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    <h1>The problem of Alzheimer&#39;s disease as a clue to immortality</h1>
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<p class="nav"><span class="nav-left">Listed under <a href="/ray-peat.html">Ray Peat</a>.</span><span class="nav-right"><a href="/theme.html">Theme</a></span></p>
<p>From the <a href="https://raypeat.com/articles/articles/alzheimers.shtml" target="_blank">original article</a> in 2006. Author: <a href="https://raypeat.com/" target="_blank">Ray Peat</a>.</p>
  <h2>Contents</h2>
  <p>
I. INTRODUCTION
  </p><p>
II. COMMON FACTORS IN INJURY DURING GROWTH AND AGING
  </p><p>
III. A VIEW OF ENTROPY--RENEWAL OF THE BRAIN
  </p><p>
IV. FALSE SIGNALS FROM THE ENVIRONMENT
  </p><p>
A. EDUCATION, DIET AND MEDICINE INTERACT
  </p><p>
B. SIGNALS IN THE ABSTRACT
  </p><p>
V. HORMONE IMBALANCE, LEADING TO FAILURE OF PROTECTIVE INHIBITION AND ALZHEIMER'S DISEASE
  </p><p>
A. THE FUNCTION OF ENERGY
  </p><p>
B. EFFECTS OF ESTROGEN AND UNSATURATED FATTY ACIDS
  </p><p>
C. VITAMIN A AND STEROIDS
  </p><p>
D. THE NATURE OF ALZHEIMER'S DISEASE
  </p><p>
E. AN EXAMPLE; DIET AFFECTS HORMONES WHICH AFFECT STRUCTURE AND LEAD TO APPARENT SELF- DESTRUCTION
  </p><p>
VI. STRUCTURE AS A REGULATORY SYSTEM--AN EMERGING VISION OF PERVASIVE EPIGENESIS
  </p>
  <h2>I. INTRODUCTION</h2>
<p>The 
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. </p>

<p>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. </p>
<h2>II. COMMON FACTORS IN BRAIN INJURY DURING GROWTH AND AGING</h2>
<p>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 
grams) is about 50%.greater than at the age of 16-20 (23.04 grams). 
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.
</p>
<p>M. C. Diamond, Enriching Heredity: 
The Importance of the Environment on the Anatomy of the Brain. Free 
Press, N.Y., 1988. C. Finch and L. Hayflick, Handbook of the Biology 
of Aging. Van Nostrand Reinhold, N.Y., 1977.</p>
<h2>III. A VIEW OF ENTROPY: RENEWAL OF THE BRAIN</h2>

<p>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 &quot;optimal brain development&quot; 
of a person, or a rat, or a chicken, as something which is clearly limited 
by &quot;the genes.&quot; 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. </p>
<p>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 &quot;genes&quot; 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 &quot;information&quot; 

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 &quot;genetic nature 
of the chicken&quot; didn't constitute a limit to the development of 
its brain. </p>
<p>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 &quot;entropic&quot; 
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.</p>
<p>If 
novelty is really appearing during development, then it is hard to maintain 
that &quot;entropy increases&quot; 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 &quot;increasing entropy with 
living&quot; 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 &quot;corruption of the body.&quot; These philosophies still motivate 
some people in aging research. The astrophysicist, N. A. Kozyrev, showed 
that the idea of an &quot;entropic cosmos&quot; derived simply from 
the assumptions of 19th century deism, &quot;God set the clockwork universe 
in motion, and left it to run down.&quot; Early in this century, Raymond 
Pearl argued that the &quot;rate of living&quot; governed the life-span, 
so that &quot;fast living&quot; 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. 

</p>
<p>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.</p>
<p>The &quot;rate of living&quot; 
theory of aging picked up the idea of aging as a natural physical property 
of time, and gave it expression in mathematical form, arguing (Hershey, 
&quot;Entropy, basal metabolism and life expectancy,&quot; Gerontologia 
7, 245-250, 1963) that &quot;the total lifetime entropy production&quot; 
could be calculated, to give insight into &quot;life expectancy and 
evolutional development.&quot; 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 &quot;put back into the body,&quot; it is necessary to 
make sure that it is appropriate for the structure as it exists. 

</p>
<p>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 (causing 
the temperature to fall)--&quot;negative heat production&quot;--but 
the exact meaning of this isn't clear. (B. C. Abbott, et al., &quot;The 
positive and negative heat production associated with a nerve impulse,&quot; 
Proc. R. Soc. B 148, 149, 1958; R. D. Keynes and J. M. Ritchie, &quot;The 
initial heat production of amphibian myelinated nerve fibres,&quot; 
Proc. Physiol. Soc., June 1970, page 29P-30P: &quot;It is now clear 
that in both crustacean...and mammalian (Howarth, et al., 1968) non-myelinated 
fibres there is an initial production of heat during (or soon after) 
the action potential, 80% of which is rapidly reabsorbed.&quot;) A. 
I. Zotin (&quot;Aging and rejuvenation from the standpoint of the thermodynamics 
of irreversible processes,&quot; Priroda, No. 9, 49-55, 1970), 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. 

</p>
<p>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 &quot;the tendency of entropy 
to increase&quot; 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 &quot;scrambled animal.&quot; This view is very much 
like Warburg's and Szent-Gyorgyi'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).</p>
<p>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 &quot;scrambling the animal.&quot; 
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 &quot;stem cells,&quot; 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 (&quot;ontogeny recapitulating 
phylogeny&quot;), then the egg, as it &quot;unscrambles&quot; 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 &quot;I want this, I don't want 
that,&quot; until it emerges as a human baby, saying &quot;I want,&quot; 

and begins eating and learning, and with luck continues the unscrambling, 
or self-actualization.. Degenerative aging, rather than being &quot;physically 
derived from the properties of time,&quot; 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. 
</p>
<p>The 
saturated fats, in themselves, seem to have no &quot;signalling&quot; 
functions, and when they are naturally modified by our desaturating 
enzymes, the substances produced behave very differently from the plant-derived 
&quot;eicosanoids.&quot; 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.</p>

<h2>IV. FALSE SIGNALS FROM THE ENVIRONMENT</h2>
<h3>EDUCATION, DIET AND MEDICINE INTERACT</h3>
<p>The environment can be supportive, 
but it can also divert development from an optimal course.
</p>
<p>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.</p>
<p>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 &quot;this 
study provides no evidence that estrogen replacement therapy has an 
effect on the risk of Alzheimer's disease in postmenopausal women,&quot; 
they reported that &quot;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....&quot; (They seem to neglect the fact 
that Alzheimer's-type disease in old people has a long developmental 
history, so it is precisely the &quot;former&quot; 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.) </p>

<p>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..</p>
<p>(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 &quot;studies,&quot; and none mentioning this one.) 
</p>
<p>D. E. Brenner, et al., Postmenopausal 
estrogen replacement therapy and the risk of Alzheimer's disease: A 
population-based case-control study,&quot; Am. J. Epidemiol. 140, 262-267, 
1994. &quot;Women tend to have higher age-specific prevalence and incidence 
rates of Alzheimer's disease than do men.&quot; A.F. Jorm, The Epidemiology 
of Alzheimer's disease and related disorders, Chapman and Hall, London, 
1990, and W. A. Rocca, et al., Ann. Neurol. 30, 381-190, 1991.</p>

<p>H. C. Liu, et al., &quot;Performance 
on a dementia screening test in relation to demographic variables--study 
of 5297 community residents in Taiwan,&quot; Arch. Neurol. 51(9), 910-915, 
1994. &quot;Commonly used dementia screening tests may be unfair to 
poorly educated individuals, especially women and rural residents.&quot;
</p>
<h3>SIGNALS IN THE ABSTRACT</h3>
</p>
<p>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 &quot;official hormones,&quot; to complex 
nervous system actions such as expectancy, and biorhythms. Certain things 
that are active in very important processes deserve special attention 
as &quot;signals,&quot; 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.</p>

<p>Adenosine: 
Sleep inducing protective effect. Adenosine is structurally very similar 
to inosine, another natural substance (found in meat, for example) which 
is a component of &quot;inosiplex,&quot; an antiviral drug (Brown and 
Gordon, Fed. Proc. 29, 684, 1970, and Can. J. Microbiol. 18, 1463, 1972) 
or immunostimulant which has also been found to have an anti-senility 
effect (Doty and Gordon, Fed. Proc. 29). Adenosine is a free radical 
scavenger, and protects against calcium and glutamate excitotoxicity. 
(I. Yokoi, et al., &quot;Adenosines scavenged hydroxyl radicals and 
prevented posttraumatic epilepsy,&quot; Free Radical Biol. Med. 19(4), 
473-479, 1995; M. P. Abbracchio, et al., &quot;Adenosine A(1) receptors 
in rat brain synaptosomes: Transductional mechanisms, efects on glutamate 
release, and preservation after metabolic inhibition,&quot; Drug Develop. 
Res. 35(3), 119-129, 1995.) It also appears to protect against the relative 
hyperventilation that wastes carbon dioxide, and endotoxin can interfere 
with its protective 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.</p>
<p>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. </p>

