690 lines
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690 lines
51 KiB
HTML
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<head><title>The problem of Alzheimer's disease as a clue to immortality - Part 1</title></head>
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<h1>
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The problem of Alzheimer's disease as a clue to immortality - Part 1
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</h1>
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<p>
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I. INTRODUCTION
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</p>
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<p>
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II. COMMON FACTORS IN INJURY DURING GROWTH AND AGING
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</p>
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<p>
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III. A VIEW OF ENTROPY--RENEWAL OF THE BRAIN
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</p>
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<p>
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IV. FALSE SIGNALS FROM THE ENVIRONMENT
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</p>
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<p>
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A. EDUCATION, DIET AND MEDICINE INTERACT
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</p>
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<p>
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B. SIGNALS IN THE ABSTRACT
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</p>
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<p>
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V. HORMONE IMBALANCE, LEADING TO FAILURE OF PROTECTIVE INHIBITION AND ALZHEIMER'S DISEASE
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</p>
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<p>
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A. THE FUNCTION OF ENERGY
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</p>
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<p>
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B. EFFECTS OF ESTROGEN AND UNSATURATED FATTY ACIDS
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</p>
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<p>
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C. VITAMIN A AND STEROIDS
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</p>
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<p>
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D. THE NATURE OF ALZHEIMER'S DISEASE
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</p>
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<p>
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E. AN EXAMPLE; DIET AFFECTS HORMONES WHICH AFFECT STRUCTURE AND LEAD TO APPARENT SELF- DESTRUCTION
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</p>
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<p>
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VI. STRUCTURE AS A REGULATORY SYSTEM--AN EMERGING VISION OF PERVASIVE EPIGENESIS
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</p>
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<p>
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<strong>I. INTRODUCTION</strong>
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</p>
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<p>
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The toxicity of estrogen and of the unsaturated fats has been known for most of the twentieth century, and
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much has been learned about their interactions in the aging process. The body, during this time, has been
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understood as a dynamic interaction of cellular trophic influences which govern both form and function. My
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argument here will be that some of our adaptive, protective regulatory processes are overridden by the
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excessive supply of unsaturated fats--supported by a few other toxins--in our diet, acting as a false-signal
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system, and that cholesterol, pregnenolone, and progesterone which are our main long-range defenses, are
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overcome by the effects of the unsaturated fats, and that the resulting cascade of ineffective and defective
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reactions (including various estrogen-stimulated processes) leads to lower and lower energy production,
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reduced function, and death. At certain times, especially childhood and old age, iron (which also has
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important regulatory roles) accumulates to the point that its signal functions may be inappropriate.
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</p>
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<p>
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It interacts with estrogen and unsaturated fats in ways that can change restraint and adaptation into sudden
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self-destruction, apoptotic cell death. If we look at the human organism from one perspective, it seems
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coherent and intelligible, but from the perspective of established academic biological doctrine, it seems
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appallingly complex, lacking any visible integrating principle, and as a result simplistic mechanical,
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pharmaceutical, or religious ideas are increasingly offered to fill the gap. But experimental data can be
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taken out of the muddle, and put to coherent human use. In what follows, I am acting as though the doctrines
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of genetic determination and regulation by membranes were mere historical relics. The emerging control
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systems are now clear enough that we can begin to use them to reverse the degenerative diseases: Alzheimer's
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dementia, epileptic dementia, arthritis, osteoporosis, depression, hypertension, hardening of the heart and
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blood vessels, diabetes, and some types of tumor, immunodeficiencies, reflex problems, and special atrophic
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problems, including clearing of amyloid and mucoid deposits. I think many people experience regenerative
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age-regressing when many circumstances are just right; for example, taking a trip to the mountains in the
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spring with friends can optimize several basic regulatory systems.
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</p>
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<p>
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<strong>II. COMMON FACTORS IN BRAIN INJURY DURING GROWTH AND AGING
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</strong>
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</p>
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<p>
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Most people are surprised by the number of cells in the prenatal brain, and in the very old brain: In the
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human fetus at 6 months of development, there are about twice as many brain cells as there are at the time
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of birth, and in old age the number of cells in the brain keeps increasing with age, so that at the age of
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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).
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In the aged brain, glial cells multiply while neurons die. In the fetus, the cells that die are apparently
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nerve cells that haven't yet matured. The factors that are known to reduce the brain size at birth are also
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factors that are involved in the degenerating brain in old age or Alzheimer's disease: lack of oxygen,
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excess unsaturated fats or deficiency of saturated fats, estrogen excess, progesterone deficiency, and lack
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of glucose. A lack of carbon dioxide is probably harmful in both. Inflammation and blood clots may be
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factors in the aging brain, and bleeding with vascular spasm is sometimes a contributing factor to brain
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damage in both the old and the fetal brain. Endotoxemia may be a factor in nerve degeneration only during
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adult life, but it is sometimes present during pregnancy.
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</p>
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<p>
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M. C. Diamond, Enriching Heredity: The Importance of the Environment on the Anatomy of the Brain. Free
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Press, N.Y., 1988. C. Finch and L. Hayflick, Handbook of the Biology of Aging. Van Nostrand Reinhold, N.Y.,
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1977.
