1189 lines
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HTML
1189 lines
87 KiB
HTML
<html>
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<head><title>The problem of Alzheimer's disease as a clue to immortality - Part 2</title></head>
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<body>
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<h1>
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The problem of Alzheimer's disease as a clue to immortality - Part 2
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</h1>
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<p>
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<strong>V. HORMONE IMBALANCE, LEADING TO FAILURE OF PROTECTIVE INHIBITION AND ALZHEIMER'S DISEASE
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</strong>
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</p>
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<p>
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<em>"All cell death is characterized by an increase of intracellular calcium...." "Increase of cytoplasmic
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free calcium may therefore be called 'the final common path' of cell disease and cell death. Aging as a
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background of diseases is also characterized by an increase of intracellular calcium. Diseases typically
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associated with aging include hypertension, arteriosclerosis, diabetes mellitus and dementia."</em>
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</p>
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<p>
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<em>T. Fujita, "Calcium, parathyroids and aging," in Calcium-Regulating Hormones. 1. Role in Disease and
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Aging, H. Morii, editor, Contrib. Nephrol. Basel, Karger, 1991, vol. 90, pp. 206-211.
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</em>
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</p>
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<p><strong>THE FUNCTION OF ENERGY</strong></p>
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<p>
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Most people are slightly demented now and then, when they are very sleepy or tired, or sick, or drunk, or
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having a hormone imbalance or extreme anxiety state. Sometimes physicians have described people as demented,
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implying that the condition would never improve, when the person was depressed or hypothyroid. If the person
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has a history of epilepsy, or is very old, the physician is more likely to diagnose dementia than if the
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same loss of mental function occurs in a younger person without a history of a nervous disorder. Even people
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with less education are at increased risk of being diagnosed as "demented."
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</p>
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<p>
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In 1976, I saw a 52 year-old woman who had the diagnosis of epileptic dementia. After 3 or 4 days of taking
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progesterone, her mental function returned to the extent that she could find her way around town by herself,
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and could work. A few months later, she returned to graduate school, got straight As and a master's degree.
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A few years later, a man in his 80s showed the classical signs of senile dementia, with childishness,
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confusion, self-centeredness, and unstable emotions. A few days after getting a mixture of thyroid,
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pregnenolone, and progesterone, his mind was again clear, and he was able to work on a research project he
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had set aside years before.
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</p>
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<p>
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When the body temperature is very much below normal, mental functioning is seriously limited. I think the
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first question that should be asked about a demented person is "is this the cold brain syndrome, or is
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something else involved?" When it is known that the brain has shrunken drastically, and filled up with
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plaques and developed gliosis, we know that something more than a "cold brain" is involved, but we don't
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know how much function could be regained if the hormones were normalized. Every moment of malfunction
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probably leaves its structural mark. Early or late, it is good to prevent the functional errors that lead to
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further damage, and to give the regenerative systems an opportunity to work. Before the final "calcium
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death" described (above) by Fujita, there are many opportunities for intervening to stop or reverse the
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process. The older the person is, the more emphasis should be put on protective inhibition, rather than
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immediately increasing energy production. Magnesium, carbon dioxide, sleep, red light, and naloxone might be
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appropriate at the beginning of therapy.
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</p>
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<p>
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The resting state of a cell is a highly energized state. To the old Pavlovians, the resting state existed at
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two energy levels, and they applied the term "protective inhibition" generally to the depleted state
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(parabiosis) that occurs in exhaustion or coma, but I am using the phrase in a more general sense, that
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seems reasonable now that the concept of "excitotoxic" injury has become current. I mean it to include
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everything which protects against excitotoxic injury. This definition therefore has the virtue of being
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biochemically and physiologically very specific, while retaining the functional and therapeutic significance
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that it had for the Pavlovians. (My book, <em>Mind and Tissue,</em> and the chapter "A unifying principle"
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in <em>
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Generative Energy,</em> discussed the idea of the resting state and protective inhibition.)
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</p>
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<p>
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Ordinary healthy sleep is an example of restorative, protective inhibition. The energy charge, including
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levels of ATP, creatine phosphate, and glycogen storage, regulates many restorative enzyme systems. I have
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suggested (1975, J. Orthomol. Psychiatry) how the entropy-sensitivity or cold-inactivation of an enzyme
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could be involved in shifting the brain toward a state of inhibition. A recent publication (J. H. Benington
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and H. C. Heller, "Restoration of brain energy metabolism as the function of sleep," Progress in Neurobiol.
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45, 347-360, 1995) has proposed that reduction of energy charge and depolarization of cells act through
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adenosine secretion to restore glycogen stores. Since glycogen stores decrease with aging, this work
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supports the idea that protective inhibition is weakened with aging. (L. N. Simanovskiy and Zh. A. Chotoyev,
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"The effect of hypoxia on glycogenolysis and glycolysis rates in the rat brain," Zhurnal Evolyutsionnoy
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Biokhimii i Fiziologii 6(5), 577-579, 1970.)
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</p>
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<p>
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J. H. Benington and H. C. Heller, "Restoration of brain energy metabolism as the function of sleep," Prog.
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in Neurobiology 45, 347-360, 1995. "...the conditions that have been demonstrated to stimulate adenosine
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release from neural tissue represent either increases in metabolic demand (...activation of excitatory
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receptors) or decreases in metabolic supply (hypoxia, ischaemia, hypoglycemia)...." "In the brain,
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adenosine-stimulated increases in potassium conductance produce hyperpolarization, thereby reducing neuronal
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responsiveness...." "Adenosine release is triggered globally in response to changes in cerebral energy
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homeostasis." "A number of findings provide indirect support for the hypothesis that glycogen stores are
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depleted during waking and restored during sleep." "Reduced availability of glycogen to astrocytes
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must...increase adenosine release...." "Because ATP concentration is 100-fold greater than AMP
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concentration, a minute decrease in cellular energy charge...is translated into a large proportional
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increase in extracellular adenosine cencentration...."
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</p>
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<p>
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The terms "functional quiescence" and "G0 quiescence" are similar in meaning to the resting state; I think
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of cells in the state of "G0 quiescence" as being stem cells, waiting for use in regeneration, but I don't
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subscribe to the idea that they can't be reconstituted from functioning, differentiated cells. In plants,
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dedifferentiation is achieved fairly easily, and in the study of animal cells the trend in that direction
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seems very obvious, though many people keep saying that it just isn't possible. In general, the things such
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as lipid peroxidation or calcium influx which cause cell replication at one level, cause cell death at a
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higher level.