<p>These 
have metabolic links with each other, with ammonia, and with stress 
and energy metabolism.</p>
<p>Estrogen 
and acetylcholine, excitotoxins; see Savolainen, et al., 1994. 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.</p>
<p>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. E. Roberts, Ann. N. Y. 
Acad. Sci. 396, 165, 1982; B. Reisberg, et al., N. Engl. J. Med. 308, 
721, 1983.</p>
<p>Endotoxin: 
Antimitochondrial action, causes elevation of estrogen. It synergizes 
with unsaturated fats, and naloxone opposes some of its toxic effects.
</p>

<p>Urea, 
cholesterol: Structural stability of proteins and lipid-protein complexes.
</p>
<p>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 &quot;cages&quot; 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.</p>
<p><strong>V.  HORMONE 
IMBALANCE, LEADING TO FAILURE OF PROTECTIVE INHIBITION AND ALZHEIMER'S 
DISEASE </strong></p>
<p><em>&quot;All 
cell death is characterized by an increase of intracellular calcium....&quot;  
&quot;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.&quot;</em>
</p>
<p><em>T. 
Fujita, &quot;Calcium, parathyroids and aging,&quot; 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>
<h3>THE FUNCTION OF ENERGY</h3>
<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 &quot;demented.&quot; </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 &quot;is this the cold brain syndrome, or 
is something else involved?&quot; 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 &quot;cold brain&quot; 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 &quot;calcium death&quot; 

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 &quot;protective inhibition&quot; 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 &quot;excitotoxic&quot; 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 &quot;A unifying principle&quot; 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, &quot;Restoration of brain energy metabolism 
as the function of sleep,&quot; 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, &quot;The effect of hypoxia on glycogenolysis and 
glycolysis rates in the rat brain,&quot; Zhurnal Evolyutsionnoy Biokhimii 
i Fiziologii 6(5), 577-579, 1970.) </p>
<p>J. 
H. Benington and H. C. Heller, &quot;Restoration of brain energy metabolism 
as the function of sleep,&quot; Prog. in Neurobiology 45, 347-360, 1995.  

&quot;...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)....&quot;  &quot;In the brain, 
adenosine-stimulated increases in potassium conductance produce hyperpolarization, 
thereby reducing neuronal responsiveness....&quot;  &quot;Adenosine 
release is triggered globally in response to changes in cerebral energy 
homeostasis.&quot;  &quot;A number of findings provide indirect 
support for the hypothesis that glycogen stores are depleted during 
waking and restored during sleep.&quot;  &quot;Reduced availability 
of glycogen to astrocytes must...increase adenosine release....&quot;  
&quot;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....&quot;</p>
<p>The 
terms &quot;functional quiescence&quot; and &quot;G0 quiescence&quot; 

are similar in meaning to the resting state; I think of cells in the 
state of &quot;G0 quiescence&quot; 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., 
&quot;Cellular aging and energetic factors,&quot; Exp. Gerontology 30(1), 
1-22, 1995.  &quot;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.&quot;  &quot;...if a supplement of energy 
is given...the toxic effect of the free radicals is much reduced....&quot;</p>
<p>The 
specific approaches of this orientation --to energize but quiet the 
brain--are diametrically opposed to some of the &quot;therapies&quot; 

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>
<h3>EFFECTS OF ESTROGEN AND UNSATURATED FATTY ACIDS</h3>
<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 &quot;anti-clotting&quot; 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., &quot;The effects of changes in diet on lipid levels 
and platelet thrombus formation in living blood vessels,&quot; 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 &quot;membrane fluidity,&quot; as a desirable 
thing, and the loss of unsaturated lipids in the aged brain, there are 
some interesting observations related to &quot;viscosity&quot; 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., &quot;The concept of trophic 
units in the central nervous system,&quot; 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, &quot;Importance of exogenous saturated fatty 
acids during brain development and myelination in mice,&quot; 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., &quot;Glial reaction after 
seizure induced hippocampal lesion:  Immunohistochemical characterization 
of proliferating glial cells,&quot; J. Neurocytol. 23(10), 641-656, 
1994:  &quot;...hippocampal astrocytes from kainate-treated rats 
experess A2B5 immunoreactivity, a marker of type-2 astrocytes.&quot;  
&quot;This suggests that in the CNS, normal resident astrocytes acquire 
the phenotypic properties of type-2 astrocytes.&quot;)</p>

<p>A 
&quot;deficiency&quot; 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>
<h3>VITAMIN A AND THE STEROIDS</h3>
<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>

<h3>THE NATURE OF ALZHEIMER'S DISEASE</h3>
<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 &quot;tangles&quot; 
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., &quot;Cortical neurochemistry 
in Alzheimer-type dementia,&quot; 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>

<h3>AN EXAMPLE OF A REGULATORY PROBLEM</h3>
<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 &quot;desorbed&quot; 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, &quot;Thoughts 
over cell biology:  A commentary,&quot; 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 
&quot;feedback.&quot;</p>
<p>Where 
before, cellular &quot;regulatory mechanisms&quot; 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 &quot;read out of the genome,&quot; 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 &quot;epigenetically.&quot;  
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, &quot;epigenetically.&quot;</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 &quot;cells are clever enough to design an organism.&quot;  
It is a significant step beyond that to the recognition that &quot;cells 
are clever enough to redesign themselves to meet situations never seen 
before.&quot;</p>
<p>Biologists 
working with bacteria and yeasts have seen them adapt in non-random 
ways to novel conditions.  &quot;Directed mutations&quot; are impossible, 
according to the &quot;central dogma&quot; 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 &quot;directed 
mutation,&quot; 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 &quot;genetically programmed,&quot; implying that whenever 
it occurs in the brain, it was destined to happen sooner or later.  
But in fact, &quot;growth factors&quot; 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 &quot;Golden 
Age&quot; 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 &quot;whirlwind of cells,&quot; 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 &quot;eicosanoid&quot; 
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 &quot;genetic surgery,&quot; transplantation, etc., which is the 
pessimistic implication of the doctrine that oxidative damage is simply 
a matter of &quot;wear and tear,&quot; &quot;somatic mutations,&quot; 

and &quot;cross-linking.&quot;  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>
<h2>References</h2>
<p>S. 
Rose, &quot;Genuine genetics or conceited convenience?&quot; Trends 
in Neuro. Sci. 17(3), 105, 1994.</p>

<p>F. 
P. Monnet, et al., &quot;Neurosteroids, via sigma receptors, modulate 
the [H3]norepinephrine release evoked by N-methyl-D-aspartate in the 
rat hippocampus,&quot; P.N.A.S. (USA) 92(9), 3773-3778, 1995. &quot;...progesterone 
may act as a sigma antagonist.&quot;</p>
<p>J. 
L. Sanne and K. E. Krueger, &quot;Expression of cytochrome P450 side-chain 
cleavage enzyme and 3 beta-hydroxysteroid dehydrogenase in the rat central 
nervous system: A study by polymerase chain reaction and in situ hybridization,&quot; 
J. of Neurochemistry 65(2), 528-536, 1995. </p>
<p>V. 
V. Zakusov and R. U. Ostrovskaya, &quot;Increased resistance of mice 
to hypoxia under the influence of tranquilizers of the benzodiazepine 
series,&quot; Byulletan Eksperimentalnoy Biologii i Meditsiny 71(2), 
45-47, 1971. [The protection was not from the sedative effects, &quot;Rather, 
the protective effect of these compounds is attributed to some specific 
intervention in the metabolism whereby the sensitivity of the tissues 
to oxygen insufficiency is reduced. ...the cortical structures of the 
brain especially appear to derive enhanced resistance to oxygen deficiency.&quot;] 

