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 &amp; 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 &amp; 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 &amp; 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 &amp; 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. 
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<hr />
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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 &lt; 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.
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