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</p>
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<p>
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<strong>III. A VIEW OF ENTROPY: RENEWAL OF THE BRAIN
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</strong>
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</p>
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<p>
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When a fertilized egg is developing into a person, each cell division creates a new environment for the
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daughter cells, to which they adapt. They may run into limits and resistances (sometimes a certain gene
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doesn't meet the need of the situation, or toxins are present, or nutrients and hormones are imperfectly
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supplied), but the process is flexible, and a way is normally found to get around the limitation. The
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embryo's brain development is my favorite example of the ways genes interact with the environment. We might
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think of the "optimal brain development" of a person, or a rat, or a chicken, as something which is clearly
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limited by "the genes." But if rats are given a stimulating environment, each generation gets a slightly
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bigger, slightly more intelligent brain. If rats are treated during pregnancy to increase the amount of
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progesterone, the offspring have bigger brains and learn more efficiently. Still, that might just be
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restoring a condition that was natural for rats in some perfect environment. Chickens develop inside an egg
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shell, and so the nutrients needed for their development are all present when the egg is laid.
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</p>
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<p>
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The brain, like the other organs, stops growing when the food supply is used up. But an experimenter
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(Zamenhof) opened the egg shells at the stage of development when the brain normally stops growing, and
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added glucose, and found that the brain continued growing, producing chickens with bigger brains. The
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"genes" of a chicken, as part of a system, have something to do with the development of that system, but the
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environment existing in and around the organism is able to guide and support the way the system develops.
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The size, complexity, and intelligence of the brain represents a very large part of the "information"
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contained in the organism, and Zamenhof's experiment showed that the ability to realize this potential, to
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create this complexity, comes from the support of the environment, and that the "genetic nature of the
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chicken" didn't constitute a limit to the development of its brain.
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</p>
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<p>
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I am going to argue that Alzheimer's disease is analogous to the situation confronted by the developing
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chicken embryo or the rat or human fetus, when the environment is unable to meet the needs of the highly
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energetic, demanding and sensitive brain cells, and the brain cells begin to die, instead of developing into
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a more complex state, passing beyond various barriers and limitations. There are two stereotypes that are in
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conflict with this view: (1) That the structure of the brain is determined at an early point in life,
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sometimes explicitly stated as the age of 12 or 16, and (2) that the structure of the brain goes into an
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"entropic" deterioration during the process of aging. My position is that the brain cells are in a vital
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developmental process at all times, and that the same things that injure the brain of a fetus also injure
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the brain of an aging person.
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</p>
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<p>
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If novelty is really appearing during development, then it is hard to maintain that "entropy increases"
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during the development of an individual. Isn't a child a richer organization than a fertilized egg? Isn't an
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adult more individualized or realized than an infant? Seen from the inside, our known world gets richer with
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experience. Learning is certainly anti-entropic. Where does the idea of "increasing entropy with living"
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come from? Many things contribute, including a doctrine of genetic determinism, the old Platonic idea of the
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imperfection of the concrete, the unreality of the existent, and the medieval idea of the "corruption of the
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body." These philosophies still motivate some people in aging research. The astrophysicist, N. A. Kozyrev,
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showed that the idea of an "entropic cosmos" derived simply from the assumptions of 19th century deism, "God
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set the clockwork universe in motion, and left it to run down." Early in this century, Raymond Pearl argued
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that the "rate of living" governed the life-span, so that "fast living" meant a short life. He based his
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argument on cantaloupe seeds: the faster they grew, the sooner they died. This was because he didn't give
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them anything but water, so they had to live on their stored energy; if they grew quickly, obviously they
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ran out of stored energy sooner. I have never heard that described as a stupid idea, but I think politeness
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is sometimes carried too far. In the clock analogy, or the seed analogy, the available energy is used up.
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</p>
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<p>
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The clock with its wound-up spring and the seed in a dish of water may be considered as closed systems, and
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we can understand their fate. But if it is foolish to argue from a confined seed to free-living organisms,
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then it is just as foolish to argue from a clock to a cosmos. Unfortunately, these inferences about closed
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systems are often applied to real situations that aren't energetically closed.
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</p>
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<p>
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The "rate of living" theory of aging picked up the idea of aging as a natural physical property of time, and
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gave it expression in mathematical form, arguing (Hershey, "Entropy, basal metabolism and life expectancy,"
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Gerontologia 7, 245-250, 1963) that "the total lifetime entropy production" could be calculated, to give
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insight into "life expectancy and evolutional development." Unfortunately, the equation Hershey used assumed
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that the flow of heat out of the body into the surroundings is reversible. This suggests an image of Dr.
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Frankenstein vivifying his monster with lightning, putting the heat back into the body. If heat is to be
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"put back into the body," it is necessary to make sure that it is appropriate for the structure as it
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exists.
