Ray Peat article, 2006. From The Collected Works of Ray Peat.

Ray Peat, "The Problem of Alzheimer's Disease as a Clue to Immortality", p. 847

T he toxicity of estrogen and of the unsaturated fats has been known for most of the twentieth century, and much has been learned about their interactions in the aging process. The body, during this time, has been understood as a dynamic interaction of cellular trophic influences which govern both form and function. My argument here will be that some of our adaptive, protective regulatory processes are overridden by the excessive supply of unsaturated fats—supported by a few other toxins—in our diet, acting as a false-signal system, and that cholesterol, pregnenolone, and progesterone which are our main long-range defenses, are overcome by the effects of the unsaturated fats, and that the resulting cascade of ineffective and defective reactions (including various estrogen-stimulated processes) leads to lower and lower energy production, reduced function, and death. At certain times, especially childhood and old age, iron (which also has important regulatory roles) accumulates to the point that its signal functions may be inappropriate. It interacts with estrogen and unsaturated fats in ways that can change restraint and adaptation into sudden self-destruction, apoptotic cell death. If we look at the human organism from one perspective, it seems coherent and intelligible, but from the perspective of established academic biological doctrine, it seems appallingly complex, lacking any visible integrating principle, and as a result simplistic mechanical, pharmaceutical, or religious ideas are increasingly offered to fill the gap. But experimental data can be taken out of the muddle, and put to coherent human use. In what follows, I am acting as though the doctrines of genetic determination and regulation by membranes were mere historical relics. The emerging control systems are now clear enough that we can begin to use them to reverse the degenerative diseases: Alzheimer’s dementia, epileptic dementia, arthritis, osteoporosis, depression, hypertension, hardening of the heart and blood vessels, diabetes, and some types of tumor, immunodeficiencies, reflex problems,

and special atrophic problems, including clearing of amyloid and mucoid deposits. I think many people experience regenerative age-regressing when many circumstances are just right; for example, taking a trip to the mountains in the spring with friends can optimize several basic regulatory systems.

II. Common Factors in Brain Injury During Growth and Aging Most people are surprised by the number of cells in the prenatal brain, and in the very old brain: In the human fetus at 6 months of development, there are about twice as many brain cells as there are at the time of birth, and in old age the number of cells in the brain keeps increasing with age, so that at the age of 90 the amount of DNA in the brain (36.94 g) is about 50 % greater than at the age of 16-20 (23.04 g). In the aged brain, glial cells multiply while neurons die. In the fetus, the cells that die are apparently nerve cells that haven’t yet matured. The factors that are known to reduce the brain size at birth are also factors that are involved in the degenerating brain in old age or Alzheimer’s disease: lack of oxygen, excess unsaturated fats or deficiency of saturated fats, estrogen excess, progesterone deficiency, and lack of glucose. A lack of carbon dioxide is probably harmful in both. Inflammation and blood clots may be factors in the aging brain, and bleeding with vascular spasm is sometimes a contributing factor to brain damage in both the old and the fetal brain. Endotoxemia may be a factor in nerve degeneration only during adult life, but it is sometimes present during pregnancy.1,2

III. A View of Entropy: Renewal of the Brain When a fertilized egg is developing into a person, each cell division creates a new environment for the daughter cells, to which they adapt. They may run into limits and resistances (sometimes a certain gene doesn’t meet the need of the situation, or toxins are present, or nutrients and hormones are imperfectly supplied), but the process is flexible, and a way is normally found to get around the limitation. The embryo’s brain development is my favorite example of the ways genes interact with the environment. We might think of the “optimal brain development” of a person, or a rat, or a chicken, as something which is clearly limited

