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I. INTRODUCTION
II. COMMON FACTORS IN INJURY DURING
GROWTH AND AGING
III. A VIEW OF ENTROPY--RENEWAL
OF THE BRAIN
IV. FALSE SIGNALS FROM THE ENVIRONMENT
A. EDUCATION, DIET AND MEDICINE INTERACT
B.
SIGNALS IN THE ABSTRACT
V. HORMONE IMBALANCE, LEADING
TO FAILURE OF PROTECTIVE INHIBITION AND ALZHEIMER'S DISEASE
A. THE FUNCTION OF ENERGY
B. EFFECTS OF ESTROGEN AND UNSATURATED FATTY ACIDS
C. VITAMIN A AND STEROIDS
D. THE NATURE OF ALZHEIMER'S DISEASE
E.
AN EXAMPLE; DIET AFFECTS HORMONES WHICH AFFECT STRUCTURE AND LEAD TO
APPARENT SELF- DESTRUCTION
VI. STRUCTURE AS A REGULATORY
SYSTEM--AN EMERGING VISION OF PERVASIVE EPIGENESIS
I. INTRODUCTION
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.
It
interacts with estrogen and unsaturated fats in ways that can change
restraint and adaptation into sudden self-destruction, apoptotic cell
death. If we look at the human organism from one perspective, it seems
coherent and intelligible, but from the perspective of established academic
biological doctrine, it seems appallingly complex, lacking any visible
integrating principle, and as a result simplistic mechanical, pharmaceutical,
or religious ideas are increasingly offered to fill the gap. But experimental
data can be taken out of the muddle, and put to coherent human use.
In what follows, I am acting as though the doctrines of genetic determination
and regulation by membranes were mere historical relics. The emerging
control systems are now clear enough that we can begin to use them to
reverse the degenerative diseases: Alzheimer's dementia, epileptic dementia,
arthritis, osteoporosis, depression, hypertension, hardening of the
heart and blood vessels, diabetes, and some types of tumor, immunodeficiencies,
reflex problems, and special atrophic problems, including clearing of
amyloid and mucoid deposits. I think many people experience regenerative
age-regressing when many circumstances are just right; for example,
taking a trip to the mountains in the spring with friends can optimize
several basic regulatory systems.
II. COMMON FACTORS IN BRAIN
INJURY DURING GROWTH AND AGING
Most
people are surprised by the number of cells in the prenatal brain, and
in the very old brain: In the human fetus at 6 months of development,
there are about twice as many brain cells as there are at the time of
birth, and in old age the number of cells in the brain keeps increasing
with age, so that at the age of 90 the amount of DNA in the brain (36.94
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.
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.
III. A VIEW OF ENTROPY: RENEWAL
OF THE BRAIN
When
a fertilized egg is developing into a person, each cell division creates
a new environment for the daughter cells, to which they adapt. They
may run into limits and resistances (sometimes a certain gene doesn't
meet the need of the situation, or toxins are present, or nutrients
and hormones are imperfectly supplied), but the process is flexible,
and a way is normally found to get around the limitation. The embryo's
brain development is my favorite example of the ways genes interact
with the environment. We might think of the "optimal brain development"
of a person, or a rat, or a chicken, as something which is clearly limited
by "the genes." But if rats are given a stimulating environment,
each generation gets a slightly bigger, slightly more intelligent brain.
If rats are treated during pregnancy to increase the amount of progesterone,
the offspring have bigger brains and learn more efficiently. Still,
that might just be restoring a condition that was natural for rats in
some perfect environment. Chickens develop inside an egg shell, and
so the nutrients needed for their development are all present when the
egg is laid.
The
brain, like the other organs, stops growing when the food supply is
used up. But an experimenter (Zamenhof) opened the egg shells at the
stage of development when the brain normally stops growing, and added
glucose, and found that the brain continued growing, producing chickens
with bigger brains. The "genes" of a chicken, as part of a
system, have something to do with the development of that system, but
the environment existing in and around the organism is able to guide
and support the way the system develops. The size, complexity, and intelligence
of the brain represents a very large part of the "information"
contained in the organism, and Zamenhof's experiment showed that the
ability to realize this potential, to create this complexity, comes
from the support of the environment, and that the "genetic nature
of the chicken" didn't constitute a limit to the development of
its brain.
I
am going to argue that Alzheimer's disease is analogous to the situation
confronted by the developing chicken embryo or the rat or human fetus,
when the environment is unable to meet the needs of the highly energetic,
demanding and sensitive brain cells, and the brain cells begin to die,
instead of developing into a more complex state, passing beyond various
barriers and limitations. There are two stereotypes that are in conflict
with this view: (1) That the structure of the brain is determined at
an early point in life, sometimes explicitly stated as the age of 12
or 16, and (2) that the structure of the brain goes into an "entropic"
deterioration during the process of aging. My position is that the brain
cells are in a vital developmental process at all times, and that the
same things that injure the brain of a fetus also injure the brain of
an aging person.
If
novelty is really appearing during development, then it is hard to maintain
that "entropy increases" during the development of an individual.
Isn't a child a richer organization than a fertilized egg? Isn't an
adult more individualized or realized than an infant? Seen from the
inside, our known world gets richer with experience. Learning is certainly
anti-entropic. Where does the idea of "increasing entropy with
living" come from? Many things contribute, including a doctrine
of genetic determinism, the old Platonic idea of the imperfection of
the concrete, the unreality of the existent, and the medieval idea of
the "corruption of the body." These philosophies still motivate
some people in aging research. The astrophysicist, N. A. Kozyrev, showed
that the idea of an "entropic cosmos" derived simply from
the assumptions of 19th century deism, "God set the clockwork universe
in motion, and left it to run down." Early in this century, Raymond
Pearl argued that the "rate of living" governed the life-span,
so that "fast living" meant a short life. He based his argument
on cantaloupe seeds: the faster they grew, the sooner they died. This
was because he didn't give them anything but water, so they had to live
on their stored energy; if they grew quickly, obviously they ran out
of stored energy sooner. I have never heard that described as a stupid
idea, but I think politeness is sometimes carried too far. In the clock
analogy, or the seed analogy, the available energy is used up.
The clock with its wound-up spring and the seed in a dish of water may be considered as closed systems, and we can understand their fate. But if it is foolish to argue from a confined seed to free-living organisms, then it is just as foolish to argue from a clock to a cosmos. Unfortunately, these inferences about closed systems are often applied to real situations that aren't energetically closed.
The "rate of living"
theory of aging picked up the idea of aging as a natural physical property
of time, and gave it expression in mathematical form, arguing (Hershey,
"Entropy, basal metabolism and life expectancy," Gerontologia
7, 245-250, 1963) that "the total lifetime entropy production"
could be calculated, to give insight into "life expectancy and
evolutional development." Unfortunately, the equation Hershey used
assumed that the flow of heat out of the body into the surroundings
is reversible. This suggests an image of Dr. Frankenstein vivifying
his monster with lightning, putting the heat back into the body. If
heat is to be "put back into the body," it is necessary to
make sure that it is appropriate for the structure as it exists.
Actually,
it is just the directed flow of energy which generates the structures.
If any biological argument can be made from the idea of entropy, it
is that it would be extremely difficult to regenerate food, by putting
heat into a person. In a few situations, it is possible to show that
living structures can directly absorb heat from their environment (causing
the temperature to fall)--"negative heat production"--but
the exact meaning of this isn't clear. (B. C. Abbott, et al., "The
positive and negative heat production associated with a nerve impulse,"
Proc. R. Soc. B 148, 149, 1958; R. D. Keynes and J. M. Ritchie, "The
initial heat production of amphibian myelinated nerve fibres,"
Proc. Physiol. Soc., June 1970, page 29P-30P: "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.") A.
I. Zotin ("Aging and rejuvenation from the standpoint of the thermodynamics
of irreversible processes," 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.
Regeneration
involves a production of entropy, as when an egg is formed. (The temperature
fluctuation at the time of ovulation might make a contribution to the
construction of the entropic egg.) The argument that aging of the animal
(like aging of the cosmos) is governed by "the tendency of entropy
to increase" has led people to say that rejuvenation would be like
unscrambling an egg. Zotin's argument is interesting, because he says
that an egg is a "scrambled animal." This view is very much
like Warburg's and Szent-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).
Estrogen
has a special place in relation to the water in an organism. It is intimately
involved with the formation of the egg cell, and wherever it operates,
it increases both the quantity of water and, apparently, the disorder
of the water. Its function, I believe, is to promote regeneration, as
in Zotin's scheme, by increasing entropy, or "scrambling the animal."
The way it promotes regeneration is by promoting water uptake, stimulating
cell division, and erasing the differentiated state to one degree or
another, providing a new supply of "stem cells," or cells
at the beginning of a certain sequence of differentiation. These more
numerous cells then must find a hospitable environment in which to develop
and adapt. If the proper support can't be found, then they will be recycled,
like the unfed cells in the brain of a fetus. If we imagine the course
of development as a summary of evolution ("ontogeny recapitulating
phylogeny"), then the egg, as it "unscrambles" itself
in embryonic development, passing through stages resembling jelly fish,
worm, fish, reptile, bird, baboon, keeps finding that the available
energy allows it to, in effect, say "I want this, I don't want
that," until it emerges as a human baby, saying "I want,"
and begins eating and learning, and with luck continues the unscrambling,
or self-actualization.. Degenerative aging, rather than being "physically
derived from the properties of time," seems to be produced situationally,
by various types of contamination of our energy supply. Unsaturated
fats, interacting with an excess of iron and a deficiency of oxygen
or usable energy, redirect our developmental path.
The
saturated fats, in themselves, seem to have no "signalling"
functions, and when they are naturally modified by our desaturating
enzymes, the substances produced behave very differently from the plant-derived
"eicosanoids." As far as their effects have been observed,
it seems that they are adaptive, rather than dysadaptive. All of the
factors that affect the brain of a fetus should be examined in relation
to the aging brain. Besides estrogen and fats, I am thinking of oxygen
and carbon dioxide, glucose, iron and calcium, cholesterol, progesterone,
pregnenolone, DHEA, the endorphins, GABA, thyroid, and vitamin A. An
additional factor, endotoxin poisoning, eventually tends to intervene
during stress and aging, exacerbating the trend begun under the influence
of the other factors.
IV. FALSE SIGNALS FROM THE
ENVIRONMENT
The environment can be supportive,
but it can also divert development from an optimal course.
Passively
taking whatever you are given, by history and nature, is entropic; choosing
intelligently from possible diets, selecting courses of action, will
create pattern and reduce entropy. If education contains an element
of choice and self-actualization, then the results seen in several Alzheimer's
studies could have a significance larger than what has been suggested
by the investigators. A diagnostic bias has been reported to result
from the use of standardized tests based on vocabulary, because education
increases vocabulary, and tends to cover up the loss of vocabulary that
occurs in dementia. In the Framingham study, it was concluded that there
was a real association of lower educational level with dementia, but
the suggestion was made that self-destructive practices such as smoking
were more common among the less educated.
The
Seattle study of the patients in a health maintenance organization showed
a very distinct difference in educational level between the demented
and the non-demented, both of whom had roughly similar frequency of
prescriptions for estrogen. The features that seemed important to me,
that weren't discussed by the authors, were that the demented women
had a much lower rate of progestogen use, and a much higher incidence
of hysterectomy, which interferes with natural progesterone production.
Although Brenner, et al., in the Seattle study concluded that "this
study provides no evidence that estrogen replacement therapy has an
effect on the risk of Alzheimer's disease in postmenopausal women,"
they reported that "Current estrogen use of both the oral and the
vaginal routes had odds ratios below 1, while former use of both types
yielded odds ratios above 1...." (They seem to neglect the fact
that Alzheimer's-type disease in old people has a long developmental
history, so it is precisely the "former" use that is relevent.
31% of the demented women had formerly used estrogen, and only 20% of
the control group. Since estrogen is a brain excitant, present use creates
exactly the same sort of effect on verbal fluency and other signs of
awareness of the environment that a little cocaine does. Anyone who
neglects this effect is probably deliberately constructing a propaganda
study.)
This
observation, that the demented had 155% as much former estrogen use
as the normal group, as well as the difference in rates of progestogen
use (normal patients had 50% more progestogen use than demented) and
hysterectomy (demented had 44.1% vs. 17% in the normals, i.e., 259%
as many; the incidence of hysterectomies after the age of 55, which
is a strong indication of a natural excess of estrogen, in the demented
was 374% of the incidence in the non-demented), should call for a larger
study to clarify these observatons, which tend to indicate that exposure
to estrogen in middle-age increases the risk of Alzheimer's disease
in old age, and that even medical progestogens offer some protection
against it..
(Although
this study might have been bigger and better, it is far better than
the junk-studies that have been promoted by the pharmaceutical publicity
machine. I have seen or heard roughly 100 mentions of the pro-estrogen
anti-scientific "studies," and none mentioning this one.)
D. E. Brenner, et al., Postmenopausal estrogen replacement therapy and the risk of Alzheimer's disease: A population-based case-control study," Am. J. Epidemiol. 140, 262-267, 1994. "Women tend to have higher age-specific prevalence and incidence rates of Alzheimer's disease than do men." 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.
H. C. Liu, et al., "Performance
on a dementia screening test in relation to demographic variables--study
of 5297 community residents in Taiwan," Arch. Neurol. 51(9), 910-915,
1994. "Commonly used dementia screening tests may be unfair to
poorly educated individuals, especially women and rural residents."
SIGNALS IN THE ABSTRACT
When
I taught endocrinology, I annoyed my tidy-minded students by urging
them to consider the potential hormone-like action of everything in
the body, and to think of layers of control, ranging from sugar, salt,
and carbon dioxide, through the "official hormones," to complex
nervous system actions such as expectancy, and biorhythms. Certain things
that are active in very important processes deserve special attention
as "signals," but they still have to be understood in context.
In this sense, we can think of Ca2+ as a signal substance, in its many
contexts; it is strongly regulated by the cell's energy charge. Magnesium
and sodium antagonize it in certain situations. Linoleic acid, linolenic
acid, arachidonic acid: Their toxicity is potentially prevented by the
Mead acids, and their eicosanoid derivatives, which behave very differently
from the familiar prostaglandins, as far as they have been compared;
can be drastically reduced by dietary changes. Prostaglandins, prostacyclin,
thromboxane: Formation is blocked by aspirin and other antiinflammatory
drugs.
Adenosine:
Sleep inducing protective effect. Adenosine is structurally very similar
to inosine, another natural substance (found in meat, for example) which
is a component of "inosiplex," 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., "Adenosines scavenged hydroxyl radicals and
prevented posttraumatic epilepsy," Free Radical Biol. Med. 19(4),
473-479, 1995; M. P. Abbracchio, et al., "Adenosine A(1) receptors
in rat brain synaptosomes: Transductional mechanisms, efects on glutamate
release, and preservation after metabolic inhibition," 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.
Iron:
Regulator of mRNA stability, heme synthesis; reacts with reductants
and unsaturated oils, to produce free radicals and lipid peroxides;
its absorption is increased by estrogen, hypothyroidism, anemia or lack
of oxygen. Glutamate and aspartate, excitotoxins, and GABA, an inhibitory
transmitter.
These
have metabolic links with each other, with ammonia, and with stress
and energy metabolism.
Estrogen
and acetylcholine, excitotoxins; 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.
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.
Endotoxin:
Antimitochondrial action, causes elevation of estrogen. It synergizes
with unsaturated fats, and naloxone opposes some of its toxic effects.
Urea,
cholesterol: Structural stability of proteins and lipid-protein complexes.
Things
that act directly on the water structure: I think all of the natural
regulators have an effect on the structure of water, but some unusual
substances seem to act primarily on the water. Noble gases, for example,
have no chemical effects, but they tend to form "cages" of
water molecules around themselves. Camphor, adamantane, and the antiviral
drug amantadine, probably have a similar water-structuring effect, and
amantadine, which is widely used as a therapy in Parkinson's disease,
has an anti-excitotoxic action.
Article continued in Part 2 - click here
Raymond Peat, Ph.D.
Copyright 1997
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