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</p>
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<p>
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Actually, it is just the directed flow of energy which generates the structures. If any biological argument
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can be made from the idea of entropy, it is that it would be extremely difficult to regenerate food, by
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putting heat into a person. In a few situations, it is possible to show that living structures can directly
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absorb heat from their environment (causing the temperature to fall)--"negative heat production"--but the
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exact meaning of this isn't clear. (B. C. Abbott, et al., "The positive and negative heat production
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associated with a nerve impulse," Proc. R. Soc. B 148, 149, 1958; R. D. Keynes and J. M. Ritchie, "The
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initial heat production of amphibian myelinated nerve fibres," Proc. Physiol. Soc., June 1970, page 29P-30P:
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"It is now clear that in both crustacean...and mammalian (Howarth, et al., 1968) non-myelinated fibres there
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is an initial production of heat during (or soon after) the action potential, 80% of which is rapidly
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reabsorbed.") A. I. Zotin ("Aging and rejuvenation from the standpoint of the thermodynamics of irreversible
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processes," Priroda, No. 9, 49-55, 1970), citing the theory of Prigogine-Wiame, argued that the aging
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process involves both a decrease in entropy and a decrease in the rate of heat production.
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</p>
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<p>
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Regeneration involves a production of entropy, as when an egg is formed. (The temperature fluctuation at the
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time of ovulation might make a contribution to the construction of the entropic egg.) The argument that
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aging of the animal (like aging of the cosmos) is governed by "the tendency of entropy to increase" has led
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people to say that rejuvenation would be like unscrambling an egg. Zotin's argument is interesting, because
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he says that an egg is a "scrambled animal." This view is very much like Warburg's and Szent-Gyorgyi's
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theory of cancer, that it is like a reversion to a simpler state of life. To sketch out what I have argued
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in different contexts, water is the part of the living substance that we can most meaningfully discuss in
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terms of entropy. In fact, much of the concept of entropy has derived from the study of water, as it changed
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state in steam engines, etc. Cancer cells, like egg cells, have a higher water content than the
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differentiated, functioning cells of an adult, and the water is less rigidly ordered by the cellular
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molecules. This different, more mobile state of the water, can be measured by the NMR (nuclear magnetic
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resonance) machines which are used for MRI (magnetic resonance imaging).
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</p>
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<p>
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Estrogen has a special place in relation to the water in an organism. It is intimately involved with the
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formation of the egg cell, and wherever it operates, it increases both the quantity of water and,
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apparently, the disorder of the water. Its function, I believe, is to promote regeneration, as in Zotin's
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scheme, by increasing entropy, or "scrambling the animal." The way it promotes regeneration is by promoting
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water uptake, stimulating cell division, and erasing the differentiated state to one degree or another,
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providing a new supply of "stem cells," or cells at the beginning of a certain sequence of differentiation.
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These more numerous cells then must find a hospitable environment in which to develop and adapt. If the
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proper support can't be found, then they will be recycled, like the unfed cells in the brain of a fetus. If
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we imagine the course of development as a summary of evolution ("ontogeny recapitulating phylogeny"), then
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the egg, as it "unscrambles" itself in embryonic development, passing through stages resembling jelly fish,
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worm, fish, reptile, bird, baboon, keeps finding that the available energy allows it to, in effect, say "I
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want this, I don't want that," until it emerges as a human baby, saying "I want," and begins eating and
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learning, and with luck continues the unscrambling, or self-actualization.. Degenerative aging, rather than
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being "physically derived from the properties of time," seems to be produced situationally, by various types
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of contamination of our energy supply. Unsaturated fats, interacting with an excess of iron and a deficiency
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of oxygen or usable energy, redirect our developmental path.
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</p>
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<p>
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The saturated fats, in themselves, seem to have no "signalling" functions, and when they are naturally
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modified by our desaturating enzymes, the substances produced behave very differently from the plant-derived
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"eicosanoids." As far as their effects have been observed, it seems that they are adaptive, rather than
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dysadaptive. All of the factors that affect the brain of a fetus should be examined in relation to the aging
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brain. Besides estrogen and fats, I am thinking of oxygen and carbon dioxide, glucose, iron and calcium,
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cholesterol, progesterone, pregnenolone, DHEA, the endorphins, GABA, thyroid, and vitamin A. An additional
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factor, endotoxin poisoning, eventually tends to intervene during stress and aging, exacerbating the trend
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begun under the influence of the other factors.
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</p>
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<p><strong>IV. FALSE SIGNALS FROM THE ENVIRONMENT</strong></p>
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<p>
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The environment can be supportive, but it can also divert development from an optimal course.
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</p>
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<p>
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Passively taking whatever you are given, by history and nature, is entropic; choosing intelligently from
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possible diets, selecting courses of action, will create pattern and reduce entropy. If education contains
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an element of choice and self-actualization, then the results seen in several Alzheimer's studies could have
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a significance larger than what has been suggested by the investigators. A diagnostic bias has been reported
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to result from the use of standardized tests based on vocabulary, because education increases vocabulary,
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and tends to cover up the loss of vocabulary that occurs in dementia. In the Framingham study, it was
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concluded that there was a real association of lower educational level with dementia, but the suggestion was
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made that self-destructive practices such as smoking were more common among the less educated.