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</p>
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<p>
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Energy to resist stress makes quiescence possible, and prevents the deterioration of cells, of the sort that
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occurs in aging. O. Toussaint, et al., "Cellular aging and energetic factors," Exp. Gerontology 30(1), 1-22,
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1995. "Experiments performed with endothelial cells in the context of the ischemia-reperfusion toxicity of
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free radicals, also offer good examples of the impact of cell energy on cell resistance to these toxic
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molecules." "...if a supplement of energy is given...the toxic effect of the free radicals is much
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reduced...."
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</p>
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<p>
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The specific approaches of this orientation --to energize but quiet the brain--are diametrically opposed to
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some of the "therapies" for Alzheimer's disease that have been promoted recently by the drug industries:
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Things to increase stimulation, especially to increase cholinergic excitation; even the excitotoxic amino
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acids themselves and their analogs; and estrogen, which is a multiple brain excitant, proconvulsant,
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excitotoxic promoter, and anti-memory agent. Those product-centered publications stand out distinctly from
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the actual research.
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</p>
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<p>
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There are many energy-related vicious circles associated with aging, but the central one seems to be the
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fat-thyroid-estrogen-free-radical-calcium sequence, in which the ability to produce stabilizing substances
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including carbon dioxide and progesterone is progressively lost, increasing susceptibility to the unstable
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unsaturated fats.
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</p>
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<p><strong>EFFECTS OF ESTROGEN AND UNSATURATED FATTY ACIDS</strong></p>
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<p>
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Estrogen production is facilitated when tissue is cooler, and it lowers body temperature. Estrogen and the
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endorphins act together in many ways (including the behavior of estrus), and naloxone (the antagonist of
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morphine and the endorphins) raises body temperature and in other ways opposes estrogen. Naloxone has been
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found to improve the symptoms of demented people, and I have seen it quickly, and dramatically, improve the
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mental clarity of a 60 year old woman who had used estrogen. It, like clonidine (the anti-adrenaline drug),
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is a good candidate for controlling the hot flashes and other symptoms of menopause.
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</p>
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<p>
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In various degenerative brain conditions, blood clotting has been implicated either as a cause or a
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complication. Many people are promoting unsaturated oils for their "anti-clotting" value, in spite of the
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older literature showing that they inhibit proteolytic enzymes and slow clot removal. Several newer
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publications have revealed other aspects of their involvement in thrombus formation. A. J. Honour, et al.,
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"The effects of changes in diet on lipid levels and platelet thrombus formation in living blood vessels,"
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Br. J. Expt. Pathol. 59(4), 390-394, 1978--corn oil caused platelets to be more sensitive to ADP.
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</p>
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<p>
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Although there is a lot of talk about "membrane fluidity," as a desirable thing, and the loss of unsaturated
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lipids in the aged brain, there are some interesting observations related to "viscosity" in Alzheimer's
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disease. The platelets of Alzheimer's patients are less viscous, and lipids extracted from the brain are
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more fluid, and contain 30% less cholesterol than normal (on a molar basis, in relation to phospholipids).
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(G. S. Roth, et al., 1995.) In general, lipid peroxidation causes cellular viscosity to increase, apparently
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by causing cross-linking of proteins, but I think the significance of the decreased cholesterol relates to
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its significance as precursor to pregnenolone and progesterone, and to the known association with
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Alzheimer's disease of a variant form of the cholesterol transporter protein, ApoE, which I suppose is a
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slightly less stable molecular form that is more susceptible to malfunction in stress.
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</p>
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<p>
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The extracellular matrix is a major factor in the function and stability of brain cells. (L. F. Agnati, et
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al., "The concept of trophic units in the central nervous system," Prog. in Neurobiol. 46, 561-574, 1995.
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Any factor producing edema tends to disrupt the extracellular matrix (Chan and Fishman, 1978, 1980, and L.
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Loeb, 1948.)
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</p>
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<p>
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Seizures are known to be promoted by estrogen, by unsaturated fats, and by lipid peroxidation, and to cause
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an increase in the size of the free fatty acid pool in the brain. Prolonged seizures cause nerve damage in
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certain areas, especially the hippocampus, thalamus, and neocortex (Siesjo, et al., 1989). Dementia is known
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to be produced by prolonged seizures.
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</p>
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<p>
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Prenatal exposure to estrogen, to oxygen deficiency, or to unsaturated fats decreases the size of the brain
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at birth. There is apparently a requirement for saturated fats during development (J. M. Bourre, N.
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Gozlan-Devillierre, O. Morand, and N. Baumann, "Importance of exogenous saturated fatty acids during brain
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development and myelination in mice," Ann. Biol. Anim., Biochim., Biophys. 19(1B), 172-180, 1979.
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</p>
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<p>
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Under the influence of estrogen, or unsaturated fats, brain cells swell, and their shape and interactions
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are altered. Memory is impaired by an excess of estrogen. Estrogen and unsaturated fat and excess iron kill
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cells by lipid peroxidation, and this process is promoted by oxygen deficiency. The fetus and the very old
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have high levels of iron in the cells. Estrogen increases iron uptake. Estrogen treatment produces elevation
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of free fatty acids in the blood, and lipid peroxidation in tissues. This tends to accelerate the
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accumulation of lipofuscin, age-pigment. Lactic acid, the production of which is promoted by estrogen,
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lowers the availability of carbon dioxide, leading to impairment of blood supply to the brain.
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</p>
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<p>
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Estrogen stimulates cell division, but can also increase the rate of cell death. Unsaturated fatty acids can
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also stimulate or kill.
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</p>
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<p>
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Both estrogen and unsaturated fats promote the formation of age-pigment. Besides increasing the free fatty
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acid concentration, estrogen possibly depresses the level of cholesterol, both of which are changes seen in
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the senile brain.
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</p>
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<p>
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Estrogen causes massive alterations of extracellular matrix, and seems to promote dissolution of
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microtubules (Nemetschek-Gannsler), as calcium does. Unsaturated fats increase calcium uptake by at least
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some brain cells (H. Katsuki and S. Okuda, 1995.) Unsaturated fats, like estrogen, increase the permeability
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of blood vessels. The unsaturated fat causes edema of the brain, inhibits choline uptake, blocking
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acetylcholine production.
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</p>
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<p>
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Progesterone is a nerve growth factor, produced by glial cells (oligodendrocytes). It promotes the
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production of myelin, protects against seizures, and protects cells against free radicals. It protects
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before conception, during gestation, during growth and puberty, and during aging. It promotes regeneration.
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Its production is blocked by stress, lipid peroxidation, and an excess of estrogen and iron.
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</p>
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<p>
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Aspirin protects against iron toxicity, clot formation, and reduces lipid peroxidation while blocking
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prostaglandin formation. Aspirin and other antiinflammatory drugs, taken for arthritis, have been clearly
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associated with a reduced incidence of Alzheimer's disease. Aspirin reduces the formation of prostaglandins
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from arachidonic acid.
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</p>
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<p>
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Unsaturated fatty acids, but not saturated fatty acids, are signals which activate cell systems.
