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    <head><title>The problem of Alzheimer's disease as a clue to immortality - Part 2</title></head>
    <body>
        <h1>
            The problem of Alzheimer's disease as a clue to immortality - Part 2
        </h1>

        <p>
            <strong>V. HORMONE IMBALANCE, LEADING TO FAILURE OF PROTECTIVE INHIBITION AND ALZHEIMER'S DISEASE
            </strong>
        </p>
        <p>
            <em>"All cell death is characterized by an increase of intracellular calcium...." "Increase of cytoplasmic
                free calcium may therefore be called 'the final common path' of cell disease and cell death. Aging as a
                background of diseases is also characterized by an increase of intracellular calcium. Diseases typically
                associated with aging include hypertension, arteriosclerosis, diabetes mellitus and dementia."</em>
        </p>
        <p>
            <em>T. Fujita, "Calcium, parathyroids and aging," in Calcium-Regulating Hormones. 1. Role in Disease and
                Aging, H. Morii, editor, Contrib. Nephrol. Basel, Karger, 1991, vol. 90, pp. 206-211.
            </em>
        </p>
        <p><strong>THE FUNCTION OF ENERGY</strong></p>
        <p>
            Most people are slightly demented now and then, when they are very sleepy or tired, or sick, or drunk, or
            having a hormone imbalance or extreme anxiety state. Sometimes physicians have described people as demented,
            implying that the condition would never improve, when the person was depressed or hypothyroid. If the person
            has a history of epilepsy, or is very old, the physician is more likely to diagnose dementia than if the
            same loss of mental function occurs in a younger person without a history of a nervous disorder. Even people
            with less education are at increased risk of being diagnosed as "demented."
        </p>
        <p>
            In 1976, I saw a 52 year-old woman who had the diagnosis of epileptic dementia. After 3 or 4 days of taking
            progesterone, her mental function returned to the extent that she could find her way around town by herself,
            and could work. A few months later, she returned to graduate school, got straight As and a master's degree.
            A few years later, a man in his 80s showed the classical signs of senile dementia, with childishness,
            confusion, self-centeredness, and unstable emotions. A few days after getting a mixture of thyroid,
            pregnenolone, and progesterone, his mind was again clear, and he was able to work on a research project he
            had set aside years before.
        </p>
        <p>
            When the body temperature is very much below normal, mental functioning is seriously limited. I think the
            first question that should be asked about a demented person is "is this the cold brain syndrome, or is
            something else involved?" When it is known that the brain has shrunken drastically, and filled up with
            plaques and developed gliosis, we know that something more than a "cold brain" is involved, but we don't
            know how much function could be regained if the hormones were normalized. Every moment of malfunction
            probably leaves its structural mark. Early or late, it is good to prevent the functional errors that lead to
            further damage, and to give the regenerative systems an opportunity to work. Before the final "calcium
            death" described (above) by Fujita, there are many opportunities for intervening to stop or reverse the
            process. The older the person is, the more emphasis should be put on protective inhibition, rather than
            immediately increasing energy production. Magnesium, carbon dioxide, sleep, red light, and naloxone might be
            appropriate at the beginning of therapy.
        </p>
        <p>
            The resting state of a cell is a highly energized state. To the old Pavlovians, the resting state existed at
            two energy levels, and they applied the term "protective inhibition" generally to the depleted state
            (parabiosis) that occurs in exhaustion or coma, but I am using the phrase in a more general sense, that
            seems reasonable now that the concept of "excitotoxic" injury has become current. I mean it to include
            everything which protects against excitotoxic injury. This definition therefore has the virtue of being
            biochemically and physiologically very specific, while retaining the functional and therapeutic significance
            that it had for the Pavlovians. (My book, <em>Mind and Tissue,</em> and the chapter "A unifying principle"
            in <em>
                Generative Energy,</em> discussed the idea of the resting state and protective inhibition.)
        </p>
        <p>
            Ordinary healthy sleep is an example of restorative, protective inhibition. The energy charge, including
            levels of ATP, creatine phosphate, and glycogen storage, regulates many restorative enzyme systems. I have
            suggested (1975, J. Orthomol. Psychiatry) how the entropy-sensitivity or cold-inactivation of an enzyme
            could be involved in shifting the brain toward a state of inhibition. A recent publication (J. H. Benington
            and H. C. Heller, "Restoration of brain energy metabolism as the function of sleep," Progress in Neurobiol.
            45, 347-360, 1995) has proposed that reduction of energy charge and depolarization of cells act through
            adenosine secretion to restore glycogen stores. Since glycogen stores decrease with aging, this work
            supports the idea that protective inhibition is weakened with aging. (L. N. Simanovskiy and Zh. A. Chotoyev,
            "The effect of hypoxia on glycogenolysis and glycolysis rates in the rat brain," Zhurnal Evolyutsionnoy
            Biokhimii i Fiziologii 6(5), 577-579, 1970.)
        </p>
        <p>
            J. H. Benington and H. C. Heller, "Restoration of brain energy metabolism as the function of sleep," Prog.
            in Neurobiology 45, 347-360, 1995. "...the conditions that have been demonstrated to stimulate adenosine
            release from neural tissue represent either increases in metabolic demand (...activation of excitatory
            receptors) or decreases in metabolic supply (hypoxia, ischaemia, hypoglycemia)...." "In the brain,
            adenosine-stimulated increases in potassium conductance produce hyperpolarization, thereby reducing neuronal
            responsiveness...." "Adenosine release is triggered globally in response to changes in cerebral energy
            homeostasis." "A number of findings provide indirect support for the hypothesis that glycogen stores are
            depleted during waking and restored during sleep." "Reduced availability of glycogen to astrocytes
            must...increase adenosine release...." "Because ATP concentration is 100-fold greater than AMP
            concentration, a minute decrease in cellular energy charge...is translated into a large proportional
            increase in extracellular adenosine cencentration...."
        </p>
        <p>
            The terms "functional quiescence" and "G0 quiescence" are similar in meaning to the resting state; I think
            of cells in the state of "G0 quiescence" as being stem cells, waiting for use in regeneration, but I don't
            subscribe to the idea that they can't be reconstituted from functioning, differentiated cells. In plants,
            dedifferentiation is achieved fairly easily, and in the study of animal cells the trend in that direction
            seems very obvious, though many people keep saying that it just isn't possible. In general, the things such
            as lipid peroxidation or calcium influx which cause cell replication at one level, cause cell death at a
            higher level.
        </p>
        <p>
            Energy to resist stress makes quiescence possible, and prevents the deterioration of cells, of the sort that
            occurs in aging. O. Toussaint, et al., "Cellular aging and energetic factors," Exp. Gerontology 30(1), 1-22,
            1995. "Experiments performed with endothelial cells in the context of the ischemia-reperfusion toxicity of
            free radicals, also offer good examples of the impact of cell energy on cell resistance to these toxic
            molecules." "...if a supplement of energy is given...the toxic effect of the free radicals is much
            reduced...."
        </p>
        <p>
            The specific approaches of this orientation --to energize but quiet the brain--are diametrically opposed to
            some of the "therapies" for Alzheimer's disease that have been promoted recently by the drug industries:
            Things to increase stimulation, especially to increase cholinergic excitation; even the excitotoxic amino
            acids themselves and their analogs; and estrogen, which is a multiple brain excitant, proconvulsant,
            excitotoxic promoter, and anti-memory agent. Those product-centered publications stand out distinctly from
            the actual research.
        </p>
        <p>
            There are many energy-related vicious circles associated with aging, but the central one seems to be the
            fat-thyroid-estrogen-free-radical-calcium sequence, in which the ability to produce stabilizing substances
            including carbon dioxide and progesterone is progressively lost, increasing susceptibility to the unstable
            unsaturated fats.
        </p>
        <p><strong>EFFECTS OF ESTROGEN AND UNSATURATED FATTY ACIDS</strong></p>
        <p>
            Estrogen production is facilitated when tissue is cooler, and it lowers body temperature. Estrogen and the
            endorphins act together in many ways (including the behavior of estrus), and naloxone (the antagonist of
            morphine and the endorphins) raises body temperature and in other ways opposes estrogen. Naloxone has been
            found to improve the symptoms of demented people, and I have seen it quickly, and dramatically, improve the
            mental clarity of a 60 year old woman who had used estrogen. It, like clonidine (the anti-adrenaline drug),
            is a good candidate for controlling the hot flashes and other symptoms of menopause.
        </p>
        <p>
            In various degenerative brain conditions, blood clotting has been implicated either as a cause or a
            complication. Many people are promoting unsaturated oils for their "anti-clotting" value, in spite of the
            older literature showing that they inhibit proteolytic enzymes and slow clot removal. Several newer
            publications have revealed other aspects of their involvement in thrombus formation. A. J. Honour, et al.,
            "The effects of changes in diet on lipid levels and platelet thrombus formation in living blood vessels,"
            Br. J. Expt. Pathol. 59(4), 390-394, 1978--corn oil caused platelets to be more sensitive to ADP.
        </p>