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</p>
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<p>
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The Seattle study of the patients in a health maintenance organization showed a very distinct difference in
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educational level between the demented and the non-demented, both of whom had roughly similar frequency of
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prescriptions for estrogen. The features that seemed important to me, that weren't discussed by the authors,
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were that the demented women had a much lower rate of progestogen use, and a much higher incidence of
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hysterectomy, which interferes with natural progesterone production. Although Brenner, et al., in the
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Seattle study concluded that "this study provides no evidence that estrogen replacement therapy has an
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effect on the risk of Alzheimer's disease in postmenopausal women," they reported that "Current estrogen use
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of both the oral and the vaginal routes had odds ratios below 1, while former use of both types yielded odds
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ratios above 1...." (They seem to neglect the fact that Alzheimer's-type disease in old people has a long
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developmental history, so it is precisely the "former" use that is relevent. 31% of the demented women had
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formerly used estrogen, and only 20% of the control group. Since estrogen is a brain excitant, present use
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creates exactly the same sort of effect on verbal fluency and other signs of awareness of the environment
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that a little cocaine does. Anyone who neglects this effect is probably deliberately constructing a
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propaganda study.)
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</p>
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<p>
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This observation, that the demented had 155% as much former estrogen use as the normal group, as well as the
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difference in rates of progestogen use (normal patients had 50% more progestogen use than demented) and
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hysterectomy (demented had 44.1% vs. 17% in the normals, i.e., 259% as many; the incidence of hysterectomies
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after the age of 55, which is a strong indication of a natural excess of estrogen, in the demented was 374%
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of the incidence in the non-demented), should call for a larger study to clarify these observatons, which
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tend to indicate that exposure to estrogen in middle-age increases the risk of Alzheimer's disease in old
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age, and that even medical progestogens offer some protection against it..
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</p>
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<p>
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(Although this study might have been bigger and better, it is far better than the junk-studies that have
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been promoted by the pharmaceutical publicity machine. I have seen or heard roughly 100 mentions of the
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pro-estrogen anti-scientific "studies," and none mentioning this one.)
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</p>
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<p>
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D. E. Brenner, et al., Postmenopausal estrogen replacement therapy and the risk of Alzheimer's disease: A
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population-based case-control study," Am. J. Epidemiol. 140, 262-267, 1994. "Women tend to have higher
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age-specific prevalence and incidence rates of Alzheimer's disease than do men." A.F. Jorm, The Epidemiology
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of Alzheimer's disease and related disorders, Chapman and Hall, London, 1990, and W. A. Rocca, et al., Ann.
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Neurol. 30, 381-190, 1991.
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</p>
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<p>
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H. C. Liu, et al., "Performance on a dementia screening test in relation to demographic variables--study of
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5297 community residents in Taiwan," Arch. Neurol. 51(9), 910-915, 1994. "Commonly used dementia screening
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tests may be unfair to poorly educated individuals, especially women and rural residents."
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</p>
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<p>
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<strong>SIGNALS IN THE ABSTRACT</strong>
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</p>
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<p>
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When I taught endocrinology, I annoyed my tidy-minded students by urging them to consider the potential
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hormone-like action of everything in the body, and to think of layers of control, ranging from sugar, salt,
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and carbon dioxide, through the "official hormones," to complex nervous system actions such as expectancy,
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and biorhythms. Certain things that are active in very important processes deserve special attention as
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"signals," but they still have to be understood in context. In this sense, we can think of Ca2+ as a signal
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substance, in its many contexts; it is strongly regulated by the cell's energy charge. Magnesium and sodium
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antagonize it in certain situations. Linoleic acid, linolenic acid, arachidonic acid: Their toxicity is
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potentially prevented by the Mead acids, and their eicosanoid derivatives, which behave very differently
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from the familiar prostaglandins, as far as they have been compared; can be drastically reduced by dietary
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changes. Prostaglandins, prostacyclin, thromboxane: Formation is blocked by aspirin and other
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antiinflammatory drugs.
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</p>
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<p>
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Adenosine: Sleep inducing protective effect. Adenosine is structurally very similar to inosine, another
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natural substance (found in meat, for example) which is a component of "inosiplex," an antiviral drug (Brown
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and Gordon, Fed. Proc. 29, 684, 1970, and Can. J. Microbiol. 18, 1463, 1972) or immunostimulant which has
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also been found to have an anti-senility effect (Doty and Gordon, Fed. Proc. 29). Adenosine is a free
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radical scavenger, and protects against calcium and glutamate excitotoxicity. (I. Yokoi, et al., "Adenosines
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scavenged hydroxyl radicals and prevented posttraumatic epilepsy," Free Radical Biol. Med. 19(4), 473-479,
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1995; M. P. Abbracchio, et al., "Adenosine A(1) receptors in rat brain synaptosomes: Transductional
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mechanisms, efects on glutamate release, and preservation after metabolic inhibition," Drug Develop. Res.