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</p>
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<p>
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Many different stimuli can induce cell activity, cell death, or change to another cell type. (J. Niquet, et
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al., "Glial reaction after seizure induced hippocampal lesion: Immunohistochemical characterization of
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proliferating glial cells," J. Neurocytol. 23(10), 641-656, 1994: "...hippocampal astrocytes from
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kainate-treated rats experess A2B5 immunoreactivity, a marker of type-2 astrocytes." "This suggests that in
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the CNS, normal resident astrocytes acquire the phenotypic properties of type-2 astrocytes.")
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</p>
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<p>
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A "deficiency" of polyunsaturated fatty acids leads to altered rates of cellular regeneration and
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differentiation, a larger brain at birth, improved function of the immune system, decreased inflammation,
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decreased mortality from endotoxin poisoining, lower susceptibility to lipid peroxidation, increased basal
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metabolic rate and respiration, increased thyroid function, later puberty and decreases other signs of
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estrogen dominance. When dietary PUFA are not available, the body produces a small amount of unsaturated
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fatty acid (Mead acids), but these do not activate cell systems in the same way that plant-derived PUFAs do,
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and they are the precursors for an entirely different group of prostaglandins.
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</p>
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<p><strong>VITAMIN A AND THE STEROIDS</strong></p>
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<p>
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In a variety of cell types, vitamin A functions as an estrogen antagonist, inhibiting cell division and
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promoting or maintaining the functioning state. It promotes protein synthesis, regulates lysosomes, and
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protects against lipid peroxidation. Just as stress and estrogen-toxicity resemble aging, so does a vitamin
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A deficiency. While its known functions are varied, I think the largest use of vitamin A is for the
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production of pregnenolone, progesterone, and the other youth-associated steroids. One of vitamin E's
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important functions is protecting vitamin A from destructive oxidation. Although little attention has been
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given to the effects of unsaturated fats on vitamin A, their destruction of vitamin E will necessarily lead
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to the destruction of vitamin A. The increased lipid peroxidation of old age represents a vicious circle, in
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which the loss of the antioxidants and vitamin A leads to their further destruction.
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</p>
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<p>
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To produce pregnenolone, thyroid, vitamin A, and cholesterol have to be delivered to the mitochondria in the
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right proportion and sufficient quantity. Normally, stress is balanced by increased synthesis of
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pregnenolone, which improves the ability to cope with stress. Lipid peroxidation, resulting from the
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accumulation of unsaturated fatty acids, iron, and energy deficiency, damages the mitochondrias' ability to
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produce pregnenolone. When pregnenolone is inadequate, cortisol is over-produced. When progesterone is
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deficient, estrogen's effect is largely unopposed. When both thyroid and progesterone are deficient, even
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fat cells synthesize estrogen.
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</p>
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<p><strong>THE NATURE OF ALZHEIMER'S DISEASE</strong></p>
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<p>
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Although Alzheimer's disease until recently referred to a certain type of organic dementia occuring in
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people in their thirties, forties and fifties (presenile dementia), structural similarities seen in senile
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dementia have caused the term to lose its original meaning. Alzheimer's sclerosis of blood vessels, and even
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the death of nerve cells, are sometimes neglected in favor of the more stylish ideas, emphasizing certain
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proteins that cause the tangles and plaques. Until recently, the "tangles" were commonly interpreted as the
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debris left after the death of a cell, rather than as one of the processes causing the death of the cell.
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</p>
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<p>
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Alzheimer-type dementia is different from other dementias, but it overlaps with them, and with age-related
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and stress-related changes in other organs.
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</p>
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<p>
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Physical signs (seen at autopsy) of AD:
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</p>
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<p>
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1) Death of neurons (increase of glial cells),
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</p>
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<p>
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2) Amyloid plaques (extracellular), associated with a particular variant of apolipoprotein E, the epsilon 4
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allele,
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</p>
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<p>
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3) Fibrillary tangles (intracellular, or remaining after the rest of the cell has disappeared),
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</p>
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<p>
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4) Amyloid in blood vessels.
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</p>
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<p>
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Functional and biochemical observations:
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</p>
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<p>
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1) The mitochondrial energy problem, cytochrome oxidase and its regulation; body temperature/pulse-rate
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cycle disturbance; lipid peroxidation; respiratory defect; altered amino acid uptake; memory impairment;
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dominance of the excitatory systems vs. the inhibitory adenosine/GABA/progesterone/pregnenolone system.
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Increased calcium uptake, which is associated with lipid peroxidation and cell death. Increased cortisol and
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DHEA.
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</p>
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<p>
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2) Deposit of abnormal proteins, such as transthyretin-amyloid; albumin binding of PUFA, vs. transport of
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thyroid and retinol.<em> </em>
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Beta-glucuronidase increases, depositing estrogen in cells.<em> </em>(A. J. Cross, et al., "Cortical
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neurochemistry in Alzheimer-type dementia," Chapter 10, pages 153-170 in<em>
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Aging of the Brain and Alzheimer's Disease, Prog. in Brain Res. 70, edited by D. F. Swaab, et al.,
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Elsevier, N.Y., 1986.</em>)
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</p>
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<p>
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<em>3) </em>
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Abnormally phosphorylated (tau) proteins; association with the variant form of Apo E; tau microtubule
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organizing proteins, microtubules are involved in transporting cholesterol; phosphorylation, by the kinase
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systems, regulated by PUFA; the intermediate filaments are generally stress-associated.
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</p>
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<p>
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4) ApoE, in cytoplasm, involved in cholesterol delivery for pregnenolone synthesis, as in the adrenal; its
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expression regulated by thyroid. Regulation of the side-chain cleaving enzymes; regulation of the
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cholesterol intake and conversion to pregnenolone by the endozepine receptor/GABA receptor, modified by
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progesterone.
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</p>
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<p><strong>AN EXAMPLE OF A REGULATORY PROBLEM</strong></p>
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<p>
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Vegetable oil suppresses the thyroid, increasing estrogen. Estrogen and calcium depolymerize microtubules.
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Microtubule transport for Apo E, transthyretin, thyroid, and cholesterol for pregnenolone synthesis is
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disrupted. Transthyretin and Apo E accumulate unused, and deposit in blood vessels, around nerves, and in
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cytoplasm. Pregnenolone and progesterone deficiency (aggravating thyroid deficiency) causes memory loss,
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destabilization of nerve cells, failure of myelin formation, and excess cortisol synthesis. Free radicals
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and calcium cause multiple cell injuries including nerve-death. Estrogen is released by elevated
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beta-glucuronidase. Imbalances of other steroids, including cortisol and DHEA, develop as cells compensate
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for pregnenolone deficiency, causing shifts in balance of glial cells. Hypothyroidism, estrogen excess, free
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unsaturated fats cause increased vascular permeability and brain edema, protein leakage, and alteration of
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the matrix..
