):1705-10. + Transport of thyroid and steroid hormones through the blood-brain barrier of the newborn rabbit: primary role of + protein-bound hormone. Pardridge WM, Mietus LJ. Endocrinology 1979 Sep; 105(3): 605-12. Carrier-mediated + transport of thyroid hormones through the rat blood-brain barrier: primary role of albumin-bound hormone. + Pardridge WM. Endocrinology 1975 Jun;96(6):1357-65. Triiodothyronine binding in rat anterior pituitary, + posterior pituitary, median eminence and brain. Gordon A, Spira O. Endocr Rev 1989 Aug;10(3):232-74. The free + hormone hypothesis: a physiologically based mathematical model. Mendel CM. Biochim Biophys Acta 1991 Mar + 4;1073(2):275-84. Transport of steroid hormones facilitated by serum proteins. Watanabe S, Tani T, Watanabe S, + Seno M Kanagawa. D Novitzky, H Fontanet, M Snyder, N Coblio, D Smith, V Parsonnet, Impact of triiodothyronine on + the survival of high-risk patients undergoing open heart surgery, Cardiology, 1996, Vol 87, Iss 6, pp 509-515. + Biochim Biophys Acta 1997. Jan 16;1318(1-2):173-83 Regulation of the energy coupling in mitochondria by some + steroid and thyroid hormones. Starkov AA, Simonyan RA, Dedukhova VI, Mansurova SE, Palamarchuk LA, Skulachev VP + Thyroid 1996 Oct;6(5):531-6. Novel actions of thyroid hormone: the role of triiodothyronine in cardiac + transplantation. Novitzky D. Rev Med Chil 1996 Oct;124(10):1248-50. [Severe cardiac failure as complication of + primary hypothyroidism]. Novik V, Cardenas IE, Gonzalez R, Pena M, Lopez Moreno JM. Cardiology 1996 + Nov-Dec;87(6):509-15. Impact of triiodothyronine on the survival of high-risk patients undergoing open heart + surgery. Novitzky D, Fontanet H, Snyder M, Coblio N, Smith D, Parsonnet V Curr Opin Cardiol 1996 + Nov;11(6):603-9. The use of thyroid hormone in cardiac surgery. Dyke C N Koibuchi, S Matsuzaki, K Ichimura, H + Ohtake, S Yamaoka. Ontogenic changes in the expression of cytochrome c oxidase subunit I gene in the cerebellar + cortex of the perinatal hypothyroid rat. Endocrinology, 1996, Vol 137, Iss 11, pp 5096-5108. Biokhimiia 1984 + Aug;49(8):1350-6. [The nature of thyroid hormone receptors. Translocation of thyroid hormones through plasma + membranes]. [Article in Russian] Azimova ShS, Umarova GD, Petrova OS, Tukhtaev KR, Abdukarimov A. The in vivo + translocation of thyroxine-binding blood serum prealbumin (TBPA) was studied. It was found that the TBPA-hormone + complex penetrates-through the plasma membrane into the cytoplasm of target cells. Electron microscopic + autoradiography revealed that blood serum TBPA is localized in ribosomes of target cells as well as in + mitochondria, lipid droplets and Golgi complex. Negligible amounts of the translocated TBPA is localized in + lysosomes of the cells insensitive to thyroid hormones (spleen macrophages). Study of T4- and T3-binding + proteins from rat liver cytoplasm demonstrated that one of them has the antigenic determinants common with those + of TBPA. It was shown autoimmunoradiographically that the structure of TBPA is not altered during its + translocation. Am J Physiol 1997 Sep;273(3 Pt 1):C859-67. Cytoplasmic codiffusion of fatty acids is not specific + for fatty acid binding protein. Luxon BA, Milliano MT [The nature of thyroid hormone receptors. Intracellular + functions of thyroxine-binding prealbumin] Azimova ShS; Normatov K; Umarova GD; Kalontarov AI; Makhmudova AA, + Biokhimiia 1985 Nov;50(11):1926-32. The effect of tyroxin-binding prealbumin (TBPA) of blood serum on the + template activity of chromatin was studied. It was found that the values of binding constants of TBPA for T3 and + T4 are 2 X 10(-11) M and 5 X 10(-10) M, respectively. The receptors isolated from 0.4 M KCl extract of chromatin + and mitochondria as well as hormone-bound TBPA cause similar effects on the template activity of chromatin. + Based on experimental results and the previously published comparative data on the structure of TBPA, nuclear, + cytoplasmic and mitochondrial receptors of thyroid hormones as well as on translocation across the plasma + membrane and intracellular transport of TBPA, a conclusion was drawn, which suggested that TBPA is the "core" of + the true thyroid hormone receptor. It was shown that T3-bound TBPA caused histone H1-dependent conformational + changes in chromatin. Based on the studies with the interaction of the TBPA-T3 complex with spin-labeled + chromatin, a scheme of functioning of the thyroid hormone nuclear receptor was proposed. [The nature of thyroid + hormone receptors. Thyroxine- and triiodothyronine-binding proteins of mitochondria] Azimova ShS; Umarova GD; + Petrova OS; Tukhtaev KR; Abdukarimov A. Biokhimiia 1984 Sep;49(9):1478-85. T4- and T3-binding proteins of rat + liver were studied. It was found that the external mitochondrial membranes and matrix contain a protein whose + electrophoretic mobility is similar to that of thyroxine-binding blood serum prealbumin (TBPA) and which binds + either T4 or T3. This protein is precipitated by monospecific antibodies against TBPA. The internal + mitochondrial membrane has two proteins able to bind thyroid hormones, one of which is localized in the cathode + part of the gel and binds only T3, while the second one capable of binding T4 rather than T3 and possessing the + electrophoretic mobility similar to that of TBPA. Radioimmunoprecipitation with monospecific antibodies against + TBPA revealed that this protein also the antigenic determinants common with those of TBPA. The in vivo + translocation of 125I-TBPA into submitochondrial fractions was studied. The analysis of densitograms of + submitochondrial protein fraction showed that both TBPA and hormones are localized in the same protein + fractions. Electron microscopic autoradiography demonstrated that 125I-TBPA enters the cytoplasm through the + external membrane and is localized on the internal mitochondrial membrane and matrix. [The nature of thyroid + hormone receptors. Translocation of thyroid hormones through plasma membranes]. Azimova ShS; Umarova GD; Petrova + OS; Tukhtaev KR; Abdukarimov A. Biokhimiia 1984 Aug;49(8):1350-6.. The in vivo translocation of thyroxine- + binding blood serum prealbumin (TBPA) was studied. It was found that the TBPA-hormone complex penetrates-through + the plasma membrane into the cytoplasm of target cells. Electron microscopic autoradiography revealed that blood + serum TBPA is localized in ribosomes of target cells as well as in mitochondria, lipid droplets and Golgi + complex. Negligible amounts of the translocated TBPA is localized in lysosomes of the cells insensitive to + thyroid hormones (spleen macrophages). Study of T4- and T3-binding proteins from rat liver cytoplasm + demonstrated that one of them has the antigenic determinants common with those of TBPA. It was shown + autoimmunoradiographically that the structure of TBPA is not altered during its translocation. Endocrinology + 1987 Apr;120(4):1590-6 Brain cortex reverse triiodothyronine (rT3) and triiodothyronine concentrations under + steady state infusions of thyroxine and rT3. Goumaz MO, Kaiser CA, Burger AG. Gen Comp Endocrinol 1996 + Aug;103(2):200-8 Characteristics of the uptake of 3,5,3'-triiodo-L-thyronine and L-thyroxine into red blood + cells of rainbow trout (Oncorhynchus mykiss). McLeese JM, Eales JG. Prog Neuropsychopharmacol Biol Psychiatry + 1998 Feb;22(2):293-310. Increase in red blood cell triiodothyronine uptake in untreated unipolar major depressed + patients compared to healthy volunteers. Moreau X, Azorin JM, Maurel M, Jeanningros R. Prog Neuropsychopharmacol + Biol Psychiatry 1998 Feb;22(2):293-310. Increase in red blood cell triiodothyronine uptake in untreated unipolar + major depressed patients compared to healthy volunteers. Moreau X, Azorin JM, Maurel M, Jeanningros R. Biochem J + 1982 Oct 15;208(1):27-34. Evidence that the uptake of tri-iodo-L-thyronine by human erythrocytes is + carrier-mediated but not energy-dependent. Docter R, Krenning EP, Bos G, Fekkes DF, Hennemann G. J Clin + Endocrinol Metab 1990 Dec;71(6):1589-95. Transport of thyroid hormones by human erythrocytes: kinetic + characterization in adults and newborns. Osty J, Valensi P, Samson M, Francon J, Blondeau JP. J Endocrinol + Invest 1999 Apr;22(4):257-61. Kinetics of red blood cell T3 uptake in hypothyroidism with or without hormonal + replacement, in the rat. Moreau X, Lejeune PJ, Jeanningros R. +

+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com +

+ + diff --git a/raypeat-articles/processed/tissue-bound-estrogen.html b/raypeat-articles/processed/tissue-bound-estrogen.html new file mode 100644 index 0000000..67f6b97 --- /dev/null +++ b/raypeat-articles/processed/tissue-bound-estrogen.html @@ -0,0 +1,864 @@ + + Tissue-bound estrogen in aging + +

+ Tissue-bound estrogen in aging +

+ +

+ The "Estrogen Replacement" industry is based on the doctrine that a woman's tissues are depleted of + estrogen after menopause. This doctrine is false. +

+

+ The concentration of a hormone in the blood doesn't directly represent the concentration in the various + organs. +

+

+ The amount of estrogen in tissue is decreased when progesterone is abundant. In the absence of + progesterone, tissues retain estrogen even when there is little estrogen circulating in the blood. +

+ +

+ Many things suggest an increased estrogenic activity at menopause. For example, melatonin decreases + sharply at puberty when estrogen increases, and then it decreases again at menopause. Prolactin + (stimulated by estrogen) increases around puberty, and instead of decreasing at menopause, it often + increases, and its increase is associated with osteoporosis and other age-related symptoms. +

+

+ Estrogen is produced in many tissues by the enzyme aromatase, even in the breast and endometrium, + although these are considered "target tissues" rather than endocrine glands. Aromatase increases with + aging. +

+

+ Estrogen is inactivated, mainly in the liver and brain, by being made water soluble by the attachment of + glucuronic acid and/or sulfuric acid. +

+

+ Estrogen's concentration in a particular tissue depends on many things, including its affinity or + binding strength for components of that tissue, relative to its affinity for the blood; the activity in + that tissue of the aromatase enzyme, which converts androgens to estrogen; the activity of the + glucuronidase enzyme, that converts water-soluble estrogen glucuronides into the oil soluble active + forms of estrogen; and the sulfatases and several other enzymes that modify the activity and solubility + of the estrogens. The "estrogen receptors," proteins which bind estrogens in cells, are inactivated by + progesterone, and activated by many physical and chemical conditions. +

+

+ Inflammation activates beta-glucuronidase, and antiinflammatory substances such as aspirin reduce many + of estrogen's effects. +

+ +
+ +

+ Doctrines are admitted into the "scientific canon" by those who have the power of censorship. In astronomy, + Halton Arp's discovery of "anomalous" galactic red-shifts is practically unknown, because the journal + editors say the observations are "just anomalies," or that the theories which could explain them are + unconventional; but the actual problem is that they are strong evidence against The Big Bang, Hubble's Law, + and the Expanding Universe. American science, since the 1940s, has probably been the most censored and + doctrinaire in the world. +

+

+ Gilbert Ling's revolution in cell biology remains outside the canon, despite the profound influence of MRI, + which grew directly out of his view of the cell, because his work provided conclusive evidence that cells + are not regulated by "semipermeable membranes and membrane pumps." Every field of science is ruled by a + doctrinaire establishment. +

+

+ Charles E. Brown-S"quard (1817-94) was a physiologist who pioneered scientific endocrinology, but who was + ridiculed because of his claim that extracts of animal glands had an invigorating effect when injected. His + place in the scientific canon is mainly as an object of ridicule, and the details of his case are perfectly + representative of the way our "canon" has been constructed. The argument for dismissing his observations was + that he used a water extract of testicles, and, according to the 20th century American biologists, + testosterone is not water soluble, and so the water extract would have "contained no hormone." The argument + is foolish, because living organs contain innumerable substances that will solublize oily molecules, but + also because Brown-Sequard was describing an effect that wasn"t necessarily limited to a single chemical + substance. (The transplanting of living cells to repair tissues is finally being accepted, but the pioneers + in promoting tissue regeneration or repair with the transplantation of living, dead, or stressed cells--V. + Filatov, L.V. Polezhaev, W.T. Summerlin, for example--were simply written out of history.) +

+

+ If Brown-S"quard"s extract couldn"t work because testosterone isn"t soluble in water, then what are we to + think of the thousands of medical publications that talk about "free hormones" as the only active hormones? + ("Free hormone" is defined as the hormone that isn"t bound to a transporting protein, with the more or less + explicit idea that it is dissolved in the water of the plasma or extracellular fluid.) Brown-S"quard"s + tissue extracts would have contained solublizing substances including proteins and phospholipids, so the + oily hormones would certainly be present (and active) in his extracts. But the thousands of people who + ridiculed him committed themselves to the fact that steroid hormones are insoluble in water. By their own + standard, they are selling an impossibility when they do calculations to reveal the amount of "free + hormone," as something distinct from the protein bound hormone, in the patient"s blood. +

+ +

+ The immense Hormone Replacement Therapy industry--which Brown-S"quard"s experiments foreshadowed--is based + on the fact that the concentrations of some hormones in the blood serum decrease with aging. +

+

+ At first, it was assumed that the amount of the hormone in the blood corresponded to the effectiveness of + that hormone. Whatever was in the blood was being delivered to the "target tissues." But as the idea of + measuring "protein bound iodine" (PBI) to determine thyroid function came into disrepute (because it never + had a scientific basis at all), new ideas of measuring "active hormones" came into the marketplace, and + currently the doctrine is that the "bound" hormones are inactive, and the active hormones are "free." The + "free" hormones are supposed to be the only ones that can get into the cells to deliver their signals, but + the problem is that "free hormones" exist only in the imagination of people who interpret certain lab tests, + as I discussed in the newsletter on thyroid tests (May, 2000). +

+

+ In the 1960s and 1970s, when the PBI test was disappearing, there was intense interest in--a kind of mania + regarding--the role of "membranes" in regulating cell functions, and the membrane was still seen by most + biologists as the "semipermeable membrane" which, "obviously," would exclude molecules as large as albumin + and the other proteins that carry thyroid and other hormones in the blood. (In reality, and experimental + observations, albumin and other proteins enter cells more or less freely, depending on prevailing + conditions.) The membrane doctrine led directly to the "free hormone" doctrine. +

+

+ This issue, of arguing about which form of a hormone is the "active" form, has to do with explaining how + much of the blood-carried hormone is going to get into the "target tissues." If the membrane is a + "semipermeable" barrier to molecules such as hormones, then specific receptors and transporters will be + needed. If the concentration of a hormone inside the cell is higher than that in the blood, a "pump" will + usually be invoked, to produce an "active transport" of the hormone against its concentration gradient. +

+

+ But if the membrane regulates the passage of hormones from blood to tissue cells, and especially if + pumps are needed to move the hormone into the cell, how relevant is the measurement of hormones in the + blood? +

+

+ Within the blood, progesterone and thyroid hormone (T3) are much more concentrated in the red blood cells + than in the serum. Since it isn"t likely that red blood cells are "targets" for the sex hormones, or for + progesterone or even thyroid, their concentration "against their gradient" in these cells suggests that a + simple distribution by solubility is involved. Oily substances just naturally tend to concentrate inside + cells because of their insolubility in the watery environment of the plasma and extracellular fluid. + Proteins that have "oily" regions effectively bind oily molecules, such as fats and steroids. Even red blood + cells have such proteins. +

+ +

+ In the case of oil soluble molecules, such as progesterone and estrogen, it"s important to explain that most + of their "binding" to proteins or other oil-loving molecules is really the nearly passive consequence of the + molecules" being forced away from the watery phase--they are hydrophobic, and although it would take a great + amount of energy to make these insoluble substances enter the watery phase, the attractive force between + them and the cell is usually small. This means that they can be freely mobile, while "bound" or concentrated + within the cell. The oxygen atoms, and especially the phenolic group of estrogen, slightly reduce the + hormones" affinity for simple oils, but they interact with other polar or aromatic groups, giving estrogen + the ability to bind more strongly and specifically with some proteins and other molecules. Enzymes which + catalyze estrogen"s oxidation-reduction actions are among the specific estrogen-binding proteins. +

+

+ Many proteins and lipoproteins bind steroids, but some intracellular proteins bind them so strongly that + they have been--in a very teleological, if not anthropomorphic, way--considered as the switch by which the + hormone turns on the cellular response. In the popular doctrine of the Estrogen Receptor, a few molecules of + estrogen bind to the receptors, which carry them to the nucleus of the cell, where the activated receptors + turn on the genes in charge of the female response. (Or the male response, or the growth response, or the + atrophy response, or whatever genetic response estrogen is producing.) Once the switch has been thrown, the + estrogen molecules have fulfilled their hormonal duty, and must get lost, so that the response isn"t + perpetuated indefinitely by a few molecules. +

+

+ Although the Estrogen Receptor doctrine is worse than silly, there are real proteins which bind estrogen, + and some of these are called receptors. The uterus, breast, and brain, which are very responsive to + estrogen, bind, or concentrate, estrogen molecules. +

+

+ When I was working on my dissertation, I tried to extract estrogens from hamster uteri, but the chemical + techniques I was using to measure estrogen weren"t accurate for such small quantities. A few years later, S. + Batra was able to extract the estrogen from human tissue in quantities large enough for accurate analysis by + radioimmunoassay. (Batra, 1976.) +

+

+ His crucial observation was that the difference in estrogen concentration between tissue and blood was + lowest in the luteal phase, when progesterone is high: +

+

+ "The tissue/plasma ratio of E2 [estradiol] ranged from + 1.45 to 20.36 with very high values in early follicular phase and the lowest in mid-luteal + phase." This means that progesterone prevents the tissue from concentrating estrogen. He made + similar observations during pregnancy, + with tissue estrogen decreasing as blood progesterone increased, so that + there is less estrogen in the tissue than in the plasma. + But in women who aren"t pregnant, and when their progesterone is low, the tissues may contain 20 to 30 times + more estrogen than the plasma (in equal volumes). +

+

+ In aging, the sharply decreased progesterone production creates a situation resembling the follicular phase + of the menstrual cycle, allowing tissues to concentrate estrogen even when the serum estrogen may be low. +

+

+ "In postmenopausal women, the tissue concentration of E2 was not significantly lower than in + menstruating women in follicular phase. . . ." (Akerlund, et al., 1981.) +

+

+ Besides the relatively direct actions of progesterone on the estrogen receptors, keeping their concentration + low, and its indirect action by preventing prolactin from stimulating the formation of estrogen receptors, + there are many other processes that can increase or decrease the tissue concentration of estrogen, and many + of these influences change with aging. +

+ +

+ There are two kinds of enzyme that produce estrogen. Aromatase converts male hormones into estrogen. + Beta-glucuronidase converts the inactive estrogen-glucuronides into active estrogen. The healthy liver + inactivates practically all the estrogen that reaches it, mostly by combining it with the "sugar acid," + glucuronic acid. This makes the estrogen water soluble, and it is quickly eliminated in the urine. But when + it passes through inflamed tissue, these tissues contain large amounts of beta-glucuronidase, which will + remove the glucuronic acid, leaving the pure estrogen to accumulate in the tissue. +

+

+ Many kinds of liver impairment decrease its ability to excrete estrogen, and estrogen contributes to a + variety of liver diseases. The work of the Biskinds in the 1940s showed that a dietary protein deficiency + prevented the liver from detoxifying estrogen. Hypothyroidism prevents the liver from attaching glucuronic + acid to estrogen, and so increases the body"s retention of estrogen, which in turn impairs the thyroid + gland"s ability to secrete thyroid hormone. Hypothyroidism often results from nutritional protein + deficiency. +

+

+ Although we commonly think of the ovaries as the main source of estrogen, the enzyme which makes it can be + found in all parts of the body. Surprisingly, in rhesus monkeys, aromatase in the arms accounts for a very + large part of estrogen production. Fat and the skin are major sources of estrogen, especially in older + people. The activity of aromatase increases with aging, and under the influence of prolactin, + cortisol, prostaglandin, and the pituitary hormones, FSH (follicle stimulating hormone) and growth + hormone. + It is inhibited by progesterone, thyroid, aspirin, and high altitude. + Aromatase can produce estrogen in fat cells, fibroblasts, smooth muscle cells, breast and uterine tissue, + pancreas, liver, brain, bone, skin, etc. Its action in breast cancer, endometriosis, uterine cancer, lupus, + gynecomastia, and many other diseases is especially important. Aromatase in mammary tissue appears to + increase estrogen receptors and cause breast neoplasia, independently of ovarian estrogen (Tekmal, et al., + 1999). +

+

+ Women who have had their ovaries removed are usually told that they need to take estrogen, but animal + experiments consistently show that removal of the gonads causes the tissue aromatases to increase. The loss + of progesterone and ovarian androgens is probably responsible for this generalized increase in the formation + of estrogen. In the brain, aromatase increases under the influence of estrogen treatment. +

+ +

+ Sulfatase is another enzyme that releases estrogen in tissues, and its activity is inhibited by + antiestrogenic hormones. +

+

+ In at least some tissues, progesterone inhibits the release or activation of beta-glucuronidase (which, + according to Cristofalo and Kabakjian, 1975, increases with aging). Glucaric acid, which inhibits this + enzyme, is being used to treat breast cancer, and glucuronic acid also tends to inhibit the intracellular + release of estrogen by beta-glucuronidase. +

+

+ Although there is clearly a trend toward the rational use of antiestrogenic treatments for breast cancer, in + other diseases the myth of estrogen deficiency still prevents even rudimentary approaches. +

+

+ Ever since Lipshutz" work in the 1940s, it has been established that the + uninterrupted effect of a little estrogen is more harmful than larger but intermittent + exposures. But after menopause, when progesterone stops its cyclic displacement of estrogen from the + tissues, the tissues retain large amounts of estrogen continuously. +

+

+ The menopause itself is produced by the prolonged exposure to estrogen beginning in puberty, in spite of the + monthly protection of the progesterone produced by cycling ovaries. The unopposed action of the high + concentration of tissue-bound estrogen after menopause must be even more harmful. +

+ +

+ The decline of the antiestrogenic factors in aging, combined with the increase of pro-estrogenic factors + such as cortisol and prolactin and FSH, occurs in both men and women. During the reproductive years, women"s + cyclic production of large amounts of progesterone probably retards their aging enough to account for their + greater longevity. Childbearing also has a residual antiestrogenic effect and is associated with increased + longevity. +

+

+ Being aware of this pervasive increase in estrogen exposure with aging should make it possible to marshal a + comprehensive set of methods for opposing that trend toward degeneration. +

+

+

REFERENCES

+

+

+ Contraception 1981 Apr;23(4):447-55. Comparison of plasma and myometrial tissue concentrations of + estradiol-17 beta and progesterone in nonpregnant women. Akerlund M, Batra S, Helm G Plasma and + myometrial tissue concentrations of estradiol (E2) and progesterone (P) were measured by radioimmunoassay + techniques in samples obtained from women with regular menstrual cycles and from women in pre- or + postmenopausal age. In women with regular cycles, the tissue concentration of E2 ranged from + 0.13 to 1.06 ng/g wet weight, with significantly higher levels around ovulation than in follicular or luteal + phases of the cycle. The tissue concentration of P ranged from 2.06 to 14.85 ng/g wet weight with + significantly higher level in luteal phase than in follicular phase. The tissue/plasma ratio of E2 ranged + from 1.45 to 20.36 with very high values in early follicular phase and the lowest in mid-luteal + phase. The ratio for P ranged from 0.54 to 23.7 and was significantly lower in the luteal phase + than in other phases of the cycle. One woman in premenopausal age with an ovarian cyst was the only case + with + a tissue/plasma ratio of E2 Less Than 1, since her plasma E2 levels were exceptionally high. In + + postmenopausal women, the tissue concentration of E2 was not significantly lower than in + menstruating women in follicular phase, and the tissue concentration of P was not significantly lower + than in fertile women in any of the phases. Neither in these women nor in menstruating women + was there + a close correlation between tissue and plasma levels. + + The present data indicate that the myometrial uptake capacity for ovarian steroids may be saturated, and also that a certain amount of these steroids is bound to tissue even if plasma levels are low. +

+

+ Biokhimiia 1984 Aug;49(8):1350-6. [The nature of thyroid hormone receptors. Translocation of thyroid + hormones through plasma membranes]. Azimova ShS, Umarova GD, Petrova OS, Tukhtaev KR, + Abdukarimov A + The in vivo translocation of thyroxine-binding blood serum prealbumin (TBPA) was studied. It was found + that the TBPA-hormone complex penetrates-through the plasma membrane into the cytoplasm of target cells. + Electron microscopic autoradiography revealed that blood serum TBPA is localized in ribosomes of target + cells as well as in mitochondria, lipid droplets and Golgi complex. Negligible amounts of the + translocated TBPA is localized in lysosomes of the cells insensitive to thyroid + hormones (spleen macrophages). Study of T4- and T3-binding proteins from rat liver cytoplasm + demonstrated that one of them has the antigenic determinants common with those of TBPA. It was shown + autoimmunoradiographically that the structure of TBPA is not altered during its translocation. +

+

+ + Biokhimiia 1985 Nov;50(11):1926-32. + [The nature of thyroid hormone receptors. Intracellular functions of thyroxine-binding + prealbumin] Azimova ShS; Normatov K; Umarova GD; Kalontarov AI; Makhmudova AA The effect of + tyroxin-binding prealbumin (TBPA) of blood serum on the template activity of chromatin was studied. It was + found that the values of binding constants of TBPA for T3 and T4 are 2 X 10(-11) M and 5 X 10(-10) M, + respectively. The receptors isolated from 0.4 M KCl extract of chromatin and mitochondria as well as + hormone-bound TBPA cause similar effects on the template activity of chromatin. Based on + experimental results and the previously published comparative data on the structure of TBPA, nuclear, + cytoplasmic and mitochondrial receptors of thyroid hormones as well as on translocation across the + plasma membrane and intracellular transport of TBPA, a conclusion was drawn, which suggested that TBPA + is the "core" of the true thyroid hormone receptor. It was shown that T3-bound TBPA caused histone + H1-dependent conformational changes in chromatin. Based on the studies with the interaction of + the TBPA-T3 complex with spin-labeled chromatin, a scheme of functioning of the thyroid hormone nuclear + receptor was proposed. +

+ +

+ Biokhimiia 1984 Sep;49(9):1478-85[The nature of thyroid hormone receptors. Thyroxine- and + triiodothyronine-binding proteins of mitochondria] + Azimova ShS; Umarova GD; Petrova OS; Tukhtaev KR; Abdukarimov A. T4- and T3-binding proteins of rat liver + were studied. It was found that the external mitochondrial membranes and matrix contain a protein whose + electrophoretic mobility is similar to that of thyroxine-binding blood serum prealbumin (TBPA) and which + binds either T4 or T3. This protein is precipitated by monospecific antibodies against TBPA. The internal + mitochondrial membrane has two proteins able to bind thyroid hormones, one of which is localized in the + cathode part of the gel and binds only T3, while the second one capable of binding T4 rather than T3 and + possessing the electrophoretic mobility similar to that of TBPA. Radioimmunoprecipitation with monospecific + antibodies against TBPA revealed that this protein also the antigenic determinants common with those of + TBPA. The in vivo translocation of 125I-TBPA into submitochondrial fractions was studied. The analysis of + densitograms of submitochondrial protein fraction showed that both TBPA and hormones are localized in + the same protein fractions. Electron microscopic autoradiography demonstrated that 125I-TBPA enters + the cytoplasm through the external membrane and is localized on the internal mitochondrial membrane and + matrix. + +

+

+ Biokhimiia 1984 Aug;49(8):1350-6. [The nature of thyroid hormone receptors. Translocation of thyroid + hormones through plasma membranes] Azimova ShS; Umarova GD; Petrova OS; Tukhtaev KR; + Abdukarimov A The in vivo translocation of thyroxine-binding blood serum prealbumin (TBPA) was studied. It + was found that the TBPA-hormone complex penetrates-through the plasma membrane into the cytoplasm of target + cells. Electron microscopic autoradiography revealed that blood serum TBPA is localized in ribosomes of + target cells as well as in mitochondria, lipid droplets and Golgi complex. Negligible amounts of the + translocated TBPA is localized in lysosomes of the cells insensitive to thyroid hormones (spleen + macrophages). Study of T4- and T3-binding proteins from rat liver cytoplasm demonstrated that one of them + has the antigenic determinants common with those of TBPA. It was shown autoimmunoradiographically that the + structure of TBPA is not altered during its translocation. +

+

+ Probl Endokrinol (Mosk), 1981 Mar-Apr, 27:2, 48-52. + [Blood estradiol level and G2-chalone content in the vaginal mucosa in rats of different ages] + Anisimov VN; Okulov VB. "17 beta-Estradiol level was higher in the blood serum of rats aged 14 to 16 + months with regular estral cycles during all the phases as compared to that in 3- to 4-month-old female + rats. + + + The latter ones had a higher vaginal mucosa G2-chalone concentration. The level of the vaginal mucosa + G2-chalone decreased in young rats 12 hours after subcutaneous benzoate-estradiol injection. . . + .". "Possible role of age-associated disturbances of the regulatory cell proliferation + stimulant (estrogen) and its inhibitor (chalone) interactions in neoplastic target tissue transformation + is discussed." +

+

+ Clin Endocrinol (Oxf) 1979 Dec;11(6):603-10. Interrelations between plasma and tissue concentrations + of 17 beta-oestradiol and progesterone during human pregnancy. Batra S, Bengtsson LP, Sjoberg + NO Oestradiol and progesterone concentration in plasma, decidua, myometrium and placenta obtained from women + undergoing Caesarian section at term and abortion at weeks 16-22 of pregnancy were determined. There was a + significant increase in oestradiol concentration (per g wet wt) both in placenta, decidua and myometrium + from mid-term to term. Both at mid-term and term oestradiol concentrations in decidua and myometrium + were much smaller than those in the plasma (per ml). + Progesterone concentration in placenta and in myometrium did not increase from mid-term to term where it + increased significantly in decidua. + Decidual and myometrial progesterone concentrations at mid-term were 2-3 times higher than those in + plasma, + + + but at term the concentrations in both these tissues were lower than in plasma. The ratio progesterone/oestradiol in plasma, decidua, myometrium and placenta at mid-term was 8.7, 112.2, 61.4 and + 370.0, respectively, and it decreased significantly in the myometrium and placenta but was + nearly unchanged in plasma and decidua at term. The general conclusion to be drawn from the present study is + the lack of correspondence between the plasma concentrations and the tissue concentrations of female + sex steroids during pregnancy. +

+

+ Endocrinology 1976 Nov; 99(5): 1178-81. Unconjugated estradiol in the myometrium of + pregnancy. Batra S. By chemically digesting myometrium in a mixture of NaOH and sodium dodecyl + sulphate, estradiol could be recovered almost completely by extraction with ethyl acetate. The concentration + of estradiol-17beta (E2) in the extracted samples could reliably be determined by radioimmunoassay. Compared + to its concentration in the plasma, E2 in the pregnant human myometrium was very low, and as a result, the + tissue/plasma estradiol concentration ratio was less than 0.5. In the pseudopregnant rabbit, this ratio + ranged between 16 and 20. +

+

+ J Steroid Biochem 1989 Jan;32(1A):35-9. Tissue specific effects of progesterone on progesterone and + estrogen receptors in the female urogenital tract. Batra S, Iosif CS. The effect of + progesterone administration on progesterone and estrogen receptors in the uterus, vagina and urethra of + rabbits was studied. After 24 h of + progesterone treatment the concentration of cytosolic progesterone receptors decreased to about 25% of + the control value in the uterus, whereas no significant change in receptor concentration was observed in + the vagina or the urethra. The concentration of the nuclear progesterone receptor did not change in any + of the three tissues studied. The apparent dissociation constant (Kd) of nuclear progesterone receptor + increased after progesterone treatment in all three tissues. Although the Kd of the cytosolic + progesterone receptor also increased in all tissues, the difference was significant for only the vagina + and + urethra. The concentration of cytosolic estrogen receptors in the uterus decreased significantly (P less + than 0.001) after progesterone treatment whereas the Kd value increased slightly (P less than 0.05). In + vagina or the urethra, + + there was no change in either estrogen receptor concentration or Kd values after progesterone treatment. + These data clearly showed that the reduction by progesterone of progesterone and estrogen receptor + concentrations occurs only in the uterus and not in the vagina or the urethra. +

+

+ Am J Obstet Gynecol 1980 Apr 15;136(8):986-91. Female sex steroid concentrations in the ampullary + and isthmic regions of the human fallopian tube and their relationship to plasma concentrations during + the menstrual cycle. + Batra S, Helm G, Owman C, Sjoberg NO, Walles B. The concentrations of estradiol-17 beta (E2) and + progesterone (P) were measured in the ampullary and isthmic portions of the fallopian tube of nonpregnant + menstruating women and the cyclic fluctuations were related to the concentrations of these hormones in + plasma. The steroid concentrations were determined by radioimmunoassays. There was no significant difference + in the isthmic and ampullary concentrations of either steroid in any of the menstrual phases. The mean value + for E2 was highest in the ovulatory phase and for P during the luteal phase. The tissue (per gm)/plasma (per + ml) ratio for the steroid concentrations was above unity in all measurements. The ratio for E2 was highest + (isthmus:12, ampulla:8) in the follicular phase and for P (isthmus:26, ampulla:18) during ovulation. Since + + these highest ratios were attained when plasma steroid concentrations were relatively low they were + interpreted as reflections of a maximal receptor contribution. +

+

+ Biol Reprod 1980 Apr;22(3):430-7. + Sex steroids in plasma and reproductive tissues of the female guinea pig. Batra S, Sjoberg NO, + Thorbert G. +

+ +

+ J Steroid Biochem Mol Biol 1997 Apr;61(3-6):323-39. + Steroid control and sexual differentiation of brain aromatase. Balthazart J. "Together, these + data indicate that + the removal of estrogens caused by steroidal inhibitors decreases the synthesis of ARO, + presumably at the transcriptional level." +

+

+ Science, Vol. 94, No. 2446 (Nov. 1941), p. 462. Diminution in Ability of the Liver to Inactivate + Estrone in Vitamin B Complex Deficiency, Biskind, M.S., and G. R. Biskind. +

+ +

+ Am. Jour. Clin. Path., Vol. 16 (1946), No. 12, pages 737-45. + The Nutritional Aspects of Certain Endocrine Disturbances, Biskind, G. R., and M. S. + Biskind. +

+

+ Biol Reprod, 1993 Oct, 49:4, 647-52. Pathologic effect of estradiol on the hypothalamus. + Brawer JR; Beaudet A; Desjardins GC; Schipper HM. Estradiol provides physiological signals to the brain + throughout life that are indispensable for the development and regulation of reproductive function. In + addition to its multiple physiological actions, we have shown that estradiol is also selectively cytotoxic + to beta-endorphin neurons in the hypothalamic arcuate nucleus. The mechanism underlying this neurotoxic + action appears to involve the conversion of estradiol to catechol estrogen and subsequent oxidation to + o-semiquinone free radicals. The estradiol-induced loss of beta-endorphin neurons engenders a compensatory + increment in mu opioid binding in the medial preoptic area rendering this region supersensitive to residual + beta-endorphin or to other endogenous opioids. The consequent persistent opioid inhibition results in a + cascade of neuroendocrine deficits that are ultimately expressed as a chronically attenuated plasma LH + pattern to which the ovaries respond by becoming anovulatory and polycystic. This neurotoxic action of + estradiol may contribute to a number of reproductive disorders in humans and in animals in which aberrant + hypothalamic function is a major component. +

+

+ Mech Ageing Dev, 1991 May, 58:2-3, 207-20. Exposure to estradiol impairs luteinizing hormone + function during aging. Collins TJ; Parkening TA Department of Anatomy and Neurosciences, + University of Texas Medical Branch, Galveston 77550. "This work evaluated the anterior pituitary (AP) + component of the H-P axis by determining the ability of perifused AP to release LH following sustained but + pulsatile LHRH stimulation. The normal dual discharge profile of LH was affected by age." "The role + of estradiol (E2) in AP aging was further tested as AP from ovariectomized (OVXed) mice, deprived of E2 + since puberty, responded as well as the mature proestrous group. In contrast, aged mice subjected to + long-term E2 exposure (cycling or OVXed plus E2 replacement) failed to produce the dual response + pattern." "Furthermore, E2 is a major factor in altering LH function and appears to act + before middle age." +

+

+ Mech Ageing Dev 1975 Jan-Feb;4(1):19-28. Lysosomal enzymes and aging in vitro: subcellular enzyme + distribution and effect of hydrocortisone on cell life-span. Cristofalo VJ, Kabakjian J. "The + acid phosphatase and beta glucuronidase activities of four subcellular fractions (nuclear, + mitochondrial-lysosomal, microsomal, supernatant) of WI-38 cells were compared during in vitro aging. + All of the fractions showed an age-associated increase in activity." +

+

+ Endocrinology, 1992 Nov, 131:5, 2482-4. + Vitamin E protects hypothalamic beta-endorphin neurons from estradiol neurotoxicity. Desjardins + GC; Beaudet A; Schipper HM; Brawer JR. Estradiol valerate (EV) treatment has been shown to result in the + destruction of 60% of beta-endorphin neurons in the hypothalamic arcuate nucleus. Evidence suggests that the + mechanism of EV-induced neurotoxicity involves the conversion of estradiol to catechol estrogen and + subsequent oxidation to free radicals in local peroxidase-positive astrocytes. In this study, we examined + whether treatment with the antioxidant, vitamin E, protects beta-endorphin neurons from the neurotoxic + action of estradiol. Our results demonstrate that chronic vitamin E treatment prevents the decrement in + hypothalamic beta-endorphin concentrations resulting from arcuate beta-endorphin cell loss, suggesting that + the latter is mediated by free radicals. Vitamin E treatment also prevented the onset of persistent vaginal + cornification and polycystic ovarian condition which have been shown to result from the EV-induced + hypothalamic pathology. +

+ +

+ Exp Gerontol, 1995 May-Aug, 30:3-4, 253-67. + Estrogen-induced hypothalamic beta-endorphin neuron loss: a possible model of hypothalamic + aging. + Desjardins GC; Beaudet A; Meaney MJ; Brawer JR. Over the course of normal aging, all female mammals with + regular cycles display an irreversible arrest of cyclicity at mid-life. Males, in contrast, exhibit + gametogenesis until death. + Although it is widely accepted that exposure to estradiol throughout life contributes to reproductive + aging, a unified hypothesis of the role of estradiol in reproductive senescence has yet to + emerge. Recent evidence derived from a rodent model of chronic estradiol-mediated accelerated + reproductive senescence now suggests such a hypothesis. It has been shown that chronic estradiol exposure + results in the destruction of greater than 60% of all beta-endorphin neurons in the arcuate nucleus + + while leaving other neuronal populations spared. This loss of opioid neurons is prevented by treatment with + antioxidants indicating that it results from estradiol-induced formation of free radicals. + Furthermore, we have shown that this beta-endorphin cell loss is followed by a compensatory upregulation + of mu opioid receptors in the vicinity of LHRH cell bodies. The increment in mu opioid + receptors presumably renders the opioid target cells supersensitive to either residual beta-endorphin or + other endogenous mu ligands, such as met-enkephalin, thus resulting in chronic opioid suppression of + the pattern of LHRH release, and subsequently that of LH. Indeed, prevention of the + neuroendocrine effects of estradiol by antioxidant treatment also prevents the cascade of + neuroendocrine aberrations resulting in anovulatory acyclicity. The loss of beta-endorphin + neurons along with the paradoxical opioid supersensitivity which ensues, provides a unifying framework in + which to interpret the diverse features that characterize the reproductively senescent female. +

+

+ Geburtshilfe Frauenheilkd 1994 Jun; 54(6):321-31. + Hormonprofile bei hochbetagten Frauen und potentielle Einflussfaktoren. Eggert-Kruse W; Kruse + W; Rohr G; Muller S; Kreissler-Haag D; Klinga K; Runnebaum B. [Hormone profile of elderly women and + potential modifiers]. + + Eggert-Kruse W, Kruse W, Rohr G, Muller S, Kreissler-Haag D, Klinga K, Runnebaum B. "In 136 women with a + median age of 78 (60-98) years the serum concentrations of FSH, LH, prolactin, estradiol-17 beta, + testosterone and DHEA-S were determined completed by GnRH and ACTH stimulation tests in a subgroup. This + resulted in median values for FSH of 15.8 ng/ml, LH 6.4 ng/ml, prolactin 6.9 ng/ml, estradiol 16 pg/ml, + testosterone 270 pg/ml and 306 ng/ml for DHEA-S. No correlation with age in this population was + found for gonadotropins as well as the other hormones for an age level of up to 98 years." +

+

+ Acta Physiol Hung 1985;65(4):473-8. Peripheral blood concentrations of progesterone and oestradiol + during human pregnancy and delivery. + + Kauppila A, Jarvinen PA To evaluate the significance of progesterone and estradiol in human uterine activity + during pregnancy and delivery the blood concentrations of these hormones were monitored weekly during the + last trimester of pregnancy and at the onset of labour in 15 women, and before and 3 hours after the + induction of term delivery in 83 parturients. Neither plasma concentrations of progesterone or estradiol nor + the ratio of progesterone to estradiol changed significantly during the last trimester of pregnancy or at + the onset of delivery. After the + induction of delivery parturients with initial progesterone dominance (ratio of progesterone to + estradiol higher than 5 before induction) demonstrated a significant fall in serum concentration of + progesterone and in the ratio of progesterone to estradiol while estradiol concentration rose + significantly. In estrogen dominant women (progesterone to estradiol ratio equal to or lower than 5) the + serum concentration of progesterone and the ratio of progesterone to estradiol rose + significantly during the 3 hours after the induction of delivery. Our results suggest that the peripheral + blood levels of progesterone and estradiol do not correlate with the tissue biochemical changes which + prepare the uterine cervix and myometrium for delivery. The observation that the ratio of progesterone to + estradiol decreased in progesterone-dominant and increased in estrogen-dominant women stresses the + importance of a well balanced equilibrium of these hormones for prostaglandin metabolism during human + delivery. +

+

+ Am J Obstet Gynecol 1984 Nov 1;150(5 Pt 1):501-5. Estrogen and progesterone receptor and hormone + levels in human myometrium and placenta in term pregnancy. Khan-Dawood FS, Dawood MY. Estradiol + and progesterone receptors in the myometrium, decidua, placenta, chorion, and amnion of eight women who + underwent elective cesarean section at term were determined by means of an exchange assay. The hormone + levels in the peripheral plasma and cytosol of these tissues were measured by radioimmunoassays. Maternal + plasma and the placenta had high concentrations of estradiol and progesterone, with the placenta having 12 + times more progesterone + than in maternal plasma but only half the concentrations of estradiol in maternal plasma. The + decidua and placenta had detectable levels of cytosol and nuclear estradiol receptors, but the myometrium + had no measurable cytosol estradiol receptors, + whereas the chorion and amnion had neither cytosol nor nuclear estradiol receptors. However, the chorion + and amnion had significantly higher concentrations of estradiol in the cytosol than those in + the decidua and myometrium. Only the decidua and myometrium had cytosol and nuclear progesterone receptors, + but the placenta, amnion, and chorion had neither cytosol nor nuclear progesterone receptors. In contrast, + progesterone hormone levels were significantly higher in the placenta, amnion, and chorion than in the + decidua and myometrium. The findings indicate that, in the term pregnant uterus, (1) the placenta, amnion, + and chorion are rich in progesterone, estradiol, and nuclear estradiol receptors but have no progesterone + receptors, (2) the decidua and myometrium have nuclear estradiol and progesterone receptors, and (3) the myometrium has a higher progesterone/estradiol ratio than that of the peripheral plasma, thus + suggesting a highly progesterone-dominated uterus. +

+

+ Biochem Biophys Res Commun 1982 Jan 29;104(2):570-6. Progesterone-induced inactivation of nuclear + estrogen receptor in the hamster uterus is mediated by acid phosphatase. MacDonald RG, Okulicz + WC, Leavitt, W.W. +

+

+ Steroids 1982 Oct;40(4):465-73. Progesterone-induced estrogen receptor-regulatory factor is not 17 + beta-hydroxysteroid dehydrogenase. MacDonald RG, Gianferrari EA, Leavitt WW These studies were + done to determine if the progesterone-induced estrogen receptor-regulatory factor (ReRF) in hamster uterus + is 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD), i.e. that rapid loss of nuclear estrogen receptor + (Re) might be due to enhanced estradiol oxidation to estrone catalyzed by 17 beta-HSD. Treatment of + proestrous hamsters with progesterone (approximately 25 mg/kg BW) for either 2 h or 4 h had no effect on 17 + beta-HSD activity measured as the rate of conversion of [6,7-3H]estradiol to [3H]estrone by whole uterine + homogenates at 35 degrees C. During this same time interval, progesterone treatment increased the rate of + inactivation of the occupied form of nuclear Re as determined during a 30 min incubation of uterine nuclear + extract in vitro at 36 degrees C. Since we previously demonstrated that such in vitro Re-inactivating + activity represents ReRF, the present studies show that ReRF is not 17 beta-HSD or a modifier of that + enzyme. +

+ +

+ Am J Obstet Gynecol 1987 Aug; 157(2):312-317. Age-related changes in the female hormonal environment + during reproductive life. Musey VC, Collins DC, Musey PI, Martino-Saltzman D, Preedy JR + Previous studies have indicated that serum levels of follicle-stimulating hormone rise with age during the + female reproductive life, but the effect on other hormones is not clear. We studied the effects of age, + independent of pregnancy, by comparing serum hormone levels in two groups of nulliparous, + premenopausal women aged 18 to 23 and 29 to 40 years. We found that increased age during reproductive + life is accompanied by a significant rise in both basal and stimulated serum follicle-stimulating + hormone levels. This was accompanied by an increase in the serum level of estradiol-17 beta and the + urine + + levels of estradiol-17 beta and 17 beta-estradiol-17-glucosiduronate. The serum level of estrone sulfate + decreased with age. Serum and urine levels of other estrogens were unchanged. The basal and stimulated + levels of luteinizing hormone were also unchanged. There was a significant decrease in basal and stimulated + serum prolactin levels. Serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate decreased + with age, but serum testosterone was unchanged. It is concluded that significant age-related changes in the + female hormonal environment occur during the reproductive years. +