by “the genes.” But if rats are given a stimulating environment, each generation gets a slightly bigger, slightly more intelligent brain. If rats are treated during pregnancy to increase the amount of progesterone, the offspring have bigger brains and learn more efficiently. Still, that might just be restoring a condition that was natural for rats in some perfect environment. Chickens develop inside an egg shell, and so the nutrients needed for their development are all present when the egg is laid. The brain, like the other organs, stops growing when the food supply is used up. But an experimenter (Zamenhof) opened the egg shells at the stage of development when the brain normally stops growing, and added glucose, and found that the brain continued growing, producing chickens with bigger brains. The “genes” of a chicken, as part of a system, have something to do with the development of that system, but the environment existing in and around the organism is able to guide and support the way the system develops. The size, complexity, and intelligence of the brain represents a very large part of the “information” contained in the organism, and Zamenhof’s experiment showed that the ability to realize this potential, to create this complexity, comes from the support of the environment, and that the “genetic nature of the chicken” didn’t constitute a limit to the development of its brain. I am going to argue that Alzheimer’s disease is analogous to the situation confronted by the developing chicken embryo or the rat or human fetus, when the environment is unable to meet the needs of the highly energetic, demanding and sensitive brain cells, and the brain cells begin to die, instead of developing into a more complex state, passing beyond various barriers and limitations. There are two stereotypes that are in conflict with this view: (1) That the structure of the brain is determined at an early point in life, sometimes explicitly stated as the age of 12 or 16, and (2) that the structure of the brain goes into an “entropic” deterioration during the process of aging. My position is that the brain cells are in a vital developmental process at all times, and that the same things that injure the brain of a fetus also injure the brain of an aging person. If novelty is really appearing during development, then it is hard to maintain that “entropy increases” during the development of an individual. Isn’t a child a richer organization than a fertilized egg? Isn’t an adult more individualized or realized than an infant? Seen from

the inside, our known world gets richer with experience. Learning is certainly anti-entropic. Where does the idea of “increasing entropy with living” come from? Many things contribute, including a doctrine of genetic determinism, the old Platonic idea of the imperfection of the concrete, the unreality of the existent, and the medieval idea of the “corruption of the body.” These philosophies still motivate some people in aging research. The astrophysicist, N. A. Kozyrev, showed that the idea of an “entropic cosmos” derived simply from the assumptions of 19th century deism, “God set the clockwork universe in motion, and left it to run down.” Early in this century, Raymond Pearl argued that the “rate of living” governed the life-span, so that “fast living” meant a short life. He based his argument on cantaloupe seeds: the faster they grew, the sooner they died. This was because he didn’t give them anything but water, so they had to live on their stored energy; if they grew quickly, obviously they ran out of stored energy sooner. I have never heard that described as a stupid idea, but I think politeness is sometimes carried too far. In the clock analogy, or the seed analogy, the available energy is used up. The clock with its wound-up spring and the seed in a dish of water may be considered as closed systems, and we can understand their fate. But if it is foolish to argue from a confined seed to free-living organisms, then it is just as foolish to argue from a clock to a cosmos. Unfortunately, these inferences about closed systems are often applied to real situations that aren’t energetically closed. The “rate of living” theory of aging picked up the idea of aging as a natural physical property of time, and gave it expression in mathematical form, arguing3 that “the total lifetime entropy production” could be calculated, to give insight into “life expectancy and evolutional development.” Unfortunately, the equation Hershey used assumed that the flow of heat out of the body into the surroundings is reversible. This suggests an image of Dr. Frankenstein vivifying his monster with lightning, putting the heat back into the body. If heat is to be “put back into the body,” it is necessary to make sure that it is appropriate for the structure as it exists. Actually, it is just the directed flow of energy which generates the structures. If any biological argument can be made from the idea of entropy, it is that it would be extremely difficult to regenerate food, by putting heat into a person. In a few situations, it is possible to show that living structures can directly absorb heat from their environment (caus-