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</p>
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<p>
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<strong>VIII: STRUCTURE AS A REGULATORY SYSTEM--AN EMERGING VISION OF PERVASIVE EPIGENESIS</strong>
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</p>
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<p>
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In the introduction I mentioned that membranous regulation and genetic determination should be considered as
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defunct theories. What I have been saying about self-actualizing systems and the factors that disrupt them
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derives from a view of cell function that has been developing since the 1920s.
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</p>
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<p>
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Around 1940, a Russian biochemist (Oparin, I think) proposed that the enzymes of glycolysis were bound to
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the structure of the cell when they were not in use, and that they were "desorbed" under the conditions that
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required abundant glycolysis. Knowing that concept, in 1970 I proposed that the cell water itself underwent
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a transition under such conditions (which could include increased temperature, reduced oxygen, or nervous or
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hormonal stimulation). Activation of glycolysis is usually explained by the availability of regulatory
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substances such as ammonia, phosphate, and NAD, and many biochemists were content to understand cells in
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terms of test-tube models. But in the last few years, it has become clear that some of these basic
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regulatory molecules do bind to structural components of the cell. (T. Henics, "Thoughts over cell biology:
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A commentary," Physiol. Chem. Phys. & Med. NMR 27, 139-140, 1995.) Although the details aren't clear, it
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is known that hormones and other factors stabilize or destabilize RNA, and that during some of these events
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relevant enzymes bind to the RNA. When these facts are combined with the information that is accumulating on
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splicing and modification of RNA, and the copying of RNA back into DNA, the hereditary system is seen to be
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much more flexible than it was believed to be.
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</p>
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<p>
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A global change of state is able to steer each part of the process, continuously. In this way, the cell
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resembles an analog, rather than a digital, control system: each part is momentarily guided, rather than
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waiting for "feedback."
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</p>
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<p>
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Where before, cellular "regulatory mechanisms" referred to certain feedback mechanisms based on interactions
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of randomly diffusing molecules, the new understanding of the cell sees a highly structured system in which
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very little is random, and the cell's adaptive possibilities, instead of being limited to a certain number
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of genetic switches, are shaped by every imaginable environmental influence. The cell's structure, far from
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being "read out of the genome," is sensitively reshaped constantly by processes that incorporate some of the
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environment in establishing each new stability. The old-model-geneticists have been forced to admit that the
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genes can't specify everything in the organism's structure, and it was the brain's complexity that forced
|
|
this recognition that certain things are developed "epigenetically." But the new fact that most biologists
|
|
are reluctant to accept is that the structure of the cell itself is developed very largely on the basis of
|
|
information received from the environment--that is, "epigenetically."
|
|
</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 "cells are clever enough to design an organism." It is a significant step beyond
|
|
that to the recognition that "cells are clever enough to redesign themselves to meet situations never seen
|
|
before."
|
|
</p>
|
|
<p>
|
|
Biologists working with bacteria and yeasts have seen them adapt in non-random ways to novel conditions.
|
|
"Directed mutations" are impossible, according to the "central dogma" that has the support of textbooks and
|
|
most biology professors, but they do occur in those single-celled organisms. Barbara McClintock showed that
|
|
in corn her mobile genes were mobilized by stress. Although this isn't exactly "directed mutation," it is an
|
|
example of a mechanism for increasing adaptation when adaptation is need. There is a certain type of enzyme
|
|
which makes specific cuts in the DNA chain. Biotechnologists find them convenient for their purposes, but
|
|
their presence serves physiological purposes, presumably in all organisms, like those described by
|
|
McClintock in corn. During the terminal stress that produces the special kind of cell death known as
|
|
apoptosis, these enzymes make confetti of the genome.
|
|
</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 "genetically programmed," implying that whenever
|
|
it occurs in the brain, it was destined to happen sooner or later. But in fact, "growth factors" of various
|
|
sorts can prevent it. It is increasingly clear that it represents excessive stress and deficient resources.
|
|
The involvement of the genetic apparatus in differentiation and radical adaptation suggests that the
|
|
(epigenetic) resources of cells are unlimited.
|
|
</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 "Golden Age" myths claim--must have had a very long life-span. As people moved north and
|
|
developed new ways of living, their consumption of unsaturated fats increased, their brain size decreased,
|
|
and they aged rapidly. Neanderthal relics show that flaxseed was a staple of their diet.
|
|
</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
|
|
"whirlwind of cells," made up of whirlwinds of atoms (in Vernadsky's phrase) in which our way of life sets
|
|
the boundaries within which our cells will restructure themselves.
|
|
</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 "eicosanoid" system and the increasingly uncontrolled production of free
|
|
radicals, and to changes in energy, thyroid activity, and steroid balance. The aging body, rather than being
|
|
like a car that needs more and more repairs until it collapses from simple wear, is more like a car
|
|
traveling a road that becomes increasingly rough and muddy, until the road becomes an impassable swamp.
|
|
</p>
|
|
<p>
|
|
The suggested therapy is a correction of the signalling process, rather than "genetic surgery,"
|
|
transplantation, etc., which is the pessimistic implication of the doctrine that oxidative damage is simply
|
|
a matter of "wear and tear," "somatic mutations," and "cross-linking." Those problems are reparable, and our
|
|
emphasis should be on the production of energy and the avoidance of the conditions that allow the
|
|
undesirable signals to accumulate.
|
|
</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>
|
|
<p>
|
|
Copyright: Raymond Peat, PhD 1997
|
|
</p>
|
|
<p>
|
|
PO Box 5764 Eugene, OR 97405
|
|
</p>
|
|
<p>
|
|
<h3>SELECTED REFERENCES</h3>
|
|
</p>
|
|
|
|
<p>
|
|
Winfried G. Rossmanith, "Gonadotropin secretion during aging in women: Review article," Exp. Gerontology
|
|
30(3/4) 369-381, 1995. "...major functional derangements, primarily at a hypothalamic rather than a
|
|
pituitary site, have been determined as concomitants of aging in women." "...aging may impair the negative
|
|
feedback sensitivity to ovarian sex steroids...." Hormonal changes at menopause "may represent the sum of
|
|
functional aberrations that were initiated much earlier in life...." "...prolonged estrogen exposure
|
|
facilitates the loss of hypothalamic neurons...."
|
|
</p>
|
|
<p>
|
|
J. R. Brawer, et al., "Ovary-dependent degeneration in the hypothalamic arcuate nucleus," Endocrinology 107,
|
|
274-279, 1980.