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35(3), 119-129, 1995.) It also appears to protect against the relative hyperventilation that wastes carbon
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dioxide, and endotoxin can interfere with its protective action. Guanosine, in this same group of
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substances, might have some similar properties. Thymidine and cytidine, which are pyrimidine-based, are
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endogenous analogs of the barbiturates, and like them, they might be regulators of the cytochrome P450
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enzymes. Uridine, in this group, promotes glycogen synthesis, and is released from bacteria in the presence
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of penicillin.
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</p>
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<p>
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Iron: Regulator of mRNA stability, heme synthesis; reacts with reductants and unsaturated oils, to produce
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free radicals and lipid peroxides; its absorption is increased by estrogen, hypothyroidism, anemia or lack
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of oxygen. Glutamate and aspartate, excitotoxins, and GABA, an inhibitory transmitter.
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</p>
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<p>
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These have metabolic links with each other, with ammonia, and with stress and energy metabolism.
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</p>
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<p>
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Estrogen and acetylcholine, excitotoxins; see Savolainen, et al., 1994. The information on this is
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overwhelmingly clear, and the publicity to the contrary is a horrifying example of the corruption of the
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mass media by the drug industry.
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</p>
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<p>
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Endorphins: Stress induced, laterally specific, involved in estrogen action, antagonized by naloxone and
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similar anti-opiate drugs. I have proposed that the endorphins can cause or sustain some of the symptoms of
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aging. Naloxone appears to be a useful treatment for senility. E. Roberts, Ann. N. Y. Acad. Sci. 396, 165,
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1982; B. Reisberg, et al., N. Engl. J. Med. 308, 721, 1983.
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</p>
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<p>
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Endotoxin: Antimitochondrial action, causes elevation of estrogen. It synergizes with unsaturated fats, and
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naloxone opposes some of its toxic effects.
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</p>
|
|
|
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<p>
|
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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 "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.
|
|
</p>
|
|
|
|
<p>
|
|
<a href="http://raypeat.com/articles/articles/alzheimers2.shtml"><strong>Article continued in Part 2 - click
|
|
here</strong></a>
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|
</p>
|
|
|
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<p>
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|
Raymond Peat, Ph.D.
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</p>
|
|
<p>
|
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Copyright 1997
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</p>
|
|
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<p>
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<strong><h3>SELECTED REFERENCES</h3></strong>
|
|
</p>
|
|
<p>
|
|
S. Rose, "Genuine genetics or conceited convenience?" Trends in Neuro. Sci. 17(3), 105, 1994.
|
|
</p>
|
|
|
|
<p>
|
|
F. P. Monnet, et al., "Neurosteroids, via sigma receptors, modulate the [H3]norepinephrine release evoked by
|
|
N-methyl-D-aspartate in the rat hippocampus," P.N.A.S. (USA) 92(9), 3773-3778, 1995. "...progesterone may
|
|
act as a sigma antagonist."
|
|
</p>
|
|
<p>
|
|
J. L. Sanne and K. E. Krueger, "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," J. of Neurochemistry 65(2), 528-536, 1995.
|
|
</p>
|
|
<p>
|
|
V. V. Zakusov and R. U. Ostrovskaya, "Increased resistance of mice to hypoxia under the influence of
|
|
tranquilizers of the benzodiazepine series," Byulletan Eksperimentalnoy Biologii i Meditsiny 71(2), 45-47,
|
|
1971. [The protection was not from the sedative effects, "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."]
|
|
</p>
|
|
<p>
|
|
A. I. Zotin, "Aging and rejuvenation from the standpoint of the thermodynamics of irreversible processes,"
|
|
Priroda 9, 49-55, 1970. [The process of aging "...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."
|
|
</p>
|
|
<p>
|
|
M. M. Tikhomirova, et al., "Mechanisms underlying the resistance of genetic material of the animal cell to
|
|
stress treatment," Genetika 30(8), 1092-1104, 1994. "...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." Gross,
|
|
"Reproductive cycle biochemistry," Fertility & Sterility 12(3), 245-260, 1961. "The maintenance of an
|
|
environment conducive to anaerobic metabolism--which may involve the maintenance of an adequate supply of
|
|
the substances that permit anaerobiosis...seems to depend primarily upon the action of estrogen."
|
|
"Glycolytic metabolism gradually increases throughout the proliferative phases of the cycle, reaching a
|
|
maximum coincident with the ovulation phase, when estrogen is at a peak. Following this, glycolysis
|
|
decreases, the respiratory mechanisms being more active during the secretory phase. Eschbach and Negelein
|
|
showed the metabolism of the infantile mouse uterus to be less anaerobic than that of the adult. If estrogen
|
|
is administered, however, there is a 98 per cent increase in glycolytic mechanisms.""The effect of the
|
|
progestational steroids may be such as to interfere with the biochemical pattern required for support of
|
|
this anaerobic environment."
|
|
</p>
|
|
<p>
|
|
M. A. G. Sissan, et al., "Effects of low-dose oral contraceptive oestrogen and progestin on lipid
|
|
peroxidation in rats," J. of International Med. Res. 23(4), 272-278, 1995. "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."