+

+ Endocrinology 1981 Dec;109(6):2273-5. Progesterone-induced estrogen receptor-regulatory factor in + hamster uterine nuclei: preliminary characterization in a cell-free system. Okulicz WC, + MacDonald RG, Leavitt WW. + "In vitro studies have demonstrated a progesterone-induced activity associated with the uterine nuclear + fraction which resulted in the loss of nuclear estrogen receptor." "This progesterone-dependent + stimulation of estrogen receptor loss was absent when nuclear extract was prepared in phosphate buffer + rather than Tris buffer. In addition, sodium molybdate and sodium metavanadate (both at 10 mM) inhibited + this activity in nuclear extract. These observations support the hypothesis that progesterone modulation of + estrogen action may be accomplished by induction (or activation) of an estrogen receptor-regulatory factor + (Re-RF), and this factor may in turn act to eliminate the occupied form of estrogen receptor from + the nucleus, perhaps through a hypothetical dephosphorylation-inactivation mechanism." +

+ +

+ American Journal of Human Biology, v.8, n.6, (1996): 751-759. Ovarian function in the latter half of + the reproductive lifespan. + O'Rourke, M T; Lipson, S F; Ellison, P T. "Thus, ovarian endocrine function over the course of + reproductive life represents a process of change, but not one of generalized functional decline." +

+

+ J Gerontol, 1978 Mar, 33:2, 191-6. + Circulating plasma levels of pregnenolone, progesterone, estrogen, luteinizing hormone, and follicle + stimulating hormone in young and aged C57BL/6 mice during various stages of pregnancy. + Parkening TA; Lau IF; Saksena SK; Chang MC Young (3-5 mo of age) and senescent (12-15 mo of age) multiparous + C57BL/6 mice were mated with young males (3-6 mo of age) and the numbers of preimplantation embryos and + implantation sites determined on days 1 (day of plug), 4, 9, and 16 of pregnancy. The numbers of viable + embryos were significantly lower (p less than 0.02 to p less than 0.001) in senescent females compared with + young females on all days except day 1 of pregnancy. Plasma samples tested by radioimmunoassay indicated + circulating estradiol-17B was significantly lower (P less than 0.05) on day 1 and higher (p less + than 0.05) on day 4 + in older females, whereas FSH was higher on days 4, 9, and 16 (p less than 0.02 to p less than + 0.001) in senescent females when compared with samples from young females. Levels of pregnenolone, + progesterone, estrone, and LH were not significantly different at any stage of pregnancy in the two age + groups. From the hormonal data it did not appear that degenerating corpora lutea were responsible for the + declining litter size in this strain of aged mouse. +

+

+ Biol Reprod, 1985 Jun, 32:5, 989-97. Orthotopic ovarian transplantations in young and aged C57BL/6J + mice. Parkening TA; Collins TJ; Elder FF. "Orthotopic ovarian transplantations were done + between young (6-wk-old) and aged (17-mo-old) C57BL/6J mice. The percentages of mice mating following + surgery from the four possible ovarian transfer combinations were as follows: young into young, 83%; young into aged, 46%; aged into young, 83%; and aged into aged, 36%." "The only + statistical differences found between the transfer groups occurred in FSH concentrations. Plasma FSH was + markedly elevated (P less than 0.005) in young recipients with ovaries transplanted from aged donors, in + comparison to young recipients with ovaries from young donors. + + + These data indicate that the aging ovary and uterus play a secondary role in reproductive failure + and that the aging hypothalamic-hypophyseal complex is primarily responsible for the loss of fecundity + in older female C57BL/6J mice." + +

+

+ J Endocrinol, 1978 Jul, 78:1, 147-8. Postovulatory levels of progestogens, oestrogens, luteinizing + hormone and follicle-stimulating hormone in the plasma of aged golden hamsters exhibiting a delay in + fertilization. Parkening TA; Saksena SK; Lau IF. +

+

+ Biology of Reproduction, v.49, n.2, (1993): 387-392. Controlled neonatal exposure to estrogens: A + suitable tool for reproductive aging studies in the female rat. Rodriguez, P; Fernandez-Galaz, + C; Tejero, A. "The present study was designed to determine whether the modification of exposure time to + large doses of estrogens provided a reliable model for early changes in reproductive aging." "Premature + occurrence of vaginal opening was observed in all three estrogenized groups independently of EB exposure. + However, females bearing implants for 24 h had first estrus at the same age as their controls and cycled + regularly, and neither histological nor gonadal alterations could be observed at 75 days. Interestingly, + they failed to cycle regularly at 5 mo whereas controls continued to cycle." "On the other hand, the + increase of EB exposure (Ei5, EI) resulted in a gradual and significant delay in the onset of first estrus + and in a high number of estrous phases, as frequently observed during reproductive decline. At 75 days, the + ovaries of these last two groups showed a reduced number of corpora lutea and an increased number of + large follicles. According to this histological pattern, ovarian weight and progesterone (P) + content gradually decreased whereas both groups showed higher estradiol (E-2) content than controls. This + resulted in a higher E-2:P ratio, comparable to that observed in normal aging rats. + The results allow us to conclude that the exposure time to large doses of estrogens is critical to + the gradual enhancement of reproductive decline. Furthermore, exposures as brief as 24 h led to a + potential early model for aging studies that will be useful to verify whether neuroendocrine changes + precede gonadal impairment." +

+ +

+ J Clin Endocrinol Metab 1996 Apr;81(4):1495-501. Characterization of reproductive hormonal dynamics + in the perimenopause. Santoro N, Brown JR, Adel T, Skurnick JH. "Overall mean estrone + conjugate excretion was +

+ and was similarly elevated in both follicular and luteal phases. + Luteal phase pregnanediol excretion was diminished in the perimenopausal women compared to + that in younger normal subjects (range for integrated pregnanediol, 1.0-8.4 vs. 1.6-12.7 +
+ + conclude that altered ovarian function in the perimenopause can be observed as early as age 43 yr and + include hyperestrogenism, hypergonadotropism, and decreased luteal phase progesterone excretion. These + hormonal alterations may well be responsible for the increased gynecological morbidity that + characterizes this period of life." + +

+

+ Brain Res, 1994 Jul 25, 652:1, 161-3. + The 21-aminosteroid antioxidant, U74389F, prevents estradiol-induced depletion of hypothalamic + beta-endorphin in adult female rats. Schipper HM; Desjardins GC; Beaudet A; Brawer JR. + "A single intramuscular injection of 2 mg estradiol valerate (EV) results in neuronal degeneration and + beta-endorphin depletion in the hypothalamic arcuate nucleus of adult female rats." "The present + findings support the hypothesis that the toxic effect of estradiol on hypothalamic beta-endorphin + neurons is mediated by free radicals." + +

+

+ Clin Exp Obstet Gynecol 2000;27(1):54-6. Hormonal reproductive status of women at menopausal + transition compared to that observed in a group of midreproductive-aged women. Sengos C, + Iatrakis G, Andreakos C, Xygakis A, Papapetrou P. CONCLUSION: The reproductive hormonal patterns + in + perimenopausal women favor a relatively hypergonadotropic hyper-estrogenic milieu. +

+ +

+ Endocr Relat Cancer 1999 Jun;6(2):307-14. + Aromatase overexpression and breast hyperplasia, an in vivo model--continued overexpression of aromatase + is sufficient to maintain hyperplasia without circulating estrogens, and aromatase inhibitors abrogate + these preneoplastic changes in mammary glands. Tekmal RR, Kirma N, Gill K, Fowler K "To test + directly the role of breast-tissue estrogen in initiation of breast cancer, we have developed the + aromatase-transgenic mouse model and demonstrated for the first time that increased mammary estrogens + resulting from the overexpression of aromatase in mammary glands lead to the induction of various + preneoplastic and neoplastic changes that are similar to early breast cancer." "Our current studies show + aromatase overexpression is sufficient to induce and maintain early preneoplastic and neoplastic changes in + female mice without circulating ovarian estrogen. Preneoplastic and neoplastic changes induced in mammary + glands as a result of aromatase overexpression can be completely abrogated with the administration of the + aromatase inhibitor, letrozole. Consistent with complete reduction in hyperplasia, + we have also seen downregulation of estrogen receptor and a decrease in cell proliferation + markers, suggesting aromatase-induced hyperplasia can be treated with aromatase inhibitors. Our studies + demonstrate that aromatase overexpression alone, without circulating estrogen, is responsible for + the induction of breast hyperplasia and these changes can be abrogated using aromatase + inhibitors." +

+

+ J Steroid Biochem Mol Biol 2000 Jun;73(3-4):141-5. Elevated steroid sulfatase expression in breast + cancers. Utsumi T, Yoshimura N, Takeuchi S, Maruta M, Maeda K, Harada N. In situ estrogen + synthesis makes an important contribution to the high estrogen concentration found in breast cancer tissues. + Steroid sulfatase which hydrolyzes several sulfated steroids such as estrone sulfate, dehydroepiandrosterone + sulfate, and cholesterol sulfate may be involved. In the present study, we therefore, assessed steroid + sulfatase mRNA levels in breast malignancies and background tissues from 38 patients by reverse + transcription and polymerase chain reaction. The levels in breast cancer tissues were significantly + increased at 1458.4+/-2119.7 attomoles/mg RNA (mean +/- SD) as compared with 535.6+/-663.4 attomoles/mg RNA + for non-malignant tissues (P<0.001). Thus, increased steroid sulfatase expression may be partly + responsible for local overproduction of estrogen and provide a growth advantage for tumor cells. +

+

+ Ann N Y Acad Sci 1986;464:106-16. Uptake and concentration of steroid hormones in mammary + tissues. Thijssen JH, van Landeghem AA, Poortman J In order to exert their biological effects, + steroid hormones must enter the cells of target tissues and after binding to specific receptor molecules + must remain for a prolonged period of time in the nucleus. Therefore the endogenous levels and the + subcellular distribution of estradiol, estrone, DHEAS, DHEA ad 5-Adiol were measured in normal breast + tissues and in malignant and nonmalignant breast tumors from pre- and postmenopausal women. For estradiol + the highest tissue levels were found in the malignant samples. No differences were seen in these + levels between pre- and postmenopausal women despite the largely different peripheral blood + levels. For estrone no differences were found between the tissues studied. Although the + estradiol concentration was higher in the estradiol-receptor-positive than in the receptor-negative tumors, + no correlation was calculated between the estradiol and the receptor consent. Striking differences were seen + between the breast and uterine tissues for the total tissue concentration of estradiol, the ratio between + estradiol and estrone, and the subcellular distribution of both estrogens. At similar receptor + concentrations in the tissues these differences cannot easily be explained. Regarding the + androgens, the tissue/plasma gradient was higher for DHEA than for 5-Adiol, and for DHEAS there was very + probably a much lower tissue gradient. The highly significant correlation between the androgens suggests an + intracellular metabolism of DHEAS to DHEA and 5-Adiol. Lower concentrations of DHEAS and DHEA were + observed in the malignant tissues compared with the normal ones and the benign lesions. For + 5-Adiol no differences were found and therefore these data do not support our original hypothesis on the + role of this androgen in the etiology of breast abnormalities. Hence the way in which adrenal androgens + express their influence on the breast cells remains unclear. +

+ +

+ Clin Endocrinol (Oxf) 1978 Jul;9(1):59-66. Sex hormone concentrations in post-menopausal + women. Vermeulen A, Verdonck L. "Plasma sex hormone concentrations (testosterone, (T), + androstenedione (A), oestrone (E1) and oestradiol (E2) were measured in forty post-menopausal women more + than 4 years post-normal menopause." "Sex hormone concentrations in this group of postmenopausal + women (greater than 4YPM) did not show any variation as a function of age, with the possible + exception of E2 which showed a tendency to decrease in the late post-menopause. E1 and to a lesser extent E2 + as well as the E1/A ratio were significantly corelated with degree of obesity or fat mass, suggesting a + possible role of fat tissue in the aromatization of androgens. Neither the T/A nor the E2/E1 ratios were + correlated with fat mass, suggesting that the reduction of 17 oxo-group does not occur in fat tissue. The + E1/A ratio was significantly higher than the reported conversion rate of A in E1." +

+

+ J Steroid Biochem 1984 Nov;21(5):607-12. The endogenous concentration of estradiol and estrone in + normal human postmenopausal endometrium. Vermeulen-Meiners C, Jaszmann LJ, Haspels AA, Poortman + J, Thijssen JH The endogenous estrone (E1) and estradiol (E2) levels (pg/g tissue) were measured in 54 + postmenopausal, atrophic endometria and compared with the E1 and E2 levels in plasma (pg/ml). The results + from the tissue levels of both steroids + showed large variations and there was no significant correlation with their plasma levels. The mean E2 + concentration in tissue was 420 pg/g, 50 times higher than in plasma and the E1 concentration of 270 + pg/g was 9 times higher. + The E2/E1 ratio in tissue of 1.6, was higher than the corresponding E2/E1 ratio in plasma, being + 0.3. We conclude that normal postmenopausal atrophic endometria contain relatively high + concentrations of estradiol and somewhat lower estrone levels. These tissue levels do not lead + to histological effects. +

+ +

+ J Clin Endocrinol Metab 1998 Dec; 83(12):4474-80. Deficient 17beta-hydroxysteroid dehydrogenase type + 2 expression in endometriosis: failure to metabolize 17beta-estradiol. Zeitoun K, Takayama K, + Sasano H, Suzuki T, Moghrabi N, Andersson S, Johns A, Meng L, Putman M, Carr B, Bulun SE. + "Aberrant aromatase expression in stromal cells of endometriosis gives rise to conversion of circulating + androstenedione to estrone in this tissue, whereas aromatase expression is absent in the eutopic + endometrium. In this study, we initially demonstrated by Northern blotting transcripts of the reductive + 17beta-hydroxysteroid dehydrogenase (17betaHSD) type 1, which catalyzes the conversion of estrone to + 17beta-estradiol, in both eutopic endometrium and endometriosis. Thus, it follows that the product + of the aromatase reaction, namely estrone, that is weakly estrogenic can be converted to the potent + estrogen, 17beta-estradiol, in endometriotic tissues. It was previously + + demonstrated that progesterone stimulates the inactivation of 17beta-estradiol through + conversion to estrone in eutopic endometrial epithelial cells." "In conclusion, inactivation of + 17beta-estradiol is impaired in endometriotic tissues due to deficient expression of 17betaHSD-2, which + is normally expressed in eutopic endometrium in response to progesterone." +

+

+ Biochem Biophys Res Commun 1999 Aug 2;261(2):499-503. Piceatannol, a stilbene phytochemical, + inhibits mitochondrial F0F1-ATPase activity by targeting the F1 complex. Zheng J, Ramirez VD. +

+

+ Eur J Pharmacol 1999 Feb 26;368(1):95-102. + Rapid inhibition of rat brain mitochondrial proton F0F1-ATPase activity by estrogens: comparison with + Na+, K+ -ATPase of porcine cortex. Zheng J, Ramirez VD. "The data indicate that the ubiquitous + mitochondrial F0F1-ATPase is a specific target site for estradiol and related estrogenic compounds; however, + under this in vitro condition, the effect seems to require pharmacological concentrations." +

+

+ J Steroid Biochem Mol Biol 1999 Jan;68(1-2):65-75. Purification and identification of an estrogen + binding protein from rat brain: oligomycin sensitivity-conferring protein (OSCP), a subunit of + mitochondrial F0F1-ATP synthase/ATPase. Zheng J, Ramirez VD. "This finding opens up the + possibility that estradiol, and probably other compounds with + similar structures, in addition to their classical genomic mechanism, may interact with ATP + synthase/ATPase by binding to OSCP, and thereby modulating cellular energy metabolism." +

+ +

© Ray Peat 2006. All Rights Reserved. www.RayPeat.com

+ + diff --git a/raypeat-articles/processed/tissue-destruction.html b/raypeat-articles/processed/tissue-destruction.html new file mode 100644 index 0000000..f7b9b50 --- /dev/null +++ b/raypeat-articles/processed/tissue-destruction.html @@ -0,0 +1,242 @@ + + Blocking Tissue Destruction + +

+ Blocking Tissue Destruction +

+

+ There always seems to be a rough balance between tissue regeneration and tissue degeneration, with growth + and repair occurring when the equilibrium shifts in one direction,and with atrophy or degeneration occurring + when the balance shifts in the other direction. If we can understand the mechanisms of atrophy, and how to + retard or to block tissue destruction, then we can restore the balance to a degree which might allow + regeneration to occur, even if we don't clearly understand the mechanisms of growth. +

+

+ Skin and bones are such different types of tissue that it will be useful to start with them, because if we + can see similar processes of degeneration or regeneration in them, then the chances are good that the same + processes will occur in other tissues too. Bone is a relatively stable tissue, while skin is a tissue whose + cells divide rapidly. +

+

+ It is common medical knowledge that cortisone and realted glucocorticioid-type hormones cause skin to + atrophy, becoming thinner. Using topical applications of a synthetic derivative of cortisione,CM Papa and A + M. Kligman showed that the atrophy extended to the pigment cells,reducing theirr size and eliminating most + of their dendritic branches. Some animal studies have found that estrogen caused the skin to become thinner. + The other steroids they tested,progesterone, testosterone,and pregnenolone, acted in the opposite direction, + making aged and atrophied skin thicker and more regular. They also made the pigment cells larger, and + increased their branchinhg.l Since these hormones were already known to have protective actions against + cortisone and estrogen, these results were not too surprising, though they did directly contradict the + claims of people who made estrogen-containing cosmetics. +

+

+ Since progesterone and pregnenolone do not cause healthy, young skin to thicken, their effect in damaged + skin is probably partly to replace the deficiency of that type of steroid which occurs with aging, and to + offset the damaging effects of the catabolic hormones, whose influence does not decrease with age. +

+ +

+

+ Many years ago it was found that in old age a woman's estrogens were increasedd relative to the 17-keto + steroids adrenal androgens. Later, it was found that the conversion of androgen to estrogen increases with + age in both men and women, and that this occurs largely in fat cells. Several years ago, P. K. Siiteri found + that low thyroid modified the enzymes of fat cells in a way that would tend to increase the conversion of + androgen to estrogen. More recently, it was found that adding progesterone to the enzymes had the opposite + effect of aging and hypothyroidism, protecting the androgen from conversion to estrogen. These researchers + (C. J. Newton and colleagues, of London) concluded that the decreased output of progesterone after the + menopause might account for the increased production of estrogen.3 Since progesterone declines in aging men, + too, this could account for the same process in men. +

+

+ Vitamin A's effect on the skin opposes that of estrogen.4 There are several mechanisms that could account + for this. Vitamin A is used in the formation of steroids, and since the skin is a major site of steroid + metabolism, vitamin A might help to maintain the level of the anti-catabolic steroids. A deficiency of + vitamin A causes excessive release of the lysosomal enzymes, acid hydrolases, resulting in tissue + catabolism.5 Also, vitamin A is necessary for the proper differentiation of cells in skin and other + membranes. A deficiency tends to cause an increased rate of cell division, with the production of abnormal + cells, and a substitution of keratinized cells for other types. Estrogen also promotes keratinization and + speeds cell division. A deficiency of vitamin A can cause leukoplakia in the mouth and on the cervix of the + uterus; although this is considered "pre-cancerous," I have found it to be very easily reversible, as I have + discussed elsewhere.6 I suspect that the intracellular fiber, keratin, is produced when a cell can't afford + to do anything more complex. Adequate vitamin A speeds protein synthesis,7 and allows it to be used more + efficiently. +

+

+ Prolactin (which is promoted by estrogen, and inhibited by progesterone) increases with stress and with age. + It probably affects every tissue, but it seems to have its greatest efects on the secretory membranes. It is + known to have strong effects on the kidney, gut and skin (sweat and oil glands, hair follicles, and feathers + inbirds), and on the gills of fish. Its involvement with milk production suggests that it might mobilize + calcium from bones, and inf fact it does contribute to osteoporosis. This was foreseen by G. Bourne, in his + book on the metabolism of hard tissues, when he suggested that estrogen, acting through the pituitary, might + be expected to promote osteoporosis. +

+

+ Since reading Bourne's book, I have doubted that it was rational to use estrogen to prevent osteoporosis, + especially when it is known to be carcinogenic and when the ratio of estrogen to and +

+

+ androgens and progesterone increases after menopause. Now that several publications have appeared clearly + showing that estrogen increases prolactin, that prolactin increases with +

+

+ cancellous bone; adrenal androgens. Thyroid. Rate of formation, overall metabolic rate. +

+

+ ARTHRITIS AND NATURAL HORMONES +

+

+ A very healthy 71 year-old man was under his house repairing the foundation, when a support slipped and let + the house fall far enough to break some facial bones. During his recovery, he developed arthritis in his + hands. It is fairly common for arthritis to appear shortly after an accident, a shock, or surgery, and Han + Selye's famous work with rats shows that when stress exhausts the adrenal glands (so they are unable to + produce normal amounts of cortisone and related steroid hormones), arthritis and other "degenerative" + diseases are likely to develop. +

+

+ But when this man went to his doctor to "get something for his arthritis," he was annoyed that the doctor + insisted on giving him a complete physical exam, and wouldn't give him a shot of cortisone. The examination + showed low thyroid function, and the doctor prescribed a supplement of thyroid extract, explaining that + arthritis is one of the many symptoms of hypothyroidism. The patient agreed to take the thyroid, but for + several days he grumbled about the doctor 'fixing something that wasn't wrong' with him, and ignoring his + arthritis. But in less than two weeks, the arthritis had entirely disappeared. He lived to be 89, without a + recurrence of arthritis. (He died iatrogenically, while in good health.) +

+

+ Selye's work with the diseases of stress, and the anti-stress hormones of the adrenal cortex, helped many + scientists to think more clearly about the interaction of the organism with its environment, but it has led + others to focus too narrowly on hormones of the adrenal cortex (such as cortisol and cortisone), and to + forget the older knowledge about natural resistance. There are probably only a few physicians now practicing + who would remember to check for hypothyroidism in an arthritis patient, or in other stress-related + conditions. Hypothyroidism is a common cause of adrenal insufficiency, but it also has some direct effects + on joint tissues. In chronic hypothyroidism (myxedema and cretinism), knees and elbows are often bent + abnormally. +

+

+ By the 1930's, it was well established that the resistance of the organism depended on the energy produced + by respiration under the influence of the thyroid gland, as well as on the adrenal hormones, and that the + hormones of pregnancy (especially progesterone) could substitute for the adrenal hormones. In a sense, the + thyroid hormone is the basic anti-stress hormone, since it is required for the production of the adrenal and + pregnancy hormones. +

+ +

+ A contemporary researcher, F. Z. Meerson, is putting together a picture of the biological processes involved + in adapting to stress, including energy production, nutrition, hormones, and changes in cell structure. +

+

+ While one of Selye's earliest observations related gastrointestinal bleeding to stress, Meerson's work has + revealed in a detailed way how the usually beneficial hormone of adaptation, cortisone, can cause so many + other harmful effects when its action is too prolonged or too intense. +

+

+ Some of the harmful effects of the cortisone class of drugs (other than gastro-intestinal bleeding) are: + Hypertension, osteoporosis, delayed healing, atrophy of the skin, convulsions, cataracts, glaucoma, + protruding eyes, psychic derangements, menstrual irregularities, and loss of immunity allowing infections + (or cancer) to spread. +

+

+ While normal thyroid function is required for the secretion of the adrenal hormones, the basic signal which + causes cortisone to be formed is a drop in the blood glucose level. The increased energy requirement of any + stress tends to cause the blood sugar to fall slightly, but hypothyroidism itself tends to depress blood + sugar. +

+ +

+ The person with low thyroid function is more likely than a normal person to require cortisone to cope with a + certain amount of stress. However, if large amounts of cortisone are produced for a long time, the toxic + effects of the hormone begin to appear. According to Meerson, heart attacks are provoked and aggravated by + the cortisone produced during stress. (Meerson and his colleagues have demonstrated that the progress of a + heart attack can be halted by a treatment including natural substances such as vitamin E and magnesium.) +

+

+ While hypothyroidism makes the body require more cortisone to sustain blood sugar and energy production, it + also limits the ability to produce cortisone, so in some cases stress produces symptoms resulting from a + deficiency of cortisone, including various forms of arthritis and more generalized types of chronic + inflammation. +

+

+ Often, a small physiological dose of natural hydrocortisone can help the patient meet the stress, without + causing harmful side-effects. While treating the symptoms with cortisone for a short time, it is important + to try to learn the basic cause of the problem, by checking for hypothyroidism, vitamin A deficiency, + protein deficiency, a lack of sunlight, etc. (I suspect that light on the skin directly increases the skin's + production of steroids, without depending on other organs. Different steroids probably involve different + frequencies of light, but orange and red light seem to be important frequencies.) Using cortisone in this + way, physiologically rather than pharmacologically, it is not likely to cause the serious problems mentioned + above. +

+

+ Stress-induced cortisone deficiency is thought to be a factor in a great variety of unpleasant conditions, + from allergies to ulcerative colitis, and in many forms of arthritis. The stress which can cause a cortisone + deficiency is even more likely to disturb formation of progesterone and thyroid hormone, so the fact that + cortisone can relieve symptoms does not mean that it has corrected the problem. +

+

+ According to the Physicians' Desk Referenc, hormones similar to cortisone are useful for treating rheumatoid + arthritis, post-traumatic osteoarthritis, synovitis of osteoarthritis, acute gouty arthritis, acute + nonspecific tenosynovitis, psoriatic arthritis, ankylosing spondylitis, acute and subacute bursitis, and + epicondylitis. +

+ +

+ Although cortisone supplementation can help in a great variety of stress-related diseases, no curewill take + place unless the basic cause is discovered. Besides the thyroid, the other class of adaptive hormones which + are often out of balance in the diseases of stress, is the group of hormones produced mainly by the gonads: + the "reproductive hormones." During pregnancy these hormones serve to protect the developing baby from the + stresses suffered by the mother, but the same hormones function as part to the protective anti-stress system + in the non-pregnant individual, though at a lower level. +

+

+ Some forms of arthritis are known to improve or even to disappear during pregnancy. As mentioned above, the + hormones of pregnancy can make up for a lack of adrenal cortex hormones. During a healthy pregnancy, many + hormones are present in increased amounts, including the thyroid hormones. Progesterone, which is the most + abundant hormone of pregnancy, has both anti-inflammatory and anesthetic actions, which would be of obvious + benefit in arthritis. +

+

+ There are other naturally anesthetic hormones which are increased during pregnancy, including DHEA, which is + being studied for its anti-aging, anti-cancer, and anti-obesity effects. (One of the reasons that is + frequently given for the fact that this hormone hasn't been studied more widely is that, as a natural + substance, it has not been monopolized by a drug patent, and so no drug company has been willing to invest + money in studying its medical uses.) These hormones also have the ability to control cell division, which + would be important in forms of arthritis that involve invasive tissue growth. +

+

+ While these substances, so abundant in pregnancy, have the ability to substitute for cortisone, they can + also be used by the adrenal glands to produce cortisol and related hormones. But probably the most + surprising property of these natural steroids is that they protect against the toxic side-effects of + excessive adrenal hormones. And they seem to have no side-effects of their own; after about fifty years of + medical use, no toxic side effects have been found for progesterone or pregnenolone. +

+

+ Pregnenolone is the material the body uses to form either progesterone or DHEA. Others, including DHEA, + haven't been studied for so long, but the high levels which are normally present in healthy people would + suggest that replacement doses, to restore those normal levels, would not be likely to produce toxic side + effects. And, considering the terrible side effects of the drugs that are now widely used, these drugs would + be justifiable simply to prevent some of the toxic effects of conventional treatment. +

+

+ It takes a new way of thinking to understand that these protective substances protect against an excess of + the adrenal steroids, as well as making up for a deficiency. Several of these natural hormones also have a + protective action against various poisons; Selye called this their "catatoxic" effect. +

+

+ Besides many people whose arthritis improved with only thyroid supplementation, I have seen 30 people use + one or more of these other natural hormones for various types of arthritis, usually with a topical + application. Often the pain is relieved within a few minutes. I know of several other people who used + progesterone topically for inflamed tendons, damaged cartilage, or other inflammations. Only one of these, a + woman with rheumatoid arthritis in many joints, had no significant improvement. An hour after she had + applied it to her hands and feet, she enthusiastically reported that her ankle had stopped hurting, but + after this she said she had no noticeable improvement. +

+

+ We often hear that "there is no cure for arthritis, because the causes are not known." If the cause is an + imbalance in the normal hormones of adaptation and resistance, then eliminating the cause by restoring + balance will produce a true cure. But if it is more profitable to sell powerful drugs than to sell the + nutrients needed to form natural hormones (or to supplement those natural hormones) we can't expect the drug + companies to spend any money investigating that sort of cure. And at present the arthritis market amounts to + billions of dollars in drug sales each year. +

+

+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com +

+ + diff --git a/raypeat-articles/processed/transparency-cataracts.html b/raypeat-articles/processed/transparency-cataracts.html new file mode 100644 index 0000000..ab7c4ba --- /dev/null +++ b/raypeat-articles/processed/transparency-cataracts.html @@ -0,0 +1,735 @@ + + The transparency of life: Cataracts as a model of age-related disease + +

+ The transparency of life: Cataracts as a model of age-related disease +

+ +

+ Cataracts can disappear when the eye's metabolic condition is corrected. A supply of energy is essential + to maintain the transparent structure. +

+ +

+ Lactic acid increases as carbon dioxide decreases, during a typical energy deficiency. Deficient + thyroid, and the resulting excess of cortisol relative to pregnenolone and progesterone, define the + energy deficiency. +

+

+ Increased lactate relative to CO2 in the cell alters cell pH and electrical charge, causing swelling. + Swelling and increased water content characterize the cataract. +

+

+ High altitude is inversely related to cataracts, despite the known role of sunlight in causing + cataracts; this is a strong confirmation of the protective role of carbon dioxide. +

+ +
+ +

+ In the markets around Lake Patzcuaro, they sell green transparent fish, about 6 inches long. When cooked, + the meat is white, like ordinary fish. Most fish filets are a little translucent, but are at least cloudy, + and usually pink by transmitted light. I don"t know how the transparent fish work, because it seems that the + blood and the network of blood vessels needed to sustain muscle activity would diffuse the light. Anyway, + cooking disrupts the mysteriously ordered state of water and proteins that makes them transparent, roughly + the way egg-white loses its transparency when it is cooked. I have never heard a convincing explanation for + the opacity of cooked egg-white, either, but anything that disrupts the original structuring of the + protein-water interaction will destroy the transparency. +

+

+ Around 1970, I used a technique called nuclear magnetic resonance (NMR), which is the basis for the + procedure known as MRI (magnetic resonance imaging), to compare the state of water in old (uterine) tissue + and young tissue. Old tissue predictably contains less water than young tissue, but I found that the water + in the old tissue was in a relatively free and uncontrolled state. When tissue swells and takes up water, + more of the water is likely to be in this uncontrolled state, and this is one of the things that makes MRI + so useful, because tumors, for example, show up vividly because of their large amount of uncontrolled + ("unbound") water. I suspect that the measurements I made on uterine tissue showed a localized effect, that + opposed the general trend toward increased dryness with aging. In the case of cataracts, this is clearly the + case: Most of the lens becomes drier with age, but at a certain point there is a reversal, + and some of the tissue takes up too much water. That"s why I refer to cataracts as a model of age-related + disease, rather than as a model of aging. In this sense, I am including them among the inflammatory diseases + of aging--colitis, arthritis, and cancer, for example. MRI now can show developing cataracts before they are + visible, because of increased water content in the area. +

+

+ The lens of the eye is a fairly dense, tough, transparent living structure, which can develop opaque areas, + cataracts, as a result of old age, poisoning, radiation, disease, or trauma. The varieties of cataract + relate to the causes. Most of the oxidative metabolism of the lens is in or near the epithelial layer that + surrounds it. Old-age cataracts most often begin in this region. +

+

+ Although the efficient oxidative energy metabolism occurs near the surface of the lens, there is a + constant flow of fluid through the lens, + entering it mainly in the front and back, and leaving on its "sides" or equator (considering the front and + back as the poles, the direction light passes through). Oxygen and nutrients are supplied to the lens by way + of this circulation of fluid, entering mostly from the aqueous humor in front (which also supplies the + cornea), but also from the vitreous humor behind the lens. +

+ +

+ When the flow of nutrients and energy is impaired, the organized state of the protein and water system in + the cell is damaged, and an excess of water is taken up by the cells, as the protein content decreases. The + loss of organization causes light to be dispersed, with a loss of transparency. +

+

+ The lens of the eye is usually treated as something so specialized that it is hardly considered to be part + of our living substance, just as dentistry has tended to treat teeth as inert things to be approached + mechanically, rather than physiologically. The lens"s circulatory system is very interesting, + because of what it says about the nature of living substance. In the absence of blood vessels, it + provides its own flow of nutrients. This flow is reminiscent of the flow of substances through + the dentine channels of the teeth, through the axons of nerves (two-way transport in a very narrow channel), + and, in some ways recalls the flow of fluids in plants, called "guttation" (drop formation), which is + disturbing to botanists, because it is contrary to the textbook descriptions of proper physiology. +

+

+ The flow of material through lens cells, dentine canals, and nerve axons should allow us to gain a + perspective in which these observable processes become a model for other biological situations + in which "transport" occurs: Kidney, intestine, or the skin of frogs, for example, in which + water, ions, and other solutes are moved in considerable quantities. +

+ +

+ When cells metabolize, they create gradients. In the cell, electrical, chemical, osmotic, and thermal + gradients, for example, are constantly being produced or maintained. The whole substance of the cell is + involved in its life processes. Because of prejudices introduced 200 years ago, the life of the cell has + been relegated to its "membrane" (where hypothetical "membrane pumps" reside) and its nucleus. + When the term "cell" (hollow space) came into use instead of "corpuscle" (little body), a mind-set came + into existence that discounted the importance of most of the living material, and claimed that + it was a mere "random solution." Random solutions don"t do much. The wonderful "membrane," under the + direction of the nucleus (and its set of instructions), took care of everything. +

+

+ Whenever assimilation or excretion took place, it was explained by inventing a property possessed by the + cell "membranes." Therefore, we have physiology textbooks that have an unfounded explanation for everything. + Before Copernicus, planetary movements were described as arbitrary "epicycles." They didn't make sense, but + people studied them and felt that they were important. "Membrane physiology" is the modern equivalent of the + Ptolemaic epicycles. +

+ +

+ We know that glucose can be metabolized into pyruvic acid, which, in the presence of oxygen, can be + metabolized into carbon dioxide. Without oxygen, pyruvic acid can be converted into lactic acid. The + production of lactic acid tends to increase the pH inside the cell, and its excretion can lower the pH + outside the cell. +

+

+ The decrease of carbon dioxide that generally accompanies increased lactic acid, corresponds to increased + intracellular pH. Carbon dioxide binds to many types of protein, for example by forming carbamino groups, + changing the protein conformation, as well as its electrical properties, such as its isoelectric point. With + increased pH, cell proteins become more strongly ionized, tending to separate, allowing water to enter the + spaces, in the same way a gel swells in an alkaline solution. +

+

+ The Bohr-Haldane effect describes the fact that hemoglobin releases oxygen in the presence of carbon + dioxide, and releases carbon dioxide in the presence of oxygen. When oxygen is too abundant, it makes + breathing more difficult, and one of its effects is to cause carbon dioxide to be lost rapidly. At high + altitude, more carbon dioxide is retained, and this makes cellular respiration more efficient. +

+

+ The importance of carbon dioxide to cell control process, and to the structure of the cell and the structure + of proteins in general suggested that degenerative diseases would be less common at high altitude. Wounds + and broken bones heal faster at high altitude, but the available statistics are especially impressive in two + of the major degenerative conditions, cancer and cataracts. +

+

+

+ The two biggest studies of altitude and cataracts (involving 12,217 patients in one study, and 30,565 + lifelong residents in a national survey in Nepal) showed a negative correlation between altitude and the + incidence of cataract. At high altitude, cataracts appeared at a later age. In Nepal, an increase of + a few thousand feet in elevation decreased the incidence of cataracts by 2.7 times. At the same time, it + was found that exposure to sunlight increased the incidence of cataracts, and since the intensity of + ultraviolet radiation is increased with altitude, this makes the decreased incidence of cataracts even + more important. +

+ +

+ All of the typical causes of cataracts, aging, poisons, and radiation, decrease the formation of carbon + dioxide, and tend to increase the formation of lactic acid. + Lactic acid excess is typically found in eyes with cataracts. +

+

+ The electrical charge on the structural proteins will tend to increase in the presence of lactic acid or the + deficiency of carbon dioxide, and the increase of charge will tend to increase the absorption of water. +

+

+ The lens can survive for a considerable length of time in vitro + (since it has its own circulatory system), + so it has been possible to demonstrate that changes in the composition of the fluid can cause opacities to + form, or to disappear. +

+ +

+ Oxidants, including hydrogen peroxide which occurs naturally in the aqueous humor, can cause opacities to + form quickly, but they will also disappear quickly in a solution that restores metabolic energy. The lens + regulates itself powerfully; for example, it will swell when put into a hypotonic solution, + but will quickly adapt, returning to approximately its normal size. +

+

+ Several years ago, I saw what appeared to be oxidant-induced cataracts. Two women had a very sudden onset of + cataracts, and I asked about their diet and supplements; it turned out that one of them had + begun taking 500 mg of zinc daily a few months earlier, and the other had begun taking 600 mg of zinc and + 250 mg of iron, on her doctor"s recommendation, just a couple of months before the cataracts appeared. +

+

+ For some reason, there have been many nutritional supplements sold as cataract remedies in the form of eye + drops. I suppose a trace of the material could diffuse through the cornea into the aqueous humor, where it + might make a difference in the lens"s nutrient supply, but it seems more reasonable to treat the body as a + whole, nourishing every part in a balanced way. +

+

+ Besides living at a high elevation or breathing extra carbon dioxide, the most certain way to increase the + amount of carbon dioxide in the eye, and to prevent an excess of lactic acid, is to make sure that your + thyroid function is adequate. +

+ +

+ One man who took thyroid, USP, and vitamin E told me that his cataracts had regressed, but I haven"t known + other people who tried this. +

+

+ If a person already has distinct cataracts, it might be worthwhile to experiment with a relatively high + degree of hypercapnia, for example, breathing a 5% mixture of CO2 in air. +

+

+ Carbon dioxide, at higher levels than are normal at sea level, has a profound effect on free radicals, + reducing the free radical activity in the blood to approximately zero, before reaching the level that + produces acidosis. +

+

+ There are several situations in which carbon dioxide affects the hydration, water content, of biological + materials, that I think give an insight into its effects on the lens. Hydrophilic glycoproteins are involved + in each case. These are proteins with attached chains of sugar molecules that make them associate with a + large amount of water. In the cornea, increased carbon dioxide strongly protects against swelling. The bulk + of the cornea is a connective tissue that is relatively simple and passive compared to the compact cellular + structure of the lens, and it is conventional to describe the thin layers of cells on the inside and outside + of the cornea as being responsible for the water content of the underlying substance. However, even when the + epithelial cells are removed, it has been demonstrated that carbon dioxide is able to prevent corneal + swelling. (M.V. Riley, et al., "The roles of bicarbonate and CO2 in transendothelial fluid movement and + control of corneal thickness," + Invest. Ophthalmol. Vis. Sci. 36(1), 103-112, 1995.) +

+ +

+ Bronchial mucous secretions are an even simpler system, so it is very interesting that carbon dioxide is + recognized as the most powerful regulator of their behavior. (This has important implications for "cystic + fibrosis," or mucoviscidosis.) Goodman and Gilman (page 1068, + Pharmacological Basis of Therapeutics, 2nd Edition, Macmillan Co., 1956), say +

+

+ "Among inhalants, steam and carbon dioxide have been found to be excellent expectorants. Relative humidity + above 85 per cent liquefies sputum, decreases its viscosity...." "Carbon dioxide is the most effective agent + of all. It not only lowers the viscosity of tenacious sputum, thereby facilitating expectoration, but it + decreases the volume of sputum by promoting its active resorption by bronchial mucosa." "A five to ten per + cent concentration of carbon dioxide is adequate and well tolerated if administered at intervals." "Oxygen + has been shown to be an antiexpectorant and has effects opposite to those of carbon" +

+

+ Oxygen tends to displace carbon dioxide from tissue, and is a source of free radicals. +

+

+ One of the best-known free radical scavenging substances that has been widely used as a drug is iodide. It + has been used to treat asthma, parasites, syphilis, cancer, Graves" disease, periodontal disease, and + arteriosclerosis. Diseases that produce tissue overgrowth associated with inflammation--granulomas--have + been treated with iodides, and although the iodide doesn"t necessarily kill the germ, it does help to break + down and remove the granuloma. Leprosy and syphilis were among the diseases involving granulomas* that were + treated in this way. In the case of tuberculosis, it has been suggested that iodides combine with + unsaturated fatty acids which inhibit proteolytic enzymes, and thus allow for the removal of the abnormal + tissue. +

+

+ In experimental animals, iodide clearly delays the appearance of cataracts. (Buchberger, et al., 199l.) +

+

+ Inflammation, edema, and free radical production are closely linked, and are produced by most things that + interfere with energy production. +

+

+ Endotoxin, produced by bacteria, mainly in the intestine, disrupts energy production, and promotes + maladaptive inflammation. The wide spectrum of benefit that iodide has, especially in diseases with an + inflammatory component, suggests first that it protects tissue by blocking free radical damage, but it also + suggests the possibility that it might specifically protect against endotoxin. +

+ +

+ There are subtler differences in transparence that probably have a variety of causes, but differences in + water content or hydration might be involved in the lower transparency that has been seen in women's lenses. + Estrogen, which tends to produce edema and hypotonic body fluids, also increases prolactin production. + Prolactin is involved in water and electrolyte regulation, and it has been found to accelerate the + development of experimental cataracts. (M. C. Ng, et al, 1987.) These hormones are associated + with the calcification of soft tissues, and cataracts contain very high levels of calcium. (Avarachan and + Rawal, 1987; Hightower and Reddy, 1982.) +

+

+ Estrogen is strongly associated with free radical processes, calcium mobilization, and acetylcholine + release, all of which are involved in the process of excitoxicity. Alvarez, et al., (1996) have shown a + possible involvement of acetylcholine in calcium mobilization in the lens. +

+

+ Serotonin is another regulatory substance strongly associated with prolactin and estrogen, and it also can + be involved in disrupting the metabolism of the lens. This is one of the potential dangers in using + supplemental tryptophan. (Candia, et al., 1980.) +

+

+ Old age commonly involves some changes in the color of tissues--loss of pigment from hair and skin, with + appearance of new pigment (age pigment, lipofuscin), which may appear as "liver spots." But there is also a + tendency of the toenails, fingernails, teeth, and lenses to turn yellow or brown. Some of this dark material + seems to be age pigment, derived from unsaturated fatty acids, but other components have been identified, + for example, tryptophan from damaged proteins. The Maillard reaction (similar to the browning that occurs in + bread crust) has often been mentioned in relation to aging, and involves the combination of protein amino + groups with sugars. But the browning of the lens tends to be associated with the general age related drying + of the lens, it isn"t irregularly distributed, and it doesn"t significantly harm vision. +

+ +

+ When I first heard about the age-related browning of the lens, I thought that the experience of colors would + be affected, so I devised a test in which the relative darkness of blue and yellow could be judged in + comparison with a graded strip of shades of grey. +

+

+ After people of ages ranging from 10 to 80 had given exactly the same matches, I realized that the nervous + system probably corrects for the "yellow filter" effect of the brown lens. +

+

+ The browning of tissues will be the subject of another newsletter. +

+

+ Among the interesting causes of cataracts: + Tamoxifen and hypotonic fluids, sodium deficiency; toxicity of tryptophan; + oxidants (metals, hydrogen peroxide, PUFA); diabetes, photosensitizers and sunlight; + + excess calcium, deficient magnesium. Excess cortisol. Radiation. Arachidonic and linoleic acids in other + situations have been found to block cells' regulation of their water content. Hypothyroidism tends to + increase the activity of serotonin, estrogen, prolactin, calcium, and the tendency of tissues to retain + water, and to decrease the level of ATP. +

+

+ Among the factors that probably have a role in preventing cataracts: + Thyroid, progesterone, pregnenolone, vitamin E, iodide, pyruvate. Increasing the carbon dioxide lowers the + cell"s pH, and tends to resist swelling. Palmitic acid (a saturated fat that can be synthesized by our + tissues) is normally oxidized by the lens. Calcium blockers experimentally prevent cataracts, suggesting + that magnesium and thyroid (which also act to exclude calcium from cells) would have the same effect. +

+

+ Thyroid hormone is essential for maintaining adequate carbon dioxide production, for minimizing lactic acid, + cortisol and prolactin, for regulating calcium and magnesium, for avoiding hypotonicity of the body fluids, + and for improving the ratio of palmitic acid to linoleic acid. +

+

.