|
|
</p>
|
|
|
|
<p>
|
|
G. C. Desjardins, "Estrogen-induced hypothalamic beta-endorphin neuron loss: A possible model of
|
|
hypothalamic aging," Exp. Gerontology 30(3/4), 253-267, 1995. "This loss of opioid neurons is prevented by
|
|
treatment with antioxidants indicating that it results from estradiol-induced formation of free radicals."
|
|
"...this beta-endorphin cell loss is followed by a compensatory upregulation of mu opioid receptors in the
|
|
vicinity of LHRH cell bodies." Resulting supersensitivity of the cells results "in chronic opioid
|
|
suppression of the pattern of LHRH release, and subsequently that of LH." The neurotoxic effects of
|
|
estradiol cause a "cascade of neuroendocrine aberrations resulting in anovulatory acyclicity." Treatment
|
|
with an opiod antagonist "reversed the cystic morphology of ovaries and restored normal ovarian cycles" in
|
|
estrogen-treated rats.
|
|
</p>
|
|
|
|
<p>
|
|
G. B. Melis, et al., "Evidence that estrogens inhibit LH secretion through opioids in postmenopausal women
|
|
using naloxone," Neuroendocrinology 39, 60-63, 1984.
|
|
</p>
|
|
<p>
|
|
H. J. Sipe, et al., "The metabolism of 17 beta-estradiol by lactoperoxidase: A possible source of oxidative
|
|
stress in breast cancer," Carcinogenesis 15(11), 2637-2643, 1994. "...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." "...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."
|
|
</p>
|
|
<p>
|
|
S. Santagati, et al., "Estrogen receptor is expressed in different types of glial cells in culture," J.
|
|
Neurochem. 63(6), 2058-2064, 1994. "...in all three types of glial cell analyzed in almost equal amounts..."
|
|
</p>
|
|
|
|
<p>
|
|
D. X. Liu and L. P. Li, "Prostaglandin F-2 alpha rises in response to hydroxyl radical generated in vivo,"
|
|
Free Radical Biol. Med. 18(3), 571-576, 1995. "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." "Prostaglandin F-2 alpha dramatically increased in response to hydroxyl radical generation...."
|
|
</p>
|
|
<p>
|
|
J. Owens and P. A. Schwartzkroin, "Suppression of evoked IPSPs by arachidonic acid and prostaglandin F-2
|
|
alpha," Brain Res. 691(1-2), 223-228, 1995. "These findings suggest that high levels of AA and its
|
|
metabolites may bias neurons towards excitation."
|
|
</p>
|
|
<p>
|
|
E. A. Quail and G. C. T. Yeoh, "The effect of iron status on glyceraldehyde 3-phosphate dehydrogenase
|
|
expression in rat liver," FEBS Lett. 359(2-3), 126-128, 1995. "...the overexpression of GAPDH mRNA in iron
|
|
deficiency is probably due to increased message stability." [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., "4-hydroxylation of estradiol by human uterine myometrium and myoma microsomes:
|
|
Implications for the mechanism of uterine tumorigenesis," Proc Natl Acad Sci USA 92(20), 9220-9224, 1995.
|
|
"... elicits biological activities distinct from estradiol, most notably an oxidant stress response induced
|
|
by free radicals generated by metabolic redox cycling reactions."
|
|
</p>
|
|
<p>
|
|
J. G. Liehr and D. Roy, "Free radical generation by redox cycling of estrogens," Free Rad. Biol. Med. 8,
|
|
415-423, 1990.
|
|
</p>
|
|
<p>
|
|
P. Aschheim, "Resultats fournis par la greffe heterochrone des ovaires dan l'etude de la regulation
|
|
hypothalamo-hypophyso-ovarienne de la ratte senile," Gerontologia 10, 65-75, 1964/65. "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." "What are the factors that cause
|
|
this diminution of the hypothalamic sensitivity...? Kennedy incriminates a decrease in the cellular
|
|
metabolism in general...."
|
|
</p>
|
|
<p>
|
|
P. Ascheim, "Aging in the hypothalamic-hypophyseal ovarian axis in the rat," pp. 376-418 in: A. V. Everitt
|
|
and J. A. Burgess, editors, Hypothalamus, Pituitary and Aging, C>C> Thomas, Springfield, 1976.
|
|
</p>
|
|
<p>
|
|
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>
|
|
C. S. Bangur, J. L. Howland, S. S. Katyare, "Thyroid hormone treatment alters phospholipid composition and
|
|
membrane fluidity of rat brain mitochondria," Biochem. J. 305(1), 29-32, 1995. (Increases fluidity.)
|
|
</p>
|
|
<p>
|
|
R. S. Sohal, et al., "Mitochondrial superoxide and hydrogen peroxide generation, protein oxidative damage,
|
|
and longevity in different species of flies," Free Rad. Biol. & 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., "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."
|
|
</p>
|
|
<p>
|
|
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.] 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.]
|
|
</p>
|
|
|
|
<p>
|
|
J. R. Pasqualini, et al., "Effect of the progestagen promegestone (R-5020) on mRNA of the oestrone
|
|
sulphatase in the MCF-7 human mammary cancer cells," 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., "Treatment of acute experimental allergic encephalomyelitis in the Lewis rat with
|
|
the sex hormone progesterone," Int. J. Immunopathol. Pharmacol. 7(3), 183-192, 1994. "...we suggest that
|
|
treatment with progesterone protected against the histological signs of EAE through a peripheral immune
|
|
mechanism."
|
|
</p>
|
|
<p>
|
|
H. L. Koenig, et al., "Progesterone synthesis and myelin formation by Schwann cells," Science (268),
|
|
1500-1503, 1995. "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."
|
|
</p>
|
|
|
|
<p>
|
|
N. C. Lan and K. W. Gee, "Neuroactive steroid actions at the GABA(A) receptor," Horm. Behav. 28(4), 537-544,
|
|
1994. Neuroactive steroids "...do not interact with any of the classical cytosolic hormonal steroid
|
|
receptors." "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."
|
|
</p>
|
|
<p>
|
|
J. F. FierroRenoy, et al., "Three different thyroid hormone receptor isoforms are detected in a pure culture
|
|
of ovine oligodendrocytes," Glia 14(4), 322-328, 1995. "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."
|
|
</p>
|
|
<p>
|
|
J. Masse, "Nutrition, thyroid hormones, body temperature, and mortality of elderly patients with acute
|
|
illnesses," Am. J. Clin. Nutr. 62(3), 647-648, 1995.
|
|
</p>
|
|
|
|
<p>
|
|
E. J. Masoro, "Dietary restriction," Exp. Gerontology 30(3/4), 291-298, 1995. "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." [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., "Pregnenolone sulfate antagonizes dizocilpine amnesia: Role for allopregnanolone,"
|
|
Neuroreport 6(12), 1697-1700, 1995. "We and others have shown that allopregnanolone potently modulate
|
|
GABA(A) receptor function whereas 5 alpha-dihydroprogesterone fails to induce rapid changes...."