        <p>
            Although there is a lot of talk about "membrane fluidity," as a desirable thing, and the loss of unsaturated
            lipids in the aged brain, there are some interesting observations related to "viscosity" in Alzheimer's
            disease. The platelets of Alzheimer's patients are less viscous, and lipids extracted from the brain are
            more fluid, and contain 30% less cholesterol than normal (on a molar basis, in relation to phospholipids).
            (G. S. Roth, et al., 1995.) In general, lipid peroxidation causes cellular viscosity to increase, apparently
            by causing cross-linking of proteins, but I think the significance of the decreased cholesterol relates to
            its significance as precursor to pregnenolone and progesterone, and to the known association with
            Alzheimer's disease of a variant form of the cholesterol transporter protein, ApoE, which I suppose is a
            slightly less stable molecular form that is more susceptible to malfunction in stress.
        </p>
        <p>
            The extracellular matrix is a major factor in the function and stability of brain cells. (L. F. Agnati, et
            al., "The concept of trophic units in the central nervous system," Prog. in Neurobiol. 46, 561-574, 1995.
            Any factor producing edema tends to disrupt the extracellular matrix (Chan and Fishman, 1978, 1980, and L.
            Loeb, 1948.)
        </p>
        <p>
            Seizures are known to be promoted by estrogen, by unsaturated fats, and by lipid peroxidation, and to cause
            an increase in the size of the free fatty acid pool in the brain. Prolonged seizures cause nerve damage in
            certain areas, especially the hippocampus, thalamus, and neocortex (Siesjo, et al., 1989). Dementia is known
            to be produced by prolonged seizures.
        </p>

        <p>
            Prenatal exposure to estrogen, to oxygen deficiency, or to unsaturated fats decreases the size of the brain
            at birth. There is apparently a requirement for saturated fats during development (J. M. Bourre, N.
            Gozlan-Devillierre, O. Morand, and N. Baumann, "Importance of exogenous saturated fatty acids during brain
            development and myelination in mice," Ann. Biol. Anim., Biochim., Biophys. 19(1B), 172-180, 1979.
        </p>
        <p>
            Under the influence of estrogen, or unsaturated fats, brain cells swell, and their shape and interactions
            are altered. Memory is impaired by an excess of estrogen. Estrogen and unsaturated fat and excess iron kill
            cells by lipid peroxidation, and this process is promoted by oxygen deficiency. The fetus and the very old
            have high levels of iron in the cells. Estrogen increases iron uptake. Estrogen treatment produces elevation
            of free fatty acids in the blood, and lipid peroxidation in tissues. This tends to accelerate the
            accumulation of lipofuscin, age-pigment. Lactic acid, the production of which is promoted by estrogen,
            lowers the availability of carbon dioxide, leading to impairment of blood supply to the brain.
        </p>
        <p>
            Estrogen stimulates cell division, but can also increase the rate of cell death. Unsaturated fatty acids can
            also stimulate or kill.
        </p>
        <p>
            Both estrogen and unsaturated fats promote the formation of age-pigment. Besides increasing the free fatty
            acid concentration, estrogen possibly depresses the level of cholesterol, both of which are changes seen in
            the senile brain.
        </p>
        <p>
            Estrogen causes massive alterations of extracellular matrix, and seems to promote dissolution of
            microtubules (Nemetschek-Gannsler), as calcium does. Unsaturated fats increase calcium uptake by at least
            some brain cells (H. Katsuki and S. Okuda, 1995.) Unsaturated fats, like estrogen, increase the permeability
            of blood vessels. The unsaturated fat causes edema of the brain, inhibits choline uptake, blocking
            acetylcholine production.
        </p>

        <p>
            Progesterone is a nerve growth factor, produced by glial cells (oligodendrocytes). It promotes the
            production of myelin, protects against seizures, and protects cells against free radicals. It protects
            before conception, during gestation, during growth and puberty, and during aging. It promotes regeneration.
            Its production is blocked by stress, lipid peroxidation, and an excess of estrogen and iron.
        </p>
        <p>
            Aspirin protects against iron toxicity, clot formation, and reduces lipid peroxidation while blocking
            prostaglandin formation. Aspirin and other antiinflammatory drugs, taken for arthritis, have been clearly
            associated with a reduced incidence of Alzheimer's disease. Aspirin reduces the formation of prostaglandins
            from arachidonic acid.
        </p>
        <p>
            Unsaturated fatty acids, but not saturated fatty acids, are signals which activate cell systems.
        </p>
        <p>
            Many different stimuli can induce cell activity, cell death, or change to another cell type. (J. Niquet, et
            al., "Glial reaction after seizure induced hippocampal lesion: Immunohistochemical characterization of
            proliferating glial cells," J. Neurocytol. 23(10), 641-656, 1994: "...hippocampal astrocytes from
            kainate-treated rats experess A2B5 immunoreactivity, a marker of type-2 astrocytes." "This suggests that in
            the CNS, normal resident astrocytes acquire the phenotypic properties of type-2 astrocytes.")
        </p>

        <p>
            A "deficiency" of polyunsaturated fatty acids leads to altered rates of cellular regeneration and
            differentiation, a larger brain at birth, improved function of the immune system, decreased inflammation,
            decreased mortality from endotoxin poisoining, lower susceptibility to lipid peroxidation, increased basal
            metabolic rate and respiration, increased thyroid function, later puberty and decreases other signs of
            estrogen dominance. When dietary PUFA are not available, the body produces a small amount of unsaturated
            fatty acid (Mead acids), but these do not activate cell systems in the same way that plant-derived PUFAs do,
            and they are the precursors for an entirely different group of prostaglandins.
        </p>
        <p><strong>VITAMIN A AND THE STEROIDS</strong></p>
        <p>
            In a variety of cell types, vitamin A functions as an estrogen antagonist, inhibiting cell division and
            promoting or maintaining the functioning state. It promotes protein synthesis, regulates lysosomes, and
            protects against lipid peroxidation. Just as stress and estrogen-toxicity resemble aging, so does a vitamin
            A deficiency. While its known functions are varied, I think the largest use of vitamin A is for the
            production of pregnenolone, progesterone, and the other youth-associated steroids. One of vitamin E's
            important functions is protecting vitamin A from destructive oxidation. Although little attention has been
            given to the effects of unsaturated fats on vitamin A, their destruction of vitamin E will necessarily lead
            to the destruction of vitamin A. The increased lipid peroxidation of old age represents a vicious circle, in
            which the loss of the antioxidants and vitamin A leads to their further destruction.
        </p>
        <p>
            To produce pregnenolone, thyroid, vitamin A, and cholesterol have to be delivered to the mitochondria in the
            right proportion and sufficient quantity. Normally, stress is balanced by increased synthesis of
            pregnenolone, which improves the ability to cope with stress. Lipid peroxidation, resulting from the
            accumulation of unsaturated fatty acids, iron, and energy deficiency, damages the mitochondrias' ability to
            produce pregnenolone. When pregnenolone is inadequate, cortisol is over-produced. When progesterone is
            deficient, estrogen's effect is largely unopposed. When both thyroid and progesterone are deficient, even
            fat cells synthesize estrogen.
        </p>