ing the temperature to fall)—“negative heat production”—but the exact meaning of this isn’t clear.4 “It is now clear that in both crustacean…and mammalian5 non-myelinated fibres there is an initial production of heat during (or soon after) the action potential, 80 % of which is rapidly reabsorbed.”6 A. I. Zotin,7 citing the theory of Prigogine-Wiame, argued that the aging process involves both a decrease in entropy and a decrease in the rate of heat production. Regeneration involves a production of entropy, as when an egg is formed. (The temperature fluctuation at the time of ovulation might make a contribution to the construction of the entropic egg.) The argument that aging of the animal (like aging of the cosmos) is governed by “the tendency of entropy to increase” has led people to say that rejuvenation would be like unscrambling an egg. Zotin’s argument is interesting, because he says that an egg is a “scrambled animal.” This view is very much like Warburg’s and Szent-Györgyi’s theory of cancer, that it is like a reversion to a simpler state of life. To sketch out what I have argued in different contexts, water is the part of the living substance that we can most meaningfully discuss in terms of entropy. In fact, much of the concept of entropy has derived from the study of water, as it changed state in steam engines, etc. Cancer cells, like egg cells, have a higher water content than the differentiated, functioning cells of an adult, and the water is less rigidly ordered by the cellular molecules. This different, more mobile state of the water, can be measured by the NMR (nuclear magnetic resonance) machines which are used for MRI (magnetic resonance imaging). Estrogen has a special place in relation to the water in an organism. It is intimately involved with the formation of the egg cell, and wherever it operates, it increases both the quantity of water and, apparently, the disorder of the water. Its function, I believe, is to promote regeneration, as in Zotin’s scheme, by increasing entropy, or “scrambling the animal.” The way it promotes regeneration is by promoting water uptake, stimulating cell division, and erasing the differentiated state to one degree or another, providing a new supply of “stem cells,” or cells at the beginning of a certain sequence of differentiation. These more numerous cells then must find a hospitable environment in which to develop and adapt. If the proper support can’t be found, then they will be recycled, like the unfed cells in the brain of a fetus. If we imagine the course of development as a summary of evolution (“ontogeny recapitulating phylogeny”), then

the egg, as it “unscrambles” itself in embryonic development, passing through stages resembling jelly fish, worm, fish, reptile, bird, baboon, keeps finding that the available energy allows it to, in effect, say “I want this, I don’t want that,” until it emerges as a human baby, saying “I want,” and begins eating and learning, and with luck continues the unscrambling, or self-actualization. Degenerative aging, rather than being “physically derived from the properties of time,” seems to be produced situationally, by various types of contamination of our energy supply. Unsaturated fats, interacting with an excess of iron and a deficiency of oxygen or usable energy, redirect our developmental path. The saturated fats, in themselves, seem to have no “signalling” functions, and when they are naturally modified by our desaturating enzymes, the substances produced behave very differently from the plant-derived “eicosanoids.” As far as their effects have been observed, it seems that they are adaptive, rather than dysadaptive. All of the factors that affect the brain of a fetus should be examined in relation to the aging brain. Besides estrogen and fats, I am thinking of oxygen and carbon dioxide, glucose, iron and calcium, cholesterol, progesterone, pregnenolone, DHEA, the endorphins, GABA, thyroid, and vitamin A. An additional factor, endotoxin poisoning, eventually tends to intervene during stress and aging, exacerbating the trend begun under the influence of the other factors.

IV. False Signals from the Environment The environment can be supportive, but it can also divert development from an optimal course. Passively taking whatever you are given, by history and nature, is entropic; choosing intelligently from possible diets, selecting courses of action, will create pattern and reduce entropy. If education contains an element of choice and self-actualization, then the results seen in several Alzheimer’s studies could have a significance larger than what has been suggested by the investigators. A diagnostic bias has been reported to result from the use of standardized tests based on vocabulary, because education increases vocabulary, and tends to cover up the loss of vocabulary that occurs in dementia. In the Framingham study, it was concluded that there was a real association of lower educational

level with dementia, but the suggestion was made that self-destructive practices such as smoking were more common among the less educated. The Seattle study of the patients in a health maintenance organization showed a very distinct difference in educational level between the demented and the non-demented, both of whom had roughly similar frequency of prescriptions for estrogen. The features that seemed important to me, that weren’t discussed by the authors, were that the demented women had a much lower rate of progestogen use, and a much higher incidence of hysterectomy, which interferes with natural progesterone production. Although Brenner, et al., in the Seattle study concluded that “this study provides no evidence that estrogen replacement therapy has an effect on the risk of Alzheimer’s disease in postmenopausal women,” they reported that “Current estrogen use of both the oral and the vaginal routes had odds ratios below 1, while former use of both types yielded odds ratios above 1…” (They seem to neglect the fact that Alzheimer’stype disease in old people has a long developmental history, so it is precisely the “former” use that is relevent. 31 % of the demented women had formerly used estrogen, and only 20 % of the control group. Since estrogen is a brain excitant, present use creates exactly the same sort of effect on verbal fluency and other signs of awareness of the environment that a little cocaine does. Anyone who neglects this effect is probably deliberately constructing a propaganda study.) This observation, that the demented had 155 % as much former estrogen use as the normal group, as well as the difference in rates of progestogen use (normal patients had 50 % more progestogen use than demented) and hysterectomy (demented had 44.1 % vs. 17 % in the normals, i.e., 259 % as many; the incidence of hysterectomies after the age of 55, which is a strong indication of a natural excess of estrogen, in the demented was 374 % of the incidence in the non-demented), should call for a larger study to clarify these observatons, which tend to indicate that exposure to estrogen in middle-age increases the risk of Alzheimer’s disease in old age, and that even medical progestogens offer some protection against it. (Although this study might have been bigger and better, it is far better than the junk-studies that have been promoted by the pharmaceutical publicity machine. I have seen or heard roughly 100 mentions of the pro-estrogen anti-scientific “studies,” and none mentioning this one.)8