+

+ +

+ +

REFERENCES

+

+

+ "Inhibition of ionic transport and ATPase activities by serotonin analogues in the isolated toad lens," + Candia OA; Lanzetta PA; Alvarez LJ; Gaines W, Biochim Biophys Acta (602)2, 389-400, 1980. "Tryptamine, + 5-methyltryptamine and 5-methoxytryptamine had dual effects: 1 mM in the posterior bathing solution + depressed the potential difference of the posterior face of the lens, which resulted in an increase in the + translenticular potential difference and short-circuit current; 1 mM in the anterior solution (in contact + with the lens epithelium) produced a quick and pronounced reduction of the potential difference of the + anterior face. This resulted in a 90-100% decline of the translenticular short-circuit current. Serotonin + and tryptamine were then tested for their effect on the ATPases of lens epithelium. Both amines inhibited + the enzymes with tryptamine at 5 mM completely inhibiting all ATPase activity. Since tryptophan is + transported from the aqueous humor into the lens and may be converted by lens enzymes to serotonin and + tryptamine, these findings may have physiological implications in cataractogenesis." +

+

+ "Effects of Ca2+ on rabbit translens short-circuit current: evidence for a Ca2+ inhibitable K+ conductance," + Alvarez LJ; Candia OA; Zamudio AC, Curr Eye Res, 1996 Dec, 15:12, 1198-207. PURPOSE: To characterize the + effects of medium Ca2+ levels on rabbit lens electrical properties. Overall, these results suggest that + lens Ca2(+)-mobilizing agents (e.g. acetylcholine) could trigger the inhibition of + epithelial K+ conductance(s) by the direct action of Ca2+ on K+ channels." +

+ +

+ "Effects of Ca2+ on rabbit translens short-circuit current: evidence for a Ca2+ inhibitable K+ conductance," + Alvarez LJ; Candia OA; Zamudio AC, Curr Eye Res, 1996 Dec, 15:12, 1198-207. "PURPOSE: To characterize the + effects of medium Ca2+ levels on rabbit lens electrical properties. Overall, these results suggest that lens + Ca2(+)-mobilizing agents (e.g. acetylcholine) could trigger the inhibition of epithelial K+ conductance(s) + by the direct action of Ca2+ on K+ channels." +

+

+ "D600 increases the resistance associated with the equatorial potassium current of the lens," Walsh SP; + Patterson JW, Exp Eye Res, 1992 Jul, 55:1, 81-5 "This effect is similar to that produced by quinine and by a + calcium-free medium, and is attributed to the prevention of an increase in the calcium-dependent conductance + produced by pCMPS." +

+

+ "Effects of hydrogen peroxide oxidation and calcium channel blockers on the equatorial potassium current of + the frog lens," Walsh SP; Patterson JW, Exp Eye Res, 1994 Mar, 58:3, 257-65. "Hydrogen peroxide, in + concentrations of 10-1000 microM, produces two major changes in the current-voltage relationships associated + with the equatorial potassium current of the lens. First, the resting and reversal potentials become more + negative than they were prior to treatment with hydrogen peroxide and second, the membrane resistance + related to the equatorial current is decreased. The shift in the resting and reversal potentials is in the + opposite direction from that produced by ouabain. Based on the Nernst equation, the shift in the reversal + potential suggests that there is an increase in the concentration of potassium in the lens. The 86Rb + uptake and efflux are increased. These observations suggest that hydrogen peroxide stimulates the + Na,K-pump. The decrease in membrane resistance is inhibited by 100 microM of quinine, a + calcium-dependent potassium channel blocker, and does not decrease in a calcium-free medium. This + suggests that the decrease in resistance may be secondary to an increase in lenticular calcium. + These effects of hydrogen peroxide are similar to those of p-chloromercuriphenylsulfonate (pCMPS), a nearly + impermeant sulfhydryl binding agent, + and suggest that permeant hydrogen peroxide may increase calcium influx by acting on sulfhydryl groups + on the outer surface of lens membranes. Verapamil, a calcium channel blocker, is reported to prevent + cataract formation." +

+

+ "Effect of prolactin on galactose cataractogenesis," Ng MC; Tsui JY; Merola LO; Unakar NJ phthalmic Res + 19:2, 82-94, 1987. "Prolactin has been known to affect the water and electrolyte balance. Because increased + lens hydration has been shown to be a common phenomenon in most, if not all types of cataracts, we have been + interested in investigating a possible role of prolactin in sugar cataract induction and progression. For + this study, we have used morphological and biochemical approaches. The prolactin delivery method involved + intraperitoneal implantation of one or more pellets in Sprague-Dawley female rats. Following implantation of + the desired number of prolactin or control (nonprolactin) pellets, animals were either fed galactose and lab + chow, or lab chow diet. Gross morphological observations of whole lenses, slit-lamp examination of lenses + and light microscopic analysis of lens sections showed that in the galactose-fed prolactin group, galactose + associated alteration progressed faster and total opacification (mature cataract development) was achieved + earlier than in the nonprolactin group. The levels of galactose and dulcitol were higher in the lenses of + galactose-fed prolactin treated rats as compared to lenses from nonprolactin (control) rats. No significant + difference in lens Na+-K+ ATPase activity between the prolactin and nonprolactin group was observed. Our + results indicate that prolactin accelerates galactose-induced cataractogenesis in rats." +

+

+ "A hypothetical mechanism for toxic cataract due to oxidative damage to the lens epithelial membrane," + Bender CJ Med Hypotheses, 1994 Nov, 43:5, 307-11 Lenticular opacities can be induced by numerous external + agents that coincide with those that catalyze oxidative damage to lipids. + One of the consequences of lipid peroxidation is that the affected membrane is rendered more + permeable to protons. A proton leak in the tight epithelium of lens would uncouple the + Na+/K(+)-ATPases that regulate the water and ionic content of the bounded tissue. Once + regulatory control of the osmotic pressure is lost, + the phase state of the cell's soluble proteins would change, + leading to refractive changes or, in extreme cases, precipitation. The same does not occur in + cornea because the stroma is an extracellular polymer blend rather than solution of soluble polymers. + Polymeric phase transitions in the cornea require that divalent cations pass the epithelial membrane, which + can occur only through the action of ionophores. +

+

+ Tsubota K; Laing RA; Kenyon KR Invest Ophthalmol Vis Sci, 1987 May, 28:5, 785-9, Abnormalities in + glucose metabolism are thought to be among the main causes of cataract formation. + + The authors have made noninvasive biochemical measurements of the lens that provide information concerning + glucose metabolism in the lens epithelium. The autofluorescence of reduced pyridine nucleotides (PN) and + oxidized flavoproteins (Fp) within the rabbit lens were noninvasively measured as a function of depth using + redox fluorometry. The peak of the autofluorescence at 440 nm (excited at 360 nm) and 540 nm (excited at 460 nm) were determined at the lens epithelium. When 8 mM sodium pentobarbital, a known + inhibitor of mitochondrial respiration, was applied to the lens, the autofluorescence peak at 440 nm + increased and that at 540 + + nm decreased. The 440 nm autofluorescence is thought to be from + + + reduced pyridine nucleotides, whereas the 540 nm autofluorescence is from the oxidized flavoprotein. + Blocking lens respiration with pentobarbital caused an increase in the PN/Fp ratio by a factor of 3 within + 3.5 hr after pentobarbital application." +

+

+ [Use of pyrimidine bases and ATP for conservative treatment of early cataracts] Larionov LN Oftalmol Zh, + 1977, 32:3, 221-2 +

+

+

+ + high levels of L-lactate and high ratios of L-lactate in the lens/L-lactate in the aqueous. 2. + Immature cataractous lenses with anterior capsular/subcapsular opacity; intermediate levels of RTP, + intermediate values for the sums of RTP, RDP, and AMP, high L-lactate levels, and intermediate + values of the ratios of L-lactate in the lens/L-lactate in the aqueous." +

+

+ Sulochana KN; Ramakrishnan S; Vasanthi SB; Madhavan HN; Arunagiri K; Punitham R, "First report of congenital + or infantile cataract in deranged proteoglycan metabolism with released xylose," Br J Ophthalmol, 1997 Apr, + 81:4, 319-23." "Of 220 children of both sexes below 12 years of age, with congenital or infantile cataract + treated in Sankara Nethralaya, Madras, India, during a period of 2 years, 145 excreted fragments of GAG + (heparan and chondroitin sulphates) in their urine. There was no such excretion among the control group of + 50 children. + The same was found accumulated in the blood and lenses of affected children. + In addition, xylose was present in small amounts in the urine and blood and xylitol was present in the lens. + There was a significant elevation in the activity of beta glucuronidase in lymphocytes and + urine, + when compared with normals. All the above findings suggest deranged proteoglycan metabolism. As the urine + contained mostly GAG fragments and very little xylose, Benedict's reagent was not reduced. This ruled out + galactosaemia.CONCLUSION: An increase of beta glucuronidase activity might have caused extensive + fragmentation of GAG with resultant accumulation in the blood and lens and excretion in urine. + Small amounts of xylose may have come from xylose links between GAG and core protein of proteoglycans. Owing + to their polyanionic nature, GAG fragments in the lens might abstract sodium, and with it water, thereby + increasing the hydration of the lens. Excessive hydration and the osmotic effect of xylitol from xylose + might cause cataract. While corneal clouding has been reported in inborn acid mucopolysaccharidosis, + congenital or infantile cataract with deranged metabolism of proteoglycans (acid + mucopolysaccharide-xylose-protein complex) is reported in children for the first time." +

+

+ "State of electrolytes, osmotic balance and the activity of ATPase in the lenses of selenite--induced + cataracts," Avarachan PJ; Rawal UM Indian J Ophthalmol, 1987, 35:5-6, 210-3. "Selenite-cataracts + incorporated many morphological characteristics observed in human senile catracts. Progressive elevation of + sodium, marked loss of potassium, several fold increment of calcium; considerable loss of magnesium + levels, + a dose-response reduction of total-ATPase activity and significant hydration are the important + features observed in the lens during the progressive treatment of selenite. The + sodium-potassium imbalance is found to be a secondary effect during the development of cataract and is + suggested to bring about by an abnormal accumulation of calcium ions and inactivation of + transport enzyme. The calcium activated proteases could be the promoting factor for the proteolysis and + insolubilization of lens proteins in the inducement of selenite cataract. The impact of selenite on the SH + containing ATPase anzymes could be the cause of impairment in energy metabolism, derangement of electrolytes + and osmotic imbalance which, in turn, accelerate the cortical involvement of lens opacities." +

+ +

+ "Glucose metabolism by human cataracts in culture," Wolfe JK; Chylack LT Jr Exp Eye Res 43:2, 243-9, 1986. + "Metabolism in human senile cataracts has been studied using uniformly labeled [14C]glucose. Intracapsularly + extracted lenses were cultured in TC-199 media with a glucose concentration of 5.5 mM. Results show that + lactate production accounts for 97% of the glucose metabolized. Under these standard incubation conditions + there is negligible accumulation of alpha-glycerol phosphate, glucose-6-phosphate, and sorbitol. The rate of + lactate production was found to be relatively uniform over a range of cataract severities which were + determined from the CCRG classification. The effects of several perturbants in the medium were + measured. + An ATP concentration of 3 mM was found to inhibit lactate production." + +

+

+ M. V. Riley, et al., "The roles of bicarbonate and CO2 in transendothelial fluid movement and control of + corneal thickness," Invest. Ophthalmol. Vis. Sci. 36(1), 103-112, 1995. "The equilibrium thickness + of deepithelialized corneas swollen with HCO-/CO2 on both surfaces was 35 microns less than that of + corneas swollen in HPO4-." "Normal corneal thickness can be maintained in vitro only in media that + contain HCO3- at concentrations of more than 20 mM." +

+ +

+ "The effect of X-irradiation on the sodium-potassium-activated adenosine triphosphatase (Na-K-ATPase) + activity in the epithelium of the rat lens. A histochemical and biochemical study," Palva M Acta Ophthalmol + (Copenh), 1978 Jun, 56:3, 431-8. "The epithelial Na-K-ATPase activity of the rat lens was studied after + X-irradiation at intervals of three to ninety days. The enzyme was demonstrated histochemically by light + microscopy and it was measured biochemically by a fluorometric method. Neither histochemical nor biochemical + changes of Na-K-ATPase content of the lens epithelium were observed during the development of cataract. In + whole-mount preparations the enzyme activity was localized in the cell membranes. However, one month after + radiation a few peripheral cells had in addition a precipitated over the whole cell. The unaltered + Na-K-ATPase + + content in the epithelium suggests that the hydration of the lens after X-irradiation is + primarily caused by changes in the passive permeability properties of the cell membranes and not by + a decreased capacity of the activity cation pump." + +

+

+ McNamara NA; Polse KA; Bonanno JA "Stromal acidosis modulates corneal swelling." + + Invest Ophthalmol Vis Sci, 1994 Mar, 35:3, 846-50 "PURPOSE. Studies have shown that stromal acidosis reduces + the rate of corneal thickness recovery after induced edema, providing the first human in vivo evidence that + corneal pH can influence corneal hydration control. This finding raises the question of the possible effect + that pH may have on induced corneal swelling. To explore this question, the corneal swelling response to + hypoxia was measured while stromal pH was controlled. METHODS. Corneal edema and stromal acidosis was + induced in ten subjects by passing a mixture of nitrogen and carbon dioxide gas across the eyes through + tight-fitting goggles. One eye of each subject received 100% N2, whereas the contralateral eye + received a mixture of 95% N2 and 5% CO2. Exposures of 95% N2 + 5% CO2 lower pH on average to 7.16 versus + 7.34 for 100% N2 alone. Before and after 2.5 hours of gas exposure, central corneal thickness + (CCT) was measured. RESULTS. Eyes exposed to the lower pH environment (eg, N2 + CO2) developed less + change in CCT compared to the eyes receiving N2 alone. Overall increase in CCT was 29.9 +/- 5.3 + microns for eyes exposed to the 95% N2 + 5% CO2 gas mixture, versus 37.1 +/- 4.8 microns for 100% N2 eyes (P < 0.0001). CONCLUSIONS. The corneal swelling response to hypoxia can be reduced by lowering + stromal pH. Because changes in corneal pH alone have not been found to alter steady-state CCT, it is + proposed that pH + + exerts its effect only under non-steady-state conditions (ie, corneal swelling and deswelling). This + suggests that acidosis may produce changes in the rate of lactate metabolism or alter + endothelial hydraulic conductivity." +

+ +

+ Buchberger W; Winkler R; Moser M; Rieger G, "Influence of iodide on cataractogenesis in Emory mice," + Ophthalmic Res, 1991, 23:6, 303-8. Cataract development was studied in two groups of Emory mice by + periodical biomicroscopic examinations (beginning at 5 weeks of age) and by a final evaluation of + water-soluble SH groups in the lenses. The experimental group was given 256 micrograms iodide/kg body weight + with the drinking water throughout the study. The untreated control group received tap water. Iodide + treatment induced a delay of cataract formation...." "A still significant difference in the + degree of cataract was also found between the two groups at week 47 of age. No difference was found in the + content of water-soluble SH groups. The results are discussed in relation to the known antioxidant + and .OH-scavenging effect of iodide and to the oxidative changes in the lens occurring during + progression of cataract development." +

+

+ "[The chemical nature of the fluorescing products accumulating in the lipids of the crystalline lenses of + mice with hereditary cataract]," Shvedova AA; Platonov ES; Polianskii NB; Babizhaev MA; Kagan VE Biull Eksp + Biol Med, 1987 Mar, 103:3, 301-4. + "The content of diene conjugates (lipid hydroperoxides) was shown to be significantly higher in lipids + extracted from the lenses of mice with hereditary cataract than in the controls. The same holds true for + characteristics of fluorescence of the end-product of lipid peroxidation." "It was established + that high-molecular weight fluorescent fractions corresponded to lipid components of + lipofuscin-like pigments. NMR and mass spectrometry of low-molecular weight fractions suggested + that they contained predominantly products of free radical oxidation of long chain polyunsaturated + fatty acids (C22:6). " +

+

+ "Formation of N'-formylkynurenine in proteins from lens and other sources by exposure to sunlight," Pirie A + Biochem J, 1971 Nov, 125:1, 203-8. +

+

+ "Lipid fluorophores of the human crystalline lens with cataract." Babizhayev MA Graefes Arch Clin Exp + Ophthalmol, 1989, 227:4, 384-91 "It has been established that the development of cataract is accompanied by + the formation of various fluorophores in the lipid fraction of the lens. These lipid-fluorescing products + have been separated chromatographically according to polarity and molecular weight. It is shown that the + initial stages of the development of cataract are characterized by the appearance of lipid fluorophores in + the near ultraviolet and violet regions of the spectrum (excitation maximum 302-330 nm, emission + maximum 411 nm) with low polarity and a small molecular weight; the maturing of the cataract + is + characterized by an increase in the intensity of the long-wave fluorescence of the lipids in the + blue-green region (430-480 nm) and by the formation of + + + polymeric high-molecular-weight fluorescing lipid products with high polarity. It has been demonstrated that + the appearance of lipid fluorophores in the crystalline lens is associated with the free radical + oxidative modification of the phospholipids and fatty acids in cataract." + +

+

+ "Incidence of cataracts in the mobile eye hospitals of Nepal," Brandt F; Malla OK; Pradhan YM; Prasad LN; + Rai NC; Pokharel RP; Lakhe S, Graefes Arch Clin Exp Ophthalmol, 1982, 218:1, 25-7 The incidence of cataract + in Nepal was determined from data collected in 14 mobile eye hospitals (called 'eye camps'). Of a total of + 12,217 patients examined in the out-patient department (OPD), cataract surgery was + performed on 2,163. The percentage of cataract patients in the OPD was less in the mountains (13.8%) + than in the Tarai plains (19.8%). + In the inhabitants of the mountains, the majority of whom belong to the Tibeto-Birman race, cataracts appeared at a significantly later age in both males and females compared to the people of the + plains, who are mostly Indo-Aryan. Cataracts were discovered in both groups at a younger age in + women than in men." +

+ +

+ "Associations among cataract prevalence, sunlight hours, and altitude in the Himalayas." Brilliant LB; + Grasset NC; Pokhrel RP; Kolstad A; Lepkowski JM; Brilliant GE; Hawks WN; Pararajasegaram R., Am J Epidemiol + 118:2, 250-64 1983. "The relationship between cataract prevalence, altitude, and sunlight hours was + investigated in a large national probability sample survey of 105 sites in the Himalayan + kingdom of Nepal, December 1980 through April 1981. Cataract of senile or unknown etiology was diagnosed by + ophthalmologists in 873 of 30,565 + full-time life-long residents of survey sites. Simultaneously, the altitude of sites was + measured using a standard mountain altimeter. Seasonally adjusted average daily duration of sunlight + exposure for each site was calculated by a method which took into account latitude and obstructions along + the skyline. Age- and sex-standardized cataract prevalence was 2.7 times higher in sites at an + altitude of 185 meters or less than in sites over 1000 meters. Cataract prevalence was negatively + correlated with altitude +

+

+

+ "The untenability of the sunlight hypothesis of cataractogenesis," Harding JJ Doc + Ophthalmol 88:3-4, 345-9, 1994-95. "The excess prevalence of cataract in third world countries led + early this century to the hypothesis that sunlight causes cataract. The hypothesis, which ignored + differences in diet, culture, poverty and prevalence of other diseases such as diarrhoea, + received little support until about thirty years ago when biochemical studies were set up to explore the + browning of lens proteins, which is a common feature of cataract on the Indian subcontinent. Initially these + studies were encouraging in that exposure to sunlight caused some changes seen in cataractous lenses, but + eventually the hypothesis was rejected because the first change in the laboratory was the destruction of + tryptophan, but this was not found in brown cataract lenses. A brown nuclear cataract could + not be produced artificially in the laboratory using sunlight or UV exposure. Exposure of laboratory animals + has produced lens opacities, but in most experiments the doses required have also caused keratitis, + conjunctivitis, iritis and inflammation. The cornea seems more sensitive than the lens, which is not + surprising, as it gets the first chance to absorb damaging UV. The biochemical rejection of the hypothesis + coincided with the re-start of the epidemiological studies. Most of these are simply latitude studies and + are no more than a repeat of what was available sixty years ago. They do not help to find a cause. Two studies showed that cataract was less common at higher altitude in the Himalayas, but unfortunately led + to opposing conclusions. On the basis of common knowledge that UV exposure was greater at + higher altitude, the first altitude study led to the rejection of the sunlight hypothesis." +

+

+ "Anticataract action of vitamin E: its estimation using an in vitro steroid cataract model," Ohta Y; Okada + H; Majima Y; Ishiguro I Ophthalmic Res, 1996, 28 Suppl 2:, 16-25 "The aim of this study was to estimate the + anticataract action of vitamin E using an in vitro methylprednisolone (MP)-induced cataract model. The same + severity of early cortical cataract was induced in lenses isolated from male Wistar rats aged 6 weeks by + incubation with MP (1.5 mg/ml) in TC-199 medium. The cataractous lenses showed slight increases in lipid + peroxide (LPO) content and Na+/K+ ratio and slight decreases in reduced glutathione (GSH) content and + glyceraldehyde-3-phosphate dehydrogenase (GAP-DH), a sensitive index of oxidative stress, and + Na+,K(+)-ATPase activities. When the cataractous lenses were further incubated in TC-199 medium with and + without vitamin E (250 micrograms/ml) for 48 h, the progression of cataract was prevented in the vitamin + E-treated lenses, but not in the vitamin E-untreated lenses. The vitamin E-untreated lenses showed a + decrease in vitamin E content and an increase in water content in addition to further increases in LPO + content and Na+/K+ ratio and further decreases in GSH content and GAP-DH and Na+,K(+)-ATPase activities. In + contrast, the changes of these components and enzymes except for GSH were attenuated in the vitamin + E-treated lenses. From these results, it can be estimated that vitamin E prevents in vitro cataractogenesis + in rat lenses treated with MP by protecting the lenses against oxidative damage and loss of membrane + function. " +

+

+ "Prevention of oxidative damage to rat lens by pyruvate in vitro: possible attenuation in vivo," Varma SD; + Ramachandran S; Devamanoharan PS; Morris SM; Ali AH,.Curr Eye Res, 1995 Aug, 14:8, 643-9 "Studies have been + conducted to assess the possible preventive effect of pyruvate against lens protein oxidation and consequent + denaturation and insolubilization. Rat lens organ culture system was used for these studies. The content of + water insoluble proteins (urea soluble) increased if the lenses were cultured in medium containing hydrogen + peroxide. Incorporation of pyruvate in the medium prevented such insolubilization. The insolubilization was + associated primarily with loss of gamma crystallin fraction of the soluble proteins. PAGE analysis + demonstrated that insolubilization is related to -S-S- bond formation which was preventable by pyruvate. + Since pyruvate is a normal tissue metabolite the findings are considered pathophysiologically significant + against cataract formation. This was apparent by the prevention of selenite cataract in vivo by + intraperitoneal administration of pyruvate." +

+ +

+ "Glucocorticoid-induced cataract in chick embryo monitored by Raman spectroscopy," Mizuno A; Nishigori H; + Iwatsuru M Invest Ophthalmol Vis Sci, 30:1, 132-7, 1989. "Glucocorticoid-induced cataract lens in chick + embryo was monitored by laser Raman spectroscopy. The lens opacity that appeared in chick embryo is a + reversible one. Raman spectra show no significant change in the relative content of water or secondary + structure of the proteins upon lens opacification. The intensity ratios of tyrosine doublet bands in Raman + spectra between clear and opaque lens portions are changes. + This change is reversible, + and is interpreted as a protein-water phase separation that occurred during lens + opacification." +

+

+ "[NMR study of the state of water in the human lens during cataract development]" Babizhaev MA; Deev AI; + Nikolaev GM, Biofizika 30:4, 671-4,1985. "Water proton spin-spin relaxation times (T2) and the content of + bound, "non-freezable" at -9 degrees C water in both normal human lenses and human lenses of different + stages of cataract progression (cataracta incipiens, nondum matura, mature hypermatura) were measured by NMR + spin echoes method. By the stage of cataracta nondum matura, increase of bound water content and + simultaneous, almost half decrease of the relaxation time (T2), were observed. However, on the following + stages of cataract evaluation (almost mature, mature cataracts) a gradual decrease of bound water + content is noted, + but only for the mature cataract stage the water content significantly differs from that of the + normal one. On the stage of hypermature cataract the presence of two unexchanged with each other fractions + of water is found. The obtained data are explained by lens protein reconstructions during the + cataract progression." +

+

+ Hightower KR; Reddy VN "Ca++-induced cataract." Invest Ophthalmol Vis Sci, 1982 Feb, 22:2, 263-7 "Cataracts + in cultured rabbit lenses were produced by elevation of internal calcium. Experimental procedures were + successful in increasing levels of total and bound Ca++, often without significant changes in sodium, + potassium, or water content. Although the excess in calcium was predominantly associated with water-soluble + proteins and was freely diffusible, a significant amount was bound to membranes and cytosol water-insoluble + proteins. Thus, in lenses with a 10-fold increase in total Ca++, the bound Ca++ increased twofold, nearly + 35% of which remained fixed to water-insoluble and membrane proteins after exhaustive (72 hr) dialysis. In + contrast, over 95% of the Ca++ in water-soluble protein fractions was removed by dialysis." +

+

+ [Use of pyrimidine bases and ATP for conservative treatment of early cataracts] Larionov LN Oftalmol Zh, + 1977, 32:3, 221-2. +

+

+ "Noninvasive measurements of pyridine nucleotide and flavoprotein in the lens," Tsubota K; Laing RA; Kenyon + KR Invest Ophthalmol Vis Sci 28:5, 785-9, 1987. "Abnormalities in glucose metabolism are thought to + be among the main causes of cataract formation. + + The authors have made noninvasive biochemical measurements of the lens that provide information concerning + glucose metabolism in the lens epithelium. The autofluorescence of reduced pyridine nucleotides (PN) and + oxidized flavoproteins (Fp) within the rabbit lens were noninvasively measured as a function of depth using + redox fluorometry. The peak of the autofluorescence at 440 nm (excited at 360 nm) and 540 nm (excited at 460 nm) were determined at the lens epithelium. When 8 mM sodium pentobarbital, a known + inhibitor of mitochondrial respiration, was applied to the lens, the autofluorescence peak at 440 nm + increased and that at 540 nm decreased. The 440 nm autofluorescence is thought to be from + + + reduced pyridine nucleotides, whereas the 540 nm autofluorescence is from the oxidized flavoprotein. + Blocking lens respiration with pentobarbital caused an increase in the PN/Fp ratio by a factor of 3 within + 3.5 hr after pentobarbital application." +

+

+

+ + high levels of L-lactate and high ratios of L-lactate in the lens/L-lactate in the aqueous. 2. + Immature cataractous lenses with anterior capsular/subcapsular opacity; intermediate levels of RTP, + intermediate values for the sums of RTP, RDP, and AMP, high L-lactate levels, and intermediate + values of the ratios of L-lactate in the lens/L-lactate in the aqueous." +

+

+ "Lipid fluorophores of the human crystalline lens with cataract," Babizhayev MA Graefes Arch Clin Exp + Ophthalmol, 1989, 227:4, 384-91. [Initial stages of cataracts are characterized by the fluorescence of the + products of fatty acid free radical oxidation.] +

+ +

© Ray Peat 2006. All Rights Reserved. www.RayPeat.com

+ + diff --git a/raypeat-articles/processed/tryptophan-serotonin-aging.html b/raypeat-articles/processed/tryptophan-serotonin-aging.html new file mode 100644 index 0000000..66d26b1 --- /dev/null +++ b/raypeat-articles/processed/tryptophan-serotonin-aging.html @@ -0,0 +1,989 @@ + + + +

+

+ + Tryptophan, serotonin, and aging +

+ +

+ Beginning with the industrial production of glutamic acid (sold as MSG, monosodium glutamate), the public + has been systematically misinformed about the effects of amino acids in the diet. The FDA has been + industry's powerful ally in misleading the public. Despite research that clearly showed that adults + assimilate whole proteins more effectively than free amino acids, much of the public has been led to believe + that "predigested" hydrolized protein and manufactured free amino acids are more easily assimilated than + real proteins, and that they are not toxic. Even if free amino acids could be produced industrially without + introducing toxins and allergens, they wouldn't be appropriate for nutritional use. +

+

+ Although some research shows that babies up to the age of 18 months can assimilate free amino acids, a baby + formula containing hydrolyzed protein was associated with decreased serum albumin, which suggests that it + interfered with protein synthesis. +

+

+ The myth that free amino acids are "natural nutritional substances" has been used to promote the use of many + products besides MSG, including aspartame, chelated minerals, and tryptophan. +

+

+ Although several amino acids can be acutely or chronically toxic, even lethal, when too much is eaten, + tryptophan is the only amino acid that is also carcinogenic. (It can also produce a variety of toxic + metabolites, and it is very susceptible to damage by radiation.) Since tryptophan is the precursor of + serotonin, the amount of tryptophan in the diet can have important effects on the way the organism responds + to stress, and the way it develops, adapts, and ages. +

+

+ When an inflammatory disease (eosinophilia-myalgia syndrome) was noticed in people using tryptophan tablets + (1989-90), there was an intense campaign to exonerate the tryptophan itself by blaming the reaction on an + impurity in one company's product. But the syndrome didn't occur only in the people who used that company's + product, and similar changes can be produced by a high-tryptophan diet (Gross, et al., 1999). +

+

+ There are people who advocate the use of tryptophan supplementation or other means to increase serotonin in + the tissues as a treatment for the fibromyalgia syndrome, but the evidence increasingly suggests that + excessive serotonin, interfering with muscle mitochondria, is a major factor in the development of that + syndrome. +

+ +

+ In 1965, Hans Selye showed that the injection of serotonin caused muscular dystrophy. Subsequent studies + suggest that serotonin excess is involved in both muscular and nervous dystrophy or degeneration. (O'Steen, + 1967; Narukami, et al., 1991; Hanna and Peat, 1989.) +

+

+ The fatigue produced by "over-training" is probably produced by a tryptophan and serotonin overload, + resulting from catabolism of muscle proteins and stress-induced increases in serotonin. Muscle catabolism + also releases a large amount of cysteine, and cysteine, methionine, and tryptophan suppress thyroid function + (Carvalho, et al., 2000). Stress also liberates free fatty acids from storage, and these fatty acids + increase the uptake of tryptophan into the brain, increasing the formation of serotonin. Since serotonin + increases ACTH and cortisol secretion, the catabolic state tends to be self-perpetuating. This process is + probably a factor influencing the rate of aging, and contributing to the physiological peculiarities of + aging and depression. +

+

+ Malnutrition, and specifically protein deficiency, produces an inflammatory state that involves extreme + serotonin dominance. Stress or malnutrition prenatally or in infancy leads to extreme serotonin dominance in + adulthood. Other functions of tryptophan are reduced, as more of it is turned into serotonin. +

+

+ Decreasing tryptophan or decreasing serotonin improves learning and alertness, while increased serotonin + impairs learning. +

+

+ Tryptophan is an essential amino acid for reproduction and growth of the young animal. Most research on the + nutritional requirements for amino acids has been done on farm animals, because of the economic incentive to + find the cheapest way to produce the fastest growth. Farmers aren't interested in the nutritional factors + that would produce the longest-lived pigs. Some research has been done on the amino acid requirements of + rats over a significant part of their short lifespans. In rats and farm animals, the amount of tryptophan + required decreases with time as the rate of growth slows. +

+

+ In some ways, rats never really mature, since they keep growing for nearly their whole lifespan. Their + growth stops just a short time before they die, which is usually around the age of two or three years. (At + this age, rats' cells still retain approximately the same high water content seen in the cells of a two + year-old child.) They usually become infertile about half-way through their lifespan. If we try to draw + conclusions about amino acid requirements from the rat studies, I think we would want to extrapolate the + curve for the decreasing need for tryptophan, far beyond the point seen during the rat's short life. And + those "requirements" were determined according to the amounts that produced a maximum rate of growth, using + the index of the pig farmers, as if the rats were being studied for possible use as meat. +

+ +

+ When rats were fed a diet completely lacking tryptophan for a short period, or a diet containing only one + fourth of the "normal" amount for a more prolonged period, the results were surprising: + They kept the ability to reproduce up to the age of 36 months (versus 17 months for the rats on the usual + diet), and both their average longevity and their maximum longevity increased significantly. They looked and + acted like younger rats. (A methionine-poor diet also has dramatic longevity-increasing effects.) +

+

+ On the tryptophan-poor diet, the amount of serotonin in the brain decreased. When brain serotonin decreases, + the level of testosterone in male animals increases. More than 20 years ago, a chemical + (p-chlorophenylalanine) that inhibits serotonin synthesis was found to tremendously increase libido. +

+

+ In old age, the amount of serotonin in the brain increases. This undoubtedly is closely related to the + relative inability to turn off cortisol production that is characteristic of old age (Sapolsky and Donnelly, + 1985). Hypothyroidism increases the formation of serotonin, as does cortisol (Henley, et al., 1997, 1998; + Neckers and Sze, 1976). +

+

+ In white hair, the amount of tryptophan is higher than in hair of any other color. Although serotonin and + tryptophan are very important during rapid growth, their presence in senile tissues is probably closely + associated with the processes of decline. The hair loss that occurs in hypothyroidism, postpartum syndrome, + and with the use of drugs such as St. John's wort (which can also cause the "serotonin syndrome") could be + another effect of excess serotonin. +

+

+ Serotonin stimulates cell division and tends to increase the formation of connective tissue, so its + formation should be closely regulated once full growth is achieved. It contributes to the age- or + stress-related thickening of blood vessels, and other fibrotic processes that impair organ function. +

+

+ The metabolic rate (eating more without gaining extra weight) and ability to regulate body temperature are + increased by early tryptophan deprivation. (Ashley and Curzon, 1981; Segall and Timiras, 1975.) The ability + to oxidize sugar is impaired by serotonin, and several drugs with antiserotonin actions are being used to + treat diabetes and its complications, such as hypertension, obesity, and foot ulcers. +

+

+ An excess of tryptophan early in life, stress, or malnutrition, activates the system for converting + tryptophan into serotonin, and that tendency persists into adulthood, modifying pituitary function, and + increasing the incidence of pituitary and other cancers. +

+ +

+ Serotonin's contribution to high blood pressure is well established. It activates the adrenal cortex both + directly and through activation of the pituitary. It stimulates the production of both cortisol and + aldosterone. It also activates aldosterone secretion by way of the renin-angiotensin system. Angiotensin is + an important promoter of inflammation, and contributes to the degeneration of blood vessels with aging and + stress. It can also promote estrogen production. +

+

+ In the traditional diet, rather than just eating muscle meats, all the animal parts were used. Since + collagen makes up about 50% of the protein in an animal, and is free of tryptophan, this means that people + were getting about half as much tryptophan in proportion to other amino acids when they used foods such as + "head cheese," ox-tails, and chicken feet. +

+

+ While some of the toxic effects of an excess of individual amino acids have been investigated, and some of + the protective or harmful interactions resulting from changing the ratios of the amino acids have been + observed, the fact that there are about 20 amino acids in our normal diet means that there is an enormous + number of possibilities for harmful or beneficial interactions. +

+

+ The optimal quantity of protein in the diet has traditionally been treated as if it were a matter that could + be resolved just by observing the rate of growth when a certain protein is given in certain quantities, + along with "standard amounts" of calories and other nutrients. This kind of research has been useful to + farmers who want to find the cheapest foods that will produce the biggest animals in the shortest time. But + that kind of research climate has spread a degraded concept of nutrition into the culture at large, + influencing medical ideas of nutrition, the attitudes of consumers, and the policies of governmental + regulatory agencies. +

+

+ When synthetic amino acids are used to supplement natural proteins, they are usually chosen according to + irrelevant models of the "ideal protein's" composition, and many toxic contaminants are invariably present + in the synthetic free amino acids. +

+

+ For the present, the important thing is to avoid the use of the least appropriate food products, while + choosing natural foods that have historical, epidemiological, and biochemical justification. +

+

+ Whey has been promoted as a protein supplement, but it contains a slightly higher proportion of tryptophan + than milk does. Cheese (milk with the whey removed) contains less tryptophan. Some people have been + encouraged to eat only the whites of eggs, "to avoid cholesterol," but the egg albumin is rich in + tryptophan. +

+ +

+ The expensive tender cuts of meat contain excessive amounts of cysteine and tryptophan, but bone broth + (gelatin) and the tougher cuts of meat contain more gelatin, which lacks those amino acids. Many fruits are + deficient in tryptophan, yet have very significant quantities of the other amino acids. They also contain + some of the "carbon skeleton" (keto-acid) equivalents of the essential amino acids, which can be converted + to protein in the body. +

+

+ Serotonin excess produces a broad range of harmful effects: Cancer, inflammation, fibrosis, + neurological damage, shock, bronchoconstriction, and hypertension, for example. Increased serotonin impairs + learning, serotonin antagonists improve it. +

+

+ The simplest, nonessential, amino acid, glycine, has been found to protect against carcinogenesis, + inflammation, fibrosis, neurological damage, shock, asthma, and hypertension. Increased glycine improves + learning (Handlemann, et al., 1989; File, et al., 1999), glycine antagonists usually impair it. Its + antitoxic and cytoprotective actions are remarkable. Collagen, besides being free of tryptophan, contains a + large amount of glycine--32% of its amino acid units, 22% of its weight. +

+

+ The varied antiinflammatory and protective effects of glycine can be thought of as an antiserotonin action. + For example, serotonin increases the formation of TNF (tumor necrosis factor, also called cachectin), + glycine inhibits it. In some situations, glycine is known to suppress the formation of serotonin. + Antagonists of serotonin can potentiate glycine's effects (Chesnoy-Marchais, et al., 2000). + People who ate traditional diets, besides getting a lower concentration of tryptophan, were getting a large + amount of glycine in their gelatin-rich diet. +

+

+ Gelatin, besides being a good source of glycine, also contains a large amount of proline, which has some + antiexcitatory properties similar to glycine. +

+ +

+ If a half-pound of steak is eaten, it would probably be reasonable to have about 20 grams of gelatin at + approximately the same time. Even a higher ratio of gelatin to muscle meat might be preferable. +

+

+ Carbon dioxide, high altitude, thyroid, progesterone, caffeine, aspirin, and decreased tryptophan + consumption protect against excessive serotonin release. When sodium intake is restricted, there is a sharp + increase in serotonin secretion. This accounts for some of the antiinflammatory and diuretic effects of + increased sodium consumption--increasing sodium lowers both serotonin and adrenalin. +

+

+ The polyunsaturated oils interact closely with serotonin and tryptophan, and the short and medium chain + saturated fatty acids have antihistamine and antiserotonin actions. Serotonin liberates free fatty acids + from the tissues, especially the polyunsaturated fats, and these in turn liberate serotonin from cells such + as the platelets, and liberate tryptophan from serum albumin, increasing its uptake and the formation of + serotonin in the brain. Saturated fats don't liberate serotonin, and some of them, such as capric acid found + in coconut oil, relax blood vessels, while linoleic acid constricts blood vessels and promotes hypertension. + Stress, exercise, and darkness, increase the release of free fatty acids, and so promote the liberation of + tryptophan and formation of serotonin. Increased serum linoleic acid is specifically associated with + serotonin-dependent disorders such as migraine. +

+

+ Coconut oil, because of its saturated fatty acids of varied chain length, and its low linoleic acid content, + should be considered as part of a protective diet. +

+

+ In the collagen theory of aging, it is argued that changes in the extracellular matrix are responsible for + isolating cells from their environment, reducing the availability of nutrients and oxygen, and reducing + their ability to send and receive the chemical signals that are needed for correct adaptive functioning. +

+

+ In diabetes, basement membranes are thickened, and in a given volume of tissue there are fewer capillaries. + This effect probably involves excessive serotonin + (Kasho, et al., 1998). Old animals contain a higher proportion of collagen. Old tendons (or tendons that + have been exposed to excessive estrogen, which stimulates the formation of collagen) are more rigid, and + behave almost as if they have been partly cooked. In diseases such as carcinoid, in which very large amounts + of serotonin are released systemically, fibrosis is exaggerated, and may be the direct cause of death. + Radiation and oxygen deprivation also lead to increased tissue fibrosis. +

+

+ In specific fibrotic conditions, such as cirrhosis of the liver, it is known that glycine and saturated fats + can reverse the fibrosis. In fibrosis of the heart, thyroid hormone is sometimes able to reverse the + condition. +

+ +

+ I think these facts imply that excessive tryptophan, estrogen, and polyunsaturated fats contribute + significantly, maybe decisively, to the degenerative changes that occur in aging. Experiments have + separately shown that reducing dietary tryptophan or unsaturated fats can extend the healthy lifespan, and + several antiestrogenic interventions (removal of the pituitary, or supplementing with progesterone) can slow + age-related changes and delay degenerative diseases. Since these factors interact, each tending to promote + the others, and also interact with exogenous toxins, excess iron accumulation, and other stressors, it would + be reasonable to expect greater results when several of the problems are corrected at the same time. +

+

REFERENCES

+

+ Toxicol Pathol 1998 May-Jun;26(3):395-402. + Glycine modulates the toxicity of benzyl acetate in F344 rats. Abdo KM, Wenk ML, Harry GJ, + Mahler J, Goehl TJ, Irwin RD. "These results suggest that the neurodegeneration induced by BA is mediated by + a depletion of the glycine pool and the subsequent excitotoxicity." +

+

+ Res Clin Stud Headache 1978;6:110-6. + Role of individual free fatty acids in migraine. + + Anthony M "Total plasma free fatty acids, platelet serotonin content and plasma stearic, palmitic, oleic and + linoleic acids were estimated in 10 migraine patients before, during and after a migraine attack. Total and + individual plasma free fatty acid levels rose and platelet serotonin content fell in most patients. The highest rise was observed in linoleic acid, which is known to be a potent liberator of platelet + serotonin in vitro and is the only precursor of all prostaglandins in the body. It is suggested + that the rise in plasma levels of + linoleic acid in migraine could be responsible for the platelet serotonin release observed during the + attack." +

+ +

+ Clin Exp Neurol 1978;15:190-6. + Individual free fatty acids and migraine. Anthony M Total plasma free fatty acids (FFAs), + platelet serotonin content and plasma stearic, palmitic, oleic and linoleic acids were estimated in 10 + migrainous patients before, during and after a migraine attack. Total and individual plasma FFA levels rose + and platelet serotonin fell in most patients. Comparison of the pre-headache and headache mean values showed + that of the FFAs linoleic acid rises most during headache. 10 non-migrainous controls had platelet + serotonin content estimated before and after the ingestion of 20g linoleic acid. All showed a + significant fall in platelet serotonin in the post-ingestion period. It is shown that linoleic acid + releases platelet serotonin in vitro, and this study suggests that it has the same action in + vivo. Further, it is the precursor of all prostaglandins in the body and its marked elevation + during migraine may serve as a source of increased prostaglandin E1 (PGE1) synthesis. It is + suggested that linoleic acid plays an important role in the biochemical process of the migraine attack, + acting both as a serotonin releasing factor and a source of PGF1, the vasodilating action of + which can aggravate the clinical symptoms of migraine. +

+

+ J Appl Physiol 1993 Jun;74(6):3006-12. + Neuroendocrine and substrate responses to altered brain 5-HT activity during prolonged exercise to + fatigue. Bailey SP, Davis JM, Ahlborn EN. "Pharmacological manipulation of brain serotonergic + [5-hydroxytryptamine (5-HT)] activity affects run time to exhaustion in the rat. These effects may be + mediated by neurochemical, hormonal, or substrate mechanisms. Groups of rats were decapitated during rest, + after 1 h of treadmill running (20 m/min, 5% grade), and at exhaustion. Immediately before exercise rats + were injected intraperitoneally with 1 mg/kg of quipazine dimaleate (QD; a 5-HT agonist), 1.5 mg/kg of LY + 53857 (LY; a 5-HT antagonist), or the vehicle (V; 0.9% saline). LY increased and QD decreased time to + exhaustion (approximately 28 and 32%, respectively; P < 0.05)." "Brain 5-HT and 5-hydroxyindole-3-acetic + acid + concentrations were higher at 1 h of exercise than at rest (P < 0.05), and the latter increased even + further at fatigue in the midbrain and striatum (P < + + 0.05)." +

+

+ Neurochem Int 1993 Sep;23(3):269-83. + Glutamate, GABA, glycine and taurine modulate serotonin synthesis and release in rostral and caudal + rhombencephalic raphe cells in primary cultures. Becquet D, Hery M, Francois-Bellan AM, Giraud + P, Deprez P, Faudon M, Fache MP, Hery F. +

+

+ Acta Physiol Scand 2001 Oct;173(2):223-30. + Exercise-induced changes in brain glucose and serotonin revealed by microdialysis in rat hippocampus: + effect of glucose supplementation. + Bequet F, Gomez-Merino D, Berthelot M, Guezennec CY. +

+

+ Amino Acids 2001;20(1):25-34. Amino acids and central fatigue. Blomstrand E. "There is an + increasing interest in the mechanisms behind central fatigue, particularly in relation to changes in brain + monoamine metabolism and the influence of specific amino acids on fatigue." "When the 5-HT level was + elevated in this way the performance was impaired in both rats and human subjects, and in accordance + with this a decrease in the 5-HT level caused an improvement in running performance in rats. The + precursor of 5-HT is the amino acid tryptophan and the synthesis of 5-HT in the brain is thought to be + regulated by the blood supply of free tryptophan in relation to other large neutral amino acids + (including the branched-chain amino acids, BCAA) since these compete with tryptophan for transport into the + brain." +

+ +

+ J Neurol Sci 1988 Apr;84(2-3):239-46. + Increased platelet aggregation and release reaction in myotonic dystrophy. + Bornstein NM, Zahavi M, Korczyn AD, Zahavi J. +

+

+ Curr Med Chem 2001 Sep;8(11):1257-74. + The inhibitory neural circuitry as target of antiepileptic drugs. + Bohme I, Luddens H. "Impairments and defects in the inhibitory neurotransmission in the CNS can contribute + to various seizure disorders, i.e., gamma-aminobutyric acid (GABA) and glycine as the main inhibitory + neurotransmitters in the brain play a crucial role in some forms of epilepsy." +

+

+ Braz J Med Biol Res 2000 Mar;33(3):355-61. + Thyroid peroxidase activity is inhibited by amino acids. Carvalho DP, Ferreira AC, Coelho SM, + Moraes JM, Camacho MA, Rosenthal D +

+ +

+ Q J Exp Psychol B 2000 Aug;53(3):225-38. + Rapid visual learning in the rat: effects at the 5-HT1a receptor subtype. + Cassaday HJ, Simpson EL, Gaffan EA. "The 5-hydroxytryptamine1a (5-HT1a) receptor agonist + 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 0.15 mg/kg) impaired rats' rapid visual learning on + a computerized maze. This treatment also increased decision time (DT) but the learning impairment was + not necessarily a side-effect of slower responding because, in this task, responses made at long DT are + more accurate than those at short DT." "Its reversal with WAY-100635 offers support to the + hypothesis that 5-HT1a receptor antagonists could improve cognitive function, under conditions of + pre-existing impairment due to overactive serotonergic inhibition, as is thought to occur in Alzheimer's + disease." +

+

+ Med Sci Sports Exerc 1997 Jan;29(1):58-62. + Effects of acute physical exercise on central serotonergic systems. + "This paper reviews data concerning the effects of acute physical exercise (treadmill running) in trained + rats. Works from the 1980's have established that + acute running increases brain serotonin (5-hydroxytryptamine: 5-HT) synthesis in two ways. + Lipolysis-elicited release of free fatty acids in the blood compartment displaces the binding of the + essential amino acid tryptophan to albumin, thereby increasing the concentration of the so-called "free + tryptophan" portion, and because exercise increases the ratio of circulating free tryptophan to the sum + of the concentrations of the amino acids that compete with tryptophan for uptake at the + blood-brain barrier level, tryptophan enters markedly in the brain compartment. However, this marked + increase in central tryptophan levels increases only to a low extent brain 5-HT synthesis, as assessed by + the analysis of 5-hydroxyindoleacetic acid levels, thereby suggesting that exercise promotes feedback + regulatory mechanisms. Indirect indices of 5-HT functions open the + possibility that acute exercise-induced increases in 5-HT biosynthesis are associated with (or lead to) + increases in 5-HT release." +

+ +

+ Int J Dev Neurosci 1997 Apr;15(2):257-63. + Postnatal changes of brain monoamine levels in prenatally malnourished and control rats. Chen + JC, Turiak G, Galler J, Volicer L. +