        <p><strong>THE NATURE OF ALZHEIMER'S DISEASE</strong></p>
        <p>
            Although Alzheimer's disease until recently referred to a certain type of organic dementia occuring in
            people in their thirties, forties and fifties (presenile dementia), structural similarities seen in senile
            dementia have caused the term to lose its original meaning. Alzheimer's sclerosis of blood vessels, and even
            the death of nerve cells, are sometimes neglected in favor of the more stylish ideas, emphasizing certain
            proteins that cause the tangles and plaques. Until recently, the "tangles" were commonly interpreted as the
            debris left after the death of a cell, rather than as one of the processes causing the death of the cell.
        </p>
        <p>
            Alzheimer-type dementia is different from other dementias, but it overlaps with them, and with age-related
            and stress-related changes in other organs.
        </p>
        <p>
            Physical signs (seen at autopsy) of AD:
        </p>
        <p>
            1) Death of neurons (increase of glial cells),
        </p>

        <p>
            2) Amyloid plaques (extracellular), associated with a particular variant of apolipoprotein E, the epsilon 4
            allele,
        </p>
        <p>
            3) Fibrillary tangles (intracellular, or remaining after the rest of the cell has disappeared),
        </p>
        <p>
            4) Amyloid in blood vessels.
        </p>
        <p>
            Functional and biochemical observations:
        </p>
        <p>
            1) The mitochondrial energy problem, cytochrome oxidase and its regulation; body temperature/pulse-rate
            cycle disturbance; lipid peroxidation; respiratory defect; altered amino acid uptake; memory impairment;
            dominance of the excitatory systems vs. the inhibitory adenosine/GABA/progesterone/pregnenolone system.
            Increased calcium uptake, which is associated with lipid peroxidation and cell death. Increased cortisol and
            DHEA.
        </p>
        <p>
            2) Deposit of abnormal proteins, such as transthyretin-amyloid; albumin binding of PUFA, vs. transport of
            thyroid and retinol.<em> </em>

            Beta-glucuronidase increases, depositing estrogen in cells.<em> </em>(A. J. Cross, et al., "Cortical
            neurochemistry in Alzheimer-type dementia," Chapter 10, pages 153-170 in<em>
                Aging of the Brain and Alzheimer's Disease, Prog. in Brain Res. 70, edited by D. F. Swaab, et al.,
                Elsevier, N.Y., 1986.</em>)
        </p>
        <p>
            <em>3) </em>
            Abnormally phosphorylated (tau) proteins; association with the variant form of Apo E; tau microtubule
            organizing proteins, microtubules are involved in transporting cholesterol; phosphorylation, by the kinase
            systems, regulated by PUFA; the intermediate filaments are generally stress-associated.
        </p>
        <p>
            4) ApoE, in cytoplasm, involved in cholesterol delivery for pregnenolone synthesis, as in the adrenal; its
            expression regulated by thyroid. Regulation of the side-chain cleaving enzymes; regulation of the
            cholesterol intake and conversion to pregnenolone by the endozepine receptor/GABA receptor, modified by
            progesterone.
        </p>

        <p><strong>AN EXAMPLE OF A REGULATORY PROBLEM</strong></p>
        <p>
            Vegetable oil suppresses the thyroid, increasing estrogen. Estrogen and calcium depolymerize microtubules.
            Microtubule transport for Apo E, transthyretin, thyroid, and cholesterol for pregnenolone synthesis is
            disrupted. Transthyretin and Apo E accumulate unused, and deposit in blood vessels, around nerves, and in
            cytoplasm. Pregnenolone and progesterone deficiency (aggravating thyroid deficiency) causes memory loss,
            destabilization of nerve cells, failure of myelin formation, and excess cortisol synthesis. Free radicals
            and calcium cause multiple cell injuries including nerve-death. Estrogen is released by elevated
            beta-glucuronidase. Imbalances of other steroids, including cortisol and DHEA, develop as cells compensate
            for pregnenolone deficiency, causing shifts in balance of glial cells. Hypothyroidism, estrogen excess, free
            unsaturated fats cause increased vascular permeability and brain edema, protein leakage, and alteration of
            the matrix..
        </p>
        <p>
            <strong>VIII: STRUCTURE AS A REGULATORY SYSTEM--AN EMERGING VISION OF PERVASIVE EPIGENESIS</strong>
        </p>
        <p>
            In the introduction I mentioned that membranous regulation and genetic determination should be considered as
            defunct theories. What I have been saying about self-actualizing systems and the factors that disrupt them
            derives from a view of cell function that has been developing since the 1920s.
        </p>
        <p>
            Around 1940, a Russian biochemist (Oparin, I think) proposed that the enzymes of glycolysis were bound to
            the structure of the cell when they were not in use, and that they were "desorbed" under the conditions that
            required abundant glycolysis. Knowing that concept, in 1970 I proposed that the cell water itself underwent
            a transition under such conditions (which could include increased temperature, reduced oxygen, or nervous or
            hormonal stimulation). Activation of glycolysis is usually explained by the availability of regulatory
            substances such as ammonia, phosphate, and NAD, and many biochemists were content to understand cells in
            terms of test-tube models. But in the last few years, it has become clear that some of these basic
            regulatory molecules do bind to structural components of the cell. (T. Henics, "Thoughts over cell biology:
            A commentary," Physiol. Chem. Phys. &amp; Med. NMR 27, 139-140, 1995.) Although the details aren't clear, it
            is known that hormones and other factors stabilize or destabilize RNA, and that during some of these events
            relevant enzymes bind to the RNA. When these facts are combined with the information that is accumulating on
            splicing and modification of RNA, and the copying of RNA back into DNA, the hereditary system is seen to be
            much more flexible than it was believed to be.
        </p>
        <p>
            A global change of state is able to steer each part of the process, continuously. In this way, the cell
            resembles an analog, rather than a digital, control system: each part is momentarily guided, rather than
            waiting for "feedback."
        </p>
        <p>
            Where before, cellular "regulatory mechanisms" referred to certain feedback mechanisms based on interactions
            of randomly diffusing molecules, the new understanding of the cell sees a highly structured system in which
            very little is random, and the cell's adaptive possibilities, instead of being limited to a certain number
            of genetic switches, are shaped by every imaginable environmental influence. The cell's structure, far from
            being "read out of the genome," is sensitively reshaped constantly by processes that incorporate some of the
            environment in establishing each new stability. The old-model-geneticists have been forced to admit that the
            genes can't specify everything in the organism's structure, and it was the brain's complexity that forced
            this recognition that certain things are developed "epigenetically." But the new fact that most biologists
            are reluctant to accept is that the structure of the cell itself is developed very largely on the basis of
            information received from the environment--that is, "epigenetically."
        </p>

        <p>
            Traditionally, epigenesis has meant that the form of an embryo or organism didn't preexist, or wasn't
            completely specified by the genes. That is, it has had to do with the relationships between cells. It
            involved a recognition that "cells are clever enough to design an organism." It is a significant step beyond
            that to the recognition that "cells are clever enough to redesign themselves to meet situations never seen
            before."
        </p>
        <p>
            Biologists working with bacteria and yeasts have seen them adapt in non-random ways to novel conditions.
            "Directed mutations" are impossible, according to the "central dogma" that has the support of textbooks and
            most biology professors, but they do occur in those single-celled organisms. Barbara McClintock showed that
            in corn her mobile genes were mobilized by stress. Although this isn't exactly "directed mutation," it is an
            example of a mechanism for increasing adaptation when adaptation is need. There is a certain type of enzyme
            which makes specific cuts in the DNA chain. Biotechnologists find them convenient for their purposes, but
            their presence serves physiological purposes, presumably in all organisms, like those described by
            McClintock in corn. During the terminal stress that produces the special kind of cell death known as
            apoptosis, these enzymes make confetti of the genome.
        </p>