“Women tend to have higher age-specific prevalence and incidence rates of Alzheimer’s disease than do men.”9,10 “Commonly used dementia screening tests may be unfair to poorly educated individuals, especially women and rural residents.”11

Signals in the Abstract When I taught endocrinology, I annoyed my tidy-minded students by urging them to consider the potential hormone-like action of everything in the body, and to think of layers of control, ranging from sugar, salt, and carbon dioxide, through the “official hormones,” to complex nervous system actions such as expectancy, and biorhythms. Certain things that are active in very important processes deserve special attention as “signals,” but they still have to be understood in context. In this sense, we can think of Ca2 + as a signal substance, in its many contexts; it is strongly regulated by the cell’s energy charge. Magnesium and sodium antagonize it in certain situations. Linoleic acid, linolenic acid, arachidonic acid: Their toxicity is potentially prevented by the Mead acids, and their eicosanoid derivatives, which behave very differently from the familiar prostaglandins, as far as they have been compared; can be drastically reduced by dietary changes. Prostaglandins, prostacyclin, thromboxane: Formation is blocked by aspirin and other antiinflammatory drugs.

• Adenosine: Sleep inducing protective effect. Adenosine is struc turally very similar to inosine, another natural substance (found in meat, for example) which is a component of “inosiplex,” an an tiviral drug12,13 or immunostimulant which has also been found to have an anti-senility effect.14 Adenosine is a free radical scavenger, and protects against calcium and glutamate excitotoxicity.15,16 It also appears to protect against the relative hyperventilation that wastes carbon dioxide, and endotoxin can interfere with its protec tive action. Guanosine, in this same group of substances, might have some similar properties. Thymidine and cytidine, which are pyrimidine-based, are endogenous analogs of the barbiturates, and like them, they might be regulators of the cytochrome P450 enzymes. Uridine, in this group, promotes glycogen synthesis, and is released from bacteria in the presence of penicillin. • Iron: Regulator of mRNA stability, heme synthesis; reacts with reductants and unsaturated oils, to produce free radicals and lipid

peroxides; its absorption is increased by estrogen, hypothyroidism, anemia or lack of oxygen. Glutamate and aspartate, excitotoxins, and GABA, an inhibitory transmitter. • These have metabolic links with each other, with ammonia, and with stress and energy metabolism. • Estrogen and acetylcholine, excitotoxins.17 The information on this is overwhelmingly clear, and the publicity to the contrary is a horrifying example of the corruption of the mass media by the drug industry. • Endorphins: Stress induced, laterally specific, involved in estrogen action, antagonized by naloxone and similar anti-opiate drugs. I have proposed that the endorphins can cause or sustain some of the symptoms of aging. Naloxone appears to be a useful treatment for senility.18,19 • Endotoxin: Antimitochondrial action, causes elevation of estrogen. It synergizes with unsaturated fats, and naloxone opposes some of its toxic effects. • Urea, cholesterol: Structural stability of proteins and lipid-protein complexes. • Things that act directly on the water structure: I think all of the natural regulators have an effect on the structure of water, but some unusual substances seem to act primarily on the water. Noble gases, for example, have no chemical effects, but they tend to form “cages” of water molecules around themselves. Camphor, adamantane, and the antiviral drug amantadine, probably have a similar water-structuring effect, and amantadine, which is widely used as a therapy in Parkinson’s disease, has an anti-excitotoxic action.