|
|
</p>
|
|
<p>
|
|
B. S. McEwen and E. Gould, "Adrenal steroid influences on the survival of hippocampal neurons," Biochem.
|
|
Pharmacol 40, 2393-2402, 1990.
|
|
</p>
|
|
|
|
<p>
|
|
P. W. Landfield, et al., "Hippocampal aging and adrenocorticoids: Quantitative correlations," Science
|
|
202(8), 1098-1101, 1978.
|
|
</p>
|
|
<p>
|
|
A. M. Dudchenko, et al., "Effect of corticosterone on the macroergic pool and membrane permeability in
|
|
sections of rat hippocampus," Bull. Exp. Biol. & Med. 116(12), 1505-1508, 1993. "...the hippocampus is
|
|
one of the most vulnerable brain structures...." "...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." "The death of
|
|
hippocampal neurons, triggered...by hyperactivation of the glutamate receptors, is accelerated in the
|
|
presence of" 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., "Individual differences in hypothalamic-pituitary-adrenal activity in later life and
|
|
hippocampal aging," Exp. Gerontology 30(3/4), 229-251, 1995. "...glucocorticoids...both increase the toxic
|
|
glutamate signal and decrease the metabolic capacity of neurons to survive." (Glucose is protective.) "Our
|
|
current foxus is on the potential role of progesterone as a modulator of glucocorticoid action."
|
|
</p>
|
|
<p>
|
|
P. Sheng, et al., "Methamphetamine causes reactive gliosis in vitro: Attenuation by the ADP-ribosylation
|
|
inhibitor, benzamide," Life Sciences 55(3), 51-54, 1994
|
|
</p>
|
|
<p>
|
|
N. S. Verkhratsky, "Limbic control of endocrine glands in aged rats," Exp. Gerontology 30(3/4, 415-421,
|
|
1995. Aging causes "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." "...stimulation of hippocampus inhibits
|
|
ACTH secretion...and causes a decrease of plasma corticosteroids...."
|
|
</p>
|
|
<p>
|
|
R. M. Sapolsky, et al., "Prolonged glucocorticoid exposure reduces hippocampal neuron number: Implications
|
|
for aging," J. Neurosci. 5 1221, 1985.
|
|
</p>
|
|
<p>
|
|
J. L. W. Yau, Mol. Brain Res. 27(1), 174-178, 1994. "Glucocorticoid excess is associated with hippocampal
|
|
neuronal dysfunction and loss, mainly affecting CA1."
|
|
</p>
|
|
<p>
|
|
B. Nasman, et al., "A subtle disturbance in the feedback regulation of the hypothalamic-pituitary-adrenal
|
|
axis in the early phase of Alzheimer's disease," Psychoneuroendocrinology 20(20, 211-220, 1995. "After 0.5
|
|
mg dexamethasone, serum cortisol levels were significantly less suppressed...."
|
|
</p>
|
|
<p>
|
|
C. Mondadori, "In search of the mechanism of action of the nootropics: New insights and potential clinical
|
|
implications," Life Sci. 55(25-26), 2171-2178, 1994. "...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."
|
|
</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>
|
|
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>
|
|
P. Corbisier, et al., "Bioenergetics of mitochondria determine cell survival in stressful conditions," Prog.
|
|
in Cell Res. (5), 237-241, 1995. "...the growth rate of young or old cells injected with coupled
|
|
mitochondria...was not statistically different."
|
|
</p>
|
|
<p>
|
|
G. Paradies, et al., "Molecular basis of the age-dependent decrease in the cytochrome oxidase activity in
|
|
rat heart mitochondria," Prog. in Cell Res. 5, 243-247, 1995. The activity of cytochrome oxidase "was
|
|
markedly decreased with aging. This decrease was associated with a parallel decrease in the mitochondrial
|
|
respiratory activity." "Cardiolipin content was significantly reduced in mitochondrial membrane from aged
|
|
rats."
|
|
</p>
|
|
|
|
<p>
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G. C. Ness and Z. H. Zhao, "Thyroid hormone rapidly induces hepatic LDL receptor mRNA levels in
|
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hypophysectomized rats," Arch. Biochem. Biophys. 315(1), 199-202, 1994.
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</p>
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<p>
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E. M. Mutisya, et al., "Cortical cytochrome oxidase activity is reduced in Alzheimer's disease," J.
|
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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>
|
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<p>
|
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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,
|
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as well as control of extracellular protease activity."
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</p>
|
|
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<p>
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V. Vandenbrouck, et al., "The modulation of apolipoprotein E gene expression by 3,3'-5-triiodothyronine in
|
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HepG(2) cells occurs at transcriptional and post-transcriptional levels," Eur. J. Biochem. 224(2), 463-471,
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1994. "...thyroid hormone stimulated apoE gene transcription threefold in 24 hours."
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</p>
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<p>
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M. J. Ignatius, et al. "Expression of apolipoprotein-E during nerve degeneration and regeneration," Proc.
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Natl. Acad. Sci. (USA) 83, 1125-1129, 1986.
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</p>
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<p>
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B. T. Stokes, et al., "Energy depletion, calcium and the cytoskeleton: A model for trophic intervention,"
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pp. 279-292, in Trophic Factors and the Nervous System, L. A. Horrocks, et al., editors, Raven Press, NY,
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|
1990. "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." "Virtually all components of the
|
|
cytoskeleton are either directly or indirectly affected by alterations in calcium metabolism."
|
|
"...calcium-activated proteases may also specifically modulate components of the cytoskeleton." "...ATP
|
|
depletion itself may directly alter the structural components of the neuronal cytoskeleton." "...major
|
|
neurodegenerative diseases such as Alzheimer's, Parkinsonian syndrome, amyotrophic lateral sclerosis...are
|
|
also characterized by changes in the neuronal cytoskeleton."
|
|
</p>
|
|
<p>
|
|
T. Gunther, et al., "Effects of magnesium and iron on lipid peroxidation in cultured hepatocytes," Mol. Cell
|
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Biochem. 144(2), 141-145, 1995. (Magnesium protects against iron.)
|
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</p>
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<p>
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K. D. Croft, et al., "Oxidation of low-density lipoproteins: Effect of antioxidant content, fatty acid
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composition and intrinsic phospholipase activity on susceptibility to metal ion-induced oxidation,"
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BBA-Lipid Lipid Metab. 1254(3), 250-256, 1995.
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</p>
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<p>
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J. H. Choi and B. P. Yu, "Brain synaptosomal aging: Free radicals and membrane fluidity," Free Radical Biol.
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Med. 18(2), 133-139, 1995 ("...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.")
|
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</p>
|
|
|
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<p>
|
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J. H. Choi and B. P. Yu, "Modification of age-related alterations of iron, ferritin, and lipid peroxidation
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in rat serum," Age 17(3), 93-97, 1994.