        <p>
            Poisons, such as estrogen, unsaturated fatty acids, or even radiation, produce different effects at
            different doses. Low doses typically stimulate cell division, larger doses produce changes of cell type and
            altered states of differentiation, and finally, adequate doses produce apoptotic cell death. There is a
            special ideology around apoptosis, which holds that it is "genetically programmed," implying that whenever
            it occurs in the brain, it was destined to happen sooner or later. But in fact, "growth factors" of various
            sorts can prevent it. It is increasingly clear that it represents excessive stress and deficient resources.
            The involvement of the genetic apparatus in differentiation and radical adaptation suggests that the
            (epigenetic) resources of cells are unlimited.
        </p>
        <p>
            The changes that are known to be produced by the poisons that we are habitually exposed to are exactly the
            changes that occur in the aging brain. As I scan over hundreds of studies that define the effects of
            estrogen, unsaturated fats, excess iron, and lipid peroxidation, my argument seems commonplace, even
            trivial, except that I know that it clearly relates to therapies for most of the degenerative diseases, and
            that the great culture-machine is propagating a different view at several points that are essential for my
            argument.
        </p>
        <p>
            They are advancing a myth about human nature, so I will advance a counter-myth. At the time people were
            growing their large brains they lived in the tropics. I suggest that in this time before the development of
            grain-based agriculture, they ate a diet that was relatively free of unsaturated fats and low in iron--based
            on tropical fruits. I suggest that the Boskop skull from Mt. Kilimanjaro was representative of people under
            those conditions, and that just by our present knowledge of the association of brain size with longevity,
            they--as various "Golden Age" myths claim--must have had a very long life-span. As people moved north and
            developed new ways of living, their consumption of unsaturated fats increased, their brain size decreased,
            and they aged rapidly. Neanderthal relics show that flaxseed was a staple of their diet.
        </p>

        <p>
            Even living in the tropics, there are many possibilities for diets rich in signal-disrupting substances,
            including iron, and in high latitudes there are opportunities for reducing our exposure to them. As a source
            of protein, milk is uniquely low in its iron content. Potatoes, because of the high quality of their
            protein, are probably relatively free of toxic signal-substances. Many tropical fruits, besides having
            relatively saturated fats, are also low in iron, and often contain important quantities of amino acids and
            proteins. In this context, Jeanne Calment's life-long, daily consumption of chocolate comes to mind: As she
            approaches her 121st birthday, she is still eating chocolate, though she has stopped smoking and drinking
            wine. The saturated fats in chocolate have been found to block the toxicity of oils rich in linoleic acid,
            and its odd proteins seem to have an anabolic action.
        </p>
        <p>
            If we really take seriously even the traditional sort of epigenesis, and especially if we accept the deeper
            idea of epigenesis on the level of cellular structure and function, we have to see the organism as a sort of
            "whirlwind of cells," made up of whirlwinds of atoms (in Vernadsky's phrase) in which our way of life sets
            the boundaries within which our cells will restructure themselves.
        </p>
        <p>
            The random production of free radicals, rather than acting only by way of genetic damage or protein
            cross-linking, is also able to act as a signalling process, that is, on a strictly physiological level. An
            excess of unsaturated fatty acids itself constitutes a massive distortion of the regulatory systems, but it
            also leads to distortions in the "eicosanoid" system and the increasingly uncontrolled production of free
            radicals, and to changes in energy, thyroid activity, and steroid balance. The aging body, rather than being
            like a car that needs more and more repairs until it collapses from simple wear, is more like a car
            traveling a road that becomes increasingly rough and muddy, until the road becomes an impassable swamp.
        </p>
        <p>
            The suggested therapy is a correction of the signalling process, rather than "genetic surgery,"
            transplantation, etc., which is the pessimistic implication of the doctrine that oxidative damage is simply
            a matter of "wear and tear," "somatic mutations," and "cross-linking." Those problems are reparable, and our
            emphasis should be on the production of energy and the avoidance of the conditions that allow the
            undesirable signals to accumulate.
        </p>
        <p>
            The absence of cancer on a diet lacking unsaturated fats, the increased rate of metabolism, decreased free
            radical production, resistance to stress and poisoning by iron, alcohol, endotoxin, alloxan and
            streptozotocin, etc., improvement of brain structure and function, decreased susceptibility to blood clots,
            and lack of obesity and age pigment on a diet using coconut oil rather than unsaturated fats, indicates that
            something very simple can be done to reduce the suffering from the major degenerative diseases, and that it
            is very likely acting by reducing the aging process itself at its physiological core.
        </p>
        <p>
            Copyright: Raymond Peat, PhD 1997
        </p>
        <p>
            PO Box 5764 Eugene, OR 97405
        </p>
        <p>
            <h3>SELECTED REFERENCES</h3>
        </p>

        <p>
            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...."
        </p>
        <p>
            J. R. Brawer, et al., "Ovary-dependent degeneration in the hypothalamic arcuate nucleus," Endocrinology 107,
            274-279, 1980.
        </p>

        <p>
            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.
        </p>

        <p>
            G. B. Melis, et al., "Evidence that estrogens inhibit LH secretion through opioids in postmenopausal women
            using naloxone," Neuroendocrinology 39, 60-63, 1984.
        </p>
        <p>
            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."
        </p>
        <p>
            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..."
        </p>

        <p>
            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...."
        </p>
        <p>
            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."
        </p>
        <p>
            E. A. Quail and G. C. T. Yeoh, "The effect of iron status on glyceraldehyde 3-phosphate dehydrogenase
            expression in rat liver," FEBS Lett. 359(2-3), 126-128, 1995. "...the overexpression of GAPDH mRNA in iron
            deficiency is probably due to increased message stability." [This is one of the points discussed by Henics.
            Estrogen, which increases iron retention, also modifies mRNA stability.]
        </p>

        <p>
            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."
        </p>
        <p>
            J. G. Liehr and D. Roy, "Free radical generation by redox cycling of estrogens," Free Rad. Biol. Med. 8,
            415-423, 1990.
        </p>
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            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>
        <p>
            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&gt;C&gt; Thomas, Springfield, 1976.
        </p>
        <p>
            Gross, "Reproductive cycle biochemistry," Fertility &amp; Sterility 12(3), 245-260, 1961. "The maintenance
            of an environment conducive to anaerobic metabolism--which may involve the maintenance of an adequate supply
            of the substances that permit anaerobiosis...seems to depend primarily upon the action of estrogen."
            "Glycolytic metabolism gradually increases throughout the proliferative phases of the cycle, reaching a
            maximum coincident with the ovulation phase, when estrogen is at a peak. Following this, glycolysis
            decreases, the respiratory mechanisms being more active during the secretory phase. Eschbach and Negelein
            showed the metabolism of the infantile mouse uterus to be less anaerobic than that of the adult. If estrogen
            is administered, however, there is a 98 per cent increase in glycolytic mechanisms.""The effect of the
            progestational steroids may be such as to interfere with the biochemical pattern required for support of
            this anaerobic environment."
        </p>
        <p>
            C. S. Bangur, J. L. Howland, S. S. Katyare, "Thyroid hormone treatment alters phospholipid composition and
            membrane fluidity of rat brain mitochondria," Biochem. J. 305(1), 29-32, 1995. (Increases fluidity.)
        </p>
        <p>
            R. S. Sohal, et al., "Mitochondrial superoxide and hydrogen peroxide generation, protein oxidative damage,
            and longevity in different species of flies," Free Rad. Biol. &amp; Med. 19(4), 499-504, 1995. Cytochrome C
            oxidase protects against free radical damage. This enzyme depends on thyroid and light.
        </p>

        <p>
            D. L. Williams, et al., "Cell surface 'blanket' of apolipoprotein E on rat adrenocortical cells," J. Lipid
            Res. 36(4), 745-758, 1995. "...the zona fasciculata cell is encircled or covered with apoE on all faces of
            the cell. ...this cell surface 'blanket' of apoE participates in the uptake of lipoprotein cholesterol by
            either the endocytic or selective uptake pathways."
        </p>
        <p>
            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.] M. Warner and J. A. Gustafsson, "Cytochrome P450 in the brain:
            Neuroendocrine functions," Front Neuroendocrinol 16(3), 224-236, 1995. [Discusses the GABA(A) receptor
            active steroids, and the accumulation of pregnenolone in the brain.]
        </p>
        <p>
            P. Robel, et al., "Biosynthesis and assay of neurosteroids in rats and mice: Functional correlates," J.
            Steroid Biochem. Mol. Biol. 53(1-6), 355-360, 1995. [Discusses the effects of pregnenolone and progesterone
            on aggression and learning. The animals which learned most easily had the highest levels of pregnenolone
            sulfate.]
        </p>