</p>
<p>A. 
I. Zotin, &quot;Aging and rejuvenation from the standpoint of the thermodynamics 
of irreversible processes,&quot; Priroda 9, 49-55, 1970. [The process 
of aging &quot;...is manifested by a decrease in entropy and...also 
by a continuous decrease in the rate of heat production.. The organism 
exhibits two types of approaches to a steady state: (i) constitutive 
movement of the system to the final steady state and (ii) inducible 
return of the system to the current steady state after deviating under 
the influence of internal or external factors. Oogenesis represents 
a constitutive deviation from the steady state; entropy reaches a level 
sufficient for the start of development and passage of the living system 
into the state of constitutive approach to the final steady state. From 
the standpoint of the thermodynamic theory of development, oogenesis 
reflects the process of regeneration of the system. In all other stages 
of life there is only the aging process accompanied by a decrease in 
entropy.&quot; </p>
<p>M. 
M. Tikhomirova, et al., &quot;Mechanisms underlying the resistance of 
genetic material of the animal cell to stress treatment,&quot; Genetika 
30(8), 1092-1104, 1994. &quot;...these studies prove that the formation 
of a mutation is a multistage process involving many cell and organism 
systems...which are affected by environmental factors.... They can hinder 
or accelerate the mutational process, in this way providing both a superadditive 
effect and adaptive response. Recent studies deal with a universal system 
of heat shock proteins, which is involved in the maintenance of resistance 
of genetic material and genetic processes in the cell.&quot;   Gross, 

&quot;Reproductive cycle biochemistry,&quot; Fertility &amp; Sterility 
12(3), 245-260, 1961. &quot;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.&quot; &quot;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.&quot;&quot;The 
effect of the progestational steroids may be such as to interfere with 
the biochemical pattern required for support of this anaerobic environment.&quot;
</p>
<p>M. 
A. G. Sissan, et al., &quot;Effects of low-dose oral contraceptive oestrogen 
and progestin on lipid peroxidation in rats,&quot; J. of International 
Med. Res. 23(4), 272-278, 1995. &quot;The levels of lipid peroxides, 
free fatty acids and glutathione in the liver, and of serum ceruloplasmin 
increased significantly with oestrogen treatment. Lipid peroxides (in 
the liver only), and serum ceruloplasmin decreased significantly when 
progestin was administered. The activities of superoxide dismutase and 
catalase decreased significantly in the oestrogen group...but increased 
in the progestin group.&quot;</p>

<p>A. 
Jendryczko, et al., &quot;Effects of two low-dose oral contraceptives 
on erythrocyte superoxide dismutase, catalase and glutathione peroxidase 
activities,&quot; Zentralbl. Gynakol. (Germany) 115(11), 469-472, 1993. 
&quot;These data suggest that low-dose oral contraceptives, by decreasing 
the activities of antioxidant enzymes and by enhancing the lipid peroxidation, 
increase the risk of cardiovascular disease.&quot; 
</p>
<p>J. 
W. Olney, &quot;Excitotoxins in foods,&quot; Neurotoxicology 15(3), 
535-544, 1994. &quot;The most frequently encountered food excitotoxin 
is glutamate which is commercially added to many foods despite evidence 
that it can freely penetrate certain brain regions and rapidly destroy 
neurons by hyperactivating the NMDA subtype of glutamate receptor.&quot; 

</p>
<p>K. 
Savolainen, et al., &quot;Phosphoinositide second messengers in cholinergic 
excitotoxicity,&quot; Neurotoxicology 15(3), 493-502, 1994. &quot;Acetylcholine 
is a powerful excitotoxic neurotransmitter in the brain. By stimulating 
calcium-mobilizing receptors, acetylcholine, through G-proteins, stimulates 
phospholipase C and cause the hydrolysis of a membrane phospholipid....&quot; 
&quot;Inositol-1,4,5-triphosphate is important in cholinergic neuronal 
stimulation, and injury. Cholinergic agonists cause tonic-clonic convulsions 
which may be either transient or persistent. Even short-term cholinergic 
convusions may be associated with neuronal injury, especially in the 
basal forebrain and the hippocampus. Cholinergic-induced convulsions 
also elevate levels of brain calcium which precede neuronal injury. 
Female sex and senescence increase the sensitivity of rats to cholinergic 
excitotoxicity.&quot; &quot;Furthermore, glutamate increases neuronal 
oxidative stress....&quot;</p>
<p>L. 
N. Simanovskiy and Zh. A. Chotoyev, &quot;The effect of hypoxia on glycogenolysis 
and glycolysis rates in the rat brain,&quot; Zhurnal Evolyutsionnoy 
Biokhimii i Fiziologii 6(5), 577-579, 1970. &quot;Glycogenolysis and 
glycolysis in the whole brain of young and old rats were studied at 
sea level and under hypoxic conditions in a low-pressure chamber or 
at an altitude of 3,200 meters. The rate of carbohydrate metabolism 
increaased during postnatal development. In the absence of hypoxia, 
the rate of accumulation of lactate from either glycogen or glucose 
increases with maturation of the animals. The brain of young rats consumes 
primarily glycogen, particularly under anaerobic conditions.&quot; &quot;Adaptation 
of mature rats to intermittent hypoxia is related to an increase in 
glycolysis, whereas adaptation of rats to high altitudes results in 
an increase in glycogenolysis. The type of carbohydrate metabolism is 
thus similar to the metabolism characteristic of the early stages of 
ontogenesis.&quot; </p>

<p>Ye. 
Sadovskiy, &quot;For the prolongation of human life,&quot; Sovetskaya 
Belorussiya 23, page 4, Dec. 1970. &quot;...the accumulation of metals 
in the organism with age is one of the most important factors in the 
development of the aging process.&quot;</p>
<p>Cerebral 
ischemia (and several other imbalances, relating to steroid regulation, 
shock) might be relieved by naloxone: D. S. Baskin and Y. Hosobuchi, 
Lancet ii, 272-275, 1981.  </p>
<p>V. 
Reynolds, et al., &quot;Heart rate variation, age, and behavior in subjects 
with senile dementia of Alzheimer type,&quot; Chronobiol. Int. 12(1), 
37-45, 1995. &quot;...circadian rhythm of SDAT may be more often unimodal 
than that of normal subjects of similar age, and that phase shift of 
the endogenous, clock-mediated component of the rhythm (with higher 
heart rate at night) is to be expected in a proportion of individuals 
with SDAT.&quot; </p>

<p>M. Martinez, et al., &quot;Glucose 
deprivation increases aspartic acid release from synaptosomes of aged 
mice,&quot; Brain Res. 673(1), 149-152, 1995. &quot;...in the absence 
of glucose in the medium of incubation aspartate and glutamate release 
was higher in old than in young animals.&quot; &quot;...there is an 
age-dependent dysfunction in this process linked to energy metabolism 
disturbance.&quot;</p>
<p>J. 
M. Pasquini and A. M. Adamo, &quot;Thyroid hormones and the central 
nervous system,&quot; Dev. Neurosci. 12(1-2), 1-8, 1994. &quot;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.&quot;

</p>
<p>G. 
C. Ness and Z. H. Zhao, &quot;Thyroid hormone rapidly induces hepatic 
LDL receptor mRNA levels in hypophysectomized rats,&quot; Arch. Biochem. 
Biophys. 315(1), 199-202, 1994.</p>
<p>E. 
M. Mutisya, et al., &quot;Cortical cytochrome oxidase activity is reduced 
in Alzheimer's disease,&quot; J. Neurochem. 63(6), 2170-2184, 1994. 
&quot;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.&quot; 

</p>
<p>G. 
J. Bu, et al., &quot;Subcellular localization and endocytic function 
of low density lipoprotein receptor-related protein in human glioblastoma 
cells,&quot; J. Biol. Chem. 269(47), 29874-29882, 1994. &quot;Our results 
thus strongly suggest several potential roles for LRP in brain protein 
and lipoprotein metabolism, as well as control of extracellular protease 
activity.&quot; </p>
<p>V. 
Vandenbrouck, et al., &quot;The modulation of apolipoprotein E gene 
expression by 3,3'-5-triiodothyronine in HepG(2) cells occurs at transcriptional 
and post-transcriptional levels,&quot; Eur. J. Biochem. 224(2), 463-471, 
1994. &quot;...thyroid hormone stimulated apoE gene transcription threefold 
in 24 hours.&quot;</p>

<p>T. 
Yamada, et al., &quot;Apolipoprotein E mRNA in the brains of patients 
with Alzheimer's disease,&quot; J. Neurol. Sci. 129(1), 56-61, 1995. 
In A.D. Apo E &quot;was decreased in relation to the apoE-epsilon 4 
gene dosage.&quot; &quot;AD patients who had long survival times showed 
high expression of apoE and low expression of GFAP [glial fibrillary 
acidic protein]. These results suggest that apoE suppresses the progression 
of AD, including gliosis, in the brain.&quot;</p>
<p>G. 
P. Jarvik, et al., &quot;Genetic influences on age-related change in 
total cholesterol, low density lipoprotein-cholesterol, and triglyceride 
levels: Longitudinal apolipoprotein E genotype effects,&quot; Genet. 
Epidemiol. 11(4), 375-384, 1994. &quot;Apo E is a component of LDL, 
is a ligand for the LDL receptor, and apo E genotype has been consistently 
associated with variation in mean levels of total cholesterol and LDL-C....&quot; 