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</p>
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<p>
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E. Chiarpotto, et al., "Metabolism of 4-hydroxy-2-nonenal and aging," Biochem. Biophys. Res. Commun. 297(2),
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477-484, 1995. (Accumulation of unsaturated fat breakdown product in old animals.)
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</p>
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<p>
|
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H. J. Sipe, et al., "The metabolism of beta-estradiol by lactoperoxidase: A possible source of oxidative
|
|
stress in breast cancer," Carcinogenesis 15(11), 2637-2643, 1994.
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</p>
|
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|
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<p>
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M. J. Endresen, et al., "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," Scan. J.
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Clin. Lab. Invest. 54(7), 549-557, 1994<em>.</em> "...levels of circulating free fatty acids are increased
|
|
in women who later develop pre-eclampsia long before the clinical onset of the disease." "...linoleic acid
|
|
reduced the thrombin-stimulated prostacyclin release by 30-60%, oleic acid by 10-30%, wheras palmitic acid
|
|
had no effect." "Linoleic acid reduced the endothelial cells" ability to inhibit platelet aggregation by
|
|
10-45%...."
|
|
</p>
|
|
<p>
|
|
L. A. Norris and J. Bonnar, "Effect of oestrogen dose on whole blood platelet activation in women taking new
|
|
low dose oral contraceptives," Thromb. Haemost. 72(6), 926-930, 1994: "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.") 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., "Interferon-gamma and polyunsaturated fatty acids increase the binding of
|
|
lipopolysaccharide to macrophages," Int. J. Exp. Pathol. 75(5), 363-368, 1994.
|
|
</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. Deficiency of "essential" fats
|
|
decreases damage from endotoxin.
|
|
</p>
|
|
<p>
|
|
N. Auge, et al., "Proliferative and cytotoxic effects of mildly oxidized low-density lipoproteins on
|
|
vascular smooth-muscle cells," Biochem. J. 309(Part 3), 1015-1020, 1995. "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."
|
|
</p>
|
|
<p>
|
|
S. K. Clinton, et al., "The combined effects of dietary fat and estrogen on survival, 7,12-dimethyl-
|
|
benz(a)-anthracene-induced breast cancer and prolactin metabolism in rats," J. Nutr. 125(5), 1192-1204,
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|
1995. "Mortality in controls was doubled by feeding a high fat diet...." "...the presence of estrogen may be
|
|
a prerequisite for significant dietary modulation."
|
|
</p>
|
|
|
|
<p>
|
|
R. Sanchez Olea, et al., "Inhibition by polyunsaturated fatty acids of cell volume regulation and osmolyte
|
|
fluxes in astrocytes," Amer. J. of Physiology--cell physiology 38(1), C96-C102, 1995. "...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."
|
|
"...polyunsaturated fatty acids directly inhibit the permeability pathways correcting cell volume after
|
|
swelling in cultured astrocytes."
|
|
</p>
|
|
<p>
|
|
M. E. Miller, et al., "Influence of hormones on platelet intracellular calcium," Thrombosis Research 77(6),
|
|
515-530, 1995. "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." "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."
|
|
</p>
|
|
|
|
<p>
|
|
F. Mercure and G. Vanderkraak, "Inhibition of gonadotropin-stimulated ovarian steroid production by PUFA in
|
|
teleost fish," Lipids 30(6), 547-554, 1995. "EPA and DHA inhibited gonadotropin-stimulated testosterone
|
|
production in a dose-related manner...."
|
|
</p>
|
|
<p>
|
|
A A Farooqui, K Wells, L A Horrocks, "Breakdown of membrane phospholipids in Alzheimer disease--involvement
|
|
of excitatory amino acid receptors," Mol Chem Neuropathol 25(2-3) 155-173, 1995. "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."
|
|
</p>
|
|
<p>
|
|
Leo Loeb, V. Suntzeff, and E. L. Burns, "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," 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, "The connective tissue and muscle appear rarefied, almost as though they were
|
|
perforated by a large number of small holes." "...this condition is presumably due to a deposit of a mixture
|
|
of hyaline material and edematous fluid...." "This process of hyalinization...is counteracted by invasion by
|
|
connective tissue." 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." "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." "As a rule, the epithelioid cells are seen alone; giant cells are more
|
|
rare." "...the connective-tissue fibrils may in places appear somewhat separated, perhaps by edematous
|
|
fluid." "The first changes consist very likely in the transudation of fluid from the vessels into the
|
|
connective tissue." "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." "...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...." "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." "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."
|
|
</p>
|
|
<p>
|
|
Leo Loeb, V. Suntzeff, and E. L. Burns, "The effects of age and estrogen on the stroma of vagina, cervix and
|
|
uterus in the mouse," Science 88(22, Nov. 4), 1938. "...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." "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." "...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."
|
|
</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."
|
|
</p>
|
|
<p>
|
|
C. LarssonBackstrom, et al., "Effects of dietary alpha- and gamma-linolenic acids on liver fatty acids,
|
|
lipid metabolism, and survival in sepsis," Shock 4(1), 11-20, 1995. "Dietary GLA reduced survival from
|
|
sepsis."
|
|
</p>
|
|
<p>
|
|
D. Chemla, et al., "Influence of dietary polyunsaturated fatty acids on contractility, inotropy and
|
|
compliance of isolated rat myocardium, J mol Cell Cardiol 27(8), 1745-1755, 1995. "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." See B. Pieske, Circul. 92(5), 1169-78
|
|
</p>
|
|
|
|
<p>
|
|
R. Lerner, et al., "Development and characterization of essential fatty acid deficiency in human endothelial
|
|
cells in culture," 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., "Dissociation of protein kinase C activities and diacylglycerol levels in liver plasma
|
|
membranes of rats on coconut oil and safflower oil diets," J. Nutr Biochem 6(10), 528-533, 1995. "The
|
|
activation of PKC is affected differently in vitro by different fatty acids." "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...." "...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." "It
|
|
seems likely that saturated fats exert various physiological effects on lipid and lipoprotein metabolism, in
|
|
part through PKC pathways."
|
|
</p>
|
|
|
|
<p>
|
|
V. Boutard, et al., "Fish oil supplementation and essential fatty acid deficiency reduce nitric oxide
|
|
synthesis by rat macrophages," Kidney Int. 46(5), 1280-1286, 1994. "Both...have been shown to exert
|
|
anti-inflammatory effects...."
|
|
</p>
|
|
<p>
|
|
A A Farooqui, K Wells, L A Horrocks, "Breakdown of membrane phospholipids in Alzheimer disease--involvement
|
|
of excitatory amino acid receptors," Mol Chem Neuropathol 25(2-3) 155-173, 1995. "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."