        <p>
            J. R. Pasqualini, et al., "Effect of the progestagen promegestone (R-5020) on mRNA of the oestrone
            sulphatase in the MCF-7 human mammary cancer cells," Anticancer Res. 14(4A), 1589-1593, 1994. Progestagen
            decreases estrogen sulfatase in mammary cancers. [Sulfatase, like beta-glucuronidase, causes active estrogen
            to be released.]
        </p>
        <p>
            W. J. Trooster, et al., "Treatment of acute experimental allergic encephalomyelitis in the Lewis rat with
            the sex hormone progesterone," Int. J. Immunopathol. Pharmacol. 7(3), 183-192, 1994. "...we suggest that
            treatment with progesterone protected against the histological signs of EAE through a peripheral immune
            mechanism."
        </p>
        <p>
            H. L. Koenig, et al., "Progesterone synthesis and myelin formation by Schwann cells," Science (268),
            1500-1503, 1995. "The high concentrations of progesterone in intact adult nerves also indicate a role for
            this neurosteroid in the slow but continuous renewal of peripheral myelin."
        </p>

        <p>
            N. C. Lan and K. W. Gee, "Neuroactive steroid actions at the GABA(A) receptor," Horm. Behav. 28(4), 537-544,
            1994. Neuroactive steroids "...do not interact with any of the classical cytosolic hormonal steroid
            receptors." "The interaction of neuroactive steroids with GABA(A) receptor is specific to a site on the
            receptor complex distinct from the benzodiazepine and barbiturate modulatory sites."
        </p>
        <p>
            J. F. FierroRenoy, et al., "Three different thyroid hormone receptor isoforms are detected in a pure culture
            of ovine oligodendrocytes," Glia 14(4), 322-328, 1995. "Our results demonstrate that differentiated
            oligodendrocytes express alpha-1 and alpha-2 variant and beta-1 isoforms of TH at the protein level and
            support the notion of a direct impact of thyroid hormones on oligodendrocytes in their regulation of myelin
            synthesis."
        </p>
        <p>
            J. Masse, "Nutrition, thyroid hormones, body temperature, and mortality of elderly patients with acute
            illnesses," Am. J. Clin. Nutr. 62(3), 647-648, 1995.
        </p>

        <p>
            E. J. Masoro, "Dietary restriction," Exp. Gerontology 30(3/4), 291-298, 1995. "These antiaging actions
            result from a reduction of energy intake by the animal but are not due to a decrease in metabolic rate per
            unit of lean body mass." [The slowed rate of aging is associated with increased metabolic rate--as if
            metabolic inhibitors accumulate at a slower rate.]
        </p>
        <p>
            D. L. Cheney, et al., "Pregnenolone sulfate antagonizes dizocilpine amnesia: Role for allopregnanolone,"
            Neuroreport 6(12), 1697-1700, 1995. "We and others have shown that allopregnanolone potently modulate
            GABA(A) receptor function whereas 5 alpha-dihydroprogesterone fails to induce rapid changes...."
        </p>
        <p>
            B. S. McEwen and E. Gould, "Adrenal steroid influences on the survival of hippocampal neurons," Biochem.
            Pharmacol 40, 2393-2402, 1990.
        </p>

        <p>
            P. W. Landfield, et al., "Hippocampal aging and adrenocorticoids: Quantitative correlations," Science
            202(8), 1098-1101, 1978.
        </p>
        <p>
            A. M. Dudchenko, et al., "Effect of corticosterone on the macroergic pool and membrane permeability in
            sections of rat hippocampus," Bull. Exp. Biol. &amp; Med. 116(12), 1505-1508, 1993. "...the hippocampus is
            one of the most vulnerable brain structures...." "...a reduction of the oxygen content...causes a sharp
            increase of membrane permeability, which is...in line with the trend toward a decrease of the macroergic
            [energy] content (especially creatine phosphate and ATP content) in the hippocampal cells." "The death of
            hippocampal neurons, triggered...by hyperactivation of the glutamate receptors, is accelerated in the
            presence of" glucocorticoids, while these hormones may be protective against oxygen deficit, by increasing
            the availability of glucose, and possibly of amino acids.
        </p>

        <p>
            M. J. Meaney, et al., "Individual differences in hypothalamic-pituitary-adrenal activity in later life and
            hippocampal aging," Exp. Gerontology 30(3/4), 229-251, 1995. "...glucocorticoids...both increase the toxic
            glutamate signal and decrease the metabolic capacity of neurons to survive." (Glucose is protective.) "Our
            current foxus is on the potential role of progesterone as a modulator of glucocorticoid action."
        </p>
        <p>
            P. Sheng, et al., "Methamphetamine causes reactive gliosis in vitro: Attenuation by the ADP-ribosylation
            inhibitor, benzamide," Life Sciences 55(3), 51-54, 1994
        </p>
        <p>
            N. S. Verkhratsky, "Limbic control of endocrine glands in aged rats," Exp. Gerontology 30(3/4, 415-421,
            1995. Aging causes "degeneration of pyramidal cells in the hippocampus of humans..., accumulation of
            lipofuscin...,a decrease in the excitability of amygdala medial nuclei and an increased excitability of its
            central nuclei..., and a deterioration of their vascularization." "...stimulation of hippocampus inhibits
            ACTH secretion...and causes a decrease of plasma corticosteroids...."
        </p>
        <p>
            R. M. Sapolsky, et al., "Prolonged glucocorticoid exposure reduces hippocampal neuron number: Implications
            for aging," J. Neurosci. 5 1221, 1985.
        </p>
        <p>
            J. L. W. Yau, Mol. Brain Res. 27(1), 174-178, 1994. "Glucocorticoid excess is associated with hippocampal
            neuronal dysfunction and loss, mainly affecting CA1."
        </p>
        <p>
            B. Nasman, et al., "A subtle disturbance in the feedback regulation of the hypothalamic-pituitary-adrenal
            axis in the early phase of Alzheimer's disease," Psychoneuroendocrinology 20(20, 211-220, 1995. "After 0.5
            mg dexamethasone, serum cortisol levels were significantly less suppressed...."
        </p>
        <p>
            C. Mondadori, "In search of the mechanism of action of the nootropics: New insights and potential clinical
            implications," Life Sci. 55(25-26), 2171-2178, 1994. "...the fact that high levels of corticosteroids
            suppress the effects of the nootropics could also have clinical implications: in the light of the
            observation that the majority of Alzheimer patients have elevated steroid levels it could explain why there
            is always only a small proportion of patients...that respond to treatment with nootropics."
        </p>
        <p>
            J. M. Pasquini and A. M. Adamo, "Thyroid hormones and the central nervous system," Dev. Neurosci. 12(1-2),
            1-8, 1994. "Among their actions, T3 and T4 have effects on the differentiation of various cell types in the
            rat brain and cerebellum as well as on the process of myelination. Recently, several investigators have
            shown effects of thyroid hormones on myelin protein gene expression."
        </p>
        <p>
            M. Martinez, et al., "Glucose deprivation increases aspartic acid release from synaptosomes of aged mice,"
            Brain Res. 673(1), 149-152, 1995. "...in the absence of glucose in the medium of incubation aspartate and
            glutamate release was higher in old than in young animals." "...there is an age-dependent dysfunction in
            this process linked to energy metabolism disturbance."
        </p>
        <p>
            P. Corbisier, et al., "Bioenergetics of mitochondria determine cell survival in stressful conditions," Prog.
            in Cell Res. (5), 237-241, 1995. "...the growth rate of young or old cells injected with coupled
            mitochondria...was not statistically different."
        </p>
        <p>
            G. Paradies, et al., "Molecular basis of the age-dependent decrease in the cytochrome oxidase activity in
            rat heart mitochondria," Prog. in Cell Res. 5, 243-247, 1995. The activity of cytochrome oxidase "was
            markedly decreased with aging. This decrease was associated with a parallel decrease in the mitochondrial
            respiratory activity." "Cardiolipin content was significantly reduced in mitochondrial membrane from aged
            rats."
        </p>

        <p>
            G. C. Ness and Z. H. Zhao, "Thyroid hormone rapidly induces hepatic LDL receptor mRNA levels in
            hypophysectomized rats," Arch. Biochem. Biophys. 315(1), 199-202, 1994.
        </p>
        <p>
            E. M. Mutisya, et al., "Cortical cytochrome oxidase activity is reduced in Alzheimer's disease," J.
            Neurochem. 63(6), 2170-2184, 1994. "These results provide further evidence of a cytochrome oxidase defect in
            Alzheimer's disease postmortem brain tissue. A deficiency in this key energy-metabolizing enzyme could lead
            to a reduction in energy stores and thereby contribute to the neurodegenerative process."
        </p>
        <p>
            G. J. Bu, et al., "Subcellular localization and endocytic function of low density lipoprotein
            receptor-related protein in human glioblastoma cells," J. Biol. Chem. 269(47), 29874-29882, 1994. "Our
            results thus strongly suggest several potential roles for LRP in brain protein and lipoprotein metabolism,
            as well as control of extracellular protease activity."
        </p>