+

+ Eur J Pharmacol 2000 Aug 25;402(3):205-13. + Glycinergic potentiation by some 5-HT(3) receptor antagonists: insight into + selectivity. Chesnoy-Marchais D, Levi S, Acher F. +

+

+ Mech Ageing Dev 1986 Oct;36(2):161-71. + Influence of low tryptophan diet on survival and organ growth in mice. + + De Marte ML, Enesco HE. Greater survival and reduced growth were found to characterize mice on a tryptophan + deficient diet as compared to fully fed control mice. The 50% survival point was reached by the tryptophan + restricted group at 683 days, and by the control group at 616 days. Measurements of body weight, organ + weight, and DNA level were made at 8, 12, 24, 36, 52 and 78 weeks of age. Both whole body weight and organ + weight of liver, kidney, heart and spleen were about 30% lower in the tryptophan restricted group as + compared to the controls, so that the ratio of organ weight to body weight remained at a constant value for + both groups. There was no significant change in cell number as determined by DNA measurements, as a result + of the tryptophan restriction. +

+

+ J Clin Psychopharmacol 1999 Dec;19(6):506-12. + Beneficial effects of glycine (bioglycin) on memory and attention in young and middle-aged + adults. File SE, Fluck E, Fernandes C. ."The effects of Bioglycin(Konapharma, Pratteln, + Switzerland), a biologically active form of the amino acid glycine, were . . . studied in healthy students + (mean age, 20.7 years) and middle-aged men (mean age, 58.9 years) with tests that measured attention, memory + and mood, using a double-blind, randomized, crossover design. Compared with the young group, the middle-aged + group had significantly poorer verbal episodic memory, focused, divided, and sustained attention; they also + differed in their subjective responses at the end of testing. Bioglycin significantly improved retrieval + from episodic memory in both the young and the middle-aged groups, but it did not affect focused or divided + attention. However, the middle-aged men significantly benefited from Bioglycin in the sustained-attention + task. The effects of Bioglycin differed from those of other cognitive enhancers in that it was without + stimulant properties or significant effects on mood, and it primarily improved memory rather than attention. + It is likely to be of benefit in young or older people in situations where high retrieval of information is + needed or when performance is impaired by jet lag, shift work, or disrupted sleep. It may also benefit the + impaired retrieval shown in patients with schizophrenia, Parkinson's disease, and Huntington's disease. +

+

+ Brain Res 1997 Sep 12;768(1-2):43-8. + Mobilization of arachidonate and docosahexaenoate by stimulation of the 5-HT2A receptor in rat C6 glioma + cells. Garcia MC, Kim HY Laboratory of Membrane Biochemistry and Biophysics, National Institute + on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD 20852, USA. + "In this study, we demonstrate that astroglial 5-HT2A receptors are linked to the mobilization of + polyunsaturated fatty acids (PUFA). Stimulation of C6 glioma cells, prelabeled with + [3H]arachidonate (AA, 20:4n6) and [14C]docosahexaenoate (DHA, 22:6n3), with serotonin and the 5-HT(2A/2C) + receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) resulted in the mobilization of + both [3H] and [14C] into the supernatant of the cell monolayers. The increased radioactivity in the + supernatant was mainly associated with free fatty acids." "These results indicate that the 5-HT2A receptor + is coupled to the mobilization of PUFA." +

+ +

+ Neurosci Lett 1995 May 5;190(2):143-5. + Serotonin involvement in the spontaneous alternation ability: a behavioral study in + tryptophan-restricted rats. Gonzalez-Burgos I, Olvera-Cortes E, Del Angel-Meza AR, + Feria-Velasco A. Laboratorio de Psicobiologia, Centro de Investigacion Biomedica de Occidente, IMSS, + Guadalajara, Jal., Mexico. Spontaneous alternation (SA) is controlled by septal cholinergic terminals in the + hippocampus. Serotoninergic terminals end on cholinergic nerve endings in the hippocampus, and their + possible role in SA was investigated in rats fed with a tryptophan-deficient diet, from weaning to 60 days + of age. A T-maze was used for the test. At the age of 40 days, an increase in SA occurred in the + tryptophan deficient rats, + + although this effect disappeared by 60 days of age. A modulatory role of serotonin in the psychoneural + control of SA is suggested, and it may be through presynaptic inhibition of hippocampal cholinergic + terminals. +

+

+ Physiol Behav 1998 Jan;63(2):165-9. + Effect of tryptophan restriction on short-term memory. Gonzalez-Burgos I, Perez-Vega MI, Del + Angel-Meza + AR, Feria-Velasco A. Centro de Investigacion Biomedica de Michoacan, Instituto Mexicano del Seguro Social, + Morelia. Several brain regions are involved in the learning process that is integrated from sensorial + inputs. It is thereafter consolidated in short- (STM) or long-term memory. Serotonin is strongly related to + both types of memory, and particularly, to STM, however, its regulatory role is still unclear. In this + study, the effects of tryptophan (TRY) restriction on learning and STM were evaluated. Ten Sprague-Dawley + female rats were fed with a TRY-restricted diet (0.15g/100g) starting from postnatal Day 21. At 21, 40, and + 60 days of age, 5 trials per animal were carried out in a "hard-floor"-Biel maze, after 24 h of water + abstinence. The number of errors per trial were registered before reaching + + the goal. + At both 40 and 60 days, experimental rats committed less errors than controls. Likewise, the + TRY-restricted group learned the task from the second trial on, whereas controls did not solve it until + the third trial. + TRY restriction, and therefore brain serotonin reduction, could impair normal cholinergic activity + in some areas such as the hippocampus and the cerebral cortex, where involvement in learning and memory is + well documented. Morphological and neurochemical plastic events could also be related to the more efficient + performance of the task by the TRY-restricted rats. +

+

+ Am J Physiol 1997 Jul;273(1 Pt 2):R324-30. + Mechanisms in the pressor effects of hepatic portal venous fatty acid infusion. Grekin RJ, + Dumont CJ, Vollmer AP, Watts SW, Webb RC Portal venous infusion of oleate solution has pressor effects. We + have examined efferent mechanisms, measured the response to sustained infusion, and determined the effect of + linoleate. Eight conscious animals received concurrent infusions of prazosin or vehicle with portal venous + infusion of oleate. Oleate alone

+
+
+

+ +

+ Adv Exp Med Biol 1999;467:507-16. + Tryptophan toxicity--time and dose response in rats. Gross B, Ronen N, Honigman S, Livne E. + "During the past decade L-tryptophan (Trp) ingestion have been associated with a multisystemic syndrome, + known as eosinophilia myalgia syndrome (EMS). Even though an epidemic studies indicated that a contaminant, + 1,1'-ethylidene-bis-L-tryptophan was involved in EMS, abnormalities in metabolism of Trp have been + reported in other similar clinical syndromes such as carcinoid syndrome, scleroderma or eosinophilic + fasciitis." + "Increased amounts of connective tissue + and induction of inflammatory cell proliferation were observed in lung, spleen and in gastrocnemia + muscle of rats treated with higher dose of Trp for longer period. Induction of kynurenine + pathway by injection of p-CPA caused more tissue damage. It is concluded that excessive Trp or elevation of + its metabolites could play a role in amplifying some of pathological features of EMS. This pathological + damage is further augmented by metabolites of the kynurenine pathway." +

+

+ Zh Nevrol Psikhiatr Im S S Korsakova 1999;99(2):12-20. [Neuroprotective effects of glycine in the + acute period of ischemic stroke.] [Article in Russian] Gusev EI, Skvortsova VI, Komissarova IA, + Dambinova SA, Raevskii KS, Alekseev AA, Bashkatova VG, Kovalenko AV, Kudrin VS, Iakovleva EV. +

+ +

+ Pharmacol Biochem Behav 1989 Dec;34(4):823-8. + Milacemide, a glycine prodrug, enhances performance of learning tasks in normal and amnestic + rodents. Handelmann GE, Nevins ME, Mueller LL, Arnolde SM, Cordi AA. "Increasing glycine + concentrations in the brain by administration of a glycine prodrug, milacemide, is shown here to enhance + performance of a shock-motivated passive avoidance task in rats, and to reverse drug-induced amnesia in a + spontaneous alternation paradigm in mice." "These studies indicate a role of glycinergic neurotransmission + in memory processes, and support the therapeutic potential of glycinergic drugs in memory impairment." +

+

+ Pain 1989 Aug;38(2):145-50. + Ketanserin in reflex sympathetic dystrophy. A double-blind placebo controlled cross-over trial. + Hanna MH, Peat SJ. +

+

+ Synapse 1997 Sep;27(1):36-44. Thyroid hormones and the treatment of depression: an examination of + basic hormonal actions in the mature mammalian brain. + + Henley WN, Koehnle TJ. "The lack of mechanistic insight reflects, in large part, + a longstanding bias that the mature mammalian central nervous system is not an important target site for + thyroid hormones." +

+ +

+ Am J Physiol 1997 Feb;272(2 Pt 2):H894-903. + Hypothyroid-induced changes in autonomic control have a central serotonergic component. + Henley WN, Vladic F. Three experiments were conducted in unanesthetized rats made hypothyroid + (Hypo) or maintained as euthyroid controls (Eu) to examine general cardiovascular responsiveness [experiment + I (Exp I)]; responsiveness to a serotonin (5-HT2) agonist, dl-2,5-dimethoxy-4-iodoamphetamine [DOI + intracerebroventricularly; experiment II (Exp II)]; or responsiveness to a 5-HT(1A) agonist + dl-8-hydroxydipropyl-aminotetralin hydrobromide [8-OH-DPAT intracerebroventricularly; experiment III (Exp + III)]. In Exp I, intravenous infusions of phenylephrine and nitroprusside provided little evidence that + findings in Exp II and III were caused by generalized impairment in cardiovascular responsiveness in Hypo. + In Exp II and III, Eu and Hypo were given either intra-arterial atropine or vehicle. Atropine significantly + elevated heart rate (Exp II and III) and mean arterial pressure (Exp II) in Eu only. When compared with Eu, + Hypo had a reduced pressor response (5.2 vs. 20.1%), an attenuated pulse pressure response (19.3 vs. 35.4%), + and a more robust bradycardia (-17.7 vs. -7.0%) in response to DOI. These differences were atropine + sensitive. In Exp III, Hypo had larger decrements in mean arterial pressure (-9.0 vs. -5.1%), heart rate ( + -13.9 vs. - 7.7%), and body temperature (-4.5 vs. -2.7%) in response to 8-OH-DPAT in comparison to Eu. + Parasympathetic involvement in the differential responses to 8-OH-DPAT was less clear than with DOI. + Deranged autonomic control in hypothyroidism may be caused, in part, by changes in central serotonergic + activity. +

+

+ Brain Res 1986 Mar;390(2):221-6. + Brain serotonin synthesis and Na+,K+-ATPase activity are increased postnatally after prenatal + administration of L-tryptophan. Hernandez-Rodriguez J, Chagoya G. The effect of prenatal + L-tryptophan supplementation on the serotonin (5-HT) synthesis and the activity of Na+,K+-ATPase in the + cerebral cortex was studied during postnatal development, from birth up to day 30. A parallel and + significant elevation of the serotonin content and the activity of tryptophan-5-hydroxylase was observed + in the brain of infant rats born to mothers treated with L-tryptophan, as related to non-treated + controls. The activity of Na+,K+-ATPase was also significantly elevated at the different ages + studied throughout the developmental period, as related to controls. These results suggest an important role + of L-tryptophan in the early regulation of the + serotonin-synthesizing machinery, which lasts postnatally. Elevation of ATPase activity seems to be + associated to the elevation in the activity of the 5-HT system. +

+

+ Brain Res 1977 Mar 4;123(1):137-45. + Daily variations of various parameters of serotonin metabolism in the rat brain. II. Circadian + variations in serum and cerebral tryptophan levels: lack of correlation with 5-HT turnover. + Hery F, Chouvet G, Kan JP, Pujol JF, Glowinski J "Significant circadian variations in 5-HT and 5-HIAA levels + were found in cerebral tissues." "Important significant circadian variations in free and total serum + tryptophan levels were also observed. In both cases, the maximal levels were found during the middle of the + dark phase after the peak of 5-HIAA levels." "The diurnal changes in tryptophan content in cerebral tissues + seemed thus related to those found in serum." +

+

+ Kidney Int 1998 Oct;54(4):1083-92. + Serotonin enhances the production of type IV collagen by human mesangial cells. Kasho M, Sakai + M, Sasahara T, Anami Y, Matsumura T, Takemura T, Matsuda H, Kobori S, Shichiri M. +

+

+ Pharmacol Biochem Behav 1977 Sep;7(3):245-52. + Fatty acid and tryptophan changes on disturbing groups of rats and caging them singly. Knott + PJ, Hutson PH, Curzon G The effects of disturbing groups of 24 hr fasted rats on plasma unesterified fatty + acid (UFA) and tryptophan concentrations and brain tryptophan concentrations were investigated. Removing + rats from cages rapidly increased plasma UFA and corticosterone and decreased plasma and whole blood + tryptophan of cage mates. The disturbance also appeared to influence biochemical values of rats in other + cages within the same chamber. Effects specific to individual cages were also suggested. In subsequent + experiments 24 fasting rats caged together were rapidly transferred to 24 separate cages and killed at + intervals. Plasma UFA rose to a maximum by 12 min and then fell toward initial values. Plasma total + tryptophan concurrently fell then rose. Its percentage in the free (ultrafilterable) state, and in some + experiments the absolute values of free tryptophan rose then fell. When the latter rise was marked then brain tryptophan and the 5-HT metabolite 5-hydroxyindoleacetic acid rose. Tyrosine changes + were negligible. Thus altered brain tryptophan level and 5-HT metabolism may be associated with plasma + tryptophan changes caused by brief environmental disturbance. +

+ +

+ J Insect Physiol 2000 May 1;46(5):793-801. + Effect of an amino acid on feeding preferences and learning behavior in the honey bee, Apis + mellifera. Kim YS, Smith BH. "Subjects preferred to feed on a sucrose stimulus that + contained glycine, and the highest relative preference was recorded for the highest concentration of + glycine." "All concentrations of glycine enhanced the rate and magnitude of a + conditioned response to an odor . . . ." +

+

+ Eur J Pharmacol 1981 May 22;71(4):495-8. + Antagonism of L-glycine to seizures induced by L-kynurenine, quinolinic acid and strychnine in + mice. Lapin IP. +

+

+ Int J Circumpolar Health 1998;57 Suppl 1:386-8. Seasonal variation of the amino acid, L-tryptophan, + in interior Alaska. Levine ME, Duffy LK. "The seasonal pattern of L-tryptophan was studied in a + Fairbanks, Alaska, population that was unadapted to the extreme light variations of the North. Previously, + this population was shown to exhibit seasonal behavior effects such as increases in fatigue and sleep + duration, as well as endocrine effects such as increases in melatonin levels and phase shifting." "Prominent + results included finding increased levels in the winter at several different diurnal time points. These + findings support hypotheses which relate underlying physiological adaptations to the North to the increased + incidence of behavioral disorders such as depression and alcoholism." +

+ +

+ Infect Immun 2001 Sep;69(9):5883-91. + Dietary glycine prevents peptidoglycan polysaccharide-induced reactive arthritis in the rat: role for + glycine-gated chloride channel. Li X, Bradford BU, Wheeler MD, Stimpson SA, Pink HM, Brodie TA, + Schwab JH, Thurman RG. +

+

+ J Neurol Sci 1989 Jan;89(1):27-35. + Polyamine biosynthetic decarboxylases in muscles of rats with different experimental myopathies. Lorenzini EC, Colombo B, Ferioli ME, Scalabrino G, Canal N. +

+

+ Int J Dev Neurosci 1996 Aug;14(5):641-8. + Nutritional recovery does not reverse the activation of brain serotonin synthesis in the ontogenetically + malnourished rat. Manjarrez GG, Magdaleno VM, Chagoya G, Hernandez J Coordinacion de + Investigacion Biomedica del Centro Medico Nacional, I.M.S.S. Mexico, D.F. In the present work we confirm + that gestational malnutrition effects body and brain composition and results in an activation of the + synthesis of the brain neurotransmitter 5-hydroxytryptamine. These results also demonstrate more activity of + the rate-limiting enzyme tryptophan hydroxylase in the malnourished fetal and postnatal brain. However, the + activity of this enzyme remains increased in the brain of nutritionally recovered animals accompanied by an + increase in the synthesis of 5-hydroxytryptamine. We therefore suggest that, in the nutritionally recovered + animal, the mechanism of activation of this biosynthetic path in the brain may be not dependent on the + increased + availability of free L-tryptophan observed in malnourished animals, but might be due to a specific + change in the enzyme complex itself. This hypothesis is supported by the fact that plasma free + and brain L-tryptophan return to normal in the recovered animal. +

+ +

+ Brain Res 1997 Nov 7;774(1-2):265-8. + Tryptophan ingestion by gestant mothers alters prolactin and luteinizing hormone release in the adult + male offspring. Martin L, Rodriguez Diaz M, Santana-Herrera C, Milena A, Santana C. +

+

+ Rev Esp Fisiol 1984 Jun;40(2):213-9. + [Lipolytic effect of serotonin in vitro]. [Article in Spanish] Martinez-Conde A, Mayor de la + Torre P, Tamarit-Torres J The lipolytic action of serotonin on isolated adipocytes from the adipose tissue + of rats has been studied. The adipocytes were incubated in serotonin 10(-6) M. Changes both in concentration + and composition of the free intra and extracellular fatty acids as well as diacylglycerides through liquid + gas chromatography were evaluated at different intervals. A lower concentration of + free fatty acids and diacylglycerides is produced during the first minutes of incubation as well as a + subsequent increase in the concentration of both, which becomes greatest after 20-30 minutes. The + composition of both lipidic fractions (FFA and DAG) into fatty acids at 5, 10, 20 and 30 + minutes, is related to the composition of the triacylglycerides (TAG), since during the + esterification + process a decline in the DAG of linoleic and palmitoleic acid is observed, both acids arranging + themselves preferably in the TAG 2 position. Whereas the inverse process occurs during lipolysis; i.e. + an increase in the proportion of the acids + + in the 2 position. In the FFA fraction, a higher proportion of fatty acids, preferential by arranged in + positions 1 + 3 of the TAG's is observed. Similarly a decrease is observed in the extracellular + concentration of FFA in the presence of serotonin with respect to the controls, a fact which has been + described by other authors. An analysis of the present data leads us to revise the possible + role of "Cahill's cycle" (simultaneous activation of the DAG-acyl-transferase and the HSL-TAG-lipase) in + the action of serotonin and other hormones. +

+

+ Nahrung 1991;35(9):961-7. [The effect of different protein diets on longevity and various + biochemical parameters of aged rats]. Medovar BJa, Petzke KJ, Semesko TG, Albrecht V, Grigorov + JuG Institut fur Gerontologie, AMW, UdSSR, Kiev. In this work 23 month old rats were fed for 200 days with + different protein diets (NT-diet: 19% protein, 72% of animal origin and LP-diet: 8.8% protein exclusively of + vegetable origin). Some metabolic parameters and lifespan (on the base of a 50% death-rate) were determined. + The relations of the liver free amino + acids glycine + alanine and tyrosine + phenylalanine + branched chain amino acids and the ratio of + phenylalanine/tyrosine were determined to be higher in the LP-group. Phenylalanine in liver and + urea concentrations in liver and serum were lower in the LP-group. Furthermore the dopamine or serotonin + levels were significantly lower in lateral and medial or lateral regions of the hypothalamus respectively in + LP-diet fed rats. The norepinephrine content was not modified by + the diets. The median lifespan of 23 month old rats was higher by 24% following LP-treatment. These + results suggest that the protein component (amino acids) of different diets may modify + metabolic parameters and lifespan of animals by mechanisms in which the central regulation may be involved. +

+

+ J Neurol Sci 1976 May;28(1):41-56. + Skeletal muscle necrosis following membrane-active drugs plus serotonin. + Meltzer HY. +

+

+ Brain Res Bull 1977 Sep-Oct;2(5):347-53. + Effects of developmental protein malnutrition on tryptophan utilization in brain and peripheral + tissues. Miller M, Leahy JP, McConville F, Morgane PJ, Resnick O. +

+

+ Exp Neurol 1977 Oct;57(1):142-57. + Tryptophan availability: relation to elevated brain serotonin in developmentally protein-malnourished + rats. Miller M, Leahy JP, Stern WC, Morgane PJ, Resnick O. +

+

+ Synapse 1990;6(4):338-43. Age-related changes of strychnine-insensitive glycine receptors in rat + brain as studied by in vitro autoradiography. Miyoshi R, Kito S, Doudou N, Nomoto T. + "3H-glycine binding sites were most concentrated in the hippocampus, cerebral cortex, and olfactory + tubercle, and moderate densities of binding sites were located in the striatum, nucleus accumbens, amygdala, + and certain thalamic nuclei." "In aged animals, severe decline of 3H-glycine binding sites was + observed in the telencephalic regions including the hippocampus and cerebral cortex." "These results + suggest that the decrease of glycine receptors in particular brain regions has some relation with + changes of neuronal functions associated with aging process in these areas." +

+

+ Enzyme 1976;21(6):481-7. Inhibition of actomyosin ATPase by high concentrations of + 5-hydroxytryptamine. Possible basis of lesion in 5HT-induced experimental myopathy. Mothersill + C, Heffron JJ, McLoughlin JV. +

+

+ Brain Res 1975 Jul 25;93(1):123-32. + Regulation of 5-hydroxytryptamine metabolism in mouse brain by adrenal glucocorticoids. Neckers + L, Sze PY "A single injection of + hydrocortisone acetate (HCA; 20 mg/kg, i.p.) accelerated the accumulation of 5-HT in whole brain after + inhibition of monoamine oxidase activity by paragyline. The hormone did not appear to change brain + tryptophan hydroxylase or 5-hydroxytryptophan decarboxylase activity. However, tryptophan levels in + brain were elevated by 50% within 1 h after treatment with HCA." +

+

+ Proc Soc Exp Biol Med 1967 Nov;126(2):579-83. + Serotonin antagonist increases longevity in mice with hereditary muscular dystrophy. O'Steen + WK. +

+

+ Mech Ageing Dev 1988 Apr;43(1):79-98. + Histology and survival in age-delayed low-tryptophan-fed rats. Ooka H, Segall PE, Timiras PS. + Diets containing tryptophan in concentrations 30 and 40 percent of those fed to controls from weaning to + 24-30 months or more, can delay aging in Long-Evans female rats. Mortality among low-tryptophan-fed rats was + greater in the juvenile period, but substantially less than controls at late ages. Histological biomarkers + of aging were also delayed after tryptophan restriction in some organs (liver, heart, uterus, ovary, adrenal + and spleen) but not in others (kidney, lung, aorta). Brain serotonin levels were low in tryptophan-deficient + rats but showed remarkable capacity for rehabilitation. Effects on early and late mortality and brain levels + of serotonin were proportional to the severity of the restriction. +

+ +

+ Age Ageing 1985 Mar;14(2):71-5. + Plasma tryptophan, age and depression. Phipps DA, Powell C. Plasma, obtained from 131 + nondepressed, otherwise healthy subjects aged from 17 to 102 years, and 22 depressed subjects aged over 70 + years, was analysed for total and free tryptophan. Variation with age was found in total tryptophan. + This association has not been described hitherto. There was a significant increase in total tryptophan + and a non-significant increase in free tryptophan with depression. This is in contrast to some studies + in younger people showing a decline in plasma tryptophan in depressed subjects. +

+

+ Bratisl Lek Listy 1975 Jul;64(1):58-63. + [The effect of serotonin on the release of free fatty acids from human and rat adipose tissue (author's + transl)]. [Article in Czech] Rath R, Kujalova V. +

+

+ Adv Exp Med Biol 1999;467:497-505. + Oxidative damage in rat tissue following excessive L-tryptophan and atherogenic diets. Ronen N, + Livne E, Gross B. +

+

+ FASEB J 1994 Dec;8(15):1302-7. + Methionine restriction increases blood glutathione and longevity in F344 rats. + Richie JP Jr, Leutzinger Y, Parthasarathy S, Malloy V, Orentreich N, Zimmerman JA "Met restriction resulted + in a 42% increase in mean and 44% increase in maximum life span, and in 43% lower body weight compared to + controls (P < 0.001). Increases in blood GSH levels of 81% and 164% were observed in mature and old + Met-restricted animals, respectively (P < 0.001)." +

+

+ Carcinogenesis 1999 Nov;20(11):2075-81. + Dietary glycine prevents the development of liver tumors caused by the peroxisome proliferator + WY-14,643. Rose ML, Cattley RC, Dunn C, Wong V, Li X, Thurman RG. +

+ +

+ Mech Ageing Dev 1983 Nov-Dec; 23(3-4):245-52. + Low tryptophan diets delay reproductive aging. Segall PE, Timiras PS, Walton JR. Newly weaned + female rats fed diets severely deficient in the essential amino acid tryptophan show marked delays in + reproductive aging, with conception and delivery occurring as late as 36 months. The rate of aging in these + rats seems inversely related to both their early growth rates and the accessibility of brain tryptophan. The + subsequent age retardation may depend on a reduction in both early cell loss and rate of brain maturation. +

+

+ Mech Ageing Dev 1978 Jan;7(1):1-17. + Neural and endocrine development after chronic tryptophan deficiency in rats: I. Brain monoamine and + pituitary responses. Segall PE, Ooka H, Rose K, Timiras PS. "Caloric restriction and tryptophan + deficient diets have been shown to delay aging in the immature laboratory rat." "Another group of animals, + in which growth and maturation was delayed by feeding d,1-parachlorophenylalanine (PCPA) showed decreases in + serotonin, norepinephrine and dopamine concentrations in all brain regions investigated. All treatments + employed to arrest growth and maturation resulted in pituitary alterations manifested by gross, histological + and ultrastructural changes. It is postulated that there maturation- and age-retarding treatments delay the + development of the central nervous system resulting in postponed maturation of the neuroendocrine axis, with + consequent hypoactivity of certain pituitary functions and a resultant delay in the onset of maturation and + senescence." +

+

+ Aktuelle Gerontol 1977 Oct;7(10):535-8. + Long-term tryptophan restriction and aging in the rat. Segall P. Growth-retarded rats fed a + tryptophan deficient diet at 21 days for periods of + 6-22 months were shown to reach normal body weight when subsequently fed Purina Rat Chow. They + demonstrated an increased ability over similar aged controls to recover from hypothermia induced by + 3-minute whole-body ice water immersion, were able to bear litters at 17--28 months of age, + showed a delay in the age of onset of visible tumors, and indicated an increase in their average lifespan + at + late ages. Animals fed on this diet from 3 months of age revealed a similar ability to reproduce at + advanced ages, but not as marked as those placed on the diet earlier. The average lifespan (in months + +/- the standard error of the mean) of the rats recovering from the long-term tryptophan-deficient diets + was 36.31 +/- 2.26 while the control rats survived an average of 30.5 +/- 1.90 months. The last + of 8 rats surviving the period of tryptophan-deficiency died at + 45.50 months (1387 days) while the last of 14 control rats died at 41.75 months (1266 days). It is + hypothesized that some kind of subtle mechanism exerts its influence on the rats during the + period of tryptophan deficiency which caused an accelerated morbidity and mortality as they approached + senescence approximately + 1 to 2 years after refeeding. + This is parallel to the situation with immature + animals subjected to long-term caloric restriction and then fed on normal diets. +

+

+ Mech Ageing Dev 1976 Mar-Apr;5(2):109-24. + Patho-physiologic findings after chronic tryptophan deficiency in rats: a model for delayed growth and + aging. Segall PE, Timiras PS. Long-Evans female rats three weeks, three months and 13-14 months + of age were placed on tryptophan-deficient diets for periods ranging from a few months to nearly two years. + Growth was interupted during the period of tryptophan-deficiency, but when the animals were returned to a + complete diet, they gained weight and grew to normal size. Ability to reproduce, as indicated + by litter production, was present at 17-28 months of age in rats which had been deprived of tryptophan, + whereas no controls over 17 months of age produced any offspring. Other signs of delayed aging in the + experimental group included, at advanced ages, greater longevity, as well as later onset in the + appearance of obvious tumors, and better coat condition and hair regrowth. Many of these effects were + also seen in pair-fed controls (fed a diet equal in amount to that eaten by the + tryptophan-deprived rats, but with 1-tryptophan added). It is hypothesized that tryptophan deficiency delays + growth, development and maturation of the central nervous system (CNS), in particular, by decreasing the + levels of the neurotransmitter serotonin, for which tryptophan is the necessary precursor. In a parallel + experiment, chronic treatment with d, 1-parachlorophenylalanine, an inhibitor of brain serotonin synthesis, + from weaning until adulthood, also inhibited growth (body weight) and delayed sexual maturation (age of + vaginal opening). These observations suggest that diets deficient in tryptophan or restricted in calories + can affect maturation and aging by interfering with CNS protein synthesis, or neurotransmitter metabolism, + or both. +

+

+ Naturwissenschaften 1965 Sep;52(18):519. + [Serotonin-caused muscular dystrophy]. [Article in German] Selye H. +

+

+ Toxicology 1999 Feb 15;132(2-3):139-46. + Protection against chronic cadmium toxicity by glycine. Shaikh ZA, Tang W +

+

+ Biosci Biotechnol Biochem 1998 Mar;62(3):580-3. + Increased conversion ratio of tryptophan to niacin in severe food restriction. + Shibata K, Kondo T, Miki A. +

+

+ Monogr Neural Sci 1976;3:94-101. + Sex, migraine and serotonin interrelationships. Sicuteri F, Del Bene E, Fonda C. "Sexual + deficiency or frank impotence in man could be due to an imbalance of monoamines, particularly 5-HT, at the + mating center level. An absolute or + relative excess of 5-HT seems to antagonize testosterone at the level of the mating center receptors in + the brain. Plasma testosterone levels in so-called psychological impotence are normal. When the 5-HT + concentration in sexually deficient men is sufficiently decreased with parachlorophenylalanine + (PCPA) treatment and testosterone levels increased following its administration, a vivid sexual + stimulation appears in about half of the untractable cases." "Yet the PCPA-MAOI treatment avoids the + prostate carcinogenic risk of testosterone administration in aging males, and seems to have euphorizing + effects stronger than those expected only from MAOI therapy. Because of the several side effects of + PCPA-MAOI testosterone, the present experiments should be interpreted very cautiously." +

+

+ Hepatology 1999 Mar;29(3):737-45. + Glycine and uridine prevent D-galactosamine hepatotoxicity in the rat: role of Kupffer cells. + Stachlewitz RF, Seabra V, Bradford B, Bradham CA, Rusyn I, Germolec D, Thurman RG. +

+

+ Eur J Appl Physiol Occup Physiol 1999 Mar;79(4):318-24. Effect of acute and chronic exercise on + plasma amino acids and prolactin concentrations and on [3H]ketanserin binding to serotonin2A receptors + on human platelets. Struder HK, Hollmann W, Platen P, Wostmann R, Weicker H, Molderings + GJ. + "The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been shown to modulate various + physiological and psychological functions such as fatigue. Altered regulation of the + serotonergic system has been suggested to play a role in response to exercise stress." "The present results + support the hypothesis that acute endurance exercise may increase 5-HT availability. + This was reflected in the periphery by increased concentration of the 5-HT precursor free TRP, by + increased plasma PRL concentration, and by a reduction of 5-HT2A receptors on platelets." +

+

+ Epilepsy Res 1999 Jan;33(1):11-21. + Pharmacokinetic analysis and anticonvulsant activity of glycine and glycinamide derivatives. + Sussan S, Dagan A, Bialer M. +

+

+ Adv Biochem Psychopharmacol 1976; 15:251-65. + Glucocorticoid regulation of the serotonergic system of the brain. + Sze PY. "Glucorticoids at concentrations above 10(-7) M stimulate the uptake of tryptophan by brain + synaptosomes." +

+

+ Neurobiol Aging 1984 Fall;5(3):235-42. + Lifetime brain serotonin: regional effects of age and precursor availability. + Timiras PS, Hudson DB, Segall PE. + "In the rat, regional brain serotonin levels which do not change from 2-30 months of age are increased + at 36 months." + "Impaired brain serotonin levels recover moderately but remain lower than controls as late as 36 + months, growth is never completely compensated, and norepinephrine levels show a rebound increase." +

+

+ Kidney Int 1996 Feb;49(2):449-60. + Cytoprotection of kidney epithelial cells by compounds that target amino acid gated chloride + channels. Venkatachalam MA, Weinberg JM, Patel Y, Saikumar P, Dong Z +

+

+ Am J Physiol Lung Cell Mol Physiol 2000 Aug;279(2):L390-8. Dietary glycine blunts lung inflammatory + cell influx following acute endotoxin. Wheeler MD, Rose ML, Yamashima S, Enomoto N, Seabra V, + Madren J, Thurman RG. +

+ +

+ Am J Physiol 1999 Nov;277(5 Pt 1):L952-9. + Production of superoxide and TNF-alpha from alveolar macrophages is blunted by glycine. Wheeler + MD, Thurman RG. +

+

+ Stroke 1991 Apr;22(4):469-76. Identification of capric acid as a potent vasorelaxant of human + basilar arteries. + White RP, Ricca GF, el-Bauomy AM, Robertson JT + "To determine whether naturally occurring fatty acids, especially saturated ones, might act directly as + vasodilators, segments of human basilar arteries and umbilical arteries were precontracted submaximally + with prostaglandin F2 alpha and then exposed to different saturated fatty acids (C4 through C16) + or +

+ Caprate also inhibited contractions elicited by KCl, serotonin, and the thromboxane analogue + U46619." +

+ +

+ Neurochem Res 1978 Jun;3(3):295-311. + Adaptive changes induced by high altitude in the development of brain monoamine enzymes. + Vaccari A, Brotman S, Cimino J, Timiras PS. +

+

+ Growth Dev Aging 1991 Winter; 55(4):275-83. + Effect of aging and diet restriction on monoamines and amino acids in cerebral cortex of Fischer-344 + rats. Yeung JM, Friedman E. +

+

+ Proc Natl Acad Sci U S A 1992 Jul 15;89(14):6443-6. + Platelet activation by simultaneous actions of diacylglycerol and unsaturated fatty acids. + Yoshida K, Asaoka Y, Nishizuka Y "Several cis-unsaturated fatty acids such as oleic, linoleic, linolenic, + eicosapentaenoic, and docosahexaenoic acids added directly to intact human platelets greatly enhance protein + kinase C activation as judged by the phosphorylation of its specific endogenous substrate, a 47-kDa + protein." "In the presence of ionomycin and either 1,2-dioctanoylglycerol or phorbol 12-myristate + 13-acetate, the release of serotonin from the platelets is also remarkably increased by cis-unsaturated + fatty acids. The effect of these fatty acids is observed at concentrations less than 50 microM. + Saturated fatty acids and trans-unsaturated fatty acids are inactive." + + ". . . cis-unsaturated fatty acids increase an apparent sensitivity of the platelet response to Ca2+. The + results suggest that cis-unsaturated fatty acids, which are presumably produced from phosphatidylcholine by + signal-dependent activation of phospholipase A2, may take part directly in cell signaling through the + protein kinase C pathway." +

+

+ Jpn J Physiol 1969 Apr 15;19(2):176-86. + Lipolytic action of serotonin in brown adipose tissue in vitro. + Yoshimura K, Hiroshige T, Itoh S +

+

+ Hepatology 2000 Sep;32(3):542-6. + Glycine prevents apoptosis of rat sinusoidal endothelial cells caused by deprivation of vascular + endothelial growth factor. Zhang Y, Ikejima K, Honda H, Kitamura T, Takei Y, Sato N +

+

+ Mol Pharmacol 1999 Sep;56(3):455-63. + Dietary glycine and renal denervation prevents cyclosporin A-induced hydroxyl radical production in rat + kidney. Zhong Z, Connor HD, Yin M, Moss N, Mason RP, Bunzendahl H, Forman DT, Thurman RG +

+ +

+ " Ray Peat 2006. All Rights Reserved. + www.RayPeat.com +

+ + diff --git a/raypeat-articles/processed/unsaturated-oils.html b/raypeat-articles/processed/unsaturated-oils.html new file mode 100644 index 0000000..14b2ffe --- /dev/null +++ b/raypeat-articles/processed/unsaturated-oils.html @@ -0,0 +1,562 @@ + + Unsaturated Vegetable Oils: Toxic + +

+ Unsaturated Vegetable Oils: Toxic +

+ +

GLOSSARY:

+

+ Immunodeficiency (weakness of the immune system) can take many forms. AIDS, for example, refers to an + immunodeficiency which is "acquired," rather than "inborn." Radiation and vegetable oils can cause "acquired + immunodeficiency." Unsaturated oils, especially polyunsaturates, weaken the immune system's function in ways + that are similar to the damage caused by radiation, hormone imbalance, cancer, aging, or viral infections. + The media discuss sexually transmitted and drug-induced immunodeficiency, but it isn't yet considered polite + to discuss vegetable oil-induced immunodeficiency. +

+

+

+ Unsaturated oils: When an oil is saturated, that means that the molecule has all the hydrogen atoms it can + hold. Unsaturation means that some hydrogen atoms have been removed, and this opens the structure of the + molecule in a way that makes it susceptible to attack by free radicals. +

+

+ Free radicals are reactive molecular fragments that occur even in healthy cells, and can damage the cell. + When unsaturated oils are exposed to free radicals they can create chain reactions of free radicals that + spread the damage in the cell, and contribute to the cell's aging. +

+

+ Rancidity of oils occurs when they are exposed to oxygen, in the body just as in the bottle. Harmful free + radicals are formed, and oxygen is used up. +

+

+ Essential fatty acids (EFA) are, according to the textbooks, linoleic acid and linolenic acid, and they are + supposed to have the status of "vitamins," which must be taken in the diet to make life possible. However, + we are able to synthesize our own unsaturated fats when we don't eat the "EFA," so they are not "essential." + The term thus appears to be a misnomer. [M. E. Hanke, "Biochemistry," Encycl. Brit. Book of the Year, 1948.] +

+ +

+ Q: You say vegetable oils are hazardous to your health. What vegetable oils are you talking about? +

+

+ Mainly, I'm referring to soybean oil, corn oil, safflower oil, canola, sesame oil, sunflower seed oil, palm + oil, and any others that are labeled as "unsaturated" or "polyunsaturated." Almond oil, which is used in + many cosmetics, is very unsaturated. +

+

+ Chemically, the material that makes these oils very toxic is the polyunsaturated fat itself. These + unsaturated oils are found in very high concentrations in many seeds, and in the fats of animals that have + eaten a diet containing them. The fresh oils, whether cold pressed or consumed as part of the living plant + material, are intrinsically toxic, and it is not any special industrial treatment that makes them toxic. + Since these oils occur in other parts of plants at lower concentration, and in the animals which eat the + plants, it is impossible to eat a diet which lacks them, unless special foods are prepared in the + laboratory. +

+ +

+ These toxic oils are sometimes called the "essential fatty acids" or "vitamin F," but this concept of the + oils as essential nutrients was clearly disproved over 50 years ago. +

+

+ Linoleic and linolenic acids, the "essential fatty acids," and other polyunsaturated fatty acids, which are + now fed to pigs to fatten them, in the form of corn and soy beans, cause the animals' fat to be chemically + equivalent to vegetable oil. In the late 1940s, chemical toxins were used to suppress the thyroid function + of pigs, to make them get fatter while consuming less food. When that was found to be carcinogenic, it was + then found that corn and soy beans had the same antithyroid effect, causing the animals to be fattened at + low cost. The animals' fat becomes chemically similar to the fats in their food, causing it to be equally + toxic, and equally fattening. +

+ +

+ These oils are derived from seeds, but their abundance in some meat has led to a lot of confusion about + "animal fats." Many researchers still refer to lard as a "saturated fat," but this is simply incorrect when + pigs are fed soybeans and corn. +

+

+ Q: How are these oils hazardous to your health? +

+

+ Ultimately, all systems of the body are harmed by an excess of these oils. There are two reasons for this. + One is that the plants produce the oils for protection, not only to store energy for the germination of the + seed. To defend the seeds from the animals that would eat them, the oils block the digestive enzymes in the + animals' stomachs. Digestion is one of our most basic functions, and evolution has built many other systems + by using variations of that system; as a result, all of these systems are damaged by the substances which + damage the digestive system. +

+

+ The other reason is that the seeds are designed to germinate in early spring, so their energy stores must be + accessible when the temperatures are cool, and they normally don't have to remain viable through the hot + summer months. Unsaturated oils are liquid when they are cold, and this is necessary for any organism that + lives at low temperatures. For example, fish in cold water would be stiff if they contained saturated fats. + These oils easily get rancid (spontaneously oxidizing) when they are warm and exposed to oxygen. Seeds + contain a small amount of vitamin E to delay rancidity. When the oils are stored in our tissues, they are + much warmer, and more directly exposed to oxygen, than they would be in the seeds, and so their tendency to + oxidize is very great. These oxidative processes can damage enzymes and other parts of cells, and especially + their ability to produce energy. +

+

+ The enzymes which break down proteins are inhibited by unsaturated fats, and these enzymes are needed not + only for digestion, but also for production of thyroid hormones, clot removal, immunity, and the general + adaptability of cells. The risks of abnormal blood clotting, inflammation, immune deficiency, shock, aging, + obesity, and cancer are increased. Thyroid and progesterone are decreased. Since the unsaturated oils block + protein digestion in the stomach, we can be malnourished even while "eating well." +

+

+ Plants produce many protective substances to repel or injure insects and other animals that eat them. They + produce their own pesticides. The oils in seeds have this function. On top of this natural toxicity, the + plants are sprayed with industrial pesticides, which can concentrate in the seed oils. +

+

+ It isn't the quantity of these polyunsaturated oils which governs the harm they do, but the relationship + between them and the saturated fats. Obesity, free radical production, the formation of age pigment, blood + clotting, inflammation, immunity, and energy production are all responsive to the ratio of unsaturated fats + to saturated fats, and the higher this ratio is, the greater the probability of harm there is. +

+

+ There are interesting interactions between these oils and estrogen. For example, puberty occurs at an + earlier age if estrogen is high, or if these oils are more abundant in the diet. This is probably a factor + in the development of cancer. +

+ +

+ All systems of the body are harmed by an excess of these oils. There are three main kinds of damage: one, + hormonal imbalances, two, damage to the immune system, and three, oxidative damage. +

+

+ Q: How do they cause hormonal imbalances? +

+

+ There are many changes in hormones caused by unsaturated fats. Their best understood effect is their + interference with the function of the thyroid gland. Unsaturated oils block thyroid hormone secretion, its + movement in the circulatory system, and the response of tissues to the hormone. When the thyroid hormone is + deficient, the body is generally exposed to increased levels of estrogen. The thyroid hormone is essential + for making the "protective hormones" progesterone and pregnenolone, so these hormones are lowered when + anything interferes with the function of the thyroid. The thyroid hormone is required for using and + eliminating cholesterol, so cholesterol is likely to be raised by anything which blocks the thyroid + function. [B. Barnes and L. Galton, Hypothyroidism, 1976, and 1994 references.] +

+

+ Q: How do they damage the immune system? +

+ +

+ Vegetable oil is recognized as a drug for knocking out the immune system. Vegetable oil emulsions were used + to nourish cancer patients, but it was discovered that the unsaturated oils were suppressing their immune + systems. The same products, in which vegetable oil is emulsified with water for intravenous injection, are + now marketed specifically for the purpose of suppressing immunity in patients who have had organ + transplants. Using the oils in foods has the same harmful effect on the immune system. [E. A. Mascioli, et + al.,Lipids 22(6) 421, 1987.] Unsaturated fats directly kill white blood cells. [C. J. Meade and J. Martin, + Adv. Lipid Res., 127, 1978.] +

+

+ Q: How do they cause oxidative damage? +

+

+ Unsaturated oils get rancid when exposed to air; that is called oxidation, and it is the same process that + occurs when oil paint "dries." Free radicals are produced in the process. +

+

+ This process is accelerated at higher temperatures. The free radicals produced in this process react with + parts of cells, such as molecules of DNA and protein and may become attached to those molecules, causing + abnormalities of structure and function. +

+

+ Q: What if I eat only organically grown vegetable oils? +

+ +

+ Even without the addition of agricultural chemicals, an excess of unsaturated vegetable oils damages the + human body. Cancer can't occur, unless there are unsaturated oils in the diet. [C. Ip, et al., Cancer Res. + 45, 1985.] Alcoholic cirrhosis of the liver cannot occur unless there are unsaturated oils in the diet. + [Nanji and French, Life Sciences. 44, 1989.] Heart disease can be produced by unsaturated oils, and + prevented by adding saturated oils to the diet. [J. K. G. Kramer, et al., Lipids 17, 372, 1983.] +

+

+ Q. What oils are safe? +

+

+ Coconut and olive oil are the only vegetable oils that are really safe, but butter and lamb fat, which are + highly saturated, are generally very safe (except when the animals have been poisoned). Coconut oil is + unique in its ability to prevent weight-gain or cure obesity, by stimulating metabolism. It is quickly + metabolized, and functions in some ways as an antioxidant. Olive oil, though it is somewhat fattening, is + less fattening than corn or soy oil, and contains an +

+

+ antioxidant which makes it protective against heart disease and cancer. +

+

+ Israel had the world's highest incidence of breast cancer when they allowed the insecticide lindane to be + used in dairies, and the cancer rate decreased immediately after the government prohibited its use. The + United States has fairly good laws to control the use of cancer-causing agents in the food supply, but they + are not vigorously enforced. Certain cancers are several times more common among corn farmers than among + other farmers, presumably because corn "requires" the use of more pesticides. This probably makes corn oil's + toxicity greater than it would be otherwise, but even the pure, organically grown material is toxic, because + of its intrinsic unsaturation. +

+

+ In the United States, lard is toxic because the pigs are fed large quantities of corn and soy beans. Besides + the intrinsic toxicity of the seed oils, they are contaminated with agricultural chemicals. Corn farmers + have a very high incidence of cancer, presumably because of the pesticides they use on their crop. +

+

+ Q: But aren't "tropical oils" bad for us? +

+

+ In general, tropical oils are much more healthful than oils produced in a cold climate. This is because + tropical plants live at a temperature that is close to our natural body temperature. Tropical oils are + stable at high temperatures. When we eat tropical oils, they don't get rancid in our tissues as the + cold-climate seed oils, such as corn oil, safflower oil and soy oil, do. [R.B. Wolf, J. Am. Oil Chem. Soc. + 59, 230, 1982; R. Wolfe, Chem 121, Univ. of Oregon, 1986.] +

+

+ When added to a balanced diet, coconut oil slightly lowers the cholesterol level, which is exactly what is + expected when a dietary change raises thyroid function. This same increase in thyroid function and metabolic + rate explains why people and animals that regularly eat coconut oil are lean, and remarkably free of heart + disease and cancer. +