V. Hormone Imbalance, Leading to Failure of Protective Inhibition and Alzheimer's Disease “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.”20

The Function of Energy 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.” 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. 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.

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, Mind and Tissue, and the chapter “A Unifying Principle” in Generative Energy, discussed the idea of the resting state and protective inhibition.) 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 suggested21 how the entropy-sensitivity or cold-inactivation of an enzyme could be involved in shifting the brain toward a state of inhibition. A recent publication22 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.23 “…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, adenosinestimulated 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…”22 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. Energy to resist stress makes quiescence possible, and prevents the deterioration of cells, of the sort that occurs in aging.24 “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…” 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. There are many energy-related vicious circles associated with aging, but the central one seems to be the fat-thyroid-estrogen-free-radicalcalcium sequence, in which the ability to produce stabilizing substances including carbon dioxide and progesterone is progressively lost, increasing susceptibility to the unstable unsaturated fats.

Effects of Estrogen and Unsaturated Fatty Acids 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.

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. Corn oil caused platelets to be more sensitive to ADP.25 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).26 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. The extracellular matrix is a major factor in the function and stability of brain cells.27 (Any factor producing edema tends to disrupt the extracellular matrix.28–30 ) 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.31 Dementia is known to be produced by prolonged seizures. 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.32 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. Estrogen stimulates cell division, but can also increase the rate of cell death. Unsaturated fatty acids can also stimulate or kill. Both estrogen and unsaturated fats promote the formation of agepigment. Besides increasing the free fatty acid concentration, estrogen possibly depresses the level of cholesterol, both of which are changes seen in the senile brain. 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.33 Unsaturated fats, like estrogen, increase the permeability of blood vessels. The unsaturated fat causes edema of the brain, inhibits choline uptake, blocking acetylcholine production. 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. 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. Unsaturated fatty acids, but not saturated fatty acids, are signals which activate cell systems. Many different stimuli can induce cell activity, cell death, or change to another cell type. (“…Hippocampal astrocytes from kainate-treated rats experess A2 B5 immunoreactivity, a marker of type-2 astrocytes.” “This suggests that in the CNS, normal resident astrocytes acquire the phenotypic properties of type-2 astrocytes.”34 ) 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.

Vitamin A and the Steroids 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. 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 overproduced. When progesterone is deficient, estrogen’s effect is largely unopposed. When both thyroid and progesterone are deficient, even fat cells synthesize estrogen.

The Nature of Alzheimer's Disease 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. Alzheimer-type dementia is different from other dementias, but it overlaps with them, and with age-related and stress-related changes in other organs. Physical signs (seen at autopsy) of AD:

1) Death of neurons (increase of glial cells),

2) Amyloid plaques (extracellular), associated with a particular vari ant of apolipoprotein E, the epsilon 4 allele,

3) Fibrillary tangles (intracellular, or remaining after the rest of the cell has disappeared),

4) Amyloid in blood vessels.

Functional and biochemical observations:

1) The mitochondrial energy problem, cytochrome oxidase and its regulation; body temperature/pulse-rate cycle disturbance; lipid peroxidation; respiratory defect; altered amino acid uptake; mem ory impairment; dominance of the excitatory systems vs. the inhibitory adenosine/GABA/progesterone/pregnenolone system. Increased calcium uptake, which is associated with lipid peroxida tion and cell death. Increased cortisol and DHEA.

2) Deposit of abnormal proteins, such as transthyretin-amyloid; al bumin binding of PUFA, vs. transport of thyroid and retinol. Beta glucuronidase increases, depositing estrogen in cells.35

3) Abnormally phosphorylated (tau) proteins; association with the variant form of Apo E; tau microtubule organizing proteins, micro tubules are involved in transporting cholesterol; phosphorylation, by the kinase systems, regulated by PUFA; the intermediate fila ments are generally stress-associated.

4) ApoE, in cytoplasm, involved in cholesterol delivery for preg nenolone 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.

An Example of a Regulatory Problem 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 betaglucuronidase. 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.

VII. Structure as a Regulatory System---An Emerging Vision of Pervasive Epigenesis 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. 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.36 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. 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.” 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.” 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.” 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 singlecelled 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. 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. 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. 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. 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 signalsubstances. 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. 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. 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. 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. 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.