        <p>
            V. Vandenbrouck, et al., "The modulation of apolipoprotein E gene expression by 3,3'-5-triiodothyronine in
            HepG(2) cells occurs at transcriptional and post-transcriptional levels," Eur. J. Biochem. 224(2), 463-471,
            1994. "...thyroid hormone stimulated apoE gene transcription threefold in 24 hours."
        </p>
        <p>
            M. J. Ignatius, et al. "Expression of apolipoprotein-E during nerve degeneration and regeneration," Proc.
            Natl. Acad. Sci. (USA) 83, 1125-1129, 1986.
        </p>
        <p>
            B. T. Stokes, et al., "Energy depletion, calcium and the cytoskeleton: A model for trophic intervention,"
            pp. 279-292, in Trophic Factors and the Nervous System, L. A. Horrocks, et al., editors, Raven Press, NY,
            1990. "Injury to neuronal cells is associated with a decline in high energy phosphates, a loss of cation
            homeostasis, and possibly, an increase in reactive oxygen radicals." "Virtually all components of the
            cytoskeleton are either directly or indirectly affected by alterations in calcium metabolism."
            "...calcium-activated proteases may also specifically modulate components of the cytoskeleton." "...ATP
            depletion itself may directly alter the structural components of the neuronal cytoskeleton." "...major
            neurodegenerative diseases such as Alzheimer's, Parkinsonian syndrome, amyotrophic lateral sclerosis...are
            also characterized by changes in the neuronal cytoskeleton."
        </p>
        <p>
            T. Gunther, et al., "Effects of magnesium and iron on lipid peroxidation in cultured hepatocytes," Mol. Cell
            Biochem. 144(2), 141-145, 1995. (Magnesium protects against iron.)
        </p>
        <p>
            K. D. Croft, et al., "Oxidation of low-density lipoproteins: Effect of antioxidant content, fatty acid
            composition and intrinsic phospholipase activity on susceptibility to metal ion-induced oxidation,"
            BBA-Lipid Lipid Metab. 1254(3), 250-256, 1995.
        </p>
        <p>
            J. H. Choi and B. P. Yu, "Brain synaptosomal aging: Free radicals and membrane fluidity," Free Radical Biol.
            Med. 18(2), 133-139, 1995 ("...fluidity loss may be influenced by factors other than cholesterol. We suggest
            that lipid peroxidation may be a major factor in the change in fluidity during the aging process.")
        </p>

        <p>
            J. H. Choi and B. P. Yu, "Modification of age-related alterations of iron, ferritin, and lipid peroxidation
            in rat serum," Age 17(3), 93-97, 1994.
        </p>
        <p>
            E. Chiarpotto, et al., "Metabolism of 4-hydroxy-2-nonenal and aging," Biochem. Biophys. Res. Commun. 297(2),
            477-484, 1995. (Accumulation of unsaturated fat breakdown product in old animals.)
        </p>
        <p>
            H. J. Sipe, et al., "The metabolism of beta-estradiol by lactoperoxidase: A possible source of oxidative
            stress in breast cancer," Carcinogenesis 15(11), 2637-2643, 1994.
        </p>

        <p>
            M. J. Endresen, et al., "Effects of free fatty acids found increased in women who develop pre-eclampsia on
            the ability of endothelial cells to produce prostacyclin, cGMP and inhibit platelet aggregation," Scan. J.
            Clin. Lab. Invest. 54(7), 549-557, 1994<em>.</em> "...levels of circulating free fatty acids are increased
            in women who later develop pre-eclampsia long before the clinical onset of the disease." "...linoleic acid
            reduced the thrombin-stimulated prostacyclin release by 30-60%, oleic acid by 10-30%, wheras palmitic acid
            had no effect." "Linoleic acid reduced the endothelial cells" ability to inhibit platelet aggregation by
            10-45%...."
        </p>
        <p>
            L. A. Norris and J. Bonnar, "Effect of oestrogen dose on whole blood platelet activation in women taking new
            low dose oral contraceptives," Thromb. Haemost. 72(6), 926-930, 1994: "Increased levels of ADP and
            arachidonic acid-induced aggregation were observed in women taking the 30 microgram ethinyloestradiol
            combination. Platelet release of beta-thromboglobulin (beta TG) was also significantly increased. Increased
            collagen-induced aggregation was observed but this failed to reach statistical significance for the
            individual treatment groups.") Estrogen dominance is an essential factor in preeclampsia. Women who have
            died of (eclamptic) convulsions have been found to have massive clots in their brain blood vessels. Much of
            this work had its origin in the 1930s (Shute and others), and was buried by the power of the estrogen
            industry.
        </p>
        <p>
            H. Darmani, et al., "Interferon-gamma and polyunsaturated fatty acids increase the binding of
            lipopolysaccharide to macrophages," Int. J. Exp. Pathol. 75(5), 363-368, 1994.
        </p>
        <p>
            G. Autore, et al., "Essential fatty acid-deficient diet modifies PAF levels in stomach and duodenum of
            endotoxin-treated rats," J. Lipid Mediators Cell Signalling 9, 145-153, 1994. Deficiency of "essential" fats
            decreases damage from endotoxin.
        </p>
        <p>
            N. Auge, et al., "Proliferative and cytotoxic effects of mildly oxidized low-density lipoproteins on
            vascular smooth-muscle cells," Biochem. J. 309(Part 3), 1015-1020, 1995. "The proliferative effect on
            smooth-muscle cells is counterbalanced at high concentrations of mildly oxidized LDLs (or at high oxidation
            levels) by their cytotoxic effect."
        </p>
        <p>
            S. K. Clinton, et al., "The combined effects of dietary fat and estrogen on survival, 7,12-dimethyl-
            benz(a)-anthracene-induced breast cancer and prolactin metabolism in rats," J. Nutr. 125(5), 1192-1204,
            1995. "Mortality in controls was doubled by feeding a high fat diet...." "...the presence of estrogen may be
            a prerequisite for significant dietary modulation."
        </p>

        <p>
            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>
        <p>
            M. E. Miller, et al., "Influence of hormones on platelet intracellular calcium," Thrombosis Research 77(6),
            515-530, 1995. "Platelet intracellular calcium concentration and release was significantly decreased in
            women ingesting tamoxifen compared to controls and significantly increased, as was platelet adhesion, in
            oral contraceptive users." "Only oral contraceptive users had increased sensitivity to aggregating agents.
            (...platelet calcium levels are closely related to the degree of platelet adhesion and aggregation in vivo."
        </p>