With aging, total cholesterol and LDL-C became significantly lower in 
the &quot;epsilon 4 genotype&quot; group; this is the group at risk 
for AD. </p>
<p>S. 
Miller and J. M. Wehner, &quot;Cholesterol treatment facilitates spatial 
learning performance in DBA/2Ibg mice,&quot; Pharmacology Biochemistry 
and Behavior 49(1) 257-261, 1994. &quot;Our results suggest that subchronic 
treatment with the steroid hormone precursor, cholesterol, enhances 
spatial learning performance in DBA mice.&quot;</p>
<p>A. 
D. Roses, &quot;Apolipoprotein E affects the rate of Alzheimer disease 
expression: beta-amyloid burden is a secondary consequence dependent 
on ApoE genotype and duration of disease,&quot; J. Neuropathol. Exp. 
Neurol. 53(5), 429-437, 1994.</p>

<p>T. 
Gunther and V. Hollriegl, &quot;Increased protein oxidation by magnesium 
deficiency and vitamin E depletion,&quot; Magnesium-Bull. 16(3), 101-103, 
1994. </p>
<p>F. 
Oyama, et al., &quot;Apolipoprotein E genotype, Alzheimer's pathologies 
and related gene expression in the aged population,&quot; Mol. Brain 
Res. 29(1), 92-98, 1995. &quot;...ApoE4/4 accelerates and ApoE2/3 decelerates 
the development of the AD pathologies in the aged brain....&quot; 
</p>

<p>M. 
L. C. Maatschieman, et al., &quot;Microglia in diffuse plaques in hereditary 
cerebral hemorrhage with amyloidosis (Dutch). An immunohistochemical 
study,&quot; J. Neuropathol. Exp. Neurol. 53(5), 483-491, 1994. &quot;Microglia 
are intimately associated with congophilic plaques in Alzheimer's disease....&quot; 
&quot;Intensely immunoreactive microglia with enlarged cell bodies and 
short, thick processes clustered in congophilic plaques.&quot; 
</p>
<p>J. 
Poirier, &quot;Apolipoprotein E in animal models of CNS injury and in 
Alzheimer's disease,&quot; Trends Neurosci. 17(12), 525-530, 1994. &quot;The 
coordinated expression of ApoE and its receptor...[low density lipoprotein 
(LDL)] receptor, appears to regulate the transport of cholesterol and 
phospholipids during the early and intermediate phases of the reinnervation 
process.&quot; &quot;...a dysfunction of the lipid-transport system 
associated with compensatory sprouting and synaptic remodeling could 
be central to the AD process.&quot;</p>

<p>P. 
H. Chan and R. A. Fishman, &quot;Brain edema: Induction in cortical 
slices by polyunsaturated fatty acids,&quot; Science 201, 358-369, 1978. 
&quot;This cellular edema was specific, since neither saturated fatty 
acids nor a fatty acid containing a single double bond had such effect.&quot; 
 R. Nogues, et al., &quot;Influence of nutrition, thyroid hormones, and 
rectal temperature on in-hospital mortality of elderly patients with 
acut illness,&quot; Am J Clin Nutr 61(3), 597-602, 1995. &quot;Serum 
albumin, body weight, and total T3 concentration were higher in survivors 
than in nonsurvivors.&quot; &quot;Mild hypothermia was a good predictor 
of death. Hypoalbuminemia and hypothermia were associated with low T3 
and high rT3 values.&quot;</p>
<p>R. 
C. Vannucci, et al., &quot;Carbon dioxide protects the perinatal brain 
from hypoxic-ischemic damage: An experimental study in the immature 
rat,&quot; Pediatrics 95(6), 868-874, 1995.</p>

<p>H. 
M. Wisniewski and P. B. Kozlowski, &quot;Evidence for blood-brain barrier 
changes in senile dementia of the Alzheimer type (SDAT)&quot;, Ann. 
N. Y. Acad. Sci. 396, 119-129, 1982. &quot;...one would expect that 
the chronic &quot;flooding&quot; of the neuronal elements with serum 
proteins would affect their performance.&quot; &quot;The cause of the 
increased BBB permeability in SDAT is unknown.&quot;
</p>
<p>J. 
S. Jensen, et al., &quot;Microalbuminuria reflects a generalized transvascular 
albumin leakiness in clinically healthy subjects,&quot; Clin. Sci. 88(6), 
629-633, 1995. &quot;It is suggested that the observed transvascular 
leakiness, in addition,may cause increased lipid insudation to the arterial 
walls.&quot;</p>

<p>C. 
Nilsson, et al., &quot;The nocturnal increase in human cerebrospinal 
fluid production is inhibited by a beta(1)-receptor antagonist,&quot; 
Amer. J. Physiol.-Regul. Integr. C 36(6), R1445-R1448, 1994. 
</p>
<p>D. 
L. Williams, et al., &quot;Cell surface 'blanket' of apolipoprotein 
E on rat adrenocortical cells,&quot; J. Lipid Res. 36(4), 745-758, 1995. 
&quot;...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.&quot;  C. A. Frye and J. D. Sturgis, &quot;Neurosteroids 
affect spatial reference, working, and long-term memory of female rats,&quot; 

Neurobiol. Learn. Memory 64(1), 83-96, 1995. [Female rats take longer 
to acquire a spatial task during behavioral estrus.)]
</p>
<p>M. 
Warner and J. A. Gustafsson, &quot;Cytochrome P450 in the brain: Neuroendocrine 
functions,&quot; 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., &quot;Biosynthesis and assay of neurosteroids in rats 
and mice: Functional correlates,&quot; 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.]  K. W. Lange and P. Riederer, 
&quot;Glutamatergic drugs in Parkinson's disease,&quot; Life Sci. 55(25-26, 
2067-2075, 1994. &quot;...excitatory amino acids such as glutamate are 
involved in the pathophysiological cascade of MPTP...-induced neuronal 
cell death.&quot; &quot;The 1-amino-adamantanes amantadine and memantine 
have recently been shown to be non-competitive NMDA antagonists and 
are widely used in Europe as antiparkinsonian agents.&quot; 

</p>
<p>R. 
A. Wallis, et al., &quot;Glycine-induced CA1 excitotoxicity in the rat 
hippocampal slice,&quot; Brain Res. 664(1-2) 115-125, 1994.  K. Ossawska, 
&quot;The role of excitatory amino acids in experimental models of Parkinson's 
disease,&quot; J. Neural Transm.-Parkinsons 8(1-2_, 39-71, 1994. 
</p>
<p>G. 
S. Roth, et al., &quot;Membrane alterations as causes of impaired signal 
transduction in Alzheimer's disease and aging,&quot; Trends Neurosci. 
18, 203-206, 1995. &quot;Reconstituted lipid membranes from cortical 
gray matter of AD brain samples were significantly thinner (that is, 
had less microviscosity) than corresponding age-matched controls.&quot; 

&quot;This change in membrane width correlated with a 30% decrease in 
the moles of cholesterol:phospholipid.&quot; &quot;Addition of cholesterol 
restored the membrane width to that of the age-matched control samples.&quot; 
</p>
<p>T. 
Reed, et al., &quot;Lower cognitive performance in normal older adult 
male twins carrying the apolipoprotein E epsilon 4 allele,&quot; Arch. 
Neurol. 51(12), 1189-1182, 1994.</p>
<p>S.Y. 
Tan and M. B. Pepys, &quot;Amyloidosis,&quot; Histopathology 25(5), 
403-414, 1994. &quot;...abnormal protein fibrils which are derived from 
different proteins in different forms of the disease. Asymptomatic amyloid 
deposition in a variety of tissues is a universal accompaniment of ageing, 
and clinical amyloidosis is not rare. Intracerebral and cerebrovascular 
beta-protein amyloid deposits are a hallmark of the pathology of ... 
Alzheimer's disease....&quot; &quot;Amyloid deposits are in a state 
of dynamic turnover and can regress if new fibril formation is halted.&quot; 

 A. V. Sirotkin, &quot;Direct influence of melatonin on steroid, nonapeptide 
hormones, and cyclic nucleotide secretion by granulosa cells isolated 
from porcine ovaries,&quot; J. Pineal Res. 17(3), 112-117, 1994. &quot;It 
was found that melatonin is able to inhibit progesterone and stimulate 
estradiol secretion.&quot; &quot;Some inhibition of vasopressin and 
cAMP and significant stimulation of cGMP also resulted from melatonin 
treatment.&quot;  R. M. Sapolsky, &quot;Glucocorticoid toxicity in the 
hippocampus: Reversal with supplementation with brain fuels,&quot; J. 
Neurosci. 6, 2240-2245, 1986.  R. M. Sapolsky, &quot;Glucocorticoids, 
hippocampal damage and the glutaminergic synapse,&quot; Prog. Brain 
Res. 86, 13-23, 1990.  M. Schwartz, et al., &quot;Growth-associated triggering 
factors and central nervous system regeneration,&quot; p. 47 in Trophic 
Factors and the Nervous System, edited by L. A. Horrocks, et al., Raven 
Press, NY, 1990.   R. W. Ordway, et al., &quot;Direct regulation of ion 
channels by fatty acids,&quot; Trends Neurosci. 14, 96-100, 1991.