+

+ Although I don't recommend "palm oil" as a food, because I think it is less stable than coconut oil, some + studies show that it contains valuable nutrients. For example, it contains antioxidants similar to vitamin + E, which lowers both LDL cholesterol and a platelet clotting factor. [B. A. Bradlow, University of Illinois, + Chicago; Science News 139, 268, 1991.] Coconut oil and other tropical oils also contain some hormones that + are related to pregnenolone or progesterone. +

+

+ Q: Isn't coconut oil fattening? +

+

+ Coconut oil is the least fattening of all the oils. Pig farmers tried to use it to fatten their animals, but + when it was added to the animal feed, coconut oil made the pigs lean [See Encycl. Brit. Book of the Year, + 1946]. +

+ +

+ Q: What about olive oil? Isn't it more fattening than other vegetable oils? +

+

+ In this case, as with coconut oil, "fattening" has more to do with your ability to burn calories than with + the caloric value of the oil. Olive oil has a few more calories per quart than corn or soy oil, but since it + doesn't damage our ability to burn calories as much as the unsaturated oils do, it is less fattening. Extra + virgin olive oil is the best grade, and contains an antioxidant that protects against cancer and heart + disease. [1994, Curr. Conts.] +

+

+ Q: Is "light" olive oil okay? +

+ +

+ No. Now and then someone learns how to make a profit from waste material. "Knotty pine" boards were changed + from a discarded material to a valued decorative material by a little marketing skill. Light olive oil is a + low grade material which sometimes has a rancid smell and probably shouldn't be used as food. +

+

+ Q: Is margarine okay? +

+

+ There are several problems with margarine. The manufacturing process introduces some toxins, including a + unique type of fat which has been associated with heart disease. [Sci. News, 1974; 1991.] There are likely + to be dyes and preservatives added to margarine. And newer products contain new chemicals that haven't been + in use long enough to know whether they are safe. +

+

+ However, the basic hardening process, hydrogenation of the oils, has been found to make the oils less likely + to cause cancer. If I had to choose between eating ordinary corn oil or corn oil that was 100% saturated, to + make a hard margarine, I would choose the hard margarine, because it resists oxidation, isn't suppressive to + the thyroid gland, and doesn't cause cancer. +

+ +

+ Q: What about butter? +

+

+ Butter contains natural vitamin A and D and some beneficial natural hormones. It is less fattening than the + unsaturated oils. There is much less cholesterol in an ounce of butter than in a lean chicken breast [about + 1/5 as much cholesterol in fat as in lean meat on a calorie basis, according to R. Reiser of Texas A & M + Univ., 1979.]. +

+

+ Q: Are fish oils good for you? +

+

+ Some of the unsaturated fats in fish are definitely less toxic than those in corn oil or soy oil, but that + doesn't mean they are safe. Fifty years ago, it was found that a large amount of cod liver oil in dogs' diet + increased their death rate from cancer by 20 times, from the usual 5% to 100%. A diet rich in fish oil + causes intense production of toxic lipid peroxides, and has been observed to reduce a man's sperm count to + zero. [H. Sinclair, Prog. Lipid Res. 25, 667, 1989.] +

+

+ Q: What about lard? +

+

+ In this country, lard is toxic beause the pigs are fed large quantities of corn and soy beans. Besides the + natural toxicity of the seed oils, the oils are contaminated with agricultural chemicals. Corn farmers have + a very high incidence of cancer, presumably because corn "requires" the use of more pesticides. This + probably makes corn oil's toxicity greater than it would be otherwise. but even the pure, organically grown + material is toxic, because of its unsaturation. +

+

+

+ Women with breast cancer have very high levels of agricultural pesticides in their breasts [See Science + News, 1992, 1994]. +

+ +

+ Israel had the world's highest incidence of breast cancer when they allowed the insecticide lindane to be + used in dairies, and the cancer rate decreased immediately after the government prohibited its use. The + United States has fairly good laws to control the use of cancer-causing agents in the food supply, but they + are not vigorously enforced. [World Incid. of Cancer, 1992] +

+

+ Q: I have no control over oils when eating out. What can I do to offset the harmful effects of + polyunsaturated oils? +

+

+ A small amount of these oils won't kill you. It is the proportion of them in your diet that matters. A + little extra vitamin E (such as 100 units per day) will take care of an occasional American restaurant meal. + Based on animal studies, it would take a teaspoonful per day of corn or soy oil added to a fat-free diet to + significantly increase our risk of cancer. Unfortunately, it is impossible to devise a fat-free diet outside + of a laboratory. Vegetables, grains, nuts, fish and meats all naturally contain large amounts of these oils, + and the extra oil used in cooking becomes a more serious problem. +

+

+ Q Why are the unsaturated oils so popular if they are dangerous? +

+

+ It's a whole system of promotion, advertising, and profitability. +

+

+ 50 years ago, paints and varnishes were made of soy oil, safflower oil, and linseed (flax seed) oil. Then + chemists learned how to make paint from petroleum, which was much cheaper. As a result, the huge seed oil + industry found its crop increasingly hard to sell. Around the same time, farmers were experimenting with + poisons to make their pigs get fatter with less food, and they discovered that corn and soy beans served the + purpose, in a legal way. The crops that had been grown for the paint industry came to be used for animal + food. Then these foods that made animals get fat cheaply came to be promoted as foods for humans, but they + had to direct attention away from the fact that they are very fattening. The "cholesterol" focus was just + one of the marketing tools used by the oil industry. Unfortunately it is the one that has lasted the + longest, even after the unsaturated oils were proven to cause heart disease as well as cancer. [Study at + L.A. Veterans Hospital, 1971.] +

+

+ I use some of these oils (walnut oil is very nice, but safflower oil is cheaper) for oil painting, but I am + careful to wash my hands thoroughly after I touch them, because they can be absorbed through the skin. +

+

SUMMARY

+

+ Unsaturated fats cause aging, clotting, inflammation, cancer, and weight gain. +

+

+ Avoid foods which contain the polyunsaturated oils, such as corn, soy, safflower, flax, cottonseed, canola, + peanut, and sesame oil. +

+

+ Mayonnaise, pastries, even candies may contain these oils; check the labels for ingredients. +

+

+ Pork is now fed corn and soy beans, so lard is usually as toxic as those oils; use only lean pork. +

+

+ Fish oils are usually highly unsaturated; "dry" types of fish, and shellfish, used once or twice a week, are + good. Avoid cod liver oil. +

+ +

+ Use vitamin E. +

+

+ Use coconut oil, butter, and olive oil. +

+

+ Unsaturated fats intensify estrogen's harmful effects. +

+

REFERENCES

+ +

+ 1. C. F. Aylsworth, C. W. Welsch, J. J. Kabora, J. E. Trosko, "Effect of fatty acids on junctional + communication: Possible role in tumor promotion by dietary fat," Lipids 22(6), 445-54, 1987. +

+

+ 2. J. M. Bell and P. K. Lundberg, "Effects of a commercial soy lecithin preparation on development of + sensorimotor behavior & brain biochemicals in the rat," Dev. Psychobiol. 8(1), 59-66, 1985. +

+

+ 3. R. S. Britton and B. R. Bacon, "Role of free radicals in liver diseases and hepatic fibrosis," + Hepatogastroenterology 41(4), 343-348, 1994. +

+

+ 4. M. S. Brown, et al., "Receptor mediated uptake of lipoprotein-cholesterol and its utilization for steroid + synthesis," Recent Progress in Hormone Res. 35, 315-257, 1979. +

+

+ 5. P. A. Cerutti, "Oxy-radicals and cancer," Lancet 455(8926), 862-863, 1994. +

+ +

+ 6. I. Davies and A. P. Fotheringham, "Lipofuscin--Does it affect cellular performance?" Exp. Gerontol. 16, + 119-125, 1981. +

+

+ 7. K. L. Erickson, et al., "Dietary lipid modulation of immune responsiveness," Lipids 18, 468-74, 1983. +

+

+ 8. V. A. Folcik and M. K. Cathcart, "Predominance of esterified hydroperoxy-linoleic acid in human + monocyte-oxidized LDL," J. Lipid Res. 35(9), 1570-1582, 1994. +

+

+ 9. Fuller, C. J. and I. Jialal, "Effects of antioxidants and fatty acids on low-density-lipoprotein + oxidation," Am. J. Clin. Nutr. 60(6 Suppl.), S1010-S1013, 1994. +

+

+ 10. M. C. Galli, et al., "Peroxidation potential of rat thymus during development and involution," Comp. + Biochem. Physiol (C) 107(3), 435-440, 1994. +

+

+ 11. J. M. Gaziano, et al., "Supplementation with beta-carotene in vivo and in vitro does not inhibit low + density lipoprotein oxidation," Atherosclerosis 112(2), 187-195, 1995. +

+

+ 12. M. B. Grisham, "Oxidants and free radicals in inflammatory bowel disease," Lancet 344(8926), 859-861, + 1994. +

+

+ 13. J. M. C. Gutteridge, "Antioxidants, nutritional supplements and life-threaening diseases," Brit. J. + Biomed. Sci. 51(3), 288-295, 1994. +

+

+ 14. D. Harman, et al., "Free radical theory of aging: effect of dietary fat on central nervous system + function," J. American Geriatrics Soc. 24(1), 292-98, 1976. +

+

+ 15. W. S. Hartroft and E. A. Porta, "Ceroid pigments," chapter VIII in Present Knowledge in Nutrition, 3rd + Edition, Nutrition Foundation, N.Y., 1967. +

+

+ 16. H. J. Helbock, et al., (Univ. of Calif. Berkeley) January, 1993 Pediatrics; in Science News 143, 78, + 1993. "Toxic 'fats' in preemie supplement." +

+

+ H. R. Hirsch, "The waste-product theory of aging: Cell division rate as a function of waste volume," Mech. + Ageing Dev. 36, 95-107, 1986. +

+ +

+ 17. S. G. Imre, et al., "Increased proportion of docosahexanoic acid and high lipid peroxidation capacity in + erythrocytes of stroke patients," Stroke 25(12), 2416-2420, 1994. +

+

+ 18. Clement Ip, et al., "Requirement of essential fatty acids for mammary tumorigenesis," Cancer Res. 45(5), + 1997-2001, 1985. +

+

+ 19. P. V. Johnston, "Dietary fat, eicosanoids, and immunity," Adv. in Lipid Res. 21, 103-41, 1985. +

+ +

+ 20. S. Kasayna, et al., "Unsaturated fatty acids are required for continuous proliferation of transformed + androgen-dependent cells by fibroblast growth factor family proteins," Cancer Research 54(24), 6441-6445, + 1994. +

+

+ 21. H. A. Kleinveld, et al., "Vitamin E and fatty acid intervention does not attenuate the progression of + atherosclerosis in watanabe heritable hyperlipidemic rabbits," Arterioscler. Thromb. Vasc. Biol. 15(2), + 290-297, 1995. +

+

+ 22. J. K. G. Kramer, et al., Lipids 17, 372, 1983. +

+

+ 23. I. A. Kudryavtsev, et al., "Character of the modifying action of polyunsaturated fatty acids on growth + of transplantable tumors of various types," Bull. Exp. Biol & Med. 105(4), 567-70, 1986. +

+

+ 24. R. D. Lynch, "Utilization of polyunsaturated fatty acids by human diploid cells aging in vitro," Lipids + 15(6), 412-20, 1967. +

+

+ 25. M. Martinez and A. Ballabriga, "Effects of parenteral nutrition with high doses of linoleate on the + developing human liver and brain," Lipids 22(3), 133-8, 1987. +

+

+ 26. R. S. Mehta, et al., "High fish oil diet increases oxidative stress potential in mammary gland of + spontaneously hypertensive rats," Clin. Exp. Pharmacol. Physiol. 21(11), 881-889, 1994. +

+

+ 27. A. A. Nanji and S. W. French, "Dietary linoleic acid is required for development of experimentally + induced alcoholic liver-injury," Life Sciences 44, 223-7, 1989. +

+

+ 28. J. A. Lindsay, et al., "Fatty acid metabolism and cell proliferation," Lipids 18, 566-9, 1983. +

+

+ 29. M. L. Pearce and S. Dayton, "Incidence of cancer in men on a diet high in polyunsaturated fat," Lancet + 1, 464-467, 1971. +

+

+ 30. Pryor, W. A., "Free radicals and lipid proxidation--what they are and how they got that way," Natural + Antioxidants in Human, pp. 1-24, 1994. +

+

+ 31. P. Purasiri, et al., "Modulation of cytokine production in vivo by dietary essential fatty acids in + patients with colorectal cancer," Clin. Sci. 87(6), 711-717, 1994. +

+

+ 32. S. Rapoport and T. Schewe, "Endogenous inhibitors of the respiratory chain," Trends in Biochemical Sci., + Aug., 1977, 186-189. +

+

+ 33. H. Selye, "Sensitization by corn oil for the production of cardiac necrosis...," Amer. J. of Cardiology + 23, 719-22, 1969. +

+

+ 34. D. A. Street, et al., "Serum antioxidants and myocardial infarction--Are low levels of carotenoids and + alpha-tocopherol risk factors for myocardial infarction?" Circulation 90(3), 1154-1161, 1994. +

+ +

+ 35. M. Takei, et al., "Inhibitory effects of calcium antagonists on mitochondrial swelling induced by lipid + peroxidation or arachidonic acid in the rat brain in vitro," Neurochem. Res. 29(9), 1199-1206, 1994. +

+

+ 36. J. P. Thomas, et al., "Involvement of preexisting lipid hydroperoxides in Cu2+-stimulated oxidation of + low-density lipoprotein," Arch. Biochem. Biophys. 315(2), 244-254, 1994. +

+

+ 37. C. W. Welsch, "Review of the effects of dietary fat on experimental mammary gland tumorigenesis: Role of + lipid peroxidation," Free Radical Biol. Med. 18(4), 757-773, 1995. +

+ +

Essential Fatty Acids ("EFA"): A Technical Point

+

+ Those fatty acids, such as linoleic acid and linolenic acid, which are found in linseed oil, soy oil, walnut + oil, almond oil, corn oil, etc., are essential for the spontaneous development of cancer, and also appear to + be decisive factors in the development of age pigment, alcoholic cirrhosis of the liver, diabetes, obesity, + stress-induced immunodeficiency, some aspects of the shock reaction, epilepsy, brain swelling, congenital + retardation, hardening of the arteries, cataracts, and other degenerative conditions. They are possibly the + most important toxin for animals. +

+

+ The suppression of an enzyme system is characteristic of toxins. The "EFA" powerfully, almost absolutely, + inhibit the enzyme systems--desaturases and elongases--which make our native unsaturated fatty acids. +

+

+ After weaning, these native fats gradually disappear from the tissues and are replaced by the EFA and their + derivatives. The age-related decline in our ability to use oxygen and to produce energy corresponds closely + to the substitution of linoleic acid for the endogenous fats, in cardiolipin, which regulates the crucial + respiratory enzyme, cytochrome oxidase. +

+

+ Although the fish oils are less effective inhibitors of the enzymes, they are generally similar to the seed + oils in their ability to promote cancer, age-pigment formation, free radical damage, etc. Their only special + nutritional value seems to be their vitamin A and vitamin D content. Since vitamin A is important in the + development of the eye, it is interesting that claims are being made for the essentiality of some of the + fatty acid components of fish oil, in relation to the development of the eye. +

+

+ The polyunsaturated oils from seeds are recommended for use in paints and varnishes, but skin contact with + these substances should be avoided. +

+

+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com +

+ + diff --git a/raypeat-articles/processed/unsuitablefats.html b/raypeat-articles/processed/unsuitablefats.html new file mode 100644 index 0000000..2303b13 --- /dev/null +++ b/raypeat-articles/processed/unsuitablefats.html @@ -0,0 +1,631 @@ + + + + Suitable Fats, Unsuitable Fats: Issues in Nutrition + + + +

+ Suitable Fats, Unsuitable Fats: Issues in Nutrition +

+ +

+ For fifty years, the mass media have been making the public think about the fats in their diet, filling the + culture with clich"s about bad saturated animal fats that raise cholesterol, or lately the trans-fats in + margarine, and images of arteries clogged by bad fats. The public instruction about the fats we should eat + resembles the owner's manual for a car, that tells you what kind of motor oil and fuel and coolant to use; + they are telling us that they know how our body works, and that they know what it needs. But now, even after + the human genome has supposedly been partly "decoded," the biological functions of the fats have hardly + begun to be investigated. +

+ +

+ To understand the present issues regarding fats in nutrition and medicine it's helpful to look at the + historical development of biochemical and physiological fat research in a variety of contexts, including + agriculture and economics, as well as considering the effects of the changing ideas about cell structure, + vitamins, hormones, immunology, brain development, evolution, and the growing understanding of the way + physiology interacts with ecology. We need to recognize the complexity of the physiology of fats, to + appreciate the complexity of the living organism. +

+

+ Financial considerations have driven fat research in very obvious ways. In 1883, Mark Twain described how + commercial fraud was making use of new technology to substitute cheap fats and oils for butter and olive + oil.. Hard fats such as tallow, which had been used for making soap and candles, began to be widely used as + a substitute for butter in the 19th century. Around 1912, chemists found economical ways to solidify (for + use as a butter substitute) the very cheap liquid oils, such as cottonseed oil, linseed oil, whale oil, and + fish oils, which been used mostly as fuels or varnish. The seed oils were so cheap that meat packers quickly + became major producers of hydrogenated cottonseed and soy oils, to extend their limited supply of lard or + tallow for sale as shortening or margarine. +

+

+ Between 1912 and 1927 there were several studies that reported that animals could live on a fat-free diet, + and that in fact they lived longer, and without the normal mortality from cancer. In the 1940s and 1950s, + most textbooks that mentioned the idea that certain fats were essential nutrients described it as a + controversial idea. But the oil industries used public relations effectively to sell the medical (heart + protective) benefits of a diet containing increased amounts of linoleic and linolenic acids, which they + called the essential fatty acids. They began citing a 1929 publication (by G. Burr and M. Burr) that claimed + to demonstrate the essentiality of those fatty acids, while ignoring the publications that pointed in + different directions. +

+

+ The cheapness of the seed oils led to their use in animal feeds, to promote growth. By the 1940s, the + polyunsaturated oils, including fish oils, were known to cause deterioration of the brain, muscles, and + gonads in a variety of animals, and this was found to be caused mainly by their destruction of vitamin E. A + little later, the disease called steatitis or yellow fat disease was found to be produced in various animals + that were fed too much fish or fish oil. +

+

+ The reason linseed oil and fish oil were used for making varnishes and paints was that they are "drying + oils," reacting with oxygen to polymerize and harden. The physical and chemical propertiess of the oils are + fairly well understood, and among the polyunsaturated fatty acids (PUFA) the omega -3 fatty acids react most + easily with oxygen. Heat, light, and moisture increase their spontaneous interactions with oxygen, and + besides polymerizing, these oils produce a variety of reactive particles, including acrolein, which combine + with other substances, such as cellular proteins and DNA, with highly toxic effects. At low temperatures and + low oxygen concentrations these oils are not highly reactive. Fats that harden at low temperatures (as + saturated fats do) wouldn't be convenient for organisms that live in a cool environment, and so organisms + regulate the type of fat they synthesize according to the temperature of their tissues. The fact that + certain types of polyunsaturated fatty acids function nicely in fish, worms, and insects, doesn't mean that + they are ideal fats for mammals. +

+ +

+ The fact that vitamin E prevented or cured some of the major diseases in farm animals caused by excessive + PUFA, and that it could retard the development of rancidity in stored oils, led quickly to the persistent + belief that lipid peroxidation is the only toxic effect of the vegetable oils. However, the oils were being + seen to cause other problems, including accelerated aging and obesity, but those problems weren't of + interest to farmers, who wanted to sell plump young animals as cheaply and quickly as possible. Even fresh + oils have toxic effects, and the oxidative damage they do is often the consequence of these other toxic + actions. +

+

+ Another cheap food additive, coconut oil, was found to increase feed consumption while slowing weight gain, + so it wasn't popular in the meat industry. The highly unsaturated seed oils had the opposite effect, of + producing a rapid fattening of the animal, while decreasing feed consumption, so by 1950 corn and soybeans + were widely considered to be optimal feeds for maximizing profits in the production of meat animals. It was + at this time that the industry found that it could market the liquid oils directly to consumers, as + health-promoting foods, without bothering to turn them into solid shortening or margarine. Somehow, few + physiologists continued to think about the implications of metabolic slowing, obesity, and the related + degenerative diseases. +

+

+ As vitamin research advanced in the 1940s, Roger Williams' lab at the Clayton Foundation Biochemical + Institute, University of Texas at Austin, recognized the "fat deficiency disease" of the Burrs as a + deficiency of vitamin B6, and showed that when they produced the condition with a diet similar to the one + the Burrs had used, they could cure it by administering vitamin B6. In the early 1930s George Burr had + discovered that animals on a fat free diet had an extremely high rate of metabolism, but he didn't + investigate the important ramifications of that observation, such as their increased need for vitamins and + minerals, in accordance with their rate of metabolism. The PUFA slowed metabolism, and that effect was good + for agriculture. +

+ +

+ The commercial pressure on fat research has created a new way of writing research reports, that several + decades earlier wouldn't have been acceptable. For example, the effects of a specific fat on a few of the + components of a complex process such as clotting are often described in the title, introduction, and + conclusion of an article as if they were revealing a way to prevent heart disease. The effects of + unsaturated fats on cells + in vitro are often the opposite of their effects in living animals, but editors are allowing + authors to claim that their in vitro + results justify dietary or therapeutic use of the fats. Journals of medicine and nutrition are now preferred + sites for commercial press releases, composed to superficially resemble scientific reports. +

+

+ The suppressive effects of unsaturated fats on mitochondrial energy production have been widely + investigated, since it is that effect that makes animal fattening with PUFA so economical. Rather than + interpreting that as a toxic effect, using the innate structure and function of the mitochondrion as a point + of reference from which to evaluate dietary components, the consumption of "good" oils is being used as the + reference point from which to evaluate the meaning of metabolism ("efficiency is good," "low oxygen + consumption is good"). Building on the idea that the oils are health-promoters which increase metabolic + efficiency, the never-viable "rate of aging" theory was resuscitated: The anti-respiratory effect of PUFA is + used (illogically) to return to the idea that aging occurs in proportion to the amount of oxygen consumed, + because animals which lack the supposedly essential nutrients ("defective animals") consume oxygen + rapidly--burning calories rapidly, they are supposed to be like a candle that won't last as long if it burns + intensely. The old theory is simply resuscitated to explain why the anti-respiratory action of PUFA might be + beneficial, justifying further promotion of their use as food and drugs. +

+ +

+ Ordinarily, in biochemistry and physiology the inhibition of an enzyme is taken as a suggestion of toxicity, + but when the point of reference is the idea of the goodness of PUFA, the activity of an intrinsic + enzyme is taken to be evidence of harm, and its inhibition (by PUFA) is taken to be the proper, + healthful situation. The enzyme that produces the Mead fatty acid is strongly inhibited by PUFA seed oils + (less strongly by fish oils), and so the presence of the Mead acid in the tissues is taken as evidence that + the animal is suffering damage resulting from the absence of PUFA. The Mead acid happens to have some + valuable anti-inflammatory effects, and is associated with many biological advantages, but research in that + direction is prevented by the lack of funding. +

+

+ By 1920, the polyunsaturated fatty acids were recognized to inhibit proteolytic enzymes. At that time, the + production of unsaturated fat was considered to be a feature of certain pathogens, able to overcome the + proteolytic-phagocytic functions of the immune system. +

+

+ Scattered studies have found that polyunsaturated fats inhibit the proteolytic enzymes involved in the + digestion of food, in the removal of clots, in the formation of thyroid hormone, and many other essential + physiological processes. But currently, the only implication being drawn from this broad class of effects of + the PUFA is that some proteolytic enzymes are involved in disease processes, and consequently increased + consumption of PUFA would be appropriate, because of their ability to suppress a conditionally harmful + proteolytic enzyme. Since the organism consists mainly of proteins, there are complex innate systems for + regulating the proteolytic enzymes, activating or inactivating them as needed, and such complexity isn't + likely to depend on variable, unstable dietary factors. Exogenous substances that inhibit some proteases + could create an unlimited variety of functional and anatomical irregularities. +

+

+ Some of the interesting enzymes affected specifically by polyunsaturated fatty acids are those involved in + hormone production. While they inhibit the formation of progesterone and androgens, they activate the + synthesis of estrogen, which in turn activates the release of more free polyunsaturated fatty acids from the + tissues, in a positive feedback pattern. +

+ +

+ The inhibition of detoxification enzymes by PUFA (Tsoutsikos, et al., 2004) affects many processes, such as + the elimination of estrogen, contributing to the positive feedback between estrogen and the oils. The + meaning of this tends to be lost, because of the estrogen industry's effective campaigns. +

+

+ Another situation in which fatty acids participate in a positive feedback system is the stress reaction, in + which the released fatty acids impair mitochondrial energy production, increasing the stress and leading to + further release of fatty acids. +

+

+ One of the perennial theories of aging that has remained viable is the metaplasm/lipofuscin/age pigment + theory, the idea that a toxic material accumulates in tissues over time. The age pigment contains proteins, + cross-linked PUFA, and metals. The inhibition of proteolytic enzymes is involved in its accumulation, and + the ratio of PUFA to saturated fatty acids is an important factor in its formation. Estrogen is one of the + factors that can promote the formation of age pigment, probably partly because its lipolytic action + increases the cells' exposure to free fatty acids. The lipofuscin contributes to inhibition of proteolysis, + probably partly through increased production of free radicals and hydrogen peroxide. +

+

+ The proteolytic enzymes are an essential part of innate immunity, and the highly unsaturated fatty acid, + EPA, which is the most immunosuppressive of the fats, strongly inhibits proteolysis in some cells. The + natural killer (NK) cells and phagocytic cells are two types of cell that are suppressed by PUFA, and they + are involved in many kinds of physiological events, not just the killing of tumor cells and virus infected + cells. +

+

+ The immunosuppressive effects of PUFA are very general. Many metabolites that are known to have harmful + effects on the immune system are increased by the PUFA (histamine [Masini, et al., 1990], serotonin, + lactate, nitric oxide [Omura, et al., 2001]). These substances are also involved in tumor development. +

+ +

+ Besides inhibiting enzymes and being converted into prostaglandins, the polyunsaturated fatty acids have + direct effects, as signals (or interference with signals) on many tissues. The belief that the PUFA are + essential nutrients has influenced the way cellular excitability thresholds are being interpreted. Anxiety + and panic may be interpreted as alertness, calmness may be interpreted as stupidity. Specifically, long-term + potentiation (LTP) may contribute to seizures, senility, and excitotoxicity, as well as to learning, but + many titles and conclusions equate increased LTP with "improved LTP," implying that it has biological value + to the animal. +

+

+ The ability of nerve cells to become quiescent after excitation is essential to learning and perception. + This ability is lost with aging, as the functional balance in the brain shifts away from GABA-ergic to + glutamatergic nerves. The polyunsaturated fatty acids promote the excitatory nervous state. The combination + of respiratory inhibition with excitation can produce excitotoxic cell death. If the doctrine of + "essentiality of PUFA" hadn't been so influential, different interpretations of excitatory thresholds, + energy metabolism, and even cell structure would have been allowed to develop more fully. +

+

+ The concentration of polyunsaturated fats in the brain has led many people to say that the "nutritionally + essential fatty acids," especially the omega -3 fatty acids, are essential for brain development (for the + formation of nerve cell membranes), and for the formation of synapses, and that increasing the amount of + those fats in the diet would be desirable. The types of argument they use simply ignore the real + evidence: + + Cells can multiply indefinitely in culture dishes without the essential fatty acids, insects can multiply + for generations on diets without the unsaturated fats, forming normal synapses and brains, and mammals fed + diets with extremely small amounts of the unsaturated fats grow with perfectly normal--possibly + superior--brains. +

+

+ One of the fats in the omega -9 series, that the human body can synthesize, nervonic acid, is a major + constituent of brain tissue, but its important functions in brain development have hardly been investigated. + Unlike the unsaturated fatty acids oleic acid, linoleic acid, and eicosapentaenoic acid (EPA), nervonic acid + isn't associated with the "coronary risk factors," and it has been suggested that it might be used in adults + to prevent obesity-related diseases. (Oda, et al., 2005). +

+

+ One major area of research that has been neglected involves the role of fats in modifying the ways in which + proteins and nucleic acids interact with water--arguably the most basic of all physiological processes. + Unsaturated fats are more water soluble than saturated fats, and they are involved in many problems of + permeability and edema. +

+

+ In aging and evolution, there are systematic changes in tissue water content that appear to correspond to + changes in rate of metabolism, to the degree of unsaturation of cellular fats, and to thyroid function and + temperature. Metabolic intensity and longevity can be modified by changing the degree of saturation of fats + in the diet and tissues, but--despite almost a century of sporadic investigations--no one has yet worked out + in detail the most appropriate way to do this. But it has become clear that the "uncoupled" mitochondrion, + that "wastes oxygen and calories," is protective against free radicals, cancer, and aging. Thyroid hormone + and the absence of PUFA are important factors in supporting the "wasteful" mitochondrion. +

+

+ Although the complex interactions of anatomy, energy, temperature, fat nutrition, tissue water content, and + hormones haven't been systematically investigated, some of the principles regarding the biological + suitability of specific fats are already being applied in the limited context of therapy. +

+

+ At present, the most important issue is to recognize the dangers presented by the intrusion of corporate + power into science, especially as it relates to nutrition and medicine, and to consider the implications of + the known effects of the PUFA on all of our biological systems. +

+

+ The food-derived polyunsaturated fatty acids play important roles in the development of all of the problems + associated with aging--reduced immunity, insomnia, decreased learning ability, substitution of fat for + muscle, susceptibility to tissue peroxidation and inflammation, growth of tumors, etc., and are probably + involved in most other health problems, even in children. If research hadn't been guided by the economic + interests of the seed oil industry, many of those problems would have been solved by now. +

+

+ The influence of the mass media on science can be seen in two issues that are currently well known. +

+ +

+ A popular test used for evaluating diabetes is the measurement of glycated hemoglobin, the attachment of a + sugar-like fragment to the protein of hemoglobin. This is used to judge whether blood sugar is being + controlled adequately. The glycation of proteins is widely believed to be a central process in aging, and is + often used to argue that people should reduce their sugar consumption. +

+

+ Another well publicized problem supposedly involving the reaction between sugars and proteins has to do with + the discovery of the carcinogen, acrylamide, in breads and french fries. The Whole Foods Market was sued in + California for selling whole wheat bread without a warning that it contained a carcinogen. +

+

+ But the changes in proteins that occur in diabetes are mainly produced by the breakdown products of + polyunsaturated fatty acids. Acrylamide is produced largely by the reaction of PUFA with proteins. +

+

+ Sugar, by reducing the level of free fatty acids in the body, actually tends to protect against these toxic + effects of the PUFA. Diabetes, like cancer, has been known for a long time to be promoted by unsaturated + oils in the diet, rather than by sugar. The seed oil industry has been more effective than the sugar + industry in lobbying and advertising, and the effects can be seen in the assumptions that shape medical and + biological research. +

+

REFERENCES

+

+ Biochem Pharmacol. 1990 Mar 1;39(5):879-89. Histamine release from rat mast cells induced by + metabolic activation of polyunsaturated fatty acids into free radicals. Masini E, Palmerani B, + Gambassi F, Pistelli A, Giannella E, Occupati B, Ciuffi M, Sacchi TB, Mannaioni PF. +

+ +

+ Int Heart J. 2005 Nov;46(6):975-85. Relationships between serum unsaturated fatty acids and coronary + risk factors: negative relations between nervonic acid and obesity-related risk factors. Oda E, + Hatada K, Kimura J, Aizawa Y, Thanikachalam PV, Watanabe K. "The objective of the present study was to + analyze the relationships between serum USFA and CRF [coronary risk factors]." "

" +

+

+ FEBS Lett. 2001 Jan 5;487(3):361-6. Eicosapentaenoic acid (EPA) induces Ca(2+)-independent + activation and translocation of endothelial nitric oxide synthase and endothelium-dependent + vasorelaxation. Omura M, Kobayashi S, Mizukami Y, Mogami K, Todoroki-Ikeda N, Miyake T, + Matsuzaki M. "EPA stimulated NO production even in endothelial cells in situ loaded with a cytosolic Ca(2+) + chelator . . . which abolished the [Ca(2+)]i elevations induced by ATP and EPA." +

+ +

+ Biochem Pharmacol. 2004 Jan 1;67(1):191-9. Evidence that unsaturated fatty acids are potent + inhibitors of renal UDP-glucuronosyltransferases (UGT): kinetic studies using human kidney cortical + microsomes and recombinant UGT1A9 and UGT2B7. Tsoutsikos P, Miners JO, Stapleton A, Thomas A, + Sallustio BC, Knights KM. +

+

+ Lipids. 1997 Dec;32(12):1265-70. Dietary fatty acid profile affects endurance in rats. Ayre + KJ, Hulbert AJ. "The diets comprised an essential fatty acid-deficient diet (containing mainly saturated + fatty acids); a diet high in n-6 fatty acids, High n-6; and a diet enriched with n-3 fatty acids, High n-3. + Submaximal endurance in rats fed the High n-3 diet was 44% less than in rats fed the High n-6 diet (P < + 0.02). All rats were then fed a standard commercial laboratory diet for a 6-wk recovery period, and their + performances were reevaluated. Although endurance in all groups was lower then at 9 wk, it was again + significantly 50% lower in the High n-3 group than the High n-6 group (P < 0.005). Although n-3 fats are + considered beneficial for cardiovascular health, they appear to reduce endurance times, and their side + effects need to be further investigated." +

+ +

+ Ann Biol Clin (Paris) 2000 Sep-Oct;58(5):595-600. [Studies on the genotoxic + + effects of crude liver oils from 3 species of Mediterranean sharks by means of in vitro micronucleus + test using human lymphocytes] + + Bartfai E, Orsiere T, Duffaud F, Villani P, Pompili J, Botta A. "The results of this experimental study show + that the crude liver oils of three species of sharks are genotoxic and confirm a high carcinogenic risk." +

+

+ Vaccine. 2002 Jan 31;20(9-10):1435-44. Long-term influence of lipid nutrition on the induction of + CD8(+) responses to viral or bacterial antigens. + Bassaganya-Riera J, Hontecillas R, Zimmerman DR, Wannemuehler MJ. +

+ +

+ J Nutr. 2001 Sep;131(9):2370-7. + Dietary conjugated linoleic acid modulates phenotype and effector functions of porcine CD8(+) + lymphocytes. + Bassaganya-Riera J, Hontecillas R, Zimmerman DR, Wannemuehler MJ. +

+

+ J Anim Sci, 1984 Apr, 58:4, 971-8. Essential fatty acid status and characteristics associated with + colostrum-deprived gnotobiotic and conventional lambs. Growth, organ development, cell membrane + integrity and factors associated with lower bowel function. Bruckner G; Grunewald KK; Tucker + RE; Mitchell GE Jr "The absence of dietary linoleic acid decreased liver and spleen weights and, in general, + suppressed development of organs except the brain." "The results indicate that neonatal colostrum-deprived + lambs have an EFA requirement, as evidenced by decreased growth and performance characteristics in the GN + linoleic deficient vs GN supplemented group, and suggests that the required level is in excess of .32% of + the total caloric intake as linoleic acid." +

+

+ Crit Care Med. 1996 Jul;24(7):1129-36. An increase in serum C18 unsaturated free fatty acids as a + predictor of the development of acute respiratory distress syndrome. + Bursten SL, Federighi DA, Parsons P, Harris WE, Abraham E, Moore EE Jr, Moore FA, Bianco JA, Singer + JW, Repine JE. +

+ +

+ Free Radic Biol Med. 1999 Jul;27(1-2):51-9. Arachidonic acid interaction with the mitochondrial + electron transport chain promotes reactive oxygen species generation. Cocco T, Di Paola M, Papa + S, Lorusso M. "It is shown that arachidonic acid causes an uncoupling effect under state 4 respiration of + intact mitochondria as well as a marked inhibition of uncoupled respiration. While, under our conditions, + the uncoupling effect is independent of the fatty acid species considered, the inhibition is stronger for + unsaturated acids. Experiments carried out with mitochondrial particles indicated that the arachidonic acid + dependent decrease of the respiratory activity is caused by a selective inhibition of Complex I and III. It + is also shown that arachidonic acid causes a remarkable increase of hydrogen peroxide production when added + to mitochondria respiring with either pyruvate+malate or succinate as substrate." +

+

+ Antioxid Redox Signal. 2005 Jan-Feb;7(1-2):256-68. Lipid peroxidation in diabetes mellitus. + Davi G, Falco A, Patrono C. +

+

+ Naunyn Schmiedebergs Arch Pharmacol. 2005 Mar;371(3):202-11. Epub 2005 Apr 15. Antiarrhythmic and + electrophysiological effects of long-chain omega-3 polyunsaturated fatty acids. + + Dhein S, Michaelis B, Mohr FW. "Atrioventricular conduction time was slowed only by DHA and + EPA." "Regarding antiarrhythmic activity we found that the threshold for elicitation of + a ventricular extrasystole was concentration-dependently enhanced by DHA and EPA, but not by ALA. DHA + dose-dependently reduced longitudinal propagation velocity V(L) + + and to a lower extent transverse velocity V(T)." +

+

+ J Biol Chem. 2002 Oct 18;277(42):39368-78. The mechanism of docosahexaenoic acid-induced + phospholipase D activation inhuman lymphocytes involves exclusion of the enzyme from lipid + rafts. Diaz O, Berquand A, Dubois M, Di Agostino S, Sette C, Bourgoin S, Lagarde M, Nemoz G, + Prigent AF. "Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid that inhibits T lymphocyte + activation, has been shown to stimulate phospholipase D (PLD) activity in stimulated human peripheral blood + mononuclear cells (PBMC)." "This PLD activation might be responsible for the immunosuppressive + effect of DHA because it is known to transmit antiproliferative signals in lymphoid cells." +

+

+ Nutrition. 2003 Feb;19(2):144-9. + Diets rich in polyunsaturated fatty acids: effect on hepatic metabolism in rats. Gaiva MH, + Couto RC, Oyama LM, Couto GE, Silveira VL, Ribeiro EB, Nascimento CM. "Male Wistar rats, just weaned, were + fed ad libitum for 8 wk with one of the following diets: rat chow (C), rat chow containing 15% (w/w) soybean + oil (S), rat chow containing 15% (w/w) fish oil (F), and rat chow containing 15% soy bean and fish oil (SF; + 5:1, w/w)." "Body weight gain was higher in F and SF than in C and S rats. Liver weight, lipid content, and + lipogenesis rate increased in F and SF rats, although adenosine triphosphate citrate lyase activity + decreased. Glycogen concentration decreased in S, F, and SF rats compared with C rats." +

+

+ Br J Nutr. 2001 Sep;86(3):371-7. Polyunsaturated fatty acid-rich diets: effect on adipose tissue + metabolism in rats. Gaiva MH, Couto RC, Oyama LM, Couto GE, Silveira VL, Riberio EB, Nascimento + CM. "Wistar rats were fed ad libitum, for 8 weeks with one of the following diets: C, rat chow; S, rat chow + containing 15 % (w/w) soyabean oil; F, rat chow containing 15 % (w/w) fish oil; SF, rat chow containing 15 % + (w/w) soyabean and fish oil (5:1, w/w)." "Energy intake was reduced while carcass lipid content was + increased in the three fat-fed groups." "These results indicate that enrichment of the diet with + polyunsaturated fatty acids causes changes in adipose tissue metabolism that favour fat deposition. + Different metabolic pathways were preferentially affected by each type of fatty acid used." +

+

+ Adv Exp Med Biol 266:3-15, 1989, "Lipofuscin and ceroid formation: the cellular recycling + system," Harman, D. +

+

+ Mech Ageing Dev 2001 Apr 15;122(4):427-43. Effect of the degree of fatty acid unsaturation of rat + heart mitochondria on their rates of H2O2 production and lipid and protein oxidative damage. + Herrero A, Portero-Otin M, Bellmunt MJ, Pamplona R, Barja G. "Previous comparative studies have shown that + long-lived animals have lower fatty acid double bond content in their mitochondrial membranes than + short-lived ones. In order to ascertain whether this trait protects mitochondria by decreasing lipid and + protein oxidation and oxygen radical generation, the double bond content of rat heart mitochondrial + membranes was manipulated by chronic feeding with semi-purified AIN-93G diets rich in highly unsaturated + (UNSAT) or saturated (SAT) oils. UNSAT rat heart mitochondria had significantly higher double bond content + and lipid peroxidation than SAT mitochondria. They also showed increased levels of the markers of protein + oxidative damage malondialdehyde-lysine, protein carbonyls, and N(e)-(carboxymethyl)lysine adducts." "These + results demonstrate that increasing the degree of fatty acid unsaturation of heart mitochondria increases + oxidative damage to their lipids and proteins, and can also increase their rates of mitochondrial oxygen + radical generation in situations in which the degree of reduction of Complex III is higher than normal. + These observations strengthen the notion that the relatively low double bond content of the membranes of + long-lived animals could have evolved to protect them from oxidative damage." +

+ +

+ Biochem J. 1994 May 15;300 ( Pt 1):251-5. Regulation of fibrinolysis by non-esterified fatty + acids. Higazi AA, Aziza R, Samara AA, Mayer M. "Examination of the fatty acid specificity + showed that a minimal chain length of 16 carbon atoms and the presence of at least one double bond, + preferably in a cis configuration, were required for inhibition of the fibrinolytic activity of plasmin." +

+

+ B. A. Houssay and C. Martinez, "Experimental diabetes and diet," + Science 105, 548-549, 1947. +

+

+ J Theor Biol. 2005 May 21;234(2):277-88. On the importance of fatty acid composition of membranes + for aging. Hulbert AJ. +

+ +

+ Mech Ageing Dev. 2006 Apr 16; Extended longevity of wild-derived mice is associated with + peroxidation-resistant membranes. + + Hulbert AJ, Faulks SC, Harper JM, Miller RA, Buffenstein R. "Muscle and liver phospholipids from these + long-living mice lines have a reduced amount of the highly polyunsaturated omega-3 docosahexaenoic acid + compared to the DC mice, and consequently their membranes are less likely to peroxidative damage. The + relationship between maximum longevity and membrane peroxidation index is similar for these mice lines as + previously observed for mammals in general. It is suggested that peroxidation-resistant membranes may be an + important component of extended longevity." +

+

+ Virchows Arch B Cell Pathol. 1975 Nov 21;19(3):239-54. + [Ultrastructure and morphogenesis of ceroid pigment. II. Late changes of lysosomes in Kupffer cells of + rat liver after phagocytosis of unsaturated lipids] + + Kajihara H, Totovic V, Gedigk P. "These lipids, which have been changed in their molecular structure, cannot + be hydrolized by lysosomal enzymes. They remain as an indigestible material, as a waste product in lysosomal + residual bodies. Both lipofuscin and ceroid are lysosomal structures containing oxidized and polymerized + lipids." +

+

+ Reprod Nutr Dev. 1998 Jan-Feb;38(1):31-7. Effect of a high linoleic acid diet on delta 9-desaturase + activity, lipogenesis and lipid composition of pig subcutaneous adipose tissue. Kouba M, Mourot + J. +

+ +

+ Gerontology 1993;39(1):7-18. + Modulation of membrane phospholipid fatty acid composition by age and food restriction. + Laganiere S, Yu BP. H.M. "Phospholipids from liver mitochondrial and microsomal membrane preparations were + analyzed to further assess the effects of age and lifelong calorie restriction on membrane lipid + composition." "The data revealed characteristic patterns of age-related changes in ad libitum (AL) fed rats: + membrane levels of long-chain polyunsaturated fatty acids, 22:4 and 22:5, increased progressively, while + membrane linoleic acid (18:2) decreased steadily with age. Levels of 18:2 fell by approximately 40%, and + 22:5 content almost doubled making the peroxidizability index increase with age." "We concluded that the + membrane-stabilizing action of long-term calorie restriction relates to the selective modification of + membrane long-chain polyunsaturated fatty acids during aging." +

+

+ Free Radic Biol Med 1999 Feb;26(3-4):260-5. Modulation of cardiac mitochondrial membrane fluidity by + age and calorie intake. Lee J, Yu BP, Herlihy JT. "The fatty acid composition of the + mitochondrial membranes of the two ad lib fed groups differed: the long-chain polyunsaturated 22:4 fatty + acid was higher in the older group, although linoleic acid (18:2) was lower. DR eliminated the differences." + "Considered together, these results suggest that DR maintains the integrity of the cardiac mitochondrial + membrane fluidity by minimizing membrane damage through modulation of membrane fatty acid profile." +

+ +

+ Lipids 2001 Jun;36(6):589-93. Effect of dietary restriction on age-related increase of liver + susceptibility to peroxidation in rats. Leon TI, Lim BO, Yu BP, Lim Y, Jeon EJ, Park DK. +

+

+ Lipids 22(3), 133-6, 1987. Effects of parenteral nutrition with high doses of linoleate on the + developing human liver and brain, Martinez, M., and A. Ballabriga. +

+

+ J Pharmacol Exp Ther. 1995 Jan;272(1):469-75. Acetic acid-induced colitis in normal and essential + fatty acid deficient rats. Mascolo N, Izzo AA, Autore G, Maiello FM, Di Carlo G, Capasso F. +

+ +

+ Biochem Pharmacol. 1990 Mar 1;39(5):879-89. Histamine release from rat mast cells induced by + metabolic activation of polyunsaturated fatty acids into free radicals. Masini E, Palmerani B, + Gambassi F, Pistelli A, Giannella E, Occupati B, Ciuffi M, Sacchi TB, Mannaioni PF. +

+

+ J Nutrit 10:63(1935). The effect of retarded growth upon length of the life span and upon the + ultimate body size. McCay, CM., Crowell, MF., and Maynard, LA. +

+

+ McCollum EV. 1957. A History of Nutrition. Boston: Houghton Mifflin. p 374. +

+ +

+ J Biol Chem. 2003 Oct 24;278(43):42012-9. Pyridoxamine traps intermediates in lipid peroxidation + reactions in vivo: evidence on the role of lipids in chemical modification of protein and development of + diabetic complications. + Metz TO, Alderson NL, Chachich ME, Thorpe SR, Baynes JW. +

+

+ FEBS Lett. 1998 Oct 16;437(1-2):24-8. Generation of protein carbonyls by glycoxidation and + lipoxidation reactions with autoxidation products of ascorbic acid and polyunsaturated fatty acids. + + Miyata T, Inagi R, Asahi K, Yamada Y, Horie K, Sakai H, Uchida K, Kurokawa K. +