        <p>
            F. Mercure and G. Vanderkraak, "Inhibition of gonadotropin-stimulated ovarian steroid production by PUFA in
            teleost fish," Lipids 30(6), 547-554, 1995. "EPA and DHA inhibited gonadotropin-stimulated testosterone
            production in a dose-related manner...."
        </p>
        <p>
            A A Farooqui, K Wells, L A Horrocks, "Breakdown of membrane phospholipids in Alzheimer disease--involvement
            of excitatory amino acid receptors," Mol Chem Neuropathol 25(2-3) 155-173, 1995. "The release of
            arachidonate from the sn-2 position of glycerophospholipids is catalyzed by phospholipases and lipases.
            These enzymes are coupled to EAA receptors. Overstimulation of these receptors may be involved in abnormal
            calcium homeostasis, degradation of membrane phospholipids, and the accumulation of free fatty acids,
            prostaglandins, and lipid peroxides. Accumulation of the mentioned metabolites, as well as abnormalities in
            signal transduction owing to stimulation of lipases and phospholipases, may be involved in the pathogenesis
            of the neurodegeneration in AD."
        </p>
        <p>
            Leo Loeb, V. Suntzeff, and E. L. Burns, "Changes in the nature of the stroma in vagina, cervix and uterus of
            the mouse produced by long-continued injections of estrogen and by advancing age," The American Journal of
            Cancer 35(2), 159-174, 1939. Loeb, et al., speak of collagenous deposits as fibrous-hyaline tissue, varying
            from a fibrillar to a homogeneous appearance, and varying in consistency from very dense and glassy in
            appearance, to the softer gelatinous substance between cells and around arteries and glands. This material
            increases with aging and eventually appears between cells in the muscular part of the uterus. With the
            injection of moderate amounts of estrogen, the quantity of the material is increased. When large amounts of
            estrogen are injected, "The connective tissue and muscle appear rarefied, almost as though they were
            perforated by a large number of small holes." "...this condition is presumably due to a deposit of a mixture
            of hyaline material and edematous fluid...." "This process of hyalinization...is counteracted by invasion by
            connective tissue." In this way there may take place in many areas a substitution and organization of the
            hyaline material by connective tissue, in which dilated capillaries may also be visible." "There is a second
            process which in many cases accompanies the invasion and organization of hyaline substance by connective
            tissue, namely a formation, at the margin of the hyaline material, of epithelioid and of small giant cells
            possessing more than one nucleus." "As a rule, the epithelioid cells are seen alone; giant cells are more
            rare." "...the connective-tissue fibrils may in places appear somewhat separated, perhaps by edematous
            fluid." "The first changes consist very likely in the transudation of fluid from the vessels into the
            connective tissue." "It seems, then, that at a very early stage after the beginning of the injections of
            effective doses of estrogen, a liquid substance which separates the connective-tissue elements makes its
            appearance, and that this represents one of the earliest changes induced by the hormone. It may be
            accompanied, or soon followed, by the deposit of a hyaline substance which occurs first between the
            connective-tissue cells, but may extend also to the muscle fibers." "...the deposit of hyaline which
            progressively becomes more and more devoid of connective-tissue cells and blood vessels, is so marked that
            the material acts like a foreign body...." "While it may be found also around blood vessels, such deposits
            are less conspicuous than in other organs in mice, such as the mammary gland.... There is a tendency for the
            hyaline substance to form sheaths around various organs and it is more prominent at the border separating
            different tissues and organs." "In its appearance and in the foreign body reactions which it initiates this
            substance somewhat resembles amyloid, which is readily produced in mice in various groups. The application
            of stains differentiating amyloid from other hyaline material, however, gave negative results."
        </p>
        <p>
            Leo Loeb, V. Suntzeff, and E. L. Burns, "The effects of age and estrogen on the stroma of vagina, cervix and
            uterus in the mouse," Science 88(22, Nov. 4), 1938. "...large amounts of a hyaline substance are deposited,
            which act as foreign bodies and cause the formation of epithelioid and giant cells and an ingrowth of
            connective tissue. Thus an organization of this substance is attempted, which is interrupted, however, by
            renewed deposition of this hyaline material." "No definite statement can be made at present as to the
            chemical nature of this substance and its possible relation to a plasma constituent, except that it is not
            amyloid." "...a very intense fibrosis and hyalinization of the stroma which may induce abnormal reactions in
            the surrounding tissue. In this way it seems to be possible to accelerate and intensify very much some of
            the old age changes in certain organs."
        </p>

        <p>
            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."
        </p>
        <p>
            C. LarssonBackstrom, et al., "Effects of dietary alpha- and gamma-linolenic acids on liver fatty acids,
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            D. Chemla, et al., "Influence of dietary polyunsaturated fatty acids on contractility, inotropy and
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            a lower peak lengthening velocity at preload in the LC (n-3) group...together with an unchanged peak rate of
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            load dependence of myocardial relaxation." See B. Pieske, Circul. 92(5), 1169-78
        </p>

        <p>
            R. Lerner, et al., "Development and characterization of essential fatty acid deficiency in human endothelial
            cells in culture," Proc Natl Acad Sci USA 92(4), 1147-1151, 1995. Oleic acid derivative
            5,8,11-eicosatrienoic acid (20:3 omega 9) (5,8,11,14,17 eicosapentaenoic, 20-5 omega 3)); 20:3 omega 9
            impaired the Ca2(i) response, indicating a suppressive effect of it. (Agonist-induced increases in
            concentrations of prostacycline PGI 2, and cytosolic Ca2+ were reduced in efad cells.)
        </p>
        <p>
            K. Imaizumi, et al., "Dissociation of protein kinase C activities and diacylglycerol levels in liver plasma
            membranes of rats on coconut oil and safflower oil diets," J. Nutr Biochem 6(10), 528-533, 1995. "The
            activation of PKC is affected differently in vitro by different fatty acids." "Rats on coconut oil...had a
            markedly lower PKC activity in liver plasma membranes with slight but significant reduction of the activity
            in the cytosol than did rats fed safflower oil...." "...coconut oil resulted in a higher content of
            diacylglycerols in these membranes than did ingestion of safflower oil, whereas the proportions of saturated
            fatty acids and phospholipids and membrane fluidity were similar between rats ingesting different fats." "It
            seems likely that saturated fats exert various physiological effects on lipid and lipoprotein metabolism, in
            part through PKC pathways."
        </p>

        <p>
            V. Boutard, et al., "Fish oil supplementation and essential fatty acid deficiency reduce nitric oxide
            synthesis by rat macrophages," Kidney Int. 46(5), 1280-1286, 1994. "Both...have been shown to exert
            anti-inflammatory effects...."
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            arachidonate from the sn-2 position of glycerophospholipids is catalyzed by phospholipases and lipases.
            These enzymes are coupled to EAA receptors. Overstimulation of these receptors may be involved in abnormal
            calcium homeostasis, degradation of membrane phospholipids, and the accumulation of free fatty acids,
            prostaglandins, and lipid peroxides. Accumulation of the mentioned metabolites, as well as abnormalities in
            signal transduction owing to stimulation of lipases and phospholipases, may be involved in the pathogenesis
            of the neurodegeneration in AD."
        </p>
        <p>
            P. H. Chan and R. A. Fishman, "Transient formation of superoxide radicals in polyunsaturated fatty
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        </p>

        <p>
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            healthy subjects," Clin Sci 88(6), 629-633, 1995. "In epidemiological studies microalbuminuria, i.e.,
            slightly elevated urinary albumin excretion rate, predicts increased atherosclerotic vascular morbidity and
            mortality." "In animal experiments the outflux of albumin and lipids to the arterial wall are highly
            correlated, and both are elevated in atherosclerosis." "...microalbuminuria is an independent marker of
            systemic transvascular albumin leakiness in clinically healthy subjects."
        </p>
        <p>
            H. M. Wisniewski and P. B. Kozlowski, "Evidence for blood-brain barrier changes in senile dementia of the
            alzheimer type (SDAT)", Ann. N. Y. Acad. Sci. 396, 119-129, 1982. "...one would expect that the chronic
            "flooding" of the neuronal elements with serum proteins would affect their performance." "The cause of the
            increased BBB permeability in SDAT is unknown."
        </p>

        <p>
            F. Laszlo, et al., "Association of microvascular leakage with induction of nitric oxide synthase: Effects of
            nitric oxide synthase inhibitors in various organs," Eur. J. Pharmacol. 283(1-3), 47-53, 1995. "...assessed
            by the vascular leakage of ... albumin." "Endotoxin...induced the expression of a calcium-independent nitric
            oxide synthase...."
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        <p>
            C. Nilsson, et al., "The nocturnal increase in human cerebrospinal fluid production is inhibited by a
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            arteries. [Also to the] ...choroid plexuses."
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            A. C. Bowling and M. F. Beal, "Bioenergetic and oxidative stress in neurodegenerative diseases," Life Sci.
            56(14), 1151-1171, 1995. "Defects in energy metabolism and increased cortical lactate levels have been
            detected in Huntington's disease patients. Studies of Alzheimer's disease patients have identified decreased
            [mitochondrial] complex IV activity...." "The age-related onset and progressive course of these
            neurodegenerative diseases may be due to a cycling process betwen impaired energy metabolism and oxidative
            stress."
        </p>
        <p>
            K. Nakai, et al., "Regeneration of norepinephrine-containing fibers in occipital cortex of adult cats,"
            Brain Res. Bull. 35(5-6), 409-412, 1994. "The present results indicate that the regenerative ability of the
            central NE neurons is universal, not limited to the immature brain. ...equipped with a transmitter-specific
            repair mechanism throughout life."
        </p>