</p>
<p>H. 
G. P. Swarts, et al., &quot;Binding of unsaturated fatty acids to Na+,K+-ATPase 
leading to inhibition and inactivation,&quot; Biochim. Biophys. Acta 
1024, 32-40, 1990.</p>
<p>G. 
Autore, et al., &quot;Essential fatty acid-deficient diet modifies PAF 
levels in stomach and duodenum of endotoxin-treated rats,&quot; J. Lipid 
Mediators Cell Signalling 9, 145-153, 1994.  J. Rafael, et al., &quot;The 
effect of essential fatty acid deficiency on basal respiration and function 
of liver mitochondria in rats,&quot; J. Nutr. 114, 255-262, 1984.

</p>
<p>A. 
M. Weiner, et al., &quot;Nonviral retroposons, genes, pseudogenes, and 
transposable elements generated by the reverse flow of genetic information,&quot; 
Ann. Rev. Biochem. 55, 631-661, 1986.  I. Zs.-Nagy, &quot;Semiconduction 
of proteins as an attribute of the living state: The ideas of Albert 
Szent-Gyorgyi revisited in light of the recent knowledge regarding oxygen 
free radicals,&quot; Exp. Gerontology 30(3-4), 327-335, 1995. &quot;In 
this assumption, the continuous radical flux is as important for the 
maintenance of the living state, as the voltage power supply is essential 
for the functioning of the computer.&quot;</p>

<p>Winfried 
G. Rossmanith, &quot;Gonadotropin secretion during aging in women:  
Review article,&quot; Exp. Gerontology 30(3/4) 369-381, 1995.  
&quot;...major functional derangements, primarily at a hypothalamic 
rather than a pituitary site, have been determined as concomitants of 
aging in women.&quot;  &quot;...aging may impair the negative feedback 
sensitivity to ovarian sex steroids....&quot;  Hormonal changes 
at menopause &quot;may represent the sum of functional aberrations that 
were initiated much earlier in life....&quot;  &quot;...prolonged 
estrogen exposure facilitates the loss of hypothalamic neurons....&quot;</p>
<p>J. 
R. Brawer, et al., &quot;Ovary-dependent degeneration in the hypothalamic 
arcuate nucleus,&quot; Endocrinology 107, 274-279, 1980.</p>

<p>G. 
C. Desjardins, &quot;Estrogen-induced hypothalamic beta-endorphin neuron 
loss:  A possible model of hypothalamic aging,&quot; Exp. Gerontology 
30(3/4), 253-267, 1995.  &quot;This loss of opioid neurons is prevented 
by treatment with antioxidants indicating that it results from estradiol-induced 
formation of free radicals.&quot;  &quot;...this beta-endorphin 
cell loss is followed by a compensatory upregulation of mu opioid receptors 
in the vicinity of LHRH cell bodies.&quot;  Resulting supersensitivity 
of the cells results &quot;in chronic opioid suppression of the pattern 
of LHRH release, and subsequently that of LH.&quot;  The neurotoxic 
effects of estradiol cause a &quot;cascade of neuroendocrine aberrations 
resulting in anovulatory acyclicity.&quot;  Treatment with an opiod 
antagonist &quot;reversed the cystic morphology of ovaries and restored 
normal ovarian cycles&quot; in estrogen-treated rats.</p>

<p>G. 
B. Melis, et al., &quot;Evidence that estrogens inhibit LH secretion 
through opioids in postmenopausal women using naloxone,&quot; Neuroendocrinology 
39, 60-63, 1984.</p>
<p>H. 
J. Sipe, et al., &quot;The metabolism of 17 beta-estradiol by lactoperoxidase:  
A possible source of oxidative stress in breast cancer,&quot; Carcinogenesis 
15(11), 2637-2643, 1994.  &quot;...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.&quot;  &quot;...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.&quot;</p>
<p>S. 
Santagati, et al., &quot;Estrogen receptor is expressed in different 
types of glial cells in culture,&quot; J. Neurochem. 63(6), 2058-2064, 
1994.  &quot;...in all three types of glial cell analyzed in almost 
equal amounts...&quot;</p>

<p>D. 
X. Liu and L. P. Li, &quot;Prostaglandin F-2 alpha rises in response 
to hydroxyl radical generated in vivo,&quot; Free Radical Biol. Med. 
18(3), 571-576, 1995.  &quot;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.&quot;  
&quot;Prostaglandin F-2 alpha dramatically increased in response to 
hydroxyl radical generation....&quot;</p>
<p>J. 
Owens and P. A. Schwartzkroin, &quot;Suppression of evoked IPSPs by 
arachidonic acid and prostaglandin F-2 alpha,&quot; Brain Res. 691(1-2), 
223-228, 1995.  &quot;These findings suggest that high levels of 
AA and its metabolites may bias neurons towards excitation.&quot;</p>
<p>E. 
A. Quail and G. C. T. Yeoh, &quot;The effect of iron status on glyceraldehyde 
3-phosphate dehydrogenase expression in rat liver,&quot; FEBS Lett. 
359(2-3), 126-128, 1995.  &quot;...the overexpression of GAPDH 
mRNA in iron deficiency is probably due to increased message stability.&quot;  
[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., &quot;4-hydroxylation of estradiol by human uterine 
myometrium and myoma microsomes:  Implications for the mechanism 
of uterine tumorigenesis,&quot; Proc Natl Acad Sci USA 92(20), 9220-9224, 
1995.  &quot;... elicits biological activities distinct from estradiol, 
most notably an oxidant stress response induced by free radicals generated 
by metabolic redox cycling reactions.&quot;</p>
<p>J. 
G. Liehr and D. Roy, &quot;Free radical generation by redox cycling 
of estrogens,&quot; Free Rad. Biol. Med. 8, 415-423, 1990.</p>
<p>P. 
Aschheim, &quot;Resultats fournis par la greffe heterochrone des ovaires 
dan l'etude de la regulation hypothalamo-hypophyso-ovarienne de la ratte 
senile,&quot; Gerontologia 10, 65-75, 1964/65.  &quot;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.&quot;  

&quot;What are the factors that cause this diminution of the hypothalamic 
sensitivity...?  Kennedy incriminates a decrease in the cellular 
metabolism in general....&quot;</p>
<p>P. 
Ascheim, &quot;Aging in the hypothalamic-hypophyseal ovarian axis in 
the rat,&quot; 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, &quot;Reproductive cycle biochemistry,&quot; Fertility &amp; 

Sterility 12(3), 245-260, 1961.  &quot;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.&quot;  &quot;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.&quot;&quot;The 
effect of the progestational steroids may be such as to interfere with 
the biochemical pattern required for support of this anaerobic environment.&quot;</p>
<p>C. 
S. Bangur, J. L. Howland, S. S. Katyare, &quot;Thyroid hormone treatment 
alters phospholipid composition and membrane fluidity of rat brain mitochondria,&quot; 
Biochem. J. 305(1), 29-32, 1995. (Increases fluidity.)</p>
<p>R. 
S. Sohal, et al., &quot;Mitochondrial superoxide and hydrogen peroxide 
generation, protein oxidative damage, and longevity in different species 
of flies,&quot; 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., &quot;Cell surface 'blanket' of apolipoprotein 
E on rat adrenocortical cells,&quot; J. Lipid Res. 36(4), 745-758, 1995.  
&quot;...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.&quot;</p>
<p>C. 
A. Frye and J. D. Sturgis, &quot;Neurosteroids affect spatial reference, 
working, and long-term memory of female rats,&quot; 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, &quot;Cytochrome P450 in the brain:  Neuroendocrine 
functions,&quot; 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., &quot;Biosynthesis and assay of neurosteroids in rats 
and mice:  Functional correlates,&quot; 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., &quot;Effect of the progestagen promegestone 
(R-5020) on mRNA of the oestrone sulphatase in the MCF-7 human mammary 
cancer cells,&quot; 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., &quot;Treatment of acute experimental allergic 
encephalomyelitis in the Lewis rat with the sex hormone progesterone,&quot; 
Int. J. Immunopathol. Pharmacol. 7(3), 183-192, 1994.  &quot;...we 
suggest that treatment with progesterone protected against the histological 
signs of EAE through a peripheral immune mechanism.&quot;</p>
<p>H. 
L. Koenig, et al., &quot;Progesterone synthesis and myelin formation 
by Schwann cells,&quot; Science (268), 1500-1503, 1995.  &quot;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.&quot;</p>