+

+ Naunyn Schmiedebergs Arch Pharmacol. 1996 Jul;354(2):109-19. Exposure to the n-3 polyunsaturated + fatty acid docosahexaenoic acid impairs alpha 1-adrenoceptor-mediated contractile responses and inositol + phosphate formation in rat cardiomyocytes. Reithmann C, Scheininger C, Bulgan T, Werdan K. "The + results presented show that chronic n-3 polyunsaturated fatty acid pretreatment of rat + cardiomyocytes leads to a marked impairment of alpha 1-adrenoceptor-induced positive inotropic effects + and induction of arrhythmias concomitant with a n-3 fatty acid-induced decrease in IP3 formation." + +

+ +

+ Nutrition. 2000 Jan;16(1):11-4. Effects of eicosapentaenoic acid intake on plasma fibrinolytic and + coagulation activity by using physical load in the young. Sakamoto N, Nishiike T, Iguchi H, + Sakamoto K. "Thus, as determined by the load, a small amount of daily EPA intake clearly decreased + fibrinolytic activity and increased coagulation activity." +

+

+ Diabetes. 2005 Aug;54(8):2314-9. Insulin resistance and type 2 diabetes in high-fat-fed mice are + linked to high glycotoxin intake. Sandu O, Song K, Cai W, Zheng F, Uribarri J, Vlassara H. + "These results demonstrate that the development of insulin resistance and type 2 diabetes during prolonged + high-fat feeding are linked to the excess AGEs/advanced lipoxidation end products inherent in fatty diets." +

+

+ Nutr Cancer 1998;30(2):137-43. Effects of dietary n-3-to-n-6 polyunsaturated fatty acid ratio on + mammary carcinogenesis in rats. Sasaki T, Kobayashi Y, Shimizu J, Wada M, In'nami S, Kanke Y, + Takita T. "Dietary fat was fed to the rats as 10% of the total feed weight, starting two weeks before the + initiation. An increase in the n-3/n-6 ratio did not suppress the incidence or reduce the latency of mammary + tumor development. The number and weight of mammary tumors per tumor-bearing rat tended to be large in the + group with an n-3/n-6 ratio of 7.84 compared with those in the other groups. As the n-3/n-6 ratios + were elevated, the total number and weight of tumors increased gradually." "These results + suggested that the increase in the n-3/n-6 ratio of dietary fat with the fixed PUFA-to-saturated fatty acid + ratio cannot suppress the mammary carcinogenesis but can promote development of tumors, despite reduced PGE2 + concentration in the tumor." +

+ +

+ J Cardiovasc Pharmacol. 2006 Mar;47(3):493-9. Mildronate, a novel fatty acid oxidation inhibitor and + antianginal agent, reduces myocardial infarct size without affecting hemodynamics. Sesti C, + Simkhovich BZ, Kalvinsh I, Kloner RA. "Mildronate is a fatty acid oxidation inhibitor approved as an + antianginal drug in parts of Europe." +

+

+ J Nutr 2000 Dec;130(12):3028-33. Polyunsaturated (n-3) fatty acids susceptible to peroxidation are + increased in plasma and tissue lipids of rats fed docosahexaenoic acid-containing oils. Song + JH, Fujimoto K, Miyazawa T.. "Thus, high incorporation of (n-3) fatty acids (mainly DHA) into plasma and + tissue lipids due to DHA-containing oil ingestion may undesirably affect tissues by enhancing susceptibility + of membranes to lipid peroxidation and by disrupting the antioxidant system." +

+

+ Diabetes Nutr Metab. 2002 Aug;15(4):205-14. Long-term effect of fish oil diet on basal and + stimulated plasma glucose and insulin levels in ob/ob mice. + + Steerenberg PA, Beekhof PK, Feskens EJ, Lips CJ, Hoppener JW, Beems RB. "We have investigated, in comparison + to low and high fat diets, the effect of a fish oil diet on basal and stimulated plasma glucose and insulin + levels in male and female ob/ob mice." "Intercurrent deaths were found especially in the fish oil diet + group. Compared to the other diet groups, plasma insulin levels of the fish oil diet group were + significantly increased 3 months after the start of the diet and remained higher for another 3 months." "At + 12 months, microscopy revealed an increased severity of hepatic brown pigment accumulation and + extramedullary haematopoiesis in the spleen of mice fed with fish oil." "Fish oil diet also increased + intercurrent mortality. However, a consistent course of death could not be established using morphological + parameters." +

+

+ J Biol Chem. 2002 Feb 15;277(7):5692-7. Unsaturated fatty acids inhibit cholesterol efflux from + macrophages by increasing degradation of ATP-binding cassette transporter A1. Wang Y, Oram JF. + "These findings raise the possibility that an increased supply of unsaturated fatty acids in the artery wall + promotes atherogenesis by impairing the ABCA1 cholesterol secretory pathway in macrophages." +

+

+ J Biol Chem. 2005 Oct 28;280(43):35896-903. Epub 2005 Aug 23. Unsaturated fatty acids phosphorylate + and destabilize ABCA1 through a phospholipase D2 pathway. Wang Y, Oram JF. "ATP-binding + cassette transporter ABCA1 mediates the transport of cholesterol and phospholipids from cells to HDL + apolipoproteins and thus modulates HDL levels and atherogenesis. Unsaturated fatty acids, which are elevated + in diabetes, impair the ABCA1 pathway in cultured cells by destabilizing ABCA1 protein." "Unsaturated but + not saturated fatty acids stimulated phospholipase D (PLD) activity, the PLD inhibitor 1-butanol prevented + the unsaturated fatty acid-induced reduction in ABCA1 levels, and the PLD2 activator mastoparan markedly + reduced ABCA1 protein levels, implicating a role for PLD2 in the ABCA1 destabilizing effects of fatty + acids." "These data provide evidence that intracellular unsaturated acyl-CoA derivatives destabilize ABCA1 + by activating a PLD2 signaling pathway." +

+ +

+ Isr J Med Sci. 1996 Nov;32(11):1134-43. Diet and disease--the Israeli paradox: possible dangers of a + high omega-6 polyunsaturated fatty acid diet. Yam D, Eliraz A, Berry EM. "Thus, rather than + being beneficial, high omega-6 PUFA diets may have some long-term side effects, within the cluster of + hyperinsulinemia, atherosclerosis and tumorigenesis." +

+ + © Ray Peat Ph.D. 2007. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/vegetables.html b/raypeat-articles/processed/vegetables.html new file mode 100644 index 0000000..3f27c37 --- /dev/null +++ b/raypeat-articles/processed/vegetables.html @@ -0,0 +1,465 @@ + + Vegetables, etc."Who Defines Food? + +

+ Vegetables, etc."Who Defines Food? +

+ +

+ Since bacteria in the rumens of cows destroy unsaturated fatty acids, but don't harm vitamin E, it seems + reasonable to suppose that beef and milk would have a better ratio of vitamin E to unsaturated fats than + do the plants eaten by the cows. +

+

+ Toxic pesticides are found in higher concentrations in the urine and fat of slaughtered animals than in + their livers, since the livers are detoxifying the chemicals and causing them to be excreted. + Presumably, the animals' livers will perform the same detoxification reactions with the phytotoxicants that occur naturally in their diet. +

+ +
+ +

+ Not long ago, breast feeding was socially unacceptable in the United States, and several manufacturers were + teaching the world"s poorest women to use their baby-food formulas even when there was no clean water for + its preparation. Industrialists have campaigned to convince the public that their by-products, from + cotton-seed oil to shrimp shells, are "health foods." In several parts of the world, desperately poor people + sometimes eat clay, and even clay has been promoted as a health food. Almost anything becomes "food," when + people are under economic and social pressure. If these things aren"t acutely toxic, they can become part of + our "normal" diet. +

+ +

+ Our instincts give us a few clues about our nutritional needs, such as thirst, the hunger for salt, the + pleasantness of sweet things, and the unpleasantness of certain odors or very acrid or bitter tastes. People + who are constitutionally unable to taste certain bitter chemicals find certain vegetables less + objectionable; their instinctive guidance has become less clear. But within the boundaries of cravings and + disgust, habits and customs become the dominant forces in diet. "Professional dietitians" and other + "experts" primarily function as enforcers of cultural prejudice. +

+

+ The manufacturers of pureed vegetables for babies used to put large amounts of salt, sugar, and monosodium + glutamate into their products, because the added chemicals served as instinctual signals that made the + material somewhat acceptable to the babies. There was no scientific basis for providing these vegetables to + babies in a form that they would accept, but it was a profitable practice that was compatible with the + social pressure against prolonged breast feeding. +

+

+ Poor people, especially in the spring when other foods were scarce, have sometimes subsisted on foliage such + as collard and poke greens, usually made more palatable by cooking them with flavorings, such as a little + bacon grease and lots of salt. Eventually, "famine foods" can be accepted as dietary staples. The fact that + cows, sheep, goats and deer can thrive on a diet of foliage shows that leaves contain essential nutrients. + Their minerals, vitamins, and amino acids are suitable for sustaining most animal life, if a sufficient + quantity is eaten. But when people try to live primarily on foliage, as in famines, they soon suffer from a + great variety of diseases. Various leaves contain antimetabolic substances that prevent the assimilation of + the nutrients, and only very specifically adapted digestive systems (or technologies) can overcome those + toxic effects. +

+ +

+ Some plants have specific "pests," such as insects, that have adapted to be resistant to that plant"s + toxins, but if the plant and its predator are to survive, there has to be a balance between the plant + tissue"s digestibility and its toxicity. Injury of a plant stimulates it to make increased amounts of its + defensive chemicals. Plant toxins are known to be specific for animal tissues; for example, a toxin will + inhibit the action of an enzyme from an animal, but a plant enzyme that catalyzes the same reaction won"t be + affected. +

+

+ Plant defensive chemicals can have beneficial uses as drugs. Plants are important sources for chemicals used + in chemotherapy of cancer, with the purpose of stopping cell division. Other plant drugs can stimulate cell + division. The drug from one plant will sometimes protect cells against the toxic effects of another plant. + The use of any drug that isn"t a natural part of animal physiology will have many biological effects, so + that a beneficial drug action will usually be accompanied by unwanted side-effects. An antioxidant may turn + out to disrupt the endocrine system, an antiinflammatory drug may be mutagenic or carcinogenic. +

+

+ A particular plant will have a variety of defensive chemicals, with specific functions. Underground, the + plant"s roots and tubers are susceptible to attack by fungi and nematodes. The leaves, stems, and seeds are + susceptible to attack by insects, birds, and grazing animals. Since the plant"s seeds are of unique + importance to the plant, and contain a high concentration of nutrients, they must have special protection. + Sometimes this consists of a hard shell, and sometimes of chemicals that inhibit the animal"s digestive + enzymes. Many plants have evolved fruits that provide concentrated food for animals, and that serve to + distribute the seeds widely, as when a bird eats a berry, and excretes the undigested seed at a great + distance. If the fruit were poisonous, it wouldn"t serve the plant"s purpose so well. In general, the + plant"s most intense toxins are in its seeds, and the fruits, when mature, generally contain practically no + toxins. Roots contain chemicals that inhibit microorganisms, but because they aren"t easily accessible by + grazing animals and insects, they don"t contain the digestive inhibitors that are more concentrated in the + above-ground organs of the plant. +

+

+ The toxins of plants include phenols, tannins, lectins/agglutinins, and trypsin-inhibitors, besides + innumerable more specific metabolic inhibitors, including "anti-vitamins." Unsaturated fats themselves are + important defenses, since they inhibit trypsin and other proteolytic enzymes, preventing the assimilation of + the proteins that are present in seeds and leaves, and disrupting all biological processes that depend on + protein breakdown, such as the formation of thyroid hormone and the removal of blood clots. +

+

+ Generally, fruits, roots, and tubers provide a high concentration of nutrients along with low concentrations + of toxic antimetabolic substances. +

+

+ While nutritional reference tables often show fruits and potatoes as having about 2% protein content, while + nuts, grains, and legumes are shown with a high protein content, often in the range of 15% to 40%, they + neglect to point out that fruits and potatoes have a very high water content, while that of the seeds is + extremely low. The protein content of milk is about 3%, which according to the charts would suggest that it + is inferior to beans and grains. In fact, the protein value of grain is negligible, mainly because seeds + contain their protein in a storage form, that is extremely rich in nitrogen, but poor in essential amino + acids. Special preparation is needed to reduce the toxicity of seeds, and in the case of beans, these + methods are never very satisfactory. +

+ +

+ Besides their specific defensive toxins and antimetabolites, plants are major sources of allergens. The + allergenicity of a food depends on the sensitivity of the individual, as well as on the growth conditions of + the plant. The use of extremely toxic pesticides has affected both the crops and the sensitivity of the + human population to allergens. Sensitivities induced originally by toxic pesticides used on certain crops + can probably persist after the industrial chemical has been eliminated, because the immune system is + susceptible to "conditioning." +

+

+ Many types of phytochemicals are mutagenic, and some of those are carcinogenic. Bruce Ames, at the + University of California, devised a method of screening for mutagens, using bacteria. One of his graduate + students using the technique found that the flame retardants in children's pajamas and bedding were powerful + mutagens, and were probably causing cancer. That event made Ames a celebrity, and in the 1980s he went on a + lecture tour supported by the American Cancer Society. His lectures reflected the doctrine of the A.C.S., + that industrial chemicals aren't responsible for cancer, but that individual actions, such as smoking or + dietary choices, are the main causes of cancer. He used a fraudulently "age adjusted" graph of cancer + mortality, that falsely showed that mortality from all types of cancer except lung cancer had leveled off + after the A.C.S. came into existence. He described tests in which he had compared DDT to extracts of food + herbs, and found DDT to be less mutagenic than several of the most commonly used flavoring herbs. His + message, which was eagerly received by his audience of chemistry and biology professors, was that we should + not worry about environmental pollution, because it's not as harmful as the things that we do to ourselves. + He said that if everyone would eat more unsaturated vegetable oil, and didn't smoke, they wouldn't have + anything to worry about. +

+

+ For me, the significance of his experiment was that plants contain natural pesticides that should be taken + more seriously, without taking industrial toxins less seriously. +

+

+ Technologies have been invented to convert vegetation into digestible protein, but at our present scientific + and technological level, it"s better to simply minimize our use of the more toxic foods, and to direct more + effort toward the elimination of the conditions that produce famine. +

+

+ Animal proteins, and fruits, because they contain the lowest levels of toxins, should form the basis of the + diet. Not all fruits, of course, are perfectly safe--avocados, for example, contain so much unsaturated fat + that they can be carcinogenic and hepatotoxic. +

+ +

+ Protein deficiency itself contributes to the harm done by toxins, since the liver"s ability to detoxify them + depends on adequate nutrition, especially good protein. In the 1940s, Biskind"s experiments showed that + protein deficiency leads to the accumulation of estrogen, because the liver normally inactivates all the + estrogen in the blood as it passes through the liver. This applies to phytoestrogens and industrial + estrogens as well as to the natural estrogens of the body. At a certain point, the increased estrogen and + decreased thyroid and progesterone cause infertility, but before that point is reached, the hyperestrogenism + causes a great variety of birth defects. Deformities of the male genitals, and later, testicular cancer in + the sons and breast cancer in the daughters, are produced by the combination of toxins and nutritional + deficiencies. +

+

REFERENCES

+

+ Onderstepoort J Vet Res 1989 Jun;56(2):145-6. Thiaminase activities and thiamine content of + Pteridium aquilinum, Equisetum ramosissimum, Malva parviflora, Pennisetum clandestinum and Medicago + sativa. Meyer P Animal and Dairy Science Research Institute, Private Bag, Irene. Thiaminase + type 1 and 2 activities and thiamine content of five plants were determined. Of these Pteridium aquilinum + and Equisetum ramosissimum were found to have considerably more thiaminase activity and lower thiamine + content than Malva parviflora, Pennisetum clandestinum and Medicago sativa. +

+

+ Nature 1994 Apr 21;368(6473):683-4. Mystery of the poisoned expedition. + + Earl JW, McCleary BV Department of Biochemistry, Royal Alexandra Hospital for Children, Camperdown, Sydney, + New South Wales, Australia. The Burke and Wills expedition through the interior of Australia in the + nineteenth century ended in calamity. But the cause of death was more pernicious than anyone at the time had + imagined: beriberi due to thiaminase poisoning. +

+

+ Comment in: Nature 1994 Aug 11; 370(6489):408. Aust Vet J 1992 Jul;69(7):165-7. + Mechanisms underlying Phalaris aquatica "sudden death" syndrome in sheep. Bourke CA, Carrigan + MJ New South Wales Agriculture, Agricultural Research and Veterinary Centre, Orange. Twenty outbreaks of + Phalaris aquatica "sudden death" syndrome in sheep were investigated between 1981 and 1991. Four were + confirmed and one was suspected, to be a cardiac disorder; 5 were confirmed and 3 were suspected, to be a + polioencephalomalacic disorder; the aetiology of the remaining 7 outbreaks could not be determined. + Potentially toxic levels of hydrocyanic acid (20 to 36 mg/100 g) were measured in the 3 toxic phalaris + pastures tested. The measurement of potentially toxic levels of nitrate nitrogen (2920 micrograms/g) in + toxic phalaris pastures by others, was noted. It is suggested that phalaris "sudden death" syndrome could + have as many as 4 different underlying mechanisms, and + that these might reflect the presence in the plant of a cardio-respiratory toxin, a thiaminase and amine + co-substate, cyanogenic compounds, and nitrate compounds. +

+ +

+ Indian J Med Res 1991 Oct;94:378-83. Genotoxic effects of some foods & food components in Swiss + mice. Balachandran B, Sivaswamy SN, Sivaramakrishnan VM Isotope Division, Cancer Institute, + Madras. A number of commonly consumed foods and food components in south India were + screened for their genotoxic effects on Swiss mice. Salted, sundried and oil fried vegetables and fishes + induced chromosomal aberrations, sperm head abnormalities and micronuclei production, which were + comparable to the effect of the positive control viz., 20-methylcholanthrene. Spices like Cissus quadrangularis (an indigenous herb used in certain south Indian dishes) and pyrolysed cumin and aniseeds + showed moderate effects. Calamus oil, widely used in pharmaceuticals was highly effective. All the three + parameters of genotoxicity gave similar results. +

+

+ In Vivo 1998 Nov-Dec;12(6):675-89. Comparative anticancer effects of vaccination and dietary factors + on experimentally-induced cancers. + Zusman I Laboratory of Teratology and Experimental Oncology, Koret School of Veterinary Medicine, Faculty of + Agriculture, Food and Environmental Quality Sciences, Hebrew University of Jerusalem, Rehovot, Israel. The + role of two major factors were analyzed in the prevention of experimentally-induced cancers: a) vaccination + of animals with polyclonal IgG generated against the soluble p53 antigen and b) feeding of animals with + diets rich with dietary fibers or fat. a) In vaccination, a few attempts have been made to utilize p53 + protein as a tumor suppressor. IgG generated against the cytoplasmic, soluble p53 antigen from tumor-bearing + rats prevents the carcinogenic effect of 1,2-dimethylhydrazine (DMH) decreasing significantly the number of + tumor-bearing rats in vaccinated group compared with non vaccinated controls and preventing benign tumors + from becoming malignant. The antitumor effect of vaccination is accompanied by a significant increase in the + serum-level of p53 antigen in vaccinated rats compared with non vaccinated controls. The immune response of + a host to vaccination activates the lymph components of the spleen, and this activation is manifested by the + multiplication of the number of lymphocytes which are generated against specific antigens. This + multiplication is achieved by the higher division of the antigen-specific lymphoblasts with their subsequent + transformation into plasma cells. These cells synthesize the specific protein (IgG). One such protein is the + tumor-associated p53 protein, which is synthesized by rats against rabbit anti-p53 IgG. b) The role of + dietary factors in the prevention of chemically induced cancer was reviewed on two models: the role of high + fiber diets in prevention of colon cancer, and the role of high fat diets in the prevention of + mammary gland cancer. Experiments in colon cancer showed that 20% cellulose decreased + significantly tumor incidence caused by DMH. The tumor-preventive effect of a cellulose diet was accompanied + by increased enzyme concentrations, such as ornithine decarboxylase, thymidine kinase and + beta-glucuronidase. This effect was accompanied by activation of some cellular mechanisms, i.e. apoptosis, + proliferating cell nuclear antigen (PCNA) and p53 protein synthesis. Experiments in mammary glands + cancer showed that a 15% olive-oil diet reduced significantly the tumor incidence caused by + 9,10-dimethyl-1,2-benzanthracene. The antitumor effect of the olive-oil diet was connected to its + content of monounsaturated fatty acids, such as oleic and palmitic acids. The promotive tumorigenic + effects of other high-fat diets (avocado, soybeans) were associated with high content of some + polyunsaturated fatty acids (linoleic and alpha-linolenic). Different diets have different + targets. The effect of the same diet depends on its anti-tumor substances content. CONCLUSIONS: Vaccination + and some diets have similar mechanism in their tumor-preventive effects. +

+ +

+ Ann Nutr Metab 1991;35(5):253-60. + Effect of dietary avocado oils on hepatic collagen metabolism. Wermam MJ, Mokady S, Neeman I + Department of Food Engineering and Biotechnology, Technion - Israel Institute of Technology, Haifa. The + effect of various avocado and soybean oils on collagen metabolism in the liver was studied in growing female + rats for 8 weeks and in day-old chicks for 1 week. In comparison with rats fed either refined avocado oil, + refined or unrefined soybean oils, rats fed unrefined avocado oil showed a significant decrease in + total collagen solubility + + in the liver, while there were no changes in total collagen, protein and moisture content. Chicks fed + unrefined avocado oil as compared to those fed refined avocado oil also showed a decrease in hepatic total + soluble collagen while hepatic total collagen remained unaffected. Electron micrographs and light-microscope + examinations of rats' liver revealed + collagen accumulation in the periportal location. This is suggestive of the early stages of + fibrosis. +

+

+ Life Sci 1997;60(19):1635-41. L-canaline: a potent antimetabolite and anti-cancer agent from + leguminous plants. Rosenthal GA Laboratory of Biochemical Ecology, University of Kentucky, + Lexington 40506, USA. garose@ukcc.uky.edu + L-Canaline, the L-2-amino-4-(aminooxy)butyric acid structural analog of L-ornithine' is a powerful + antimetabolite stored in many leguminous plants. This nonprotein amino acid reacts vigorously with + the pyridoxal phosphate moiety of vitamin B6-containing enzymes to form a covalently-bound oxime that + inactivates, often irreversibly, the enzyme. + + + Canaline is not only capable of inhibiting ornithine-dependent enzymic activity, but it also can function as + a lysine antagonist. Recently, this natural product was found to possess significant antineoplastic in vitro + activity against human pancreatic cancer cells. +

+

+ Food Chem Toxicol 1999 May;37(5):481-91. Occurrence of emodin, chrysophanol and physcion in + vegetables, herbs and liquors. Genotoxicity and anti-genotoxicity of the anthraquinones and of the whole + plants. Mueller SO, Schmitt M, Dekant W, Stopper H, Schlatter J, Schreier P, Lutz WK Department + of Toxicology, University of Wurzburg, Germany. + 1,8-Dihydroxyanthraquinones, present in laxatives, fungi imperfecti, Chinese herbs and possibly + vegetables, are in debate as human carcinogens. We screened a variety of vegetables (cabbage lettuce, + beans, peas), some herbs and herbal-flavoured liquors for their content of the 'free' anthraquinones + emodin, chrysophanol and physcion. For qualitative and quantitative analysis, reversed-phase HPLC + (RP-LC), gas chromatography-mass spectrometry (GC-MS) and RP-LC-MS were used. The vegetables showed a + large batch-to-batch variability, from 0.04 to 3.6, 5.9 and 36 mg total anthraquinone per kg fresh + weight in peas, cabbage lettuce, and beans, + respectively. Physcion predominated in all vegetables. In the herbs grape vine leaves, couch grass + root and plantain herb, anthraquinones were above the limit of detection. Contents ranged below 1 + mg/kg (dry weight). All three anthraquinones were also found in seven of 11 herbal-flavoured + liquors, in a range of 0.05 mg/kg to 7.6 mg/kg. The genotoxicity of the analysed anthraquinones was + investigated in the comet assay, the micronucleus test and the mutation assay in mouse lymphoma L5178Y + tk+/- + cells. Emodin was genotoxic, whereas chrysophanol and physcion showed no effects. Complete vegetable + extract on its own did not show any effect in the micronucleus test. A lettuce extract completely + abolished the induction of micronuclei by the genotoxic anthraquinone danthron. Taking into + consideration the measured concentrations of anthraquinones, estimated daily intakes, the + genotoxic potency, as well as protective effects of the food matrix, the analysed constituents do not + represent a high priority genotoxic risk in a balanced human diet. +

+ +

+ Int J Food Sci Nutr 1998 Sep;49(5):343-52. Lipid content and fatty acid composition in foods + commonly consumed by nursing Congolese women: incidences on their essential fatty acid intakes and + breast milk fatty acids. + Rocquelin G, Tapsoba S, Mbemba F, Gallon G, Picq C Tropical Nutrition Unit, ORSTOM, Montpellier, France. The + fat content and fatty acid (FA) composition of nearly 40 foods, currently consumed by 102 nursing Congolese + mothers living in Brazzaville, were determined to assess their impact on mothers' essential fatty acid (EFA) + intakes and breast milk FA. Data on mothers' milk FA and dietary habits which allowed food selection were + recently published (Rocquelin et al., 1998). Most foods were locally produced. Food samples were collected + at local markets, bleached if necessary to avoid microbial degradation, and stored at +4 degrees C or -20 + degrees C. They were lyophilized upon their arrival in the laboratory before lipid analyses. FA composition + of food lipids was determined by capillary gas chromatography. Staple diets included low-fat, + high-carbohydrate foods (processed cassava roots, wheat bread) and high-polyunsaturated fatty acid (PUFA) + foods: soybean oil (high in 18 : 2 n-6 and alpha-18 : 3 n-3), bushbutter + (dacryodes edulis), peanuts, avocado (high in fat and 18 : 2 n-6), freshwater + and salt-water fish (high in LC n-3 and/or n-6 PUFA), and leafy green vegetables + (low in fat but very high in alpha-18 : 3 n-3). Their frequent consumption by nursing mothers + provided enough EFA to meet requirements due to lactation. It + also explains why mothers' breast milk was rich in C8-C14 saturated FA (26% of total FA) and in + n-6, n-3 PUFA (respectively 15.0% and 2.4% of total FA) highly profitable for breastfed infants' + development. From this point of view, dietary habits of Congolese mothers have to be sustained for they are + more adequate than most Western-type diets. +

+ +

+ Med Oncol Tumor Pharmacother 1990;7(2-3):69-85. + Dietary carcinogens, environmental pollution, and cancer: some misconceptions. Ames BN, Gold LS + Division of Biochemistry and Molecular Biology, University of California, Berkeley 94720. Various + misconceptions about dietary carcinogens, pesticide residues, and cancer + causation are discussed. The pesticides in our diet are 99.99% natural, since plants make an enormous + variety of toxins against fungi, insects, and animal predators. Although only 50 of these natural + pesticides have been tested in animal cancer tests, about half of them are carcinogens. About + half of all chemicals tested in animal cancer tests are positive. The proportion of natural pesticides + positive in animal tests of clastogenicity is also the same as for synthetic chemicals. It is argued that + testing chemicals in animals at the maximum tolerated dose primarily measures chronic cell proliferation, a + threshold process. Cell proliferation is mutagenic in several ways, including inducing mitotic + recombination, and therefore chronic induction of cell proliferation is a risk factor for cancer. +

+

+ Proc Natl Acad Sci U S A 1980 Aug;77(8):4961-5. Fecalase: a model for activation of dietary + glycosides to mutagens by intestinal flora. Tamura G, Gold C, Ferro-Luzzi A, Ames BN Many + substances in the plant kingdom and in man's diet occur as glycosides. Recent studies have indicated that + many glycosides that are not mutagenic in tests such as the Salmonella test become mutagenic upon hydrolysis + of the glycosidic linkages. The Salmonella test utilizes a liver homogenate to approximate mammalian + metabolism but does not provide a source of the enzymes present in intestinal bacterial flora that hydrolyze + the wide variety of glycosides present in nature. We describe a stable cell-free extract of human feces, + fecalase, which is shown to contain various glycosidases that allow the in vitro activation of many natural + glycosides to mutagens in the Salmonella/liver homogenate test. Many beverages, such as red wine (but + apparently not white wine) and tea, contain glycosides of the mutagne quercetin. Red wine, red grape juice, + and tea were mutagenic in the test when fecalase was added, and red wine contained considerable direct + mutagenic activity in the absence of fecalase. The implications of quercetin mutagenicity and + carcinogenicity are discussed. +

+ +

+ Br J Rheumatol 1994 Aug;33(8):790-1. Even garlic. Sweetman BJ +

+

+ Nutr Cancer 1988;11(4):251-7. Cytotoxicity of extracts of spices to cultured cells. + Unnikrishnan MC, Kuttan R Amala Cancer Research Centre, Kerala, India. The cytotoxicity of the extracts from + eight different spices used in the Indian diet was determined using Dalton's lymphoma ascites tumor cells + and human lymphocytes in vitro and Chinese Hamster Ovary cells and Vero cells in tissue culture. Alcoholic + extracts of the spices were found to be more cytotoxic to these cells than their aqueous extracts. Alcoholic + extracts of several spices inhibited cell growth at concentrations of 0.2-1 mg/ml in vitro and 0.12-0.3 + mg/ml in tissue culture. + Ginger, pippali (native to India; also called dried catkins), pepper, and garlic showed the highest + activity followed by asafetida, mustard, and horse-gram (native to India). These extracts also inhibited + the thymidine uptake into DNA. +

+

+ J Toxicol Sci 1984 Feb;9(1):77-86. + [Mutagenicity and cytotoxicity tests of garlic]. [Article in Japanese] Yoshida S, Hirao Y, + Nakagawa S Mutagenicity and cytotoxicity of fresh juice and alcohol extract from garlic were studied by + Ames' test, Rec assay, Micronucleus test and the check of the influence to HEp 2 and chinese hamster embryo + (CHE) primary cultured cells. No evidence of mutagenicity of these samples were observed in Ames' test and + Rec assay, while there was dose dependent increase of micronucleated cells and polychromatocytes on the bone + marrow cells of mice and chinese hamsters treated with garlic juice. There were severe damages, e.g. growth + inhibition and morphological changes of both cultured cells due to garlic juice, but no or slightly + cytotoxic signs were observed even in high concentration of garlic extract. A higher sensitivity to the + cytotoxic effects of garlic was seen by the present findings with CHE primary cells than HEp 2 cell line. +

+

+ Chung Hua Chung Liu Tsa Chih 1985 Mar;7(2):103-5 [Comparison of the cytotoxic effect of fresh + garlic, diallyl trisulfide, 5-fluorouracil (5-FU), mitomycin C (MMC) and Cis-DDP on two lines of gastric + cancer cells]. + [Article in Chinese] Pan XY Teratog Carcinog Mutagen 1998; 18(6):293-302 + In vitro and in vivo study of the clastogenicity of the flavone cirsitakaoside extracted from Scoparia + dulcis L. (Scrophulariaceae). Pereira-Martins SR, Takahashi CS, Tavares DC, Torres LM + Department of Biology, Federal University of Maranhao, Sao Luis, MA. Brazil. smartins@rgm.fmrp.usp.br The mutagenic effect of the flavone cirsitakaoside extracted from the + medicinal herb Scoparia dulcis was evaluated in vitro by using human peripheral blood cultures treated with + doses of 5, 10, and 15 microg of the flavone/ml culture medium for 48 h. The compound proved to be mutagenic + at the highest concentration tested (15 microg/ml). Furthermore, the proliferative index was significantly + reduced in all cultures treated with the flavone, although the mitotic index was not reduced. However, the + clastogenic activity of the flavone cirsitakaoside was not observed when Swiss mice were treated orally with + doses of 10, 20, and 30 mg/animal for 24 h. +

+

+ Proc Nutr Soc 1977 Sep;36(2):51A.Attempts to overcome anti-nutritive factors in field beans (Vicia + faba L) and field peas (Pisum sativum) fed in diets to laying hens. + + + Davidson J +

+

+ Am J Clin Nutr 1995 Sep;62(3):506-11. The influence of genetic taste markers on food + acceptance. Drewnowski A, Rock CL Human Nutrition Program, School of Public Health, University + of Michigan, Ann Arbor 48109-2029, USA. Genetically mediated sensitivity to the bitter taste of + phenylthiocarbamide + (PTC) and 6-n-propylthiouracil (Prop) has long been associated with enhanced sensitivity to other sweet + and bitter compounds. New studies suggest that tasters and supertasters of Prop may also differ from + notasters in their taste preferences and in their patterns of food rejection and food acceptance. One + question is whether the acceptability of bitter-tasting vegetables is influenced by Prop taster status. + Cruciferous vegetables are among the major dietary sources of potentially chemoprotective + agents in cancer control, and their consumption is reported to alter cancer risk. Strategies aimed at + dietary change in individuals or groups should consider the role of genetic taste markers and their + potential influences on food preferences and dietary habits. +

+

+ J Environ Sci Health B 1999 Jul;34(4):681-708. Accumulation of potentially toxic elements in plants + and their transfer to human food chain. + Dudka S, Miller WP University of Georgia, Department of Crop and Soil Sciences, Athens 30602-2727, USA. + Contaminated soils can be a source for crop plants of such elements like As, Cd, Cr, Cu, Ni, Pb, and Zn. The + excessive transfer of As, Cu, Ni, and Zn to the food chain is controlled by a "soil-plant barrier"; however, for some elements, including Cd, the soil-plant barrier fails. The level of Cd ingested + by average person in USA is about 12 micrograms/day, which is relatively low comparing to Risk Reference + Dose (70 micrograms Cd/day) established by USEPA. Food of plant origin is a main source of Cd intake + by modern society. Fish and shellfish may be a dominant dietary sources of Hg for some human + populations. About half of human Pb intake is through food, of which more than half originates from + plants. + + Dietary intake of Cd and Pb may be increased by application of sludges on cropland with already high levels + of these metals. Soils amended with sludges in the USA will be permitted (by USEPA-503 regulations) + to accumulate Cr, Cd, Cu, Pb, Hg, Ni, and Se, and Zn to levels from 10 to 100 times the present baseline + concentrations. + These levels are very permissive by international standards. Because of the limited supply of toxicity data + obtained from metals applied in sewage sludge, predictions as to the new regulations will protect crop + plants from metal toxicities, and food chain from contamination, are difficult to make. +

+

+ BJU Int 2000 Jan;85(1):107-13. A maternal vegetarian diet in pregnancy is associated with + hypospadias. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. + North K, Golding J Unit of Paediatric and Perinatal Epidemiology, Division of Child Health, University of + Bristol, UK. OBJECTIVE: To investigate the possible role of the maternal diet, particularly vegetarianism + and consumption of phytoestrogens, in the origin of hypospadias, which is reported to be increasing in + prevalence. SUBJECTS AND METHODS: Detailed information was obtained prospectively from mothers, including + previous obstetric history, lifestyle and dietary practices, using structured self-completed questionnaires + during pregnancy. Previously recognized associations with environmental and parental factors were examined, + focusing particularly on the hypothesized hormonal link. Multivariate logistic regression was used to + identify independent associations. RESULTS: Of 7928 boys born to mothers taking part in the Avon + Longitudinal Study of Pregnancy and Childhood, 51 hypospadias cases were identified. There were no + significant differences in the proportion of hypospadias cases among mothers who smoked, consumed alcohol or + for any aspect of their previous reproductive history (including the number of previous pregnancies, number + of miscarriages, use of the contraceptive pill, time to conception and age at menarche). Significant + differences were detected for some aspects of the maternal diet, i.e. vegetarianism and iron + supplementation in the first half of pregnancy. Mothers who were vegetarian in pregnancy had an adjusted + odds ratio (OR) of 4.99 (95% confidence interval, CI, 2.10-11.88) of giving birth to a boy with + hypospadias, compared with omnivores who did not supplement their diet with iron. Omnivores who + supplemented their diet with iron had an adjusted OR of 2.07 (95% CI, 1.00-4.32). The only + other statistically significant association for hypospadias was with influenza in the first 3 months of + pregnancy (adjusted OR 3.19, 95% CI 1.50-6.78). CONCLUSION: As vegetarians have a greater exposure to + phytoestrogens than do omnivores, these results support the possibility that phytoestrogens have a + deleterious effect on the developing male reproductive system. +

+ +

+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com +

+ + diff --git a/raypeat-articles/processed/vitamin-e.html b/raypeat-articles/processed/vitamin-e.html new file mode 100644 index 0000000..4f01012 --- /dev/null +++ b/raypeat-articles/processed/vitamin-e.html @@ -0,0 +1,783 @@ + + Vitamin E: Estrogen antagonist, energy promoter, and anti-inflammatory + +

+ Vitamin E: Estrogen antagonist, energy promoter, and anti-inflammatory +

+ +

+ Vitamin E, like progesterone and aspirin, acts within the cellular regulatory systems, to prevent + inflammation and inappropriate excitation. Since uncontrolled excitation causes destructive oxidations, + these substances prevent those forms of oxidation. +

+

+ Molecules that can easily be oxidized and reduced can function as antioxidants, and vitamin E does + function as that kind of antioxidant in many chemical environments. But it is highly misleading to + consider that as the explanation for its many beneficial biological effects. That kind of reasoning + contributed to the use of the antioxidant carcinogens BHT and BHA as food additives and "antiaging" + supplements, and many other chemicals are being promoted on the basis of their abstract antioxidant + function. +

+

+ Becoming aware of the real value of vitamin E will have far reaching implications in nutrition and + medicine. +

+ +

+ In determining criminal or civil legal responsibility, the concept "should have known" is recognized and + used. In science, which is all about knowing, there is certainly a responsibility to be informed when + the subject involves the life and health of millions of people. The science establishment of government + and industry should be held responsible for the information it hides, destroys, or ignores for its own + benefit. The US government has an agency for prosecuting research fraud, but the concept is applied so + narrowly as to be meaningless, when deception has become the rule. And since it controls the court + system, govenment agencies and their functionaries won't be prosecuted, even when their crimes become + well known. +

+

+ "Vitamin E was advocated as an effective treatment for heart disease by Dr. Evan Shute of London, + Ontario more than 50 years ago. + + His pioneering claims, which were unacceptable to the medical community at large, have been + confirmed by recent findings from epidemiologic studies and clinical trials. + " +

+ +
+ +

+ Political scientists have recognized the process in which big corporations "capture" the governmental + agencies that were created to regulate them. The editorial boards of professional journals can be captured + even more cheaply than the agencies of government, and their influence can be even more valuable to + industry. +

+

+ If science impinges upon the plans of an industry, it can be managed into compliance, when the industry + controls the journals and the agencies that fund research. +

+

+ In the 1940s, it had already become clear to the estrogen industry that vitamin E research was impinging on + its vital interests. +

+

+ The Manhattan Project, that created the atomic bomb, also created a generation of scientific and + bureaucratic zealots who ignored public health and safety to advance their projects and their careers, and + changed the way science was done. At exactly the same time, the pharmaceutical industry was using its + financial and political power to change the way medicine was practiced and taught, and the consequences for + world health rivalled those of the nuclear industry. +

+

+ In 1933 the physician R.J. Shute was aware of the problems associated with toxemia of pregnancy or + preeclampsia. Especially among poorly nourished women, many pregnancies were complicated by circulatory + problems, including cyclic bleeding, thrombosis, stroke, and hypertension, and these difficult pregnancies + often ended in miscarriage or premature delivery, resulting in many serious health problems among the babies + that survived. +

+

+ At that time, both estrogen and vitamin E were being widely studied, though the exact structure of the + tocopherol molecule wasn't defined until 1936-37. Vitamin E had been found to improve fertility of both male + and female animals, and to prevent intrauterine death of the embryo or fetus, so it was called the + "antisterility vitamin." Using it to prevent women from having miscarriages must have occurred to many + people. +

+ +

+ Animal research in the 1930s was also showing that estrogen had many toxic effects, including causing + infertility or intrauterine death, connective tissue abnormalities, and excessive blood clotting. Dr. Shute + and his sons, Wilfred and Evan, were among those who considered vitamin E to be an antiestrogen. They found + that it was very effective in preventing the clotting diseases of pregnancy. +

+

+ Other researchers, who knew that progesterone protected against the toxic effects of estrogen, described + vitamin E as the "progesterone-sparing agent," since so many of its antiestrogenic effects resembled those + of progesterone. +

+

+ The Shute brothers began using vitamin E to treat circulatory diseases in general, rather than just in + pregnant women--blood clots, phlebitis, hypertension, heart disease, and diabetes all responded well to + treatment with large doses. +

+

+ Vitamin E, as its name indicates, was the fifth type of "vitamin" factor to be identified, and it received + its name in 1922, even though its chemical structure hadn't been identified. The public quickly understood + and accepted that certain substances in food were essential for life and health, so by 1940 practically all + physicians were recommending the use of nutritional supplements. +

+ +

+ If vitamin E was essential for human health, and achieved at least some of its amazing effects by opposing + estrogen, then the synthetic estrogen industry had a problem. +

+

+ Edward L. Bernays had already been in business for decades, teaching corporations and governments how to + "engineer consent." After his work for the government to engineer support for entering the first world war, + Bernays' next big job was for the tobacco industry. To convince women to smoke cigarettes, to achieve + equality with men, he organized an Easter parade, Torches of Freedom, in which thousands of women marched + smoking their freedom torches. In association with the American Medical Association (the editor of JAMA + actually helped the tobacco industry design its campaigns), Bernays ran a campaign to convince Americans + that smoking was good for the health. +

+

+ The drug industry began using his techniques in sometimes crude but always effective ways. Estrogen was + named "the female hormone;" natural hormones, including estrogen and progesterone, were claimed, without any + research, to be inactive when taken orally. Physician-shills were created to claim wonderful effects for + estrogen. The vitamin status of the tocopherols was denied; as recently as the 1970s (and maybe later), + university professors of dietetics were flatly saying "no one needs vitamin E." +

+ +

+ Very little research showing the curative effects of vitamin E in human diseases was allowed to be + published, so it was only occasionally necessary to openly denounce vitamin E as worthless or dangerous. In + 1981, the journal of the AMA published an article reviewing the "toxic" effects of vitamin E. Since I had + read all of the articles cited, I realized that the author was claiming that whenever vitamin E changed + something, the change was harmful, even though the original publication had described the effect as + beneficial. +

+

+ Although JAMA was eventually forced to give up its revenue from cigarette advertising, it didn't suffer at + all, because of the vast advertising campaigns of the estrogen industry. JAMA obviously wouldn't want to + publish anything suggesting that vitamin E, or progesterone, or thyroid, might be beneficial because of its + antagonism of the harmful effects of estrogen. +

+

+ Estrogen causes changes in the uterus that prevent implantation of the embryo, and that impair support for + its development if it has already implanted. It decreases the availability of oxygen to the embryo, while + vitamin E increases it. +

+

+ My dissertation adviser, A.L. Soderwall, did a series of experiments in which he showed that providing + hamsters with extra vitamin E postponed the onset of infertility in middle age. In my experiments, vitamin E + increased the amount of oxygen in the uterus, correcting an oxygen deficiency produced either by + supplemental estrogen or by old age. Progesterone has similar effects on the delivery of oxygen to the + uterus. +

+

+ In the 1940s, the official definition of vitamin E's activity was changed. Instead of its effectiveness in + preventing the death and resorption of embryos, or the degeneration of the testicles or brain or muscles, it + was redefined as an antioxidant, preventing the oxidation of unsaturated oils. +

+ +

+ Although some people continued to think of it as a protective factor against thrombosis, heart attacks, + diabetes, and infertility, the medical establishment claimed that the prevention or cure of diseases in + animals wasn't relevant to humans, and that a mere antioxidant couldn't prevent or cure any human disease. +

+

+ The experiments that led to the identification of vitamin E involved feeding rats a diet containing rancid + lard and, as a vitamin A supplement, cod liver oil. Both of these contained large amounts of polyunsaturated + oils. +

+

+ From 1929 to the early 1930s, other researchers were claiming to have demonstrated that the polyunsaturated + fatty acids were nutritionally essential. These experiments, like the vitamin E experiments, were done on + rats, but the medical establishment was satisfied that rat experiments proved that humans need linoleic or + linolenic acid, while they refused to accept that vitamin E was essential for humans. When, in the 1940s, a + group of vitamin B6 researchers showed that the supposed "essential fatty acid deficiency" could be cured by + a supplement of vitamin B6, it became apparent that the polyunsaturated fatty acids slowed metabolism, and + reduced all nutritional needs. The thyroid hormone was powerfully suppressed by the "essential" fatty acids. +

+

+ When we consider the two sets of experiments together, their outstanding feature is the toxicity of the + polyunsaturated oils, which in one kind of experiment suppressed metabolism, and in the other kind of + experiment created a variety of degenerative conditions. +

+ +

+ By the late 1940s and early 1950s, estrogens of various sorts had been synthesized from hydrocarbons, and + were being recommended to prevent miscarriages, because "estrogen is the female hormone." The meat industry + had found that the polyunsaturated oils were valuable in animal feed, since they suppressed metabolism and + made it cheaper to fatten the animals, and these antithyroid oils were next marketed as "heart protective" + human foods, though by suppressing the thyroid and destroying vitamin E, they actually contributed to both + heart disease and cancer. (Giving estrogen to livestock to improve their feed efficiency, and to people "to + prevent heart attacks," was an interesting parallel to the oil promotional campaigns.) +

+

+ The influence of the food oil industry kept researchers away from the idea that these oils were not safe for + food use, and instead tended to support the idea that vitamin E is just an antioxidant, and that the seed + oils were the best way to get vitamin E in the diet. +

+

+ The antifertility effects of the polyunsaturated oils, demonstrated in the vitamin E experiments, weren't at + the time understood to have anything to do with estrogen's antifertility effects. But to understand vitamin + E, I think we have to consider the close interactions between estrogen and the polyunsatured fatty acids + (PUFA). Their actions are closely intertwined, and are antagonized by a variety of energizing and + stabiliizing substances, including saturated fats, progesterone, thyroid, vitamin E, and aspirin. +

+ +

+ Generally, chemicals that inhibit enzymes are toxic, producing some sort of symptom or deterioration. But a + group of enzymes related to estrogen and PUFA are inhibited by these protective substances. Although under + our present diet, these enzymes metabolize the PUFA, in the fetus and newborn they act on our endogenous + fats, the series related to the Mead acids. The Mead acid is antiinflammatory, and broadly protective. The + dietary PUFA interfere with these natural protective substances, +