|
|
</p>
|
|
<p>
|
|
P. H. Chan and R. A. Fishman, "Transient formation of superoxide radicals in polyunsaturated fatty
|
|
acid-induced brain swelling," J. of Neurochemistry 35, 1004-1007, 1980.
|
|
</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. "In epidemiological studies microalbuminuria, i.e.,
|
|
slightly elevated urinary albumin excretion rate, predicts increased atherosclerotic vascular morbidity and
|
|
mortality." "In animal experiments the outflux of albumin and lipids to the arterial wall are highly
|
|
correlated, and both are elevated in atherosclerosis." "...microalbuminuria is an independent marker of
|
|
systemic transvascular albumin leakiness in clinically healthy subjects."
|
|
</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>
|
|
F. Laszlo, et al., "Association of microvascular leakage with induction of nitric oxide synthase: Effects of
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|
nitric oxide synthase inhibitors in various organs," Eur. J. Pharmacol. 283(1-3), 47-53, 1995. "...assessed
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|
by the vascular leakage of ... albumin." "Endotoxin...induced the expression of a calcium-independent nitric
|
|
oxide synthase...."
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|
</p>
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|
<p>
|
|
C. Nilsson, et al., "The nocturnal increase in human cerebrospinal fluid production is inhibited by a
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|
beta(1)-receptor antagonist," Amer. J. Physiol.--Regul. Integr. C 36(6), R1445-R1448, 1994.
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</p>
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|
<p>
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|
S. Capsoni, et al., "Reduction of regional cerebral blood flow by melatonin in young rats," Neuroreport
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|
6(9), 1346-1348, 1995. "...reduced in the cerebral areas supplied by circle of Willis and the basilar
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|
arteries. [Also to the] ...choroid plexuses."
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|
</p>
|
|
<p>
|
|
A. C. Bowling and M. F. Beal, "Bioenergetic and oxidative stress in neurodegenerative diseases," Life Sci.
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|
56(14), 1151-1171, 1995. "Defects in energy metabolism and increased cortical lactate levels have been
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|
detected in Huntington's disease patients. Studies of Alzheimer's disease patients have identified decreased
|
|
[mitochondrial] complex IV activity...." "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."
|
|
</p>
|
|
<p>
|
|
K. Nakai, et al., "Regeneration of norepinephrine-containing fibers in occipital cortex of adult cats,"
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|
Brain Res. Bull. 35(5-6), 409-412, 1994. "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."
|
|
</p>
|
|
|
|
<p>
|
|
A. Bhatnagar, "Biochemical mechanism, of irreversible cell injury caused by free radical-initiated
|
|
reactions," Mol. Cell. Biochem. 137(1), 9-16, 1994. "...free radical-induced irreversible cell injury
|
|
results from a loss of protein thiols."
|
|
</p>
|
|
<p>
|
|
L. Balazs and M. Leon, "Evidence of an oxidative challenge in the Alzheimer's brain," Neurochem. Res. 19(9),
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|
1131-1137, 1994. "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."
|
|
</p>
|
|
<p>
|
|
J. A. Court and E. K. Perry, "CNS nicotinic receptors--possible therapeutic targets in neurodegenerative
|
|
disorders," CNS Drugs 2(3), 216-233, 1994. "...epidemiological evidence suggests that later in life tobacco
|
|
smoking may offer some protection against Parkinson's and Alzheimer's diseases."
|
|
</p>
|
|
|
|
<p>
|
|
N. A. Simonian and B. T. Hyman, "Functional alterations in Alzheimer's disease: Selective loss of
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|
mitochondrial-encoded cytochrome oxidase mRNA in the hippocampal formation," J. Neuropathol. Exp. Neurol.
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53(5), 508-512, 1994.
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|
</p>
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|
<p>
|
|
A. M. Proenze, et al., "Estrogen effects on blood amino acid compartmentation," Life Sci. 57(17), 1589-1587,
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|
1995.
|
|
</p>
|
|
<p>
|
|
S. S. Smith, "Sensorimotor-correlated discharge recorded from ensembles of cerebellar Purkinje cells varies
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|
across the estrous cycle of the rat," J. Neurophysiol. 74(3), 1095-1108, 1995. "...estradiol augments
|
|
excitatory responses of cerebellar Purkinje cells to...glutamate...."
|
|
</p>
|
|
|
|
<p>
|
|
C. F. Lim, et al., "Influence of nonesterified fatty acid and lysolecithins on thyroxine binding to
|
|
thyroxine-binding globulin and transthyretin," Thyroid 5(4), 319-324, 1995. "Unsaturated nonesterified fatty
|
|
acids...inhibited T4 binding to TBG." "Saturated NEFAs...were inactive."
|
|
</p>
|
|
<p>
|
|
O. V. Sviridov, "Specific binding of thyroid hormones by human plasma apolipoproteins: A new property of
|
|
known proteins," Biochemistry (Engl. translation) 59(5), 457-466, 1884.
|
|
</p>
|
|
<p>
|
|
T. Parasassi, et al., "Cholesterol protects the phospholipid bilayer from oxidative damage," Free Radical
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|
Biology & Medicine 19(4), 511-516, 1995.
|
|
</p>
|
|
|
|
<p>
|
|
A. G. Herzog, "Progesterone therapy in women with complex partial and secondary generalized seizures,"
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|
Neurology 45(9), 1660-1662, 1995.
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|
</p>
|
|
<p>
|
|
Z. Q. Ma, et al., Estrogenic control of monoamine oxidase A activity in human neuroblastoma cells expressing
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|
physiological concentrations of estrogen receptor," Eur. J. Pharmacol. 284(1-2), 171-176, 1995.
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|
</p>
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|
<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, "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," 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, "The connective tissue and muscle appear rarefied, almost as though they were
|
|
perforated by a large number of small holes." "...this condition is presumably due to a deposit of a mixture
|
|
of hyaline material and edematous fluid...." "This process of hyalinization...is counteracted by invasion by
|
|
connective tissue." 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." "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." "As a rule, the epithelioid cells are seen alone; giant cells are more
|
|
rare." "...the connective-tissue fibrils may in places appear somewhat separated, perhaps by edematous
|
|
fluid." "The first changes consist very likely in the transudation of fluid from the vessels into the
|
|
connective tissue." "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." "...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...." "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." "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."
|
|
</p>
|
|
<p>
|
|
Leo Loeb, V. Suntzeff, and E. L. Burns, "The effects of age and estrogen on the stroma of vagina, cervix and
|
|
uterus in the mouse," Science 88(22, Nov. 4), 1938. "...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." "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." "...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."
|
|
</p>
|
|
|
|
<p>
|
|
Winfried G. Rossmanith, "Gonadotropin secretion during aging in women: Review article," Exp. Gerontology
|