<p>N. 
C. Lan and K. W. Gee, &quot;Neuroactive steroid actions at the GABA(A) 
receptor,&quot; Horm. Behav. 28(4), 537-544, 1994.  Neuroactive 
steroids &quot;...do not interact with any of the classical cytosolic 
hormonal steroid receptors.&quot;  &quot;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.&quot;</p>
<p>J. 
F. FierroRenoy, et al., &quot;Three different thyroid hormone receptor 
isoforms are detected in a pure culture of ovine oligodendrocytes,&quot; 
Glia 14(4), 322-328, 1995.  &quot;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.&quot;</p>
<p>J. 
Masse, &quot;Nutrition, thyroid hormones, body temperature, and mortality 
of elderly patients with acute illnesses,&quot; Am. J. Clin. Nutr. 62(3), 
647-648, 1995.</p>

<p>E. 
J. Masoro, &quot;Dietary restriction,&quot; Exp. Gerontology 30(3/4), 
291-298, 1995.  &quot;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.&quot;  [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., &quot;Pregnenolone sulfate antagonizes dizocilpine 
amnesia:  Role for allopregnanolone,&quot; Neuroreport 6(12), 1697-1700, 
1995.  &quot;We and others have shown that allopregnanolone potently 
modulate GABA(A) receptor function whereas 5 alpha-dihydroprogesterone 
fails to induce rapid changes....&quot;</p>
<p>B. 
S. McEwen and E. Gould, &quot;Adrenal steroid influences on the survival 
of hippocampal neurons,&quot; Biochem. Pharmacol 40, 2393-2402, 1990.</p>

<p>P. 
W. Landfield, et al., &quot;Hippocampal aging and adrenocorticoids:  
Quantitative correlations,&quot; Science 202(8), 1098-1101, 1978.</p>
<p>A. 
M. Dudchenko, et al., &quot;Effect of corticosterone on the macroergic 
pool and membrane permeability in sections of rat hippocampus,&quot; 
Bull. Exp. Biol. &amp; Med. 116(12), 1505-1508, 1993.  &quot;...the 
hippocampus is one of the most vulnerable brain structures....&quot;  
&quot;...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.&quot;  &quot;The death 
of hippocampal neurons, triggered...by hyperactivation of the glutamate 
receptors, is accelerated in the presence of&quot; 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., &quot;Individual differences in hypothalamic-pituitary-adrenal 
activity in later life and hippocampal aging,&quot; Exp. Gerontology 
30(3/4), 229-251, 1995.  &quot;...glucocorticoids...both increase 
the toxic glutamate signal and decrease the metabolic capacity of neurons 
to survive.&quot;  (Glucose is protective.)  &quot;Our current 
foxus is on the potential role of progesterone as a modulator of glucocorticoid 
action.&quot;</p>
<p>P. 
Sheng, et al., &quot;Methamphetamine causes reactive gliosis in vitro:  
Attenuation by the ADP-ribosylation inhibitor, benzamide,&quot; Life 
Sciences 55(3), 51-54, 1994</p>
<p>N. 
S. Verkhratsky, &quot;Limbic control of endocrine glands in aged rats,&quot; 

Exp. Gerontology 30(3/4, 415-421, 1995.  Aging causes &quot;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.&quot;  &quot;...stimulation of hippocampus 
inhibits ACTH secretion...and causes a decrease of plasma corticosteroids....&quot;</p>
<p>R. 
M. Sapolsky, et al., &quot;Prolonged glucocorticoid exposure reduces 
hippocampal neuron number:  Implications for aging,&quot; J. Neurosci. 
5 1221, 1985.</p>
<p>J. 
L. W. Yau, Mol. Brain Res. 27(1), 174-178, 1994.  &quot;Glucocorticoid 
excess is associated with hippocampal neuronal dysfunction and loss, 
mainly affecting CA1.&quot; </p>
<p>B. 
Nasman, et al., &quot;A subtle disturbance in the feedback regulation 
of the hypothalamic-pituitary-adrenal axis in the early phase of Alzheimer's 
disease,&quot; Psychoneuroendocrinology 20(20, 211-220, 1995.  

&quot;After 0.5 mg dexamethasone, serum cortisol levels were significantly 
less suppressed....&quot;</p>
<p>C. 
Mondadori, &quot;In search of the mechanism of action of the nootropics:  
New insights and potential clinical implications,&quot; Life Sci. 55(25-26), 
2171-2178, 1994.  &quot;...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.&quot;</p>
<p>J. 
M. Pasquini and A. M. Adamo, &quot;Thyroid hormones and the central 
nervous system,&quot; Dev. Neurosci. 12(1-2), 1-8, 1994.  &quot;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.&quot;</p>
<p>M. 
Martinez, et al., &quot;Glucose deprivation increases aspartic acid 
release from synaptosomes of aged mice,&quot; Brain Res. 673(1), 149-152, 
1995.  &quot;...in the absence of glucose in the medium of incubation 
aspartate and glutamate release was higher in old than in young animals.&quot;  

&quot;...there is an age-dependent dysfunction in this process linked 
to energy metabolism disturbance.&quot;</p>
<p>P. 
Corbisier, et al., &quot;Bioenergetics of mitochondria determine cell 
survival in stressful conditions,&quot; Prog. in Cell Res. (5), 237-241, 
1995.  &quot;...the growth rate of young or old cells injected 
with coupled mitochondria...was not statistically different.&quot;</p>
<p>G. 
Paradies, et al., &quot;Molecular basis of the age-dependent decrease 
in the cytochrome oxidase activity in rat heart mitochondria,&quot; 
Prog. in Cell Res. 5, 243-247, 1995.  The  activity of cytochrome 
oxidase &quot;was markedly decreased with aging.  This decrease 
was associated with a parallel decrease in the mitochondrial respiratory 
activity.&quot;  &quot;Cardiolipin content was significantly reduced 
in mitochondrial membrane from aged rats.&quot;</p>

<p>G. 
C. Ness and Z. H. Zhao, &quot;Thyroid hormone rapidly induces hepatic 
LDL receptor mRNA levels in hypophysectomized rats,&quot; Arch. Biochem. 
Biophys. 315(1), 199-202, 1994.</p>
<p>E. 
M. Mutisya, et al., &quot;Cortical cytochrome oxidase activity is reduced 
in Alzheimer's disease,&quot; J. Neurochem. 63(6), 2170-2184, 1994.  
&quot;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.&quot;</p>
<p>G. 
J. Bu, et al., &quot;Subcellular localization and endocytic function 
of low density lipoprotein receptor-related protein in human glioblastoma 
cells,&quot; J. Biol. Chem. 269(47), 29874-29882, 1994.  &quot;Our 
results thus strongly suggest several potential roles for LRP in brain 
protein and lipoprotein metabolism, as well as control of extracellular 
protease activity.&quot;</p>

<p>V. 
Vandenbrouck, et al., &quot;The modulation of apolipoprotein E gene 
expression by 3,3'-5-triiodothyronine in HepG(2) cells occurs at transcriptional 
and post-transcriptional levels,&quot; Eur. J. Biochem. 224(2), 463-471, 
1994.  &quot;...thyroid hormone stimulated apoE gene transcription 
threefold in 24 hours.&quot;</p>
<p>M. 
J. Ignatius, et al. &quot;Expression of apolipoprotein-E during nerve 
degeneration and regeneration,&quot; Proc. Natl. Acad. Sci. (USA) 83, 
1125-1129, 1986.</p>
<p>B. 
T. Stokes, et al., &quot;Energy depletion, calcium and the cytoskeleton:  
A model for trophic intervention,&quot; pp. 279-292, in Trophic Factors 
and the Nervous System, L. A. Horrocks, et al., editors, Raven Press, 
NY, 1990.  &quot;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.&quot;  &quot;Virtually 
all components of the cytoskeleton are either directly or indirectly 
affected by alterations in calcium metabolism.&quot;  &quot;...calcium-activated 
proteases may also specifically modulate components of the cytoskeleton.&quot;  