|
|
</p>
|
|
|
|
<p>
|
|
A. Jendryczko, et al., "Effects of two low-dose oral contraceptives on erythrocyte superoxide dismutase,
|
|
catalase and glutathione peroxidase activities," Zentralbl. Gynakol. (Germany) 115(11), 469-472, 1993.
|
|
"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."
|
|
</p>
|
|
<p>
|
|
J. W. Olney, "Excitotoxins in foods," Neurotoxicology 15(3), 535-544, 1994. "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."
|
|
</p>
|
|
<p>
|
|
K. Savolainen, et al., "Phosphoinositide second messengers in cholinergic excitotoxicity," Neurotoxicology
|
|
15(3), 493-502, 1994. "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...." "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." "Furthermore, glutamate increases neuronal oxidative stress...."
|
|
</p>
|
|
<p>
|
|
L. N. Simanovskiy and Zh. A. Chotoyev, "The effect of hypoxia on glycogenolysis and glycolysis rates in the
|
|
rat brain," Zhurnal Evolyutsionnoy Biokhimii i Fiziologii 6(5), 577-579, 1970. "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." "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."
|
|
</p>
|
|
|
|
<p>
|
|
Ye. Sadovskiy, "For the prolongation of human life," Sovetskaya Belorussiya 23, page 4, Dec. 1970. "...the
|
|
accumulation of metals in the organism with age is one of the most important factors in the development of
|
|
the aging process."
|
|
</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., "Heart rate variation, age, and behavior in subjects with senile dementia of Alzheimer
|
|
type," Chronobiol. Int. 12(1), 37-45, 1995. "...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."
|
|
</p>
|
|
|
|
<p>
|
|
M. Martinez, et al., "Glucose deprivation increases aspartic acid release from synaptosomes of aged mice,"
|
|
Brain Res. 673(1), 149-152, 1995. "...in the absence of glucose in the medium of incubation aspartate and
|
|
glutamate release was higher in old than in young animals." "...there is an age-dependent dysfunction in
|
|
this process linked to energy metabolism disturbance."
|
|
</p>
|
|
<p>
|
|
J. M. Pasquini and A. M. Adamo, "Thyroid hormones and the central nervous system," Dev. Neurosci. 12(1-2),
|
|
1-8, 1994. "Among their actions, T3 and T4 have effects on the differentiation of various cell types in the
|
|
rat brain and cerebellum as well as on the process of myelination. Recently, several investigators have
|
|
shown effects of thyroid hormones on myelin protein gene expression."
|
|
</p>
|
|
<p>
|
|
G. C. Ness and Z. H. Zhao, "Thyroid hormone rapidly induces hepatic LDL receptor mRNA levels in
|
|
hypophysectomized rats," Arch. Biochem. Biophys. 315(1), 199-202, 1994.
|
|
</p>
|
|
<p>
|
|
E. M. Mutisya, et al., "Cortical cytochrome oxidase activity is reduced in Alzheimer's disease," J.
|
|
Neurochem. 63(6), 2170-2184, 1994. "These results provide further evidence of a cytochrome oxidase defect in
|
|
Alzheimer's disease postmortem brain tissue. A deficiency in this key energy-metabolizing enzyme could lead
|
|
to a reduction in energy stores and thereby contribute to the neurodegenerative process."
|
|
</p>
|
|
<p>
|
|
G. J. Bu, et al., "Subcellular localization and endocytic function of low density lipoprotein
|
|
receptor-related protein in human glioblastoma cells," J. Biol. Chem. 269(47), 29874-29882, 1994. "Our
|
|
results thus strongly suggest several potential roles for LRP in brain protein and lipoprotein metabolism,
|
|
as well as control of extracellular protease activity."
|
|
</p>
|
|
<p>
|
|
V. Vandenbrouck, et al., "The modulation of apolipoprotein E gene expression by 3,3'-5-triiodothyronine in
|
|
HepG(2) cells occurs at transcriptional and post-transcriptional levels," Eur. J. Biochem. 224(2), 463-471,
|
|
1994. "...thyroid hormone stimulated apoE gene transcription threefold in 24 hours."
|
|
</p>
|
|
|
|
<p>
|
|
T. Yamada, et al., "Apolipoprotein E mRNA in the brains of patients with Alzheimer's disease," J. Neurol.
|
|
Sci. 129(1), 56-61, 1995. In A.D. Apo E "was decreased in relation to the apoE-epsilon 4 gene dosage." "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."
|
|
</p>
|
|
<p>
|
|
G. P. Jarvik, et al., "Genetic influences on age-related change in total cholesterol, low density
|
|
lipoprotein-cholesterol, and triglyceride levels: Longitudinal apolipoprotein E genotype effects," Genet.
|
|
Epidemiol. 11(4), 375-384, 1994. "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...."
|
|
With aging, total cholesterol and LDL-C became significantly lower in the "epsilon 4 genotype" group; this
|
|
is the group at risk for AD.