+

+ The enzymes that, if we didn"t eat PUFA, would be regulating the Mead series, being activated in response to + stress, would be producing antistress substances, which would limit the stress reaction. But as we become + increasingly saturated with the anti-vitamin E fats, these enzymes, instead of stopping inflammation, + promote it and cause tissue injury. The remaining stress limiting factors, such as progesterone, by + correcting the distortions caused by stress, tend to eliminate the conditions which activated the + enzymes--in a very indirect form of inhibition. +

+

+ Many of the events involved in inflammation are increased by estrogen, and decreased by vitamin E. Estrogen + causes capillaries to become leaky; vitamin E does the opposite. Estrogen increases platelet aggregation, + and decreases a factor that inhibits platelet aggregation; vitamin E does the opposite. +

+

+ Excess clotting is known to be caused by too much estrogen, and also by a vitamin E deficiency. +

+

+ Clotting leads to fibrosis, and there is clear evidence that vitamin E prevents and cures fibrotic diseases, + but this still isn't generally accepted by the powerful medical institutions. Estrogen and polyunsaturated + fats increase fibrosis. +

+

+ Estrogen increases progstaglandin synthesis, vitamin E decreases their synthesis; estrogen increases the + activity of the enzymes COX and LOX, vitamin E decreases their activitiy. (Jiang, et al., 2000; Ali, et al., + 1980; Parkhomets, et al., 2001.) Estrogen releases enzymes from lysosomes, vitamin E inhibits their release. + Beta-glucuronidase, one of these enzymes, can release estrogen at the site of an inflammation. +

+ +

+ Estrogen often increases intracellular calcium and protein kinase C, vitamin E has generally opposite + effects. +

+

+ The polyunsaturated fatty acids and their derivatives, the prostaglandins, act as effectors, or amplifiers, + of estrogen's actions. +

+

+ If vitamin E is acting as a protectant against the polyunsaturated fatty acids, that in itself would account + for at least some of its antiestrogenic effects. +

+

+ Besides antagonizing some of the end effects of the toxic fatty acids, vitamin E inhibits lipolysis, + lowering the concentration of free fatty acids (the opposite of estrogen"s effect), and it also binds to, + and inactivates, free fatty acids. The long saturated carbon chain is very important for its full + functioning, and this saturated chain might allow it to serve as a substitute for the omega -9 fats, from + which the Mead acid is formed. The unsaturated tocotrienols have hardly been tested for the spectrum of true + vitamin E activity, and animal studies have suggested that it may be toxic, since it caused liver + enlargement. +

+

+ One possibly crucial protective effect of vitamin E against the polyunsaturated fatty acids that hasn't been + explored is the direct destruction of linolenic and linoleic acid. It is known that bacterial + vitamin E is involved in the saturation of unsaturated fatty acids, and it is also known that intestinal + bacteria turn linoleic and linolenic acids into the fully saturated stearic acid. +

+ +

+ "No metabolic function is known for alpha-tocopherolquinol or its quinone other than as a cofactor + in the biohydrogenation of unsaturated fatty acids that can be carried out by only a few + organisms." +

+

+ + P.E. Hughes and S.B. Tove, 1982. +

+

+ "Linoleic acid was significantly decreased (P < 0.001) and there was a significant rise (P + < 0.05) in its hydrogenation product, stearic acid. Linolenic acid was also significantly + decreased. . . ." "The study provides evidence that bacteria from the human colon can hydrogenate + C18 essential polyunsaturated fatty acids." +

+

+ + F.A. Howard & C. + + Henderson, 1999 +

+ +

+ Because of the way in which the decision to call vitamin E a simple antioxidant was conditioned by the + historical setting, there has been a reluctance, until recently, to give much weight to the pathogenicity of + lipid peroxidation and free radicals, partly because lipid peroxidation is only a minor part of the toxicity + of the polyunsaturated oils, and there was little support for the investigation of the real nature of their + toxicity. This environment has even distorted the actual antioxidant value of the various forms of vitamin + E. (For example, see Chen, et al., 2002.) +

+

+ The people who say that vitamin E is nothing but an antioxidant sometimes take other antioxidants, with, or + instead of, vitamin E. BHT, BHA, and many natural compounds (derived from industrial and agricultural + wastes) are often said to be "better than vitamin E" as antioxidants. Anything that can be oxidized and + reduced (melatonin, estrogen, tryptophan, carotene, etc.) will function as an antioxidant in some system, + but in other circumstances, it can be a pro-oxidant. +

+

+ The people who think there is benefit in the abstract "antioxidant" function seem to be thinking in terms of + something that will, like a ubiquitous fire department, put out every little fire as soon as it starts. I + think it's more appropriate to think of the biological antioxidant systems as programs for controlling the + arsonists before they can set the fires. +

+

+ Since the requirement for vitamin E decreases as the consumption of unsaturated fats decreases, the + requirement, if any, would be very small if we didn't eat significant quantities of those fats. +

+ +

+ In the years since the tocopherols were identified as vitamin E, the material sold for research and for use + as a nutritional supplement has changed drastically several times, even when it has been given a specific + chemical identity, such as mixed tocopherols or d-alpha tocopherol. Variations in viscosity and color, + caused by changes in the impurities, have undoubtedly influenced its biological effects, but the ideology + about its antioxidant value has kept researchers from finding out what a particular batch of it really is + and what it really does. +

+

+ "We compared the effect of a mixed tocopherol preparation with that of alpha-tocopherol alone on + superoxide dismutase (SOD) activity and iNOS expression in cultured myocytes exposed to + + H-R." "Both tocopherol preparations attenuated cell injury. . . ." "However, mixed-tocopherol + preparation was much superior to alpha-tocopherol in terms of myocyte protection. . . ." "Lack of + efficacy of commercial tocopherol preparations in clinical trials may reflect absence of gamma- and + delta-tocopherols." +

+

+ Chen + H, Li D, Saldeen T, Romeo F, Mehta JL,Biochem Biophys Res Commun 2002 "Mixed tocopherol preparation + is superior to alpha-tocopherol alone against hypoxia-reoxygenation injury." +

+

+ Keeping our diet as free as possible of the polyunsaturated fats, to create something like the "deficiency" + state that is so protective (against cancer, trauma, poison, shock, inflammation, infection, etc.) in the + animal experiments, seems preferable to trying to saturate ourselves with antioxidants, considering the + imperfectly defined nature of the vitamin E products, and the known toxicity of many of the other + antioxidants on the market. +

+ +

+ The carcinogenic properties of the polyunsaturated fats have been known for more than 50 years, as has the + principle of extending the life span by restricted feeding. More recently several studies have demonstrated + that the long lived species contain fewer highly unsaturated fats than the short lived species. Restriction of calories prevents the lipids in the brain, heart, and liver from becoming more unsaturated + with aging. + (Lee, et al., 1999; Laganiere, et al., 1993; Tacconi, et al., 1991; R. Patzelt-Wenczler, 1981.) +

+

+ When cells are grown in tissue culture without the "essential fatty acids," they become "deficient," and in + that state are very resistant to chemical injury, and can be grown indefinitely. Besides being a simple + demonstration of the way in which the polyunsaturated fats sensitize cells to injury (Wey, et al., 1993), + these experiments must be an embarrassment to the people who base their argument for the oils" essentiality + on a supposed requirement for "making cell membranes." Since the cells can multiply nicely in their + deficient state, we have to conclude that the oils aren"t needed for "membranes," or maybe that cells resist + injury better "without membranes." +

+

+ In the opposite direction, an excess of insulin or prolactin, or a deficiency of vitamin E, increases the + activity of the enzymes that convert linoleic acid into the more highly unsaturated fatty acids. Excess + insulin and prolactin are crucially involved in many degenerative diseases. +

+

+ The highly unsaturated fats suppress respiration in many ways, and these trends toward increased + unsaturation with aging, endocrine stress, and vitamin E deficiency parallel the life-long trend toward + lower energy production from respiration. Many studies show that vitamin E can protect and improve + mitochondrial energy production. (Kikuchi, et al., 1991; Donchenko, et al., 1990, 1983; Guarnieri, et al., + 1981, 1982.) But the state of so-called essential fatty acid deficiency not only makes mitochondria very + resistant to injury, it greatly intensifies their energy production. Vitamin E supplementation is seldom as + effective as the absence of the toxic oils. +

+

+ Many nutrition charts no longer list liver as a good source of vitamin E, but a large portion of an animal"s + vitamin E is in its liver. This bias in the dietetic literature can be traced to various sources, but a + major influence was the campaign in the 1970s by the drug companies that had patented new forms of synthetic + "vitamin A." They had physicians and professors fabricate stories about the great toxicity of natural + vitamin A, and placed the stories in national magazines, to clear the field for their supposedly non-toxic + products, which have turned out to be disastrously toxic. The result is that many people have fearfully + stopped eating liver, because of its vitamin A. The other vitamins in liver, including vitamin K, function + very closely with vitamin E, and the stably stored forms of vitamin E are likely to be a good approximation + for our needs. +

+ +

+ There is still a strong division between what people can say in their professional publications, and what + they believe. A man who was influential in designating vitamin E as an antioxidant, M.K. Horwitt, complained + when the government raised its recommended vitamin E intake by 50%, because it wasn"t supported by new data, + and because millions of people get only ten milligrams per day and "are healthy." But he has been taking 200 + mg daily (plus aspirin) for many years. He apparently doesn't have very much confidence in the ideas he + advocates publicly. +

+

REFERENCES

+

+ Prostaglandins Med 1980 Feb;4(2):79-85. Inhibition of human platelet cyclooxygenase by + alpha-tocopherol. Ali M, Gudbranson CG, McDonald JW. Alpha-tocopherol, an inhibitor of platelet + aggregation, was evaluated for its + effects on the synthesis of thromboxane and prostaglandins. A dose-dependent reduction in thromboxane B2 + and prostaglandin D2 synthesis was observed with + + approximately 60% inhibition at 5.0 IU or alpha-tocopherol. Alpha-tocopherol produced a time-dependent, + irreversible inhibition. +

+

+ Int J Vitam Nutr Res 2001 Jan;71(1):18-24. Vitamin E and the prevention of atherosclerosis. + Bron D, Asmis R. "Recent new findings have shed new light + on the physiological role of vitamin E and suggest that it has a much broader array of biological + activities than originally expected. In addition to its well described role as an antioxidant, it is + becoming evident that vitamin E also can modulate the immune system, suppress local and chronic + inflammation, reduce blood coagulation and thrombus formation, and enhance cell function and + survival." +

+

+ Plast Reconstr Surg 1981 Nov;68(5):696-9. The effectiveness of alpha-tocopherol (vitamin E) in + reducing the incidence of spherical contracture around breast implants. Baker JL Jr. Vitamin E + appears to be a safe, simple, and inexpensive means of reducing the number of postoperative capsular + contractures following breast augmentation. The synthetic form of vitamin E (alpha-tocopherol) is + recommended to avoid nausea or skin eruptions in patients with oily skin, which are frequently encountered + when the natural form is taken. No harmful side effects have been noted in any of the patients to date. + Vitamin E has no effect on coagulation systems and does not cause excessive bleeding either during or after + surgery. The recommended dosage of synthetic vitamin E is 1000 IU, b.i.d., for 2 years beginning 1 week + before surgery. If no contracture exists at that time, the dosage may be reduced to 1000 IU daily + thereafter. +

+

+ Carcinogenesis 1999 Jun;20(6):1019-24. Decrease in linoleic acid metabolites as a potential + mechanism in cancer risk reduction by conjugated linoleic acid. Banni S, Angioni E, Casu V, + Melis MP, Carta G, Corongiu FP, Thompson H, Ip C. +

+ +

+ Mech Ageing Dev 1978 Nov;8(5):311-28. Anomalous vitamin E effects in mitochondrial oxidative + metabolism. Baumgartner WA, Hill VA, Wright ET. Three different vitamin E effects, suggestive + of specific antioxidant effects, were discovered in the protective action of vitamin E against respiratory + decline (a decrease in mitochondrial respiration attributed to a "leakage" of electron transport radicals). + + No correlation was found between respiraotry decline and random lipid peroxidation. The + mechanisms behind two of the three atypical vitamin E effects were defined. Both involve an artifact in the + TBA assay for lipid peroxidation. This artifact occurs when TBA assays are carried + out in the presence of sucrose and acetaldehyde; the latter is produced from ethanol, the solvent used + to add vitamin E to preparations. The artifact in the TBA assay for peroxidations appears also to be + responsible for differing interpretations of the hepatotoxic effect of ethanol. +

+

+ Eur J Biochem 1990 Mar 10;188(2):327-32. Polychlorinated biphenyls increase fatty acid desaturation + in the proliferating endoplasmic reticulum of pigeon and rat livers. Borlakoglu JT, + Edwards-Webb JD, Dils RR. +

+ +

+ Nutr Cancer 2000;38(1):87-97. Effects of topical and oral vitamin E on pigmentation and skin cancer + induced by ultraviolet irradiation in Skh:2 hairless mice. Burke KE, Clive J, Combs GF Jr, + Commisso J, Keen CL, Nakamura RM. "Results showed that the skin concentrations of Eol, as well as + levels in the adipose tissue, were increased after topical application. Mice treated with each form of + vitamin E showed no signs of toxicity and had significantly less acute and chronic skin damage induced + by UV irradiation, as indicated by reduced inflammation and pigmentation and by later onset and lesser + incidence of skin cancer." +

+

+ Am J Physiol 1991 Jun;260(6 Pt 2):R1235-40. Acute phase response in exercise. II. Associations + between vitamin E, cytokines, and muscle proteolysis. Cannon JG, Meydani SN, Fielding RA, + Fiatarone MA, Meydani M, Farhangmehr M, Orencole SF, Blumberg JB, Evans WJ. +

+

+ Vrach Delo 1990 Dec;(12):6-8. [The effect of tocopherol and nicotinic acid on the microcirculation + and blood coagulability in patients with ischemic heart disease] Chernomorets NN, Kotlubei GV, + Vatutin NT, Zhivotovskaia IA, Gnilitskaia VB, Alifanova RE, Lobach EIa, Mal'tseva NV, Mitrofanov AN. + "Complex treatment using tocopherol acetate produced a positive effect on the coagulation properties of the + blood and did essentially influence the fibrinolytic activity and microcirculation. Tocopherol plus + nicotinic acid resulted in normalization of the blood coagulation process, + favoured activation of fibrinolysis and improvement of the microcirculatory bed." +

+ +

+ Free Radic Biol Med 1991;10(5):325-38. Oxidative status and oral contraceptive. Its relevance to + platelet abnormalities and cardiovascular risk. Ciavatti M, Renaud S. INSERM Unit 63, Bron, + France. "Oral contraceptive (OC) use is a risk for thrombogenic events." "From these data + we conclude that: + 1. OC use modifies slightly but significantly the oxidative status in women and in animals by decreasing + in plasma and blood cells the antioxidant defenses (vitamins and enzymes). 2. The changes in + the oxidative status are related to an increase in plasma lipid peroxides apparently responsible for the + hyperaggregability and possibly the imbalance in clotting factors associated with the OC-induced + prethrombotic state. + 3. These effects of OC appear to be increased by a high intake of polyunsaturated fat and counteracted + by supplements of vitamin E. 4. The risk factors acting synergistically with OC, have all been + shown to increase platelet reactivity." +

+ +

+ Bol Med Hosp Infant Mex 1980 May-Jun;37(3):457-67. [Jaundice caused by microangiopathic hemolysis + associated to septicemia in the newborn] + Covarrubias Espinoza G, Lepe Zuniga JL. "These infants with over 3% fragmented cells + were found to have a significant association with: sepsis, jaundice, crenated RBC's, low levels of + hemoglobin, increased reticulocyte count, and low vitamin E levels." +

+

+ Endocrinology 1992 Nov;131(5):2482-4. Vitamin E protects hypothalamic beta-endorphin neurons from + estradiol neurotoxicity. Desjardins GC, Beaudet A, Schipper HM, Brawer JR. + "Estradiol valerate (EV) treatment has been shown to result in the destruction of 60% of beta-endorphin + neurons in the hypothalamic arcuate nucleus. Evidence suggests that the mechanism of EV-induced + neurotoxicity involves the conversion of estradiol to catechol estrogen and subsequent oxidation to free + radicals in local peroxidase-positive astrocytes. In this study, we examined whether treatment + with the antioxidant, vitamin E, protects beta-endorphin neurons from the neurotoxic action of estradiol. + Our results demonstrate that chronic vitamin E treatment prevents the decrement in hypothalamic + beta-endorphin concentrations resulting from arcuate beta-endorphin cell loss, suggesting that the + latter is mediated by free radicals. + Vitamin E treatment also prevented the onset of persistent vaginal cornification and polycystic + ovarian condition which have been shown to result from the EV-induced hypothalamic pathology." +

+ +

+ Free Radic Biol Med 2000 Dec 15;29(12):1302-6. Hyperinsulinemia: the missing link among oxidative + stress and age-related diseases? + Facchini FS, Hua NW, Reaven GM, Stoohs RA. "Other proaging effects of insulin involve the inhibition + of proteasome and the stimulation of polyunsaturated fatty acid (PUFA) synthesis and of nitric oxide + (NO). The hypothesis that hyperinsulinemia accelerates aging also offers a + metabolic explanation for the life-prolonging effect of calorie restriction and of + mutations decreasing the overall activity of insulin-like receptors in the nematode Caenorhabditis elegans." +

+

+ J Bacteriol 1982 Sep;151(3):1397-402. Occurrence of alpha-tocopherolquinone and + alpha-tocopherolquinol in microorganisms. + Hughes PE, Tove SB. "Both alpha-tocopherolquinol and alpha-tocopherolquinone were found in 56 of 93 strains + of microorganisms examined." "Those microorganisms that did not contain alpha-tocopherolquinol or + alpha-tocopherolquinone tended to fall into two groups. One group consisted of gram-positive, anaerobic or + facultative bacteria with a low content of guanine and cytosine, and the second group encompassed all of the + filamentous microorganisms studied." "No metabolic function is known for alpha-tocopherolquinol or + its quinone other than as a cofactor in the biohydrogenation of unsaturated fatty acids that can be + carried out by only a few organisms." +

+ +

+ J Biol Chem 1980 Dec 25;255(24):11802-6. Identification of deoxy-alpha-tocopherolquinol as another + endogenous electron donor for biohydrogenation. Hughes PE, Tove SB. +

+

+ J Biol Chem 1980 May 25;255(10):4447-52. Identification of an endogenous electron donor for + biohydrogenation as alpha-tocopherolquinol. Hughes PE, Tove SB. "The ratio of + alpha-tocopherolquinone produced to fatty acid reduced was 2:1 when the tocopherol derivatives were + extracted aerobically. When the extraction was carried out anaerobically, the ratio was 1. It is suggested + that the oxidation of 2 molecules of alpha-tocopherolquinol, each to the semiquinone, provides the electrons + required for the reduction of the cis-bond of the conjugated dienoic fatty acid." +

+

+ Lett Appl Microbiol 1999 Sep;29(3):193-6. Hydrogenation of polyunsaturated fatty acids by human + colonic bacteria. Howard FA, Henderson C. Emulsions of the fatty acids linoleic (C18:2 n-6), + alpha-linolenic (C18:3 n-3) and arachidonic acid (C20:4 n-6) were incubated for 4 h under anaerobic + conditions with human faecal suspensions. Linoleic acid was significantly decreased (P < 0.001) + and there was a significant rise (P < 0.05) in its hydrogenation product, stearic acid. Linolenic + acid was also significantly decreased (P < 0.01), and significant increases in C18:3 cis-trans + isomers (P < 0.01) and linoleic acid (P < 0.05) were seen. With each acid, there were + non-significant increases in acids considered to be intermediates in biohydrogenation. The study + provides evidence that bacteria from the human colon can hydrogenate C18 essential polyunsaturated fatty + acids. + + However, with arachidonic acid there was no evidence of hydrogenation. +

+

+ Prostaglandins Leukot Essent Fatty Acids 1998 Dec;59(6):395-400. Modulation of rat liver lipid + metabolism by prolactin. Igal RA, de Gomez Dumm IN, Goya RG. +

+

+ Clin Chim Acta 1994 Mar;225(2):97-103. Vitamin E and the hypercoagulability of neonatal + blood. Jain SK, McCoy B, Wise R.

" +

+ +

+ Proc Natl Acad Sci U S A 2000 Oct 10;97(21):11494-9. gamma-tocopherol and its major metabolite, in + contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial + cells. Jiang Q, Elson-Schwab I, Courtemanche C, Ames BN. "Cyclooxygenase-2 + (COX-2)-catalyzed synthesis of prostaglandin E(2) (PGE(2)) plays a key role in inflammation and its + associated diseases, such as cancer and vascular heart disease. Here we report that gamma-tocopherol + (gammaT) reduced PGE(2) synthesis in both lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and + IL-1beta-treated A549 human epithelial cells with an apparent IC(50) of 7.5 and 4 microM, respectively." + "The inhibitory effects of gammaT and gamma-CEHC stemmed from their inhibition of COX-2 activity, rather + than affecting protein expression or substrate availability, and appeared to be independent of + antioxidant activity." + "The inhibitory potency of gammaT and gamma-CEHC was diminished by an increase in AA concentration, + suggesting that they might compete with AA at the active site of COX-2. We also observed a moderate + reduction of nitrite accumulation and suppression of inducible nitric oxide synthase expression by gammaT in + lipopolysaccharide-treated macrophages. These findings indicate that gammaT and its major metabolite possess + anti-inflammatory activity and that gammaT at physiological concentrations may be important in human disease + prevention." +

+

+ Biosci Biotechnol Biochem 1992 Sep;56(9):1420-3. + Effects of alpha-tocopherol and tocotrienols on blood pressure and linoleic acid metabolism in the + spontaneously hypertensive rat (SHR). Koba K, Abe K, Ikeda I, Sugano M. Both alpha-tocopherol + and a 1:1.7 mixture of alpha-tocopherol and tocotrienols at a 0.2% dietary level significantly depressed the + age-related increase in the systolic blood pressure of spontaneously hypertensive rats (SHRs) after 3 weeks + of feeding. The aortic production of prostacyclin was increased 1.5 times both by alpha-tocopherol + and a tocotrienol mixture, suggesting a possible relevance to their hypotensive effect. These + vitamins did not influence the delta 6- and delta 5-desaturase activities of liver microsomes, but + fatty acid profiles of the liver phospholipids predicted a reduction of linoleic acid + desaturation. These effects were in general more clear with tocotrienols than with + alpha-tocopherol. Platelet aggregation by 5 microM ADP remained uninfluenced. Thus, tocotrienols may have + effects on various lipid parameters somewhat different from those of alpha-tocopherol. +

+ +

+ Gerontology 1993;39(1):7-18. Modulation of membrane phospholipid fatty acid composition by age and + food restriction. + Laganiere S, Yu BP. H.M. "Phospholipids from liver mitochondrial and microsomal membrane preparations were + analyzed to further assess the effects of age and lifelong calorie restriction on membrane lipid + composition." "The data revealed characteristic patterns of age-related changes in ad libitum (AL) + fed rats: + membrane levels of long-chain polyunsaturated fatty acids, 22:4 and 22:5, increased progressively, + while membrane linoleic acid (18:2) decreased steadily with age. Levels of 18:2 fell by approximately + 40%, and 22:5 content almost doubled making the peroxidizability index increase with age." + "We concluded that the membrane-stabilizing action of long-term calorie restriction relates to the + selective modification of membrane long-chain polyunsaturated fatty acids during aging." +

+

+ Free Radic Biol Med 1999 Feb;26(3-4):260-5. Modulation of cardiac mitochondrial membrane fluidity by + age and calorie intake. Lee J, Yu BP, Herlihy JT. "The fatty acid composition of the + mitochondrial membranes of the two ad lib fed groups differed: the long-chain polyunsaturated 22:4 fatty + acid was higher in the older group, although linoleic acid (18:2) was lower. DR eliminated the + differences." + + "Considered together, these results suggest that DR maintains the integrity of the cardiac + mitochondrial membrane fluidity by minimizing membrane damage through modulation of membrane fatty acid + profile." +

+

+ Lipids 2001 Jun;36(6):589-93. Effect of dietary restriction on age-related increase of liver + susceptibility to peroxidation in rats. Leon TI, Lim BO, Yu BP, Lim Y, Jeon EJ, Park DK. +

+

+ Jpn J Pharmacol 1979 Apr;29(2):179-86. + Effect of linoleic acid hydroperoxide on liver microsomal enzymes in vitro. Masuda Y, Murano T. + "Rat liver microsomes incubated with linoleic acid hydroperoxide (LAHPO) lost cytochrome P-450 specifically + among the enzymes of microsomal electron transport systems. The loss of cytochrome P-450 content and + glucose-6-phosphatase activity by LAHPO was accompanied by an increase in malondialdehyde (MDA) production." + "These results suggest the possibility that the loss of microsomal enzyme activities during lipid + peroxidation may be attributed + largely to a direct attack on enzyme proteins by lipid peroxides rather than + + indirectly to a structural damage of microsomal membranes resulting from peroxidative breakdown of membrane + lipids." +

+

+ Ukr Biokhim Zh 2001 Jan-Feb;73(1):43-7. [Effect of alpha-tocopherol, tocopheryl quinone and other + complexes with tocopherol-binding proteins on the activity of enzymes metabolizing arachidonic + acid] Parkhomets' VP, Silonov SB, Donchenko HV. Palladin Institute of Biochemistry, National + Academy of Science of Ukraine, Kyiv. alpha-Tocopherol, tocopherylquinon jointly with the proteins tocopherol + acceptors from cytosole were identified to inhibit the activity of 5-lipoxigenase and so the + synthesis of leukotriene A4 at the early stages providing for A4 hydrolase activation and C4 + synthesase, as well as accelerate leukotrienes B4 and C4 synthesis at the further stages + respectively changing the final spectrum of leukotriens in the organism tissues. Firstly, the leading role + of proteins complexes capable to strengthen the effect of alpha-tocopherol and tocopherylquinon on + arachidonic acid oxidative metabolism was determined. +

+

+ Int J Vitam Nutr Res 1981;51(1):26-33. [Effect of vitamin E on the synthesis of polyunsaturated + fatty acids] Patzelt-Wenczler R. The formation of polyunsaturated fatty acids is influenced by + vitamin E. The enzyme of the endoplasmic reticulum isolated from rat liver responsible for chain elongation + and desaturation showed higher activity under vitamin E-deficiency. The activity was raised both per mg + protein and per mg DNA. The application of alpha-Tocopherol to the vitamin E-deficient animals caused the + normalization of the enzyme activity within 48 hours. This indicates a regulatory function of + alpha-Tocopherol in the process of oxidation. +

+ +

+ Lipids 2001 May;36(5):491-8. Correlation of fatty acid unsaturation of the major liver mitochondrial + phospholipid classes in mammals to their maximum life span potential. + Portero-Otin M, Bellmunt MJ, Ruiz MC, Barja G, Pamplona R. +

+

+ Free Radic Biol Med 1999 Oct;27(7-8):729-37. Age-dependent increase of collagenase expression can be + reduced by alpha-tocopherol via protein kinase C inhibition. Ricciarelli R, Maroni P, Ozer N, + Zingg JM, Azzi A. "Our in vitro experiments with skin fibroblasts suggest that alpha-tocopherol may protect + against skin aging by decreasing the level of collagenase expression, which is induced by environmental + insults and by aging." +

+

+ Prostaglandins Leukot Essent Fatty Acids 1991 Oct;44(2):89-92. Inhibition of PGE2 production in + macrophages from vitamin E-treated rats. Sakamoto W, Fujie K, Nishihira J, Mino M, Morita I, + Murota S. +

+ +

+ Int J Vitam Nutr Res 1990;60(1):26-34. The influence of vitamin E on rheological parameters in high + altitude mountaineers. Simon-Schnass I, Korniszewski L. "The erythrocyte filterability + was unaltered in the vitamin E group in comparison with baseline but was significantly impaired in the + control group." +

+

+ Neurobiol Aging 1991 Jan-Feb;12(1):55-9. Aging and food restriction: effect on lipids of cerebral + cortex. Tacconi MT, Lligona L, Salmona M, Pitsikas N, Algeri S. In experimental animals dietary + restriction reduces the body weight increase due to aging, increases longevity and delays the onset of + age-related physiological deterioration, including age-related changes in serum lipids. Little is known + about the influence of food restriction on brain lipids, whose concentration and composition have been shown + to change with age. We studied whether some biochemical and biophysical parameters of rat brain membranes, + known to be modified with age, were affected by a diet low in calories, in which 50% of lipids and 35% of + carbohydrates have been replaced by fibers. The diet was started at weaning and maintained throughout the + animal's entire life span. Animals fed the low calorie diet survived longer and gained less body weight than + standard diet fed rats. Age-related increases in microviscosity, cholesterol/phospholipid and + sphingomyelin/phosphatidylcholine ratios were reduced or restored to the levels of young animals in + cortex membranes of 32 old rats fed the low calorie diet, while the age-related increase in mono- to + polyunsaturated fatty acid ratios in phospholipids was further raised. In conclusion we have + shown that a diet low in calories and high in fibers affects lipid composition in the rat brain, in + a direction opposite to that normally believed to reduce age-related deterioration of brain + functions. +

+ +

+ Toxicol Appl Pharmacol 1993 May;120(1):72-9. Essential fatty acid deficiency in cultured human + keratinocytes attenuates toxicity due to lipid peroxidation. Wey HE, Pyron L, + Human keratinocytes are commonly grown in culture with a serum-free medium. Under these conditions, + keratinocytes become essential fatty acid deficient (EFAD), as determined by gas chromatographic + analysis of cell phospholipid fatty acid composition. Exposure of EFAD keratinocytes for 2 hr to + concentrations of t-butyl hydroperoxide (tBHP) up to 2 mM did not result in toxicity assessed by lactate + dehydrogenase (LDH) release and only a small indication of lipid peroxidation assessed by the release of + thiobarbituric acid-reactive substances (TBARS). Addition of 10 microM linoleic acid (LA) to + serum-free medium alleviated the EFAD condition by increasing the phospholipid content of LA and its + elongation and desaturation products, arachidonic acid and docosatetraenoic acid. Exposure of + LA-supplemented keratinocytes to tBHP resulted in significant LDH (at 1 and 2 mM tBHP) and TBARS (tBHP + concentration dependent) release. TBARS release was also significantly elevated in unexposed LA-supplemented + keratinocytes (basal release). Co-supplementation with the antioxidant, + alpha-tocopherol succinate (TS) prevented tBHP (1 mM)-induced LDH release in LA-supplemented cultures. + TS supplementation also attenuated the effect of tBHP on TBARS release, but when compared to + TS-supplemented EFAD cultures, LA supplementation still led to increased tBHP-induced TBARS + release. Keratinocyte cultures are potentially useful as an alternative to animals in toxicology research + and testing. It is important, however, that the cell model provide a response to toxic insult similar to + that experienced in vivo. Our results suggest that fatty acid and antioxidant nutrition of cultured + keratinocytes are important parameters in mediating the toxic effects of lipid peroxidation. +

+

+ Cancer Lett 1997 Jan 1;111(1-2):179-85. Subcutaneous, omentum and tumor fatty acid composition, and + serum insulin status in patients with benign or cancerous ovarian or endometrial tumors. Do tumors + preferentially utilize polyunsaturated fatty acids? Yam D, Ben-Hur H, Dgani R, Fink A, Shani A, + Berry EM. +

+ + + AC Chan, J. of Nutrition, 1998 + + "The response-to-injury hypothesis explains atherosclerosis as a chronic inflammatory response to injury of the + endothelium, which leads to complex cellular and molecular interactions among cells derived from the + endothelium, smooth muscle and several blood cell components. Inflammatory and other stimuli trigger an + overproduction of free radicals, which promote peroxidation of lipids in LDL trapped in the subendothelial + space. Products of LDL oxidation are bioactive, and they induce endothelial expression and secretion of + cytokines, growth factors and several cell surface adhesion molecules. The last-mentioned are capable of + recruiting circulating monocytes and T lymphocytes into the intima where monocytes are differentiated into + macrophages, the precursor of foam cells. In response to the growth factors and cytokines, smooth muscle cells + proliferate in the intima, resulting in the narrowing of the lumen. Oxidized LDL can also inhibit endothelial + production of prostacyclin and nitric oxide, two potent autacoids that are vasodilators and inhibitors of + platelet aggregation. Evidence is presented that vitamin E is protective against the development of + atherosclerosis. Vitamin E enrichment has been shown to retard LDL oxidation, inhibit the proliferation of + smooth muscle cells, inhibit platelet adhesion and aggregation, inhibit the expression and function of adhesion + molecules, attenuate the synthesis of leukotrienes and potentiate the release of prostacyclin through + up-regulating the expression of cytosolic phospholipase A2 and cyclooxygenase. Collectively, these biological + functions of vitamin E may account for its protection against the development of atherosclerosis." +

+ 6: Early Hum Dev 1994 Nov 18;39(3):177-88 Vitamin A and related essential nutrients in cord blood: + relationships with anthropometric measurements at birth. Ghebremeskel K, Burns L, Burden TJ, Harbige L, + Costeloe K, Powell JJ, Crawford M. Institute of Brain Chemistry and Human Nutrition, Queen Elizabeth + Hospital for Children, London, UK. Following the advice given by the Department of Health to women who are, + or may become pregnant, not to eat liver and liver products because of the risk of vitamin A toxicity, the + concentrations of vitamins A and E, and copper, magnesium and zinc in cord blood were investigated. The + study was conducted in Hackney, an inner city area of London. Esters of vitamin A were not detected in any + of the samples, indicating that there was no biochemical evidence of a risk of toxicity. Indeed, vitamin A + correlated significantly with birthweight, head circumference, length, and gestation period. There was also + a significant positive relationship between zinc and birthweight. In contrast, copper showed a negative + correlation with birthweight and head circumference. Vitamin E and magnesium were not associated with any of + the anthropometric measurements, although magnesium showed an increasing trend with birthweight. The data + suggest that most of the mothers of the subjects studied may have been marginal with respect to vitamins A + and E and zinc. In those with low birthweight babies. a higher intake would have improved their nutritional + status and possibly the outcome of their pregnancy. For these low-income mothers, liver and liver products + are the cheapest and the best source of vitamins A and E, haem iron, B vitamins and several other essential + nutrients; hence the advice of the Department of Health may have been misplaced. +

+ +

+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com +

+ + diff --git a/raypeat-articles/processed/water.html b/raypeat-articles/processed/water.html new file mode 100644 index 0000000..193ccf3 --- /dev/null +++ b/raypeat-articles/processed/water.html @@ -0,0 +1,928 @@ + + Water: swelling, tension, pain, fatigue, aging + +

+ Water: swelling, tension, pain, fatigue, aging +

+ +

+ I have spoken to many people who believe they should drink "8 glasses of water every day," in addition to + their normal foods, even if they don't feel thirsty. Many doctors still recite this dangerous slogan, but + the addition of the qualifying phrase, "or other liquids," has become common. +

+

+ The amount of water a person needs is extremely variable, depending on things such as metabolic rate, + activity, and the temperature and humidity of the air. Working hard in hot, dry weather, it's possible to + drink more than two quarts per hour for more than eight hours, without forming any urine, because all of the + water is lost by evaporation. But in very hot, humid weather, a person with a low metabolic rate can be + endangered by the smallest amount of water (e.g., "Meteorological relations of eclampsia in Lagos, Nigeria," + Agobe, et al., 1981). +

+

+ Most foods contain a considerable amount of water, usually more than 70% of their weight, and some water is + produced in cells by metabolism. The function of water in the organism has been mystified and neglected + because of some deeply rooted cultural images of the nature of organisms and their cellular make-up. +

+

+ One silly image that has been perpetuated by schools and textbooks is that biochemistry consists of chemical + reactions that occur in substances dissolved in water, and that the water is retained by cells because they + are enclosed by an oily membrane, and because of the osmotic forces produced by the dissolved substances. + Most grade school kids have seen an osmometer made from an egg, in which the egg causes a column of water to + rise, and have heard the explanation that this has something to do with the way cells work. Membrane pumps + are invoked to explain the differences in solute concentrations and "osmotic pressure" inside and outside + cells. The story is that invisible things on the surface of a cell (in its "membrane") force dissolved + molecules to move in ways that they wouldn't move spontaneously by diffusion, and that water passively + follows the "actively transported" solutes. But the evidence shows that both water and its solutes are + regulated by the bulk phase of the cell, not its surface. +

+ +

+ In some cultural settings, animism has a kind of charm (water sprites, and such), but in the culture of + medicine and biology, the animistic conceptualization of cells and their mechanisms has been very + destructive, because it gets in the way of coherent understanding of physiology. Practically every disease + would be approached differently if the physiology of water and ions were allowed to advance beyond the + animistic doctrines of mainstream medicine, such as the "membrane pumps." If all the substances that are + said to be "actively transported" by pumps into, or out of, cells are considered, the amount of energy + required to operate the pumps is at least 15 times larger than the total energy available to cells. + "Specific" pumps are commonly invoked even for novel synthetic chemicals, to explain their unequal + distribution, inside and outside cells. In many biological situations water is ignored, but when it becomes + an issue, its distribution is usually mechanistically subordinated to the solutes that are actively + "pumped." +

+

+ Cells aren't osmometers, in the sense the textbooks say. They do control their water content, but no + "membrane pumps" are needed. It's more accurate to think of the water of cells as being "dissolved in + cells," somewhat the way water is contained in jello or boiled eggs. The cell controls its hydration by the + processes that control its structure, its metabolism, and movements, because water is part of its deepest + structures and essential functions. The cell's adjustments to changes of hydration and volume appear to be + regulated by contractile proteins and energy metabolism (Minkoff and Damadian, 1976). +

+ +

+ Any stress or energy deficit that disturbs cellular structure or function disturbs the interactions among + water, proteins, and other components of the cell. Excitation causes a cell to take up extra water, not by + osmosis resulting from an increase in the concentration of solutes in the cell, or because the membrane has + become porous, but because the structural proteins of the cell have momentarily increased their affinity for + water. +

+

+ This increased affinity is similar to the process that causes a gel to swell in the presence of alkalinity, + and it is related to the process called electroosmosis, in which water moves toward a higher negative + charge. Intense excitation or stress increases the cell's electrically negative charges, and causes it to + become more alkaline and to swell. Swelling and alkalinity cause the cell to begin the synthesis of DNA, in + preparation for cell division. Mitogens and carcinogens, including estrogen, cause cells to become alkaline + and to swell, and substances that block the cell's alkalinization (such as the diuretics acetazolamide and + amiloride) inhibit cell division. Prolonged alkaline stress alone can cause malignant transformation of + kidney cells (Oberleithner, et al., 1991). +

+

+ The general idea of "stress" is useful, because it includes processes such as fatigue, osmotic pressure + changes, disturbed pH, and the enzyme changes that follow, producing substances such as lactic acid, nitric + oxide, polyamines, estrogen, serotonin, and many more specific mediators. But paying attention to the + physical factors involved in a stress reaction is important, if we are to see the organism integrally, + rather than as a collection of "specific biological mechanisms," involving things like the pixie-powered + "membrane pumps." +

+ +

+ When a cell shrinks under hyperosmolar conditions, its metabolism becomes catabolic, breaking down proteins + and glycogen, and sometimes producing lactic acid, which results in an alkaline shift, increasing the cell's + affinity for water, and causing it to return to normal size. A slight degree of hyperosmolarity increases + the cell's metabolic rate. +

+

+ Swelling in hypo-osmolar conditions, i.e,, with an excess of water, is anabolic, leading to cellular + proliferation, and inhibiting the breakdown of protein and glycogen. +

+

+ Respiring cells are always producing some water, by transferring hydrogen from fuel molecules to oxygen. + Respiration also produces carbon dioxide, which in itself is a Lewis acid (meaning that it binds electrons, + rather than releasing protons), that associates with cellular proteins, acidifying them in the process. A + large amount of carbon dioxide can exist inside cells in the bound form. Acidified cytoplasm (like any other + mostly acidic polymer-gel) releases water and sodium. (This process is physically analogous to the process + of flushing a water softener with salt, or a demineralizer with acid, to reactivate it.) +

+

+ Besides binding with the cytoplasm, the carbon dioxide can be changed into carbonic acid, by chemically + combining with water. Carbonic acid is hydrophilic, and so it quickly leaves the cell, taking with it some + of the oppositely charged ions, such as calcium and sodium. The formation of carbonic acid, which is + constantly streaming out of the respiring cell, causes some water and some positively ionized metals to + leave the cell, in an "active" process, that doesn't require any mysterious pumps. +

+ +

+ As the blood passes through the lungs, carbon dioxide leaves the system, and as carbonic acid is converted + to carbon dioxide, water is left behind in the blood, along with the counterions (of alkaline metals or + earths), accounting for slight differences in pH and osmolarity between the bloodstream and the tissue + cells. Some experiments suggest that the normal osmolarity of various tissues is 2 or 3 times higher than + that of the blood, which is called "isosmolar" or isotonic. +

+

+ The kidneys adjust the osmolarity of the blood by allowing water and solutes to leave the bloodstream, in + proportions that usually keep the body fluids in balance with cells. The kidneys are able to compensate for + many of the imbalances produced by stress and inappropriate diets, for example by forming ammonia and carbon + dioxide, to compensate for imbalances in the alkalis and acids that are being delivered to the blood by + other organs. Because of the kidneys' great ability to regulate the flow of solutes between the blood and + the forming urine, the "membrane pumps" have great importance for medical nephrologists. But the more + extreme the "active transport" is, the more obvious it becomes that processes other than "membrane pumps" + are responsible. +

+ +

+ Some lizards and sea birds have glands near their noses that are called salt glands, because of their + ability to secrete salt. The salt gland is probably the most extreme case of active transport, but its + physiology is very similar to the physiology of any other secretory gland or membrane, such as tear glands + and sweat glands. The mechanism of salt excretion in these glands should really settle the issue of how + active transport works, but most nephrologists, oculists, and medical researchers in general aren't + interested in salt glands. +

+

+ Carbon dioxide is the driving force in the salt gland. The constant formation of CO2, and its loss into the + air, allows a high concentration of salt to be excreted. Blocking the interchange of CO2 and carbonic acid, + with acetazolamide, or inhibiting the formation of CO2, prevents the excretion of salt. +

+

+ Since respiratory metabolism, governed by the thyroid hormone, is our main source of carbon dioxide, it's + obvious that thyroid deficiency should impair our ability to regulate water and solutes, such as salt. An + organism that illustrates this function of thyroid is the young salmon, when it leaves a freshwater river to + begin its life in the ocean. As it converts its physiology to tolerate the salty environment, its thyroid + hormone surges. When it's mature, and returns to the fresh water to spawn, its prolactin rises sharply. In + experiments with rodents, it has been found that drinking a large amount of water increases their prolactin, + but the same amount of water, with added salt, doesn't. +

+

+ Hypothyroidism is typically associated with increased prolactin secretion. Hypothyroid people typically + retain water, while losing salt, so the hypothyroid state is analogous to the salmon that has returned to + the river, and to the mice that drink too much salt-free water. +

+

+ The typical hypothyroid person loses salt rapidly in the urine (and probably in the sweat, too, though that + is usually diagnosed as cystic fibrosis), and retains water, diluting the urine less than normal. The + reduced production of carbon dioxide, with increased susceptibility to producing lactate and ammonium, + causes the cells to be more alkaline than normal, increasing their affinity for water. The rise of estrogen + that usually accompanies hypothyroidism also increases intracellular pH, loss of sodium, and over-hydration + of the blood. +

+ +

+ Hypothyroid muscles typically retain excess water, and fatigue easily, taking up more water than normal + during exertion. In childhood, mild hypothyroidism often causes the leg muscles to swell and ache in the + evenings, with what have been called "growing pains." When the problem is more extreme, all the skeletal + muscles can become very large (Hoffman syndrome), because of the anabolic effect of over-hydration. + Enlargement of any muscle can result from the excessive hydration produced by thyroid deficiency, but when + it happens to the muscles behind the eyes (Itabashi, et al., 1988), it often leads to a diagnosis of + hyperthyroidism, rather than hypothyroidism. +

+

+ The little kids with the Hoffman syndrome don't have the bloated myxedematous appearance that's often + associated with hypothyroidism. They look athletic to a ridiculous degree, like miniature body-builders. But + after a few weeks of treatment with thyroid, they regain the slender appearance that's normal for their age. + The swollen state actually supports enlargement of the muscle, and the cellular processes are probably + closely related to the muscle swelling and growth produced by exercise. The growth of the muscle cell during + swelling seems to be the result of normal repair processes, in a context of reduced turnover of cellular + proteins. +

+

+ The people who believe in membrane pumps that maintain normal solute distributions by active transport know + that the pumps would require energy (far more than the cell can produce, but they don't confront that + issue), and so their view requires that they assign a great part of the cell's resources just to maintaining + ionic homeostasis, and the result of that is that they tend to neglect the actual energy economy of the + cell, which is primarily devoted to the adaptive renewal of the cell structure and enzyme systems, not to + driving the systems that don't exist. +

+ +

+ The "anabolic" balance of the swollen cell is the result of decreased turnover of the cell's components. The + higher rate of metabolism produced by adequate thyroid function maintains a high rate of renewal of the + cell's systems, keeping the cell constantly adjusted to slight changes in the organism's needs. The evidence + of a high rate of bone turnover is sometimes taken as evidence that thyroid can cause osteoporosis. +

+

+ Later, in a more mature person, chronically fatigued and painful muscles that at one time would have been + diagnosed as rheumatism, may be diagnosed as fibromyalgia. Most doctors are reluctant to prescribe thyroid + supplements for the problem, but the association of elevated prolactin with the muscle disorder is now + generally recognized. +

+

+ The hypo-osmolar blood of hypothyroidism, increasing the excitability of vascular endothelium and smooth + muscle, is probably a mechanism contributing to the high blood pressure of hypothyroidism. The swelling + produced in vascular endothelium by hypo-osmotic plasma causes these cells to take up fats, contributing to + the development of atherosclerosis. The generalized leakiness affects all cells (see "Leakiness" + newsletter), and can contribute to reduced blood volume, and problems such as orthostatic hypotension. The + swollen endothelium is stickier, and this is suspected to support the metastasis of cancer cells. + Inflammation-related proteins, including CRP, are increased by the hypothyroid hyperhydration. The heart + muscle itself can swell, leading to congestive heart failure. +

+ +

+ Some of the nerve problems associated with hypothyroidism (e.g., carpal tunnel syndrome and "foot drop") are + blamed on compression of the nerves, from swelling of surrounding tissues, but the evidence is clear that + hypothyroidism causes swelling in the nerve cells themselves. For example, in hypothyroidism, nerves are + slow to respond to stimulation, and their conduction of the impulse is slow. These changes are the same as + those produced by hyper-hydration caused by other means. Hypothyroid nerves are easily fatigued, and + fatigued nerves take up a large amount of water. Swelling of the spinal cord is probably responsible for the + "spinal stenosis" commonly seen in domestic animals and people; the mobility of intracellular water + molecules is distinctly increased in patients with compression of the spinal cord (Tsuchiya, et al., 2003; + Ries, et al., 2001). +