&quot;...ATP depletion itself may directly alter the structural components 
of the neuronal cytoskeleton.&quot;  &quot;...major neurodegenerative 
diseases such as Alzheimer's, Parkinsonian syndrome, amyotrophic lateral 
sclerosis...are also characterized by changes in the neuronal cytoskeleton.&quot;</p>
<p>T. 
Gunther, et al., &quot;Effects of magnesium and iron on lipid peroxidation 
in cultured hepatocytes,&quot; Mol. Cell Biochem. 144(2), 141-145, 1995.  
(Magnesium protects against iron.)</p>
<p>K. 
D. Croft, et al., &quot;Oxidation of low-density lipoproteins:  
Effect of antioxidant content, fatty acid composition and intrinsic 
phospholipase activity on susceptibility to metal ion-induced oxidation,&quot; 
BBA-Lipid Lipid Metab. 1254(3), 250-256, 1995.</p>
<p>J. 
H. Choi and B. P. Yu, &quot;Brain synaptosomal aging:  Free radicals 
and membrane fluidity,&quot; Free Radical Biol. Med. 18(2), 133-139, 
1995  (&quot;...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.&quot;)</p>

<p>J. 
H. Choi and B. P. Yu, &quot;Modification of age-related alterations 
of iron, ferritin, and lipid peroxidation in rat serum,&quot; Age 17(3), 
93-97, 1994.</p>
<p>E. 
Chiarpotto, et al., &quot;Metabolism of 4-hydroxy-2-nonenal and aging,&quot; 
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., &quot;The metabolism of beta-estradiol by lactoperoxidase:  
A possible source of oxidative stress in breast cancer,&quot; Carcinogenesis 
15(11), 2637-2643, 1994.</p>

<p>M. 
J. Endresen, et al., &quot;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,&quot; 
Scan. J. Clin. Lab. Invest. 54(7), 549-557, 1994<em>.</em>  &quot;...levels 
of circulating free fatty acids are increased in women who later develop 
pre-eclampsia long before the clinical onset of the disease.&quot;  
&quot;...linoleic acid reduced the thrombin-stimulated prostacyclin 
release by 30-60%, oleic acid by 10-30%, wheras palmitic acid had no 
effect.&quot;  &quot;Linoleic acid reduced the endothelial cells&quot; 
ability to inhibit platelet aggregation by 10-45%....&quot;  </p>
<p>L. 
A. Norris and J. Bonnar, &quot;Effect of oestrogen dose on whole blood 
platelet activation in women taking new low dose oral contraceptives,&quot; 

Thromb. Haemost. 72(6), 926-930, 1994:  &quot;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.&quot;)  
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., &quot;Interferon-gamma and polyunsaturated fatty acids 
increase the binding of lipopolysaccharide to macrophages,&quot; Int. 
J. Exp. Pathol. 75(5), 363-368, 1994.</p>
<p>G. 
Autore, et al., &quot;Essential fatty acid-deficient diet modifies PAF 
levels in stomach and duodenum of endotoxin-treated rats,&quot; J. Lipid 
Mediators Cell Signalling 9, 145-153, 1994.  Deficiency of &quot;essential&quot; 

fats decreases damage from endotoxin.</p>
<p>N. 
Auge, et al., &quot;Proliferative and cytotoxic effects of mildly oxidized 
low-density lipoproteins on vascular smooth-muscle cells,&quot; Biochem. 
J. 309(Part 3), 1015-1020, 1995.  &quot;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.&quot;</p>
<p>S. 
K. Clinton, et al., &quot;The combined effects of dietary fat and estrogen 
on survival, 7,12-dimethyl- benz(a)-anthracene-induced breast cancer 
and prolactin metabolism in rats,&quot; J. Nutr. 125(5), 1192-1204, 
1995.  &quot;Mortality in controls was doubled by feeding a high 
fat diet....&quot;  &quot;...the presence of estrogen may be a 
prerequisite for significant dietary modulation.&quot; </p>

<p>R. Sanchez Olea, 
et al., &quot;Inhibition by polyunsaturated fatty acids of cell volume 
regulation and osmolyte fluxes in astrocytes,&quot; Amer. J. of Physiology--cell 
physiology 38(1), C96-C102, 1995.  &quot;...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.&quot;  
&quot;...polyunsaturated fatty acids directly inhibit the permeability 
pathways correcting cell volume after swelling in cultured astrocytes.&quot; </p>
<p>M. 
E. Miller, et al., &quot;Influence of hormones on platelet intracellular 
calcium,&quot; Thrombosis Research 77(6), 515-530, 1995.  &quot;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.&quot;  
&quot;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.&quot;</p>

<p>F. 
Mercure and G. Vanderkraak, &quot;Inhibition of gonadotropin-stimulated 
ovarian steroid production by PUFA in teleost fish,&quot; Lipids 30(6), 
547-554, 1995.  &quot;EPA and DHA inhibited gonadotropin-stimulated 
testosterone production in a dose-related manner....&quot;</p>
<p>A 
A Farooqui, K Wells, L A Horrocks, &quot;Breakdown of membrane phospholipids 
in Alzheimer disease--involvement of excitatory amino acid receptors,&quot;  
Mol Chem Neuropathol 25(2-3) 155-173, 1995.  &quot;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.&quot;</p>
<p>Leo 
Loeb, V. Suntzeff, and E. L. Burns, &quot;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,&quot; 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, &quot;The 
connective tissue and muscle appear rarefied, almost as though they 
were perforated by a large number of small holes.&quot;  &quot;...this 
condition is presumably due to a deposit of a mixture of hyaline material 
and edematous fluid....&quot;  &quot;This process of hyalinization...is 
counteracted by invasion by connective tissue.&quot;  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.&quot;  &quot;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.&quot;  &quot;As a rule, the epithelioid cells are 
seen alone; giant cells are more rare.&quot;  &quot;...the connective-tissue 
fibrils may in places appear somewhat separated, perhaps by edematous 
fluid.&quot;  &quot;The first changes consist very likely in the 
transudation of fluid from the vessels into the connective tissue.&quot;  

&quot;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.&quot;  &quot;...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....&quot;  &quot;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.&quot;  &quot;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.&quot;</p>
<p>Leo 
Loeb, V. Suntzeff, and E. L. Burns, &quot;The effects of age and estrogen 
on the stroma of vagina, cervix and uterus in the mouse,&quot; Science 
88(22, Nov. 4), 1938.  &quot;...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.&quot;  
&quot;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.&quot;  &quot;...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.&quot;</p>

<p>P. 
H. Chan and R. A. Fishman, &quot;Brain edema:  Induction in cortical 
slices by polyunsaturated fatty acids,&quot; Science 201, 358-369, 1978.  
&quot;This cellular edema was specific, since neither saturated fatty 
acids nor a fatty acid containing a single double bond had such effect.&quot;  </p>
<p>C. 
LarssonBackstrom, et al., &quot;Effects of dietary alpha- and gamma-linolenic 
acids on liver fatty acids, lipid metabolism, and survival in sepsis,&quot; 
Shock 4(1), 11-20, 1995.  &quot;Dietary GLA reduced survival from 
sepsis.&quot;</p>
<p>D. 
Chemla, et al., &quot;Influence of dietary polyunsaturated fatty acids 
on contractility, inotropy and compliance of isolated rat myocardium, 
J mol Cell Cardiol 27(8), 1745-1755, 1995.  &quot;There was a trend 
towards a lower peak lengthening velocity at preload in the LC (n-3) 
group...together with an unchanged peak rate of isometric force decline.  
This resulted in a significant impairment of the two mechanical indexes 
testing the load dependence of myocardial relaxation.&quot;  See 
B. Pieske, Circul. 92(5), 1169-78</p>

<p>R. 
Lerner, et al., &quot;Development and characterization of essential 
fatty acid deficiency in human endothelial cells in culture,&quot; 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., &quot;Dissociation of protein kinase C activities 
and diacylglycerol levels in liver plasma membranes of rats on coconut 
oil and safflower oil diets,&quot; J. Nutr Biochem 6(10), 528-533, 1995.  
&quot;The activation of PKC is affected differently in vitro by different 
fatty acids.&quot;  &quot;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....&quot;  &quot;...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.&quot;  &quot;It seems likely that saturated fats exert various 
physiological effects on lipid and lipoprotein metabolism, in part through 
PKC pathways.&quot;</p>