|
|
</p>
|
|
<p>
|
|
S. Miller and J. M. Wehner, "Cholesterol treatment facilitates spatial learning performance in DBA/2Ibg
|
|
mice," Pharmacology Biochemistry and Behavior 49(1) 257-261, 1994. "Our results suggest that subchronic
|
|
treatment with the steroid hormone precursor, cholesterol, enhances spatial learning performance in DBA
|
|
mice."
|
|
</p>
|
|
<p>
|
|
A. D. Roses, "Apolipoprotein E affects the rate of Alzheimer disease expression: beta-amyloid burden is a
|
|
secondary consequence dependent on ApoE genotype and duration of disease," J. Neuropathol. Exp. Neurol.
|
|
53(5), 429-437, 1994.
|
|
</p>
|
|
|
|
<p>
|
|
T. Gunther and V. Hollriegl, "Increased protein oxidation by magnesium deficiency and vitamin E depletion,"
|
|
Magnesium-Bull. 16(3), 101-103, 1994.
|
|
</p>
|
|
<p>
|
|
F. Oyama, et al., "Apolipoprotein E genotype, Alzheimer's pathologies and related gene expression in the
|
|
aged population," Mol. Brain Res. 29(1), 92-98, 1995. "...ApoE4/4 accelerates and ApoE2/3 decelerates the
|
|
development of the AD pathologies in the aged brain...."
|
|
</p>
|
|
|
|
<p>
|
|
M. L. C. Maatschieman, et al., "Microglia in diffuse plaques in hereditary cerebral hemorrhage with
|
|
amyloidosis (Dutch). An immunohistochemical study," J. Neuropathol. Exp. Neurol. 53(5), 483-491, 1994.
|
|
"Microglia are intimately associated with congophilic plaques in Alzheimer's disease...." "Intensely
|
|
immunoreactive microglia with enlarged cell bodies and short, thick processes clustered in congophilic
|
|
plaques."
|
|
</p>
|
|
<p>
|
|
J. Poirier, "Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease," Trends Neurosci.
|
|
17(12), 525-530, 1994. "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." "...a dysfunction of the lipid-transport system
|
|
associated with compensatory sprouting and synaptic remodeling could be central to the AD process."
|
|
</p>
|
|
|
|
<p>
|
|
P. H. Chan and R. A. Fishman, "Brain edema: Induction in cortical slices by polyunsaturated fatty acids,"
|
|
Science 201, 358-369, 1978. "This cellular edema was specific, since neither saturated fatty acids nor a
|
|
fatty acid containing a single double bond had such effect." R. Nogues, et al., "Influence of nutrition,
|
|
thyroid hormones, and rectal temperature on in-hospital mortality of elderly patients with acut illness," Am
|
|
J Clin Nutr 61(3), 597-602, 1995. "Serum albumin, body weight, and total T3 concentration were higher in
|
|
survivors than in nonsurvivors." "Mild hypothermia was a good predictor of death. Hypoalbuminemia and
|
|
hypothermia were associated with low T3 and high rT3 values."
|
|
</p>
|
|
<p>
|
|
R. C. Vannucci, et al., "Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: An
|
|
experimental study in the immature rat," Pediatrics 95(6), 868-874, 1995.
|
|
</p>
|
|
|
|
<p>
|
|
H. M. Wisniewski and P. B. Kozlowski, "Evidence for blood-brain barrier changes in senile dementia of the
|
|
Alzheimer type (SDAT)", Ann. N. Y. Acad. Sci. 396, 119-129, 1982. "...one would expect that the chronic
|
|
"flooding" of the neuronal elements with serum proteins would affect their performance." "The cause of the
|
|
increased BBB permeability in SDAT is unknown."
|
|
</p>
|
|
<p>
|
|
J. S. Jensen, et al., "Microalbuminuria reflects a generalized transvascular albumin leakiness in clinically
|
|
healthy subjects," Clin. Sci. 88(6), 629-633, 1995. "It is suggested that the observed transvascular
|
|
leakiness, in addition,may cause increased lipid insudation to the arterial walls."
|
|
</p>
|
|
|
|
<p>
|
|
C. Nilsson, et al., "The nocturnal increase in human cerebrospinal fluid production is inhibited by a
|
|
beta(1)-receptor antagonist," Amer. J. Physiol.-Regul. Integr. C 36(6), R1445-R1448, 1994.
|
|
</p>
|
|
<p>
|
|
D. L. Williams, et al., "Cell surface 'blanket' of apolipoprotein E on rat adrenocortical cells," J. Lipid
|
|
Res. 36(4), 745-758, 1995. "...the zona fasciculata cell is encircled or covered with apoE on all faces of
|
|
the cell. ...this cell surface 'blanket' of apoE participates in the uptake of lipoprotein cholesterol by
|
|
either the endocytic or selective uptake pathways." C. A. Frye and J. D. Sturgis, "Neurosteroids affect
|
|
spatial reference, working, and long-term memory of female rats," Neurobiol. Learn. Memory 64(1), 83-96,
|
|
1995. [Female rats take longer to acquire a spatial task during behavioral estrus.)]