        <p>
            A. Bhatnagar, "Biochemical mechanism, of irreversible cell injury caused by free radical-initiated
            reactions," Mol. Cell. Biochem. 137(1), 9-16, 1994. "...free radical-induced irreversible cell injury
            results from a loss of protein thiols."
        </p>
        <p>
            L. Balazs and M. Leon, "Evidence of an oxidative challenge in the Alzheimer's brain," Neurochem. Res. 19(9),
            1131-1137, 1994. "These data suggest that the entire Alzheimer's brain may be subject to an oxidative
            challenge, but that some brain areas may be more vulnerable than others to the consequent neural damage that
            characterizes the disease."
        </p>
        <p>
            J. A. Court and E. K. Perry, "CNS nicotinic receptors--possible therapeutic targets in neurodegenerative
            disorders," CNS Drugs 2(3), 216-233, 1994. "...epidemiological evidence suggests that later in life tobacco
            smoking may offer some protection against Parkinson's and Alzheimer's diseases."
        </p>

        <p>
            N. A. Simonian and B. T. Hyman, "Functional alterations in Alzheimer's disease: Selective loss of
            mitochondrial-encoded cytochrome oxidase mRNA in the hippocampal formation," J. Neuropathol. Exp. Neurol.
            53(5), 508-512, 1994.
        </p>
        <p>
            A. M. Proenze, et al., "Estrogen effects on blood amino acid compartmentation," Life Sci. 57(17), 1589-1587,
            1995.
        </p>
        <p>
            S. S. Smith, "Sensorimotor-correlated discharge recorded from ensembles of cerebellar Purkinje cells varies
            across the estrous cycle of the rat," J. Neurophysiol. 74(3), 1095-1108, 1995. "...estradiol augments
            excitatory responses of cerebellar Purkinje cells to...glutamate...."
        </p>

        <p>
            C. F. Lim, et al., "Influence of nonesterified fatty acid and lysolecithins on thyroxine binding to
            thyroxine-binding globulin and transthyretin," Thyroid 5(4), 319-324, 1995. "Unsaturated nonesterified fatty
            acids...inhibited T4 binding to TBG." "Saturated NEFAs...were inactive."
        </p>
        <p>
            O. V. Sviridov, "Specific binding of thyroid hormones by human plasma apolipoproteins: A new property of
            known proteins," Biochemistry (Engl. translation) 59(5), 457-466, 1884.
        </p>
        <p>
            T. Parasassi, et al., "Cholesterol protects the phospholipid bilayer from oxidative damage," Free Radical
            Biology &amp; Medicine 19(4), 511-516, 1995.
        </p>

        <p>
            A. G. Herzog, "Progesterone therapy in women with complex partial and secondary generalized seizures,"
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        </p>
        <p>
            Z. Q. Ma, et al., Estrogenic control of monoamine oxidase A activity in human neuroblastoma cells expressing
            physiological concentrations of estrogen receptor," Eur. J. Pharmacol. 284(1-2), 171-176, 1995.
        </p>
        <p>
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        <p>
            Leo Loeb, V. Suntzeff, and E. L. Burns, "Changes in the nature of the stroma in vagina, cervix and uterus of
            the mouse produced by long-continued injections of estrogen and by advancing age," The American Journal of
            Cancer 35(2), 159-174, 1939. Loeb, et al., speak of collagenous deposits as fibrous-hyaline tissue, varying
            from a fibrillar to a homogeneous appearance, and varying in consistency from very dense and glassy in
            appearance, to the softer gelatinous substance between cells and around arteries and glands. This material
            increases with aging and eventually appears between cells in the muscular part of the uterus. With the
            injection of moderate amounts of estrogen, the quantity of the material is increased. When large amounts of
            estrogen are injected, "The connective tissue and muscle appear rarefied, almost as though they were
            perforated by a large number of small holes." "...this condition is presumably due to a deposit of a mixture
            of hyaline material and edematous fluid...." "This process of hyalinization...is counteracted by invasion by
            connective tissue." In this way there may take place in many areas a substitution and organization of the
            hyaline material by connective tissue, in which dilated capillaries may also be visible." "There is a second
            process which in many cases accompanies the invasion and organization of hyaline substance by connective
            tissue, namely a formation, at the margin of the hyaline material, of epithelioid and of small giant cells
            possessing more than one nucleus." "As a rule, the epithelioid cells are seen alone; giant cells are more
            rare." "...the connective-tissue fibrils may in places appear somewhat separated, perhaps by edematous
            fluid." "The first changes consist very likely in the transudation of fluid from the vessels into the
            connective tissue." "It seems, then, that at a very early stage after the beginning of the injections of
            effective doses of estrogen, a liquid substance which separates the connective-tissue elements makes its
            appearance, and that this represents one of the earliest changes induced by the hormone. It may be
            accompanied, or soon followed, by the deposit of a hyaline substance which occurs first between the
            connective-tissue cells, but may extend also to the muscle fibers." "...the deposit of hyaline which
            progressively becomes more and more devoid of connective-tissue cells and blood vessels, is so marked that
            the material acts like a foreign body...." "While it may be found also around blood vessels, such deposits
            are less conspicuous than in other organs in mice, such as the mammary gland.... There is a tendency for the
            hyaline substance to form sheaths around various organs and it is more prominent at the border separating
            different tissues and organs." "In its appearance and in the foreign body reactions which it initiates this
            substance somewhat resembles amyloid, which is readily produced in mice in various groups. The application
            of stains differentiating amyloid from other hyaline material, however, gave negative results."
        </p>
        <p>
            Leo Loeb, V. Suntzeff, and E. L. Burns, "The effects of age and estrogen on the stroma of vagina, cervix and
            uterus in the mouse," Science 88(22, Nov. 4), 1938. "...large amounts of a hyaline substance are deposited,
            which act as foreign bodies and cause the formation of epithelioed and giant cells and an ingrowth of
            connective tissue. Thus an organization of this substance is attempted, which is interrupted, however, by
            renewed deposition of this hyaline material." "No definite statement can be made at present as to the
            chemical nature of this substance and its possible relation to a plasma constituent, except that it is not
            amyloid." "...a very intense fibrosis and hyalinization of the stroma which may induce abnormal reactions in
            the surrounding tissue. In this way it seems to be possible to accelerate and intensify very much some of
            the old age changes in certain organs."
        </p>

        <p>
            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...."
        </p>
        <p>
            J. R. Brawer, et al., "Ovary-dependent degeneration in the hypothalamic arcuate nucleus," Endocrinology 107,
            274-279, 1980.
        </p>

        <p>
            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 causes 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.
        </p>

        <p>
            G. B. Melis, et al., "Evidence that estrogens inhibit LH secretion through opioids in postmenopausal women
            using naloxone," Neuroendocrinology 39, 60-63, 1984.
        </p>
        <p>
            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."
        </p>
        <p>
            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..."
        </p>

        <p>
            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...."
        </p>
        <p>
            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."
        </p>
        <p>
            E. A. Quail and G. C. T. Yeoh, "The effect of iron status on glyceraldehyde 3-phosphate dehydrogenase
            expression in rat liver," FEBS Lett. 359(2-3), 126-128, 1995. "...the overexpression of GAPDH mRNA in iron
            deficiency is probably due to increased message stability." [This is one of the points discussed by Henics.
            Estrogen, which increases iron retention, also modifies mRNA stability.]
        </p>

        <p>
            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."
        </p>
        <p>
            J. G. Liehr and D. Roy, "Free radical generation by redox cycling of estrogens," Free Rad. Biol. Med. 8,
            415-423, 1990.
        </p>
        <p>
            F. Fourrier, Circ. Shock 43(4), 171-178, 1994, "High estrogen levels were specifically observed in patients
            with sepsis and septic shock, either males or females." "Circulating T levels were decreased in all male
            patients."
        </p>

        <p>
            J. A. Jarvis, et al., "H-1 NMR analysis of fibril-forming peptide fragments of transthyretin," Int. J. Pept.
            Protein Res. 44(4), 388-398, 1994. "...fragments of the protein transthyretin, previously shown to form
            cross beta-sheet amyloid-like fibrils in vitro, were investigated...."
        </p>

        <p>
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