<p>V. 
Boutard, et al., &quot;Fish oil supplementation and essential fatty 
acid deficiency reduce nitric oxide synthesis by rat macrophages,&quot; 
Kidney Int. 46(5), 1280-1286, 1994.  &quot;Both...have been shown 
to exert anti-inflammatory effects....&quot;</p>
<p>A 
A Farooqui, K Wells, L A Horrocks, &quot;Breakdown of membrane phospholipids 
in Alzheimer disease--involvement of excitatory amino acid receptors,&quot;  
Mol Chem Neuropathol 25(2-3) 155-173, 1995.  &quot;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.&quot;</p>
<p>P. 
H. Chan and R. A. Fishman, &quot;Transient formation of superoxide radicals 
in polyunsaturated fatty acid-induced brain swelling,&quot; J. of Neurochemistry 
35, 1004-1007, 1980.</p>

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

<p>F. 
Laszlo, et al., &quot;Association of microvascular leakage with induction 
of nitric oxide synthase:  Effects of nitric oxide synthase inhibitors 
in various organs,&quot; Eur. J. Pharmacol. 283(1-3), 47-53, 1995.  
&quot;...assessed by the vascular leakage of ... albumin.&quot;  
&quot;Endotoxin...induced the expression of a calcium-independent nitric 
oxide synthase....&quot;</p>
<p>C. 
Nilsson, et al., &quot;The nocturnal increase in human cerebrospinal 
fluid production is inhibited by a beta(1)-receptor antagonist,&quot; 
Amer. J. Physiol.--Regul. Integr. C 36(6), R1445-R1448, 1994.</p>
<p>S. 
Capsoni, et al., &quot;Reduction of regional cerebral blood flow by 
melatonin in young rats,&quot; Neuroreport 6(9), 1346-1348, 1995.  

&quot;...reduced in the cerebral areas supplied by circle of Willis 
and the basilar arteries. [Also to the]  ...choroid plexuses.&quot; </p>
<p>A. C. Bowling and 
M. F. Beal, &quot;Bioenergetic and oxidative stress in neurodegenerative 
diseases,&quot; Life Sci. 56(14), 1151-1171, 1995.  &quot;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....&quot;  &quot;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.&quot;</p>
<p>K. 
Nakai, et al., &quot;Regeneration of norepinephrine-containing fibers 
in occipital cortex of adult cats,&quot;  Brain Res. Bull. 35(5-6), 
409-412, 1994.  &quot;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.&quot;</p>

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

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

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

<p>A. 
G. Herzog, &quot;Progesterone therapy in women with complex partial 
and secondary generalized seizures,&quot; Neurology 45(9), 1660-1662, 
1995.</p>
<p>Z. 
Q. Ma, et al., Estrogenic control of monoamine oxidase A activity in 
human neuroblastoma cells expressing physiological concentrations of 
estrogen receptor,&quot; Eur. J. Pharmacol. 284(1-2), 171-176, 1995.</p>
<p>J. 
G. Belasco and G. Brawerman, Control of Messenger RNA Stability, Academic 
Press, NY, 1994. </p>
<p>Leo 
Loeb, V. Suntzeff, and E. L. Burns, &quot;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,&quot; 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, &quot;The 
connective tissue and muscle appear rarefied, almost as though they 
were perforated by a large number of small holes.&quot;  &quot;...this 
condition is presumably due to a deposit of a mixture of hyaline material 
and edematous fluid....&quot;  &quot;This process of hyalinization...is 
counteracted by invasion by connective tissue.&quot;  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.&quot;  &quot;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.&quot;  &quot;As a rule, the epithelioid cells are 
seen alone; giant cells are more rare.&quot;  &quot;...the connective-tissue 
fibrils may in places appear somewhat separated, perhaps by edematous 
fluid.&quot;  &quot;The first changes consist very likely in the 
transudation of fluid from the vessels into the connective tissue.&quot;  

&quot;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.&quot;  &quot;...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....&quot;  &quot;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.&quot;  &quot;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.&quot;</p>
<p>Leo 
Loeb, V. Suntzeff, and E. L. Burns, &quot;The effects of age and estrogen 
on the stroma of vagina, cervix and uterus in the mouse,&quot; Science 
88(22, Nov. 4), 1938.  &quot;...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.&quot;  
&quot;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.&quot;  &quot;...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.&quot;</p>

<p>Winfried 
G. Rossmanith, &quot;Gonadotropin secretion during aging in women:  
Review article,&quot; Exp. Gerontology 30(3/4) 369-381, 1995.  
&quot;...major functional derangements, primarily at a hypothalamic 
rather than a pituitary site, have been determined as concomitants of 
aging in women.&quot;  &quot;...aging may impair the negative feedback 
sensitivity to ovarian sex steroids....&quot;  Hormonal changes 
at menopause &quot;may represent the sum of functional aberrations that 
were initiated much earlier in life....&quot;  &quot;...prolonged 
estrogen exposure facilitates the loss of hypothalamic neurons....&quot;</p>
<p>J. 
R. Brawer, et al., &quot;Ovary-dependent degeneration in the hypothalamic 
arcuate nucleus,&quot; Endocrinology 107, 274-279, 1980.</p>

<p>G. 
C. Desjardins, &quot;Estrogen-induced hypothalamic beta-endorphin neuron 
loss:  A possible model of hypothalamic aging,&quot; Exp. Gerontology 
30(3/4), 253-267, 1995.  &quot;This loss of opioid neurons is prevented 
by treatment with antioxidants indicating that it results from estradiol-induced 
formation of free radicals.&quot;  &quot;...this beta-endorphin 
cell loss is followed by a compensatory upregulation of mu opioid receptors 
in the vicinity of LHRH cell bodies.&quot;  Resulting supersensitivity 
of the cells results &quot;in chronic opioid suppression of the pattern 
of LHRH release, and subsequently that of LH.&quot;  The neurotoxic 
effects of estradiol causes a &quot;cascade of neuroendocrine aberrations 
resulting in anovulatory acyclicity.&quot;  Treatment with an opiod 
antagonist &quot;reversed the cystic morphology of ovaries and restored 
normal ovarian cycles&quot; in estrogen-treated rats.</p>

<p>G. 
B. Melis, et al., &quot;Evidence that estrogens inhibit LH secretion 
through opioids in postmenopausal women using naloxone,&quot; Neuroendocrinology 
39, 60-63, 1984.</p>
<p>H. 
J. Sipe, et al., &quot;The metabolism of 17 beta-estradiol by lactoperoxidase:  
A possible source of oxidative stress in breast cancer,&quot; Carcinogenesis 
15(11), 2637-2643, 1994.  &quot;...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.&quot;  &quot;...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.&quot;</p>
<p>S. 
Santagati, et al., &quot;Estrogen receptor is expressed in different 
types of glial cells in culture,&quot; J. Neurochem. 63(6), 2058-2064, 
1994.  &quot;...in all three types of glial cell analyzed in almost 
equal amounts...&quot;</p>

<p>D. 
X. Liu and L. P. Li, &quot;Prostaglandin F-2 alpha rises in response 
to hydroxyl radical generated in vivo,&quot; Free Radical Biol. Med. 
18(3), 571-576, 1995.  &quot;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.&quot;  
&quot;Prostaglandin F-2 alpha dramatically increased in response to 
hydroxyl radical generation....&quot;</p>
<p>J. 
Owens and P. A. Schwartzkroin, &quot;Suppression of evoked IPSPs by 
arachidonic acid and prostaglandin F-2 alpha,&quot; Brain Res. 691(1-2), 
223-228, 1995.  &quot;These findings suggest that high levels of 
AA and its metabolites may bias neurons towards excitation.&quot;</p>
<p>E. 
A. Quail and G. C. T. Yeoh, &quot;The effect of iron status on glyceraldehyde 
3-phosphate dehydrogenase expression in rat liver,&quot; FEBS Lett. 
359(2-3), 126-128, 1995.  &quot;...the overexpression of GAPDH 
mRNA in iron deficiency is probably due to increased message stability.&quot;  
[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., &quot;4-hydroxylation of estradiol by human uterine 
myometrium and myoma microsomes:  Implications for the mechanism 
of uterine tumorigenesis,&quot; Proc Natl Acad Sci USA 92(20), 9220-9224, 
1995.  &quot;... elicits biological activities distinct from estradiol, 
most notably an oxidant stress response induced by free radicals generated 
by metabolic redox cycling reactions.&quot;</p>
<p>J. 
G. Liehr and D. Roy, &quot;Free radical generation by redox cycling 
of estrogens,&quot; Free Rad. Biol. Med. 8, 415-423, 1990.</p>
<p>F. 
Fourrier, Circ. Shock 43(4), 171-178, 1994, &quot;High estrogen levels 
were specifically observed in patients with sepsis and septic shock, 
either males or females.&quot;  &quot;Circulating T levels were 
decreased in all male patients.&quot;</p>

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