+

+ The hyperhydration of hypothyroidism has been known to cause swelling and softening of cartilage, with + deformation of joints, but somehow it has never dawned on surgeons that this process would lead to + deformation of intervertebral disks. +

+

+ It has been known for a long time that hyperhydration can produce seizures; + at one time, neurologists would test for epilepsy by having the patient drink a pint of water. Although + there are many reasons to think that the hyperhydration produced by hypothyroidism is a factor in epilepsy, + physicians have been very reluctant to consider the possibility, because they generally think of thyroid + hormone as a stimulant, and believe that "stimulants" are necessarily inappropriate for people with + epilepsy. +

+ +

+ While it's true that the thyroid hormone increases sensitivity to adrenaline, its most noticeable effect is + in improving the ability to relax, including the ability to sleep soundly and restfully. And it happens that + increasing norepinephrine (the brain's locally produced form of adrenaline) helps to prevent seizures + (Giorgi, et al., 2004). +

+

+ Cell swelling increases the sensitivity of nerves, and hyperosmotic shrinkage lowers their sensitivity. + Increasing carbon dioxide helps to reduce the hydration of tissue (for example, the hydration and thickness + of the cornea are decreased when carbon dioxide is increased), and increasing carbon dioxide is known to + inhibit epileptic seizures. Another diagnostic trick of neurologists was to have the patient hyperventilate; + it would often bring on a seizure. The diuretic acetazolamide, which increases the body's carbon dioxide and + reduces water retention, is very effective for preventing seizures. +

+

+ The sleep-inducing effect of salty food is probably related to the anti-excitatory effects of + hyperosmolarity, of adequate thyroid function, and of carbon dioxide. +

+

+ Degenerative diseases, especially cancer, heart disease, and brain diseases, are less prevalent in + populations that live at a high altitude. When oxygen pressure is low, the lungs lose carbon dioxide more + slowly, and so the amount of carbon dioxide retained in the body is greater. If the basic problem in + hypothyroidism is the deficient production of carbon dioxide causing excessive loss of salt and retention of + water, resulting in hypo-osmotic body fluids, then we would expect people at high altitude to have better + retention of salt, more loss of water, and more hypertonic body fluids. That has been observed in many + studies. The increased rate of metabolism at altitude would be consistent with the relatively active + "catabolism" of the slightly hyperosmotic condition. +

+ +

+ After the drug companies began, in the late 1950s, marketing some newly discovered (thiazide) diuretics, + which cause sodium to be lost in the urine, their advertising campaigns created a cultish belief that salt + caused hypertension. They convinced a whole generation of physicians that pregnant women should limit salt + in their diet, take a diuretic preventively, and restrict calories to prevent "excessive" weight gain. + Millions of women and their babies were harmed by that cult. +

+

+ Pre-eclampsia and pregnancy toxemia have been corrected (Shanklin and Hodin, 1979) by both increased dietary + protein and increased salt, which improve circulation, lower blood pressure, and prevent seizures, while + reducing vascular leakiness. The effectiveness of increased salt in pre-eclampsia led me to suggest it for + women with premenstrual edema, because both conditions typically involve high estrogen, hyponatremia, and a + tendency toward hypo-osmolarity. Estrogen itself causes sodium loss, reduced osmolarity, and increased + capillary leakiness. Combined with a high protein diet, eating a little extra salt usually helps to correct + a variety of problems involving edema, poor circulation, and high blood pressure. +

+

+ The danger of salt restriction in pregnancy has hardly been recognized by most physicians, and its danger in + analogous physiological situations is much farther from their consideration. +

+

+ One of the things that happen when there isn't enough sodium in the diet is that more aldosterone is + synthesized. Aldosterone causes less sodium to be lost in the urine and sweat, but it achieves that at the + expense of the increased loss of potassium, magnesium, and probably calcium. The loss of potassium leads to + vasoconstriction, which contributes to heart and kidney failure and high blood pressure. The loss of + magnesium contributes to vasoconstriction, inflammation, and bone loss. Magnesium deficiency is extremely + common, but a little extra salt in the diet makes it easier to retain the magnesium in our foods. +

+

+ Darkness and hypothyroidism both reduce the activity of cytochrome oxidase, making cells more susceptible to + stress. A promoter of excitotoxicity, ouabain, or a lack of salt, can function as the equivalent of + darkness, in resetting the biological rhythms (Zatz, 1989, 1991). +

+ +

+ Bone loss occurs almost entirely during the night, and the nocturnal rise in cortisol and prolactin has + strongly catabolic effects, but many other pro-inflammatory substances also rise during the night, and are + probably the basic cause of the increased catabolism. Increased salt in the diet appears to improve some + aspects of calcium metabolism, such as reducing parathyroid hormone and increasing ionized calcium, when the + diet is deficient in calcium (Tordoff, 1997). +

+

+ The kidneys can produce large amounts of carbon dioxide and ammonia, in the process of preventing the loss + of electrolytes, while allowing acid to be lost in the urine. The ammonia is produced by the breakdown of + protein. During stress or fasting, the loss of tissue protein can be minimized by supplementing the + minerals, potassium, sodium, magnesium, and calcium. Salt restriction can cause aldosterone to increase, and + excess aldosterone causes potassium loss, and increases the use of protein to form ammonia (Norby, et al., + 1976; Snart and Taylor, 1978; Welbourne and Francoeur, 1977). +

+

+ Aldosterone secretion increases during the night, and its rise is greater in depressed and stressed people. + It inhibits energy metabolism, increases insulin resistance, and increases the formation of proinflammatory + substances in fat cells (Kraus, et al., 2005). During aging, salt restriction can produce an exaggerated + nocturnal rise in aldosterone. +

+

+ During the night, there are many changes that suggest that the thyroid functions are being blocked, for + example a surge in the thyroid stimulating hormone, with T4 and T3 being lowest between 11 PM and 3 AM + (Lucke, et al., 1977), while temperature and energy production are at their lowest. This suggests that the + problems of hypothyroidism will be most noticeable during the night. +

+

+ Rheumatoid arthritis and asthma are two inflammatory conditions that are notoriously worse during the night. + Melatonin has been reported to be higher in patients with severe asthma and rheumatoid arthritis, and to + promote the secretion of a variety of other pro-inflammatory substances. The peak of melatonin secretion is + followed by the peak of aldosterone, and a little later by the peak of cortisol. +

+

+ The use of bright light (which suppresses melatonin) to treat depression probably helps to inhibit the + production of aldosterone, which is strongly associated with depression. +

+ +

+ Both aldosterone and melatonin can contribute to the contraction of smooth muscle in blood vessels. + Constriction of blood vessels in the kidneys helps to conserve water, which is adaptive if blood volume has + been reduced because of a sodium deficiency. When blood vessels are inappropriately constricted, the blood + pressure rises, while organs don't receive as much blood circulation as they need. This impaired circulation + seems to be what causes the kidney damage associated with high blood pressure, which can eventually lead to + heart failure and multiple organ failure. +

+

+ Progesterone, which helps to maintain blood volume (partly by preventing vascular leakiness, preventing + excessive sodium loss and by supporting albumin synthesis) antagonizes aldosterone. Aldosterone antagonists + are now being recognized as effective treatments for hypertension, water retention, congestive heart + failure, arrhythmia, diabetes, kidney disease, and a great variety of inflammatory problems. (Synthetic + drugs to antagonize aldosterone are most effective when they are most like natural progesterone.) Since + aldosterone contributes to fibrosis of the heart and kidneys (nephrosclerosis), progesterone, the + "antifibromatogenic steroid," should be helpful for those problems that have been considered irreversible. + Aldosterone appears to contribute to the hyperglycemia of diabetes itself, and not just to its + complications, by interfering with the interactions of insulin and cortisol (Yamashita, et al., 2004). +

+

+ One of progesterone's fundamental actions is to cause estrogen "receptors" to disintegrate; hypertonicity + has this effect in some situations. Estrogen's effects are largely produced by increased tissue hydration. +

+ +

+ Aldosterone causes cells to take up sodium, while increasing their pH, i.e., raising their alkalinity + (Mihailidou and Funder, 2005). Intracellular sodium has long been known to be a factor, along with swelling + and alkalinity, in stimulating cell division (Cone and Tongier, 1971). A lack of salt stimulates the + formation of serotonin, which in turn stimulates aldosterone synthesis--that is, a sodium restricted diet + activates processes that cause cells to take up sodium inappropriately, in a situation reminiscent of the + calcium deficient diet causing inappropriate calcification. +

+

+ Aldosterone, like stress or hypo-osmolarity, activates the enzyme (ODC) which produces the polyamines, that + promote cell division, and that can probably account for some of the harmful effects of excessive + aldosterone. +

+

+ Eating salty food around bedtime usually has a sleep-inducing effect, and it helps to maintain blood volume + (which tends to decrease during the night), and to restrain the nocturnal rise of aldosterone, and other + indicators of stress or inflammation. Eating gelatin, which lacks tryptophan, will reduce the formation of + serotonin, and is likely to limit the formation of aldosterone. +

+

+ Pregnenolone can sometimes very quickly allow swollen tissues to release their water. This function is + probably closely related to its antifibromatogenic function, since swelling and leaking set the stage for + fibrosis. +

+

+ Hyperosmotic sodium chloride solutions (e.g., 7.5%) are being used more often for treating trauma and shock, + because the concentrated solution increases blood volume by removing water from the extravascular spaces, + unlike the "isotonic" saline (0.9% sodium chloride), which usually adds to the edema by leaking out of the + blood vessels. +

+ +

+ A 5% sodium chloride solution is effective for promoting healing of damaged corneas, and solutions of 5% to + 10% sodium chloride are effective for accelerating the healing of wounds and ulcers. Other hypertonic + solutions, for example glucose or urea, have been used therapeutically, but sodium chloride seems to be the + most effective in a variety of situations. +

+

+ Thyroid hormone, by maintaining oxidative metabolism with the production of carbon dioxide, is highly + protective against excessive water retention and loss of sodium and magnesium. +

+

+ Sometimes doctors recommend that constipated people should drink extra water, "to soften the stool." The + colon is where water is removed from the intestinal contents, and when it is inflamed, it removes too much + water. Several decades ago, it was recognized (Orr, et al., 1931) that hypertonic saline, given + intravenously, would stimulate intestinal peristalsis, and could be used to treat paralytic ileus and + intestinal obstruction. +

+

+ When water is taken orally, it is absorbed high in the intestine, long before it reaches the colon, so the + recommendation to drink water for constipation can produce a situation that's the opposite of intravenous + hypertonic saline, by diluting the blood. Using a hypertonic salt solution as an enema can have the same + beneficial effect on the intestine as the intravenous treatment. +

+

+ Constipation physiology is probably analogous to the physiology of congestive heart failure, in which + muscles are weakened and fatigued by swelling. +

+ +

+ In recent decades, the prevalence of congestive heart failure has increased tremendously, so that it is now + often called an epidemic. Hyponatremia (too little salt, or too much water) is a recognized "risk factor" + for congestive heart failure. In the failing heart, the muscle cells are swollen, causing the heart wall to + stiffen, weakening its ability to pump. Osmotically shrinking the cells can restore their function. +

+

+ The swollen heart, like any muscle, loses the ability to quickly and completely relax, and so it doesn't + fill adequately between contractions. Elastic tissues, such as arteries and lungs, stiffen when they are + over-hydrated, losing their normal functions. In small blood vessels, swelling narrows the channel, + increasing resistance to the flow of blood. +

+

+ When people force themselves to drink a certain amount of water every day, even when they don't feel + thirsty, they are activating complex adaptive processes unnecessarily. Thirst is the best guide to the + amount of fluid needed. +

+

+ When extra water consumption is combined with a low salt diet--as physicians have so often recommended--a + healthy person can adapt easily, but for a hypothyroid person it can have disastrous effects. +

+

REFERENCES

+

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+

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+ +

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+ +

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www.gilbertling.org

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+

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+ +

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+

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+ +

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+ +

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+

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+

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+

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+ +

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+ + © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com + + diff --git a/raypeat-articles/processed/william-blake.html b/raypeat-articles/processed/william-blake.html new file mode 100644 index 0000000..46e4a6b --- /dev/null +++ b/raypeat-articles/processed/william-blake.html @@ -0,0 +1,675 @@ + + Can art instruct science? William Blake as biological visionary + +

+ Can art instruct science? William Blake as biological visionary +

+ +

+ "As the true method of knowledge is experiment, the true faculty of knowing must be the faculty + which experiences." +

+ +

+ "Seest thou the little winged fly, smaller than a grain of sand? It has a heart like thee; a + brain open to heaven & hell...." +

+

"Energy is the only life, and is from the Body.... Energy is eternal delight."

+ +

+ "Then tell me, what is the material world, and is it dead?" He, laughing. answer'd: "I will + write a book on leaves of flowers, if you will feed me on love thoughts & give me now and then A + cup of sparkling poetic fancies; so, when I am tipsie, I'll sing to you to this soft lute, and shew + you all alive The world, where every particle of dust breathes forth its joy." (1794) +

+ +
+ +

+ When I started studying William Blake in the 1950s, it seemed that only English majors knew who he was, but + today, I think more people might recognize The Tyger as Blake"s than would be able to identify poems by + Keats, Byron, Shelley, or Wordsworth. After 200 years, his writing seems contemporary, while other poets" + works have become dated, and are valued mostly as cultural background. But I don"t think this means that his + work is any easier to understand than it was when he wrote it. It means that other poets tied their writing + to frameworks which have receded into the background, while Blake"s words were chosen in a way that allowed + them to travel across the centuries without loss. Even though such universality is a goal of science as well + as of art, most of what passed for science in the 18th century is today of only historical + interest. +

+ +

+ Everywhere in our culture, authoritarian ignorance has disproportionate influence. Most of the published + work in our culture treats the succession of authoritarian academic/scien- tific/political cults as if this + were simply the way history and human nature work, and must work. But this mechanical historical process is + only superficial, and below this surface, individuals and groups have always lived as though time behaved + very differently for them. William Blake was a person who investigated this discrepancy between official + cultural progression, and real human possibility, and his ideas might be able to do essentially what he + suggested they could do: Provide a way to by-pass the officially established mechanistic + view of reality, into a more fully human reality. Since Blake ridiculed established doctrines in medicine, + chemistry, mathematics, and Newtonian physics, many people have dismissed him as a religious nut, but the + way in which he criticized them indicates that he simply believed that they were bad science; he also criticized conventional art and morality, because he believed that they were destroying + art and morality. +

+

+ A group that was active in the 1950s, called Synectics, developed several mental procedures that they found + to be useful in teaching people to solve problems creatively. These included ways to improve thinking by + analogy, to get people out of the ruts of conventional thinking. Personification, fantasy, biological + imagery, "making the familiar strange," they found, seemed to tap into natural biological and mental + processes to increase the ability to direct energy toward valid solutions to practical or artistic problems. + They found that experts had to overcome their special knowledge before they could usefully solve problems in + "their field," and they showed that much of the mystery could be removed from the creative process. Simply + putting aside dogmatic mental frameworks was crucial. +

+

+ When you believe that you have adequate, expert knowledge, a passive, logical, deductive form of mental + activity seems appropriate. Deduction always goes from a higher level of generality to a lower level of + generality. Mental passivity therefore is likely to be associated with the belief that we have the decisive + knowledge already stored in memory. If we believe that we create higher degrees of generality, as + appropriate solutions to novel problems, then we are committed to an active mental life. Perception, + combined with the discovery and invention of new patterns in the world, will be actively oriented toward the + future, while the deductive, merely analytical, manner of thought will be tied to the past. +

+ +

+ Blake"s work, I think, is of continued and increased interest because he discovered something of great + importance, namely, how to avoid dogmatisms of all sorts. Many students who are assigned to write about a + poem of Blake"s are puzzled, and ask what it means. When they find out that they understand the words and + the syntax, it turns out that the only problem was that they were taught that they had to "interpret" + poetry. And that they don"t think he could have meant what he said. Most twentieth century students are too + stodgy to accept Blake"s writing easily. In the 1950s, some people couldn"t understand Alan Ginsberg"s + poetry, because they didn"t think anyone was allowed to say such things. That is the kind of problem + students have with Blake. +

+

+ But it"s not just high school and college students who can"t believe that Blake meant what he said. I + recently reviewed the comments on The Tyger that have been published in the forty years since I wrote my MA + thesis on Blake, and it seems that these academic experts are having the same kind of problem. Dostoyevsky + wrote about this problem in The Double"it is the problem of self-assertion, of seeing oneself reflected + everywhere in the world. In Dostoyevsky"s story, Dream of an Odd Fellow, the theme is stated even more + clearly"the world is very boring, and everything seems the same as everything else, until you can escape from a certain interpretive framework, to see what is really present to you. In + Blake"s phrase, if the many become the same as the few when possessed, "more, more," is the + cry of a mistaken soul; Blake said, over and over, that the many do not become the same as + the few, that we are always moving into a new world as we learn more, except when we find ourselves in the + mental manacles of interpretation. +

+ +

+ It"s easy to forget how pervasive philosophical interpretation is in everyday life and in the so-called + sciences, and how much the sciences owe to long-standing theological commitments. Within the last + generation, many influential people have said that facts don"t matter (and I suspect that their favorable + reception has owed everything to that attitude.) In the early 1960s, there was a controversy going on + between two schools of thought in linguistics and the philosophy of science, the Katz and Fodor controversy. + I think Fodor was in the minority at that time, at least among the most prestigious professors in the United + States. Fodor said that if we wanted to know about language, we should find out how the language is used, by + watching a variety of people using it. His opponents said that, if they were competent to speak the + language, they didn"t need to do anything except to think, to understand everything about the language. + Fodor was an empiricist, his opponents were rationalists. In mathematics, most people are still + rationalists. A large school of contemporary thought about computers, called "Artificial Intelligence," is + operating within a rationalistic framework. Chomsky"s "generative grammar" was ultra-rationalistic, and was + easy to set up in computers, though it was perfectly useless in itself. Some physicists hold a philosophy of + science that is essentially rationalistic. In Plato"s time, + all knowledge could supposedly be derived by introspection and the analysis of innate ideas, and + education consisted in "drawing out" the knowledge that was innate. (Aristotle, who didn"t subscribe to + Plato"s rationalism, has nevertheless been blamed for holding opinions that weren"t sufficiently supported + by observation. This was probably because he occasionally relied on the opinions of others, rather than + because of any serious defect in his philosophical-scientific method.) +

+

+ It"s important to remember that Rationalism, as used here, isn"t simply a "love of reason," which is what is + often meant when people speak of "rationalism." In its historical use among philosophers, rather than being + just a devotion to rationality, it is a specific doctrine which denies that experience is the source of + knowledge. Historically, Rationalism has been closely allied with mysticism, as an affirmation that + knowledge comes from a source beyond the ordinary world of experience and beyond the individual. At the + present time, it serves authoritarian science rather than authoritarian theology, though the basic doctrine + is the same. +

+

+ Several contemporary schools of literary theory, sociology, anthropology, even biology, trace their ideas + back to Ferdinand de Saussure"s analysis of language, reading into it a highly rationalistic doctrine for + which there is no actual basis. Saussure"s most important idea was that it is impossible to analyze language + into its structural units without simultaneously seeing its use in relation to the world of meanings. + Without its meanings, it just isn"t language. This is a profoundly anti-rationalist insight, since it shows + that symbols take their existence from the experience of communication. But once the symbols exist, they + function by the ways they establish distinctions, "this" being defined by the ways it has been used in + distinction to "those," "that," etc. Every time a word is used, its meaning changes a little, since every + use occurs in a new communicative situation. The contemporary rationalistic academic trends prefer to + isolate only the principle of "meaning through opposition," since it supports the rationalistic illusion of + operating strictly on the symbolic level. The "symbolic level" is only an abstraction, and doesn"t exist + independently. +

+ +

+ A few decades ago, there was a movement called General Semantics that tried to make people more conscious of + the way symbols relate to reality. Their ideas were based on a distinction between the "concrete" use of + symbols, and the various levels of abstraction. These distinctions, however, made sense only within a + certain theory of how language works, which I think was wrong: It asserted that, if time + and space were divided into sufficiently small units, symbols and language could be precise and factual. It + ignored the distinction between reality as experienced, and reality as represented in theory. If you keep + subdividing a person, John Smith, into smaller moments, you find that there is nothing that represents the + known person. The person that you are really referring to is actually a summation of many moments"the + summation is the only "concreteness." The person you know is a synthesis, and it is that imaginative + synthesis of facts to which the concrete symbol refers. Generality exists in our knowledge of the world, and + the distinction between concrete and abstract is likely to create confusion, and reinforces a specific + ideological system. Incidentally, the word "concrete" derives from the roots "grown" and "together," so it + is very close in its core meaning to "synthesis." A well constructed generalization can be concrete, and a + seemingly simple term, such as "electron," can be "abstract." (Blake said that a line, no matter how finely + divided, was still a line; a line exists in our imaginative synthesis of the world, and it is only a denial + of that synthesis that can divide its unity into "infinitesimals.") +

+

+ Mathematics has its value in representing certain relationships or patterns, but the rationalistic illusion + that the meaning is independently contained and fulfilled by the "algorithm," has led many people into + dogmatisms and serious errors. "Coefficients of reality" are often neglected. In practice, you are not very + likely to be mistaken if you assume that mathematical descriptions of physical states are always erroneous. +

+

+ In the 17th and 18th centuries, progress in technology and industry was already making + rationalism seem inadequate, but it still served the social purpose of allowing the ruling class to claim + that the doctrines it wished to enforce had the support of timeless, innate and universal principles. There + was supposed to be a Great Chain of Being, a hierarchy in which the king and the lords were just below the + angels, and Reason was a mathematically clear description of the way things were, and should be. As the + chain of being finally broke up at the end of the 18th century, the king brought in the Rev. + Malthus to explain how war, poverty, and disease served the divine, or kingly, purpose, by controlling + population growth, justifying misery and social antagonism in a new way. +

+ +

+ There were philosophers, such as John Locke and David Hume, who argued that much of our knowledge is gained + through the senses, and there were satirists, such as Henry Fielding, who ridiculed the supposedly divinely + sanctioned class system, but Blake took a much simpler, but more radical position, in saying that "Reason + isn"t the same that it will be when we know more," and that reason is only the ratio of things that are + presently known, and not the source of new knowledge. Blake kept the idea that experience is the source of + knowledge, without reducing "experience" to the "senses." Blake didn"t deny the existence of some innate + ideas; he didn"t think we were born as a "blank slate," but there is more to the mind than + what we are born with. Imagination and invention and mental striving were able to generate new forms. This + commitment to experience as the source of knowledge, rather than just analyzing a stock of "innate ideas," + made Blake"s world one that was oriented toward the future, toward invention and discovery, rather than to + memory, established knowledge, and tradition. In its essence, it was antidogmatic. +

+

+ Rationalism is a system of symbols, in which each symbol is demonstrated to have its own proper place and + status. To the extent that reason is held to be "innate," the system will be prescriptive and judgmental, + rather than simply descriptive, explanatory, and illuminating. When an alternative system is proposed, it + may be considered a "heresy," if the system from which it dissents is both rationalistic and authoritarian. +

+

+ Except for the dangers involved in committing a heresy, it is very easy to follow the implications of the + system that one finds in one"s own mind, since self-assertion contains no principle of corrective + contradiction. Essentially, rationalism consists of thinking something is true because you thought + of it. + +

+

+ I think of the philosophical Rationalists as being the bureaucrats of the mind, making everything tedious + and boring and repetitive. Eliminating Rationalism, then actual individualized full mental life can begin. +

+ +

+ Even a heresy, if it is based on rationalism, is past-oriented, and dogmatic. Over the years, scholars have + ascribed most of the important heresies, as well as mainstream religious ideas, to Blake. Whatever + interpretive system the scholars favor, they are able to find it in Blake"s work. Calling Blake "a mystic" + is especially useful when the goal is to claim that the critic is getting at the deepest levels of meaning + in Blake, even though there is no clear meaning for the word in contemporary English, and Blake didn"t use + the term in a way that suggested he would approve of having the word applied to himself. +

+

+ Blake"s notes written in the margins of books make it clear that he wasn"t simply adopting anyone"s + doctrinaire opinions, and that he was able to find useful ideas in the thoughts of others even when he + disagreed with them on important issues. Blake was not a rationalist, but he agreed with Bishop Berkeley"s + understanding of the importance of distinguishing thought from language. He recognized that Descartes, + Locke, Hume, Newton, had inadequate ideas about the nature of "matter," but he didn"t accept the simplistic + doctrine of extreme rationalism that matter doesn"t exist. +

+

+ When people consider Leonardo de Vinci, they usually make the point that he had mastered every field of + knowledge, and so the question of "sources" and "influences" doesn"t come up. In the 18th + century, London was the cultural center of the world; + European, Asian, and ancient cultures and ideas were discussed in books, magazines, and conversations. Being + an engraver, a painter, a poet, and a political activist, Blake"s circle of acquaintances was as wide as + anyone"s could be. England has had, probably since the 17th century or earlier, a counter-culture + of opinionated dissenters. I suspect that the people who spent several years studying the classics for a + university education were somewhat culturally deprived, relative to the people who participated in the rich + unofficial culture, where new ideas in art, science, and philosophy were being discussed. London was also + the center of a world-spanning empire, a tyrannical class-system, and an industrial-commercial revolution. + The past and the possible futures could be seen from Blake"s vantage point. +

+ +

+ Among all the published opinions about things that influenced Blake, I have seen only a few discussions of + his treatment of scientific ideas, mainly his rejections of Newton"s mathematical and physical assumptions, + and very few comments on Blake"s position on the major philosophical controversies of his time. A biologist, + Jacob Bronowsky, wrote a book about Blake, but Bronowsky"s own biological, historical, and linguistic ideas + were relatively conventional. Even though Blake"s work is full of images from biology, the critics ignore + the fact that Emanuel Swedenborg published very advanced biological research in the middle of the 18th century, and that Erasmus Darwin was known for presenting his ideas on biological evolution in + poetry (especially Zoonomia). The title of Blake"s book, The Four Zoas, has apparently never led scholars to + ask whether it had anything in common with Zoonomia. Even though Blake made many disparaging remarks about + Swedenborg"s religious books, many people have claimed that Blake was influenced by Swedenborg"s religious + doctrines, while ignoring the possible influence of the scientific work. +

+

+ Although the idea that "contradiction produces change" is associated with Hegel"s "Dialectic," it was an old + and well known theme in philosophy. When Blake"s idea, that "without Contraries there is no progression," is + seen in context, I think it is appropriate to think that to a great extent, Blake derived the idea from a + consideration of the sexes. "Generation," so often discussed in relation to the biblical "fall of man," + always leads to the issue of the productive interaction of the sexual contraries. The issue of sexual love + permeates Blake"s work. I suspect that Blake produced even more explicitly sexual work, but since most of + his work wasn"t really published, when his wife died in 1831, the bulk of his manuscripts and paintings were + subject to the whims of their unsophisticated owners. But on the basis of his existing work, it is + reasonable to say that sexual and imaginative energy was the motor that Blake saw producing intellectual + advancement. This male-female principle of change was more fully explored by Blake than by anyone + previously, since he made it concrete and personal, rather than abstract. Working in history, human energy + ran into the constrictive, limiting elements, the tyrannies of policy, philosophy, and commerce. For Blake, + the interaction of energy with those limits became a philosophy of freedom and revolution. +

+

+ While Blake discussed the importance of perception in understanding the world, he was remarkable in the care + he took to make it clear that he saw the world "all alive," in which grains of dust or sand, birds, worms, + ants, flies, etc., perceived and experienced in ways that were not different from those of human life. + Bishop Berkeley, who said that the material world outside the philosopher"s mind doesn"t exist, added as an + afterthought that it exists in the mind of God. If consciousness is the only guarantee of existence, there + was no problem in the existence of Blake"s world, in which everything was alive and conscious. +

+

+ Everyone finds it almost obligatory to describe The Lamb as a symbol for Jesus, but then they find the + Tyger"s symbolic meaning more problematic, and"from Coleridge in the early 19th century down to + the newest publications at the end of the 20th century"people are boggled by the "obscurity" of + The Fly. But in that poem, Blake makes it clear that there is no obscure symbolism, when he says "then am I + a happy fly, if I live or if I die," etc. The animal poems are expressions of Blake"s evolutionary, + vitalistic, cosmology. The tyger, at least, would be too much for a creationist doctrine to handle. If worms + and flies and ants are conscious and in the same situation as human beings, the bonds of sympathy and + forgiveness are universal. +

+ +

+ In a world that"s alive and developing, new knowledge is always possible, and imagination has the prophetic + function of reporting the trends and processes of development, illuminating the paths toward the future. + Reason is subordinate to invention and discovery. +

+

+ The dualistic conception of matter as distinct from energy and consciousness is a constrictive illusion put + in place by the forces of empire, and the living reality would be freed from the inert husks of the wrongly + conceived natural world, when in the future the world was freed of tyranny. After Blake, it would be nearly + another century before others would see that the crude materialism of Newton and the Natural Philosophers + was essentially a life-denying culmination of the worst trends of official religious dogma. +

+

+ A complete survey of Blake"s references to Christianity would be voluminous, and not all of them are + immediately clear, + and require a careful placing in the context of the ideas that were being discussed in London at that time. + But it"s hard to reconcile the common description of him as a mystic with his reference to "Old Nobodaddy + aloft," or with his comment that Jehovah gives us a knock on the head, and Jesus soothes it. He always + defines god in human terms, so from the conventional viewpoint, he would probably be considered as an + atheist or pantheist, but he didn"t describe himself or his friends as atheists. When people called Tom + Paine an atheist, Blake defended him against the charge. Other friends, Mary Wollstonecraft and William + Godwin, were sometimes called atheists, but in their writings, they never expressed very unconventional + religious ideas. When we recall that in the early 1990s, George Bush expressed the idea that atheism should + be illegal, it is easy to imagine that people in 18th century England wouldn"t have felt that it + was safe to be called atheists. +

+

+ In 1803, Blake apparently said something like "damn the king," while getting a drunk soldier out of his + yard, and was tried for sedition or treason. He was acquitted, because his far more scurrilous written + comments hadn"t been published, and it didn"t occur to the government to look for documentary evidence to + support their case. The fact that he printed his own work, and sold only a few copies of his books to + affluent friends, probably saved his life, but it accounts for his obscurity during his own lifetime. +

+ +

+ Tom Paine"s writing was published and widely read in prerevolutionary America, but he was considered a + criminal in England, and Blake was credited with saving his life by helping him escape to France. + Politically and ethically, Blake"s writing is similar to that of Paine, Godwin, and Wollstonecraft (often + called the "first feminist"), but his language is usually more vivid. It was probably the clarity of his + political opposition that made his work unpublishable during his lifetime. The first "complete" collection + of his work was published in 1927, and until that year, very few people had seen more than a few of his most + famous poems. +

+

+ Blake printed his work by hand, without a press, by writing the text backwards on copper plates, surrounded + by his drawings, and then etching away the surrounding copper, so that the image remained elevated, and + could be inked and printed as if it were a wood-block. If he hadn"t devised this method for printing a few + copies of his books, it isn"t likely that much of the work would have survived. +

+

+ Shortly after the French Revolution, William Wordsworth was associated with the Blake-Wollstonecraft-Godwin + group"s defense of the revolution, but he moved away from the ideals of that group, and adopted more + socially acceptable ideas. He finally became England"s poet laureate. Liberty, equality, and brotherhood + were replaced by blandly conformist ideas. +

+ +

+ The type of individualism that Wordsworth came to advocate was interesting because it was a rejection of + exactly that part of Blake"s belief that Blake considered to be the essence of Christianity, namely, + forgiveness, brotherhood, and bonds of sympathy connecting all beings. In its place, Wordsworth adopted a + memory-centered doctrine. During Wordsworth"s lifetime, his ideology was exceedingly successful, but its + rationalistic overtones have kept it tied to the past; it had nothing to offer the future. + I think we can get some insight into Wordsworth"s mind by considering that, on the basis of reading Blake"s + Songs of Innocence and Experience, he decided that they were written by an insane person. (Blake + was aware that slow-witted people, who couldn"t follow unconventional thoughts, often considered him to be + crazy.} +

+ +

+ Everywhere in Blake"s work, it is clear that he never underestimated the possibilities of the future, and + never imposed false limits onto anything, but he didn"t tolerate vagueness or empty abstraction. Sharp + definition was essential, and unique particulars were the basis for beauty and knowledge. +

+

+ For Blake, the dialectical principal was a feature of the world itself, but it also informed his method, his + technique, and his "rhetoric." One of Blake"s powerful insights was that intellectual clarity is achieved by + contradiction, opposition, contrast, making distinctions as well as comparisons. The principle of + intensification through opposition had special features when it was developed in his painting and writing. + Blake gave much of the credit for his style of thinking to the process of spending thousands of hours in the + practice of etching. The image you create in the conventional etching technique is made when acid "bites" + into the lines that will be inked; + in Blake"s new technique, the image is made permanent by the acid"s corroding away of everything except the + sharply defined image. The decisive, dividing, line is essential. Anyone who has spent even a few hours of + intense effort working in dry-point or etching understands that, when you stop, the appearance of the world + is altered by changes that have taken place in your eyes and brain. Often, his "metaphors" are literal + imaginative insights that have great generality. This kind of knowledge distinguishes the work of a + craftsman from that of an academic. The probability is that Blake"s art led him to appreciate compatible + ideas when he found them, and it doesn"t seem likely that he was "influenced" by them the way an academic is + influenced by books, since Blake had his own "sources" that are generally neglected by intellectuals. +

+

+ Blake found that contrasts made meanings clear, and made language vivid. Heaven and Hell, Clod and Pebble, + Lamb and Tyger, Angel and Devil, Greek and Jew, Innocence and Experience, presented contrasts that + encouraged the reader to think about the range of possibilities Blake had in mind. He was always consciously + trying to energize the reader"s mind to get out of dogmatic ruts, to look at things freshly, so he often + used the polarities in ways that would surprise the reader, ironically reversing familiar references. A + pious commonplace would be contrasted with the disturbing realities that it normally hid. Both in his + writing and in conversation, Blake was often playful and teasing, and over-serious people have usually taken + him too literally. +

+

+ Academic commentators are so often attached to their erudite pieties that it seems that they can"t read + English. In the 18th century, a clod meant just what it means in the 20th century, + either a lump of dirt, or a lunkhead. In the Clod and the Pebble, when the Clod speaks the properly + sanctimonious phrases, justifying its oppressed misery with a dogma, we have a clue regarding Blake"s + attitude, but then he makes it perfectly clear by speaking of Heaven"s despite, literally, Heaven"s malice + (a concept that appears many times in different forms in other parts of his work). Either the commentators + assume that the word "despite" had a different meaning in the 18th + + century (it didn"t), or they assume that Blake made an error of diction, because they choose to alter the + meaning to "despite Heaven." Just as judges aren"t allowed to change the wording of the laws that they + interpret, literary experts aren"t allowed to rewrite texts to make them better suit their interpretation. +

+

+ The same insensitivity to the world of concrete experience that has allowed so many commentators to read + their own ideas into Blake, ignoring what he said in plain English, makes satire and irony and sarcasm + inaccessible to many people who otherwise seem intelligent; this is especially apparent + when scientists comment on literature. Forming an imaginative synthesis of the writer and his meaning + requires mental flexibility and energy, rather than just analytical acuity. +

+

+ Everyone who described Blake"s physical appearance remarked on his large head. Blake commented that he + didn"t like to travel or undergo physical strain, because of its effects on his health. The brain is an + energetically expensive organ, which consumes large amounts of glucose. A very large brain puts a special + burden on the liver"s ability to store energy, and is likely to make a person conscious of physiological + processes. Blake"s descriptions of the process of seeing show that he was integrating his experience into + his knowledge, describing brain physiology, incorporating his perceptions and the best scientific knowledge + that was available to him, into a philosophical description of the place of conscious life in the world. The + pulsation of an artery was the unit of time, a red blood corpuscle was the unit of space, enclosing eternity + and infinity, eliminating arbitrary and abstract entities, and placing human life within cosmic life, while + revealing cosmic life within the individual. +

+

+ The idea of a "biological cosmos" seems strange only when it is considered against an ideology which + maintains that life is alone in an immense dead universe. The assumption of a dead, unintelligent, randomly + moving physical world is the creation of a series of theological ideas, which Blake perceived as essentially + Satanic. Blake used the language of these theologies, but inverted them, showing the ways they were used to + obscure reality, and to impose a perverse way of life onto the living world. +

+

+ Fred Hoyle, the astronomer, said "If this were an entirely scientific matter, there is little doubt from the + evidence that the case for a fundamentally biological universe would be regarded as substantially proven." + (1989) +

+

+ Over the last few decades, biologists feel that they have established the "biochemical unity of life," in + which biochemical cycles and genetic codes are widely shared. The idea of ecological interdependence has + come to be recognized as an essential part of life, or (as demonstrated by Vernadsky, and suggested by + Hoyle) a cosmic principle. Blake often called himself a Christian, and defined Christianity in many novel + ways, as art, love, politics, science, but specifically, in his version of Christianity, forgiveness was an + essential idea, and nothing lives for itself only. Blake"s Christianity as Art was a concrete part of + living, and he ridiculed some of the abstract theosophical definitions of god that were common in his time. + When his remarks are considered against the background of Spinozistic pantheism, it is the intensification + and personalization, the avoidance of abstractions that could permit the attribution of passivity or + inertness to any part of reality, that stand out. When he said that the world is alive, he meant that it is + a defect of perception that makes Newton"s world seem passive, empty, and dead. A few years ago, a movement + that called itself "deep ecology" tried to absolutize the ideas of ecology; + Blake"s view of the interactive unity of life was as well thought out as any that preceded Vernadsky"s + cosmology. +

+

+ Rather than elevating any of the ideas of Christianity to an absolute doctrine, Blake used them as parts of + an organic whole. The principle of forgiveness was presented as the appropriate response to a world which is + always new. The desire for vengeance comes from a delusive commitment to the world of memory. Virginity is + constantly renewed in the world of imaginative life. While Blake said that you can"t forgive someone until + they stop hurting you, the desire to be forgiven indicates that there is an opportunity to resolve the + problem. +

+

+ Although most mathematicians and computer-so-called-scientists are committed to a rationalistic, + past-oriented view of their mental operations, and some scientists accept that ideology along with + mathematics, the valid, discovery-oriented sciences have to be future-oriented. A first step in avoiding + dogmatic assumptions might be phrased as "remembering what you are," a living being, and asking how you know + things: + The interaction with other beings, exchanging energy and information with the environment, experiencing + yourself in the world. +

+

+ Holistic medicine and holistic psychology came into existence as attempts to overcome the dogmatic + compartmentalization of reality that is endemic. Whenever rigidity is a problem, looking for ways to create + new patterns that by-pass the petrified pattern can lead to a solution. Parkinson"s disease and other + physical problems have been approached using techniques of intensified or varied stimulation. Increased + stimulation--even electromagnetic stimulation-- appears to open alternative patterns. Music, dance, and + swimming have been used successfully to improve fluidity in various neurological diseases. Kurt Goldstein + (The Organism) worked with brain injuries, and found that the brain has a variety of ways to + restore a new balance. Raising the amount of energy that"s available can allow natural processes to create a + better synthesis. Political and social problems that are culturally determined may follow rules similar to + those of organic brain disease. +

+ +

+ Optimal assumptions, when assumptions are necessary, are those that don"t commit you to undesirable + conclusions. For example, in the 1950s, some people made the assumption that nuclear war was inevitable, and + made large investments in "fallout shelters," which were conceived in terms of world war II bomb shelters, + and so resources were diverted from other investments, such as education, which didn"t in themselves + foreclose future possibilities. Self-fulfilling prophecies and self-limiting assumptions are often built + into supposedly practical activities. +

+

+ The assumption that cancer is genetically determined, and the assumption that regeneration is impossible in + the heart or brain, are self-limiting assumptions that have been immensely destructive in biology and + medicine. There was no reason to make those assumptions, except for the rationalist culture. Physics, + biology, and cosmology are manacled by many unnecessary assumptions. The limits of adaptation, the extent of + life"s potential, can"t be discovered unless you look for them, but the sciences have built many artificial + limitations into their systems. +

+

+ Avoiding unnecessarily limiting assumptions, looking for patterns rather than randomness, looking for larger + patterns rather than minimal forms, avoiding reliance on verbal and symbolic formulations, expecting the + future to be different"these are abstract ways of formulating the idea that the world should be seen with + sympathetic involvement, rather than with analytical coldness. +

+

+ Almost everything which has been denounced as "teleological" has turned out to be much closer to the truth + than the mechanistic views that were promoted as "more scientific," and many horrors have been committed by + people who have said that nature shouldn"t be "anthropomorphized," that subjective feelings shouldn"t be + attributed to "the experimental material." The surgeons who operate on babies without anesthesia are + operating on the assumption that any being which can"t say "I"m going to sue you" is unable to experience + pain. +

+

+ When we analyze the ideas of chemical reaction equilibrium (burning something, for example), or biological + adaptation or growth or learning, and see that they are strictly directional in time (which is the basic + meaning of "teleological"), and consistent with Aristotle"s description of causality, we can see the + mysticism that has been imposed on our culture with the idea that "teleological explanations are + unscientific." +

+

+ Blake was clearly aware that the reason for making limiting assumptions was to maintain control, and to + profit from another"s suffering. Seeing that the sadistic assumptions that were put in place to regulate + human life rested on a dichotomizing of soul from body, Blake"s correction was to replace them with a unity + of consciousness and substance, a living world rather than a dead world. +

+ +

+ An imaginative study of his work has the potential to rouse one"s abilities and to open an unlimited world + of possibilities. "I give you the end of a golden string, Only wind it into a ball, It will lead you in at + Heaven"s gate, Built in Jerusalem"s wall." Blake knew that his work, like anything new in the world, could + be understood only by an active mental process. +

+

+ Every communicative act is original, and understanding it is an invention, a projection, an + imaginative synthesis. We can sometimes finish another person"s sentence, the way we + anticipate the notes in a melody; we predict the intended meaning. If the symbols carried + the meaning in a passive rationalistic way, the person receiving the symbols would receive nothing new. Intellect is a process of imaginative synthesis, or it is nothing. +

+

+ Blake devised "a system" that would make it possible to think about the world without unconsciously making a + commitment to the false limits. He showed, by working within this new philosophical synthesis, that Art, + Science, and Politics are structurally and substantially interdependent. The question I asked in the title, + "can art instruct science?" isn"t the right question once you see the world from Blake"s perspective, since + Science is Art, and both must be based on experience and imagination. +

+

+ Blake used, in a new way, the things that were available in his culture, to reveal the process of creation, + on all its levels. He consciously used language in a new way, to free the reader from the stereotypes of + conventional language. His methods are relevant, as he knew they would be, for other times and situations. +

+ +

+

+ + NOTES AND QUOTATIONS +

+

+ I happened to read Swedenborg's scientific work just as I was getting interested in concentrating on + becoming a biologist, and I realized that it was his scientific knowledge that shows up in Blake's imagery, + far more than his theology, which Blake obviously despised. By chance, just after I finished my master's + thesis on Blake, I got a job at a Swedenborgian college (Urbana University), where I saw in traditional form + the small minded theologism that Blake had seen in Swedenborg. As a result of those experiences, I greatly + appreciated the book, + The Heaven and Hell of William Blake, by Gholam-Reza Sabri-Tabrizi, which apparently hasn't been + very well received academically. +

+

+ Blake"s imagery indicates that he had a great interest in the physical and biological sciences, and he + apparently had some direct contacts with the leading scientists in London, some of whom are lampooned in Island in the Moon. + Some of Swedenborg"s discoveries were probably discussed in these groups. +

+ +

+ Although Swedenborg"s original works in anatomy and physiology were probably his most impressive + contributions, he was also a pioneer in paleontology, cosmology (the nebular hypothesis, in particular), + magnetism, crystallography, metallurgy, and endocrinology. +

+

+ E. P. Thompson"s Witness against the Beast is an extremely valuable source for clarifying Blake"s + vocabulary. +

+

+ Synectics, + W. J. J. Gordon, Harper & Row, 1961. Describes how metaphorical thinking was used for solving practical + problems, in the Synectics Research Group in Cambridge, Mass. +

+ +

+ In the "scientific" philosophies of Blake"s time, it was common to speak of matter and its primary and + secondary qualities. Blake understood that this view of matter was a derivative of awful theologies: +

+

+ "And this is the manner of the Sons of Albion in their strength +

+

+ They take the Two Contraries which are calld Qualities, with which +

+

+ Every Substance is clothed, they name them Good & Evil +

+ +

+ From them they make an Abstract, which is a Negation +

+

+ Not only of the Substance from which it is derived +

+

+ A murderer of its own Body: but also a murderer +

+

+ Of every Divine Member: it is the Reasoning Power +

+

+ An Abstract objecting power, that Negatives every thing +

+

+ This is the Spectre of Man: the Holy Reasoning Power +

+ +

+ And in its Holiness is closed the Abomination of Desolation" +

+

+ [Jerusalem, 10] +

+

+ What is a Church and What Is a Theatre? are they Two & not One? can they Exist Separate? +

+

+ Are not Religion & Politics the Same Thing? Brotherhood is Religion +

+ +

+ O Demonstrations of Reason Dividing Families in Cruelty & Pride! [Jerusalem plate 57] +

+

+ And he who takes vengeance alone is the criminal of Providence; +

+

+ If I should dare to lay my finger on a grain of sand +

+

+ In way of vengeance; I punish the already punishd: O whom +

+ +

+ Should I pity if I pity not the sinner who is gone astray! [Jerusalem plate 45] +

+

+ "Imagination has nothing to do with memory." (comment on Wordsworth). "Knowledge is + not by deduction, but Immediate by Perception or Sense at once." + (comment on Berkely). +

+

+ With Demonstrative Science piercing Apollyon with his own bow! J12.14; E155 +

+ +

+ Generalizing Art & Science till Art & Science is lost. J38.54; E185 +

+

+ "For Art & Science cannot exist but in minutely organized Particulars" +

+ +

+ Since the difference between a Rationalistic view of the world and a creative view is largely a question of + the reality of time, it"s worth mentioning the work of an astronomer whose cosmological view was based on + the reality of time:"Possibility of experimental study of properties of time," N. A. Kozyrev, Russian, + September 1967, USIA document in English, 49 pages, 1971. J. Narlikar more recently did similar work, + including his collaboration with H. Arp, described in Arp"s + Seeing Red: Redshifts, Cosmology, and Academic Science, Apeiron, Montreal, 1998. +

+ +

+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com +

+ +