|
|
</p>
|
|
<p>
|
|
M. Warner and J. A. Gustafsson, "Cytochrome P450 in the brain: Neuroendocrine functions," Front
|
|
Neuroendocrinol 16(3), 224-236, 1995. [Discusses the GABA(A) receptor active steroids, and the accumulation
|
|
of pregnenolone in the brain.]
|
|
</p>
|
|
<p>
|
|
P. Robel, et al., "Biosynthesis and assay of neurosteroids in rats and mice: Functional correlates," J.
|
|
Steroid Biochem. Mol. Biol. 53(1-6), 355-360, 1995. [Discusses the effects of pregnenolone and progesterone
|
|
on aggression and learning. The animals which learned most easily had the highest levels of pregnenolone
|
|
sulfate.] K. W. Lange and P. Riederer, "Glutamatergic drugs in Parkinson's disease," Life Sci. 55(25-26,
|
|
2067-2075, 1994. "...excitatory amino acids such as glutamate are involved in the pathophysiological cascade
|
|
of MPTP...-induced neuronal cell death." "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."
|
|
</p>
|
|
<p>
|
|
R. A. Wallis, et al., "Glycine-induced CA1 excitotoxicity in the rat hippocampal slice," Brain Res. 664(1-2)
|
|
115-125, 1994. K. Ossawska, "The role of excitatory amino acids in experimental models of Parkinson's
|
|
disease," J. Neural Transm.-Parkinsons 8(1-2_, 39-71, 1994.
|
|
</p>
|
|
<p>
|
|
G. S. Roth, et al., "Membrane alterations as causes of impaired signal transduction in Alzheimer's disease
|
|
and aging," Trends Neurosci. 18, 203-206, 1995. "Reconstituted lipid membranes from cortical gray matter of
|
|
AD brain samples were significantly thinner (that is, had less microviscosity) than corresponding
|
|
age-matched controls." "This change in membrane width correlated with a 30% decrease in the moles of
|
|
cholesterol:phospholipid." "Addition of cholesterol restored the membrane width to that of the age-matched
|
|
control samples."
|
|
</p>
|
|
<p>
|
|
T. Reed, et al., "Lower cognitive performance in normal older adult male twins carrying the apolipoprotein E
|
|
epsilon 4 allele," Arch. Neurol. 51(12), 1189-1182, 1994.
|
|
</p>
|
|
<p>
|
|
S.Y. Tan and M. B. Pepys, "Amyloidosis," Histopathology 25(5), 403-414, 1994. "...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...." "Amyloid deposits are in a state of dynamic turnover and can regress if new fibril
|
|
formation is halted." A. V. Sirotkin, "Direct influence of melatonin on steroid, nonapeptide hormones, and
|
|
cyclic nucleotide secretion by granulosa cells isolated from porcine ovaries," J. Pineal Res. 17(3),
|
|
112-117, 1994. "It was found that melatonin is able to inhibit progesterone and stimulate estradiol
|
|
secretion." "Some inhibition of vasopressin and cAMP and significant stimulation of cGMP also resulted from
|
|
melatonin treatment." R. M. Sapolsky, "Glucocorticoid toxicity in the hippocampus: Reversal with
|
|
supplementation with brain fuels," J. Neurosci. 6, 2240-2245, 1986. R. M. Sapolsky, "Glucocorticoids,
|
|
hippocampal damage and the glutaminergic synapse," Prog. Brain Res. 86, 13-23, 1990. M. Schwartz, et al.,
|
|
"Growth-associated triggering factors and central nervous system regeneration," 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., "Direct
|
|
regulation of ion channels by fatty acids," Trends Neurosci. 14, 96-100, 1991.
|
|
</p>
|
|
<p>
|
|
H. G. P. Swarts, et al., "Binding of unsaturated fatty acids to Na+,K+-ATPase leading to inhibition and
|
|
inactivation," Biochim. Biophys. Acta 1024, 32-40, 1990.
|
|
</p>
|
|
<p>
|
|
G. Autore, et al., "Essential fatty acid-deficient diet modifies PAF levels in stomach and duodenum of
|
|
endotoxin-treated rats," J. Lipid Mediators Cell Signalling 9, 145-153, 1994. J. Rafael, et al., "The effect
|
|
of essential fatty acid deficiency on basal respiration and function of liver mitochondria in rats," J.
|
|
Nutr. 114, 255-262, 1984.
|
|
</p>
|
|
<p>
|
|
A. M. Weiner, et al., "Nonviral retroposons, genes, pseudogenes, and transposable elements generated by the
|
|
reverse flow of genetic information," Ann. Rev. Biochem. 55, 631-661, 1986. I. Zs.-Nagy, "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," Exp. Gerontology 30(3-4), 327-335, 1995. "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."
|
|
</p>
|
|
|
|
<p>
|
|
<a href="http://raypeat.com/articles/articles/alzheimers2.shtml"><strong>Article continued in Part 2 - click
|
|
here</strong></a>
|
|
</p>
|
|
<strong>
|
|
<p>
|
|
© Ray Peat 2006. All Rights Reserved. www.RayPeat.com
|
|
</p>
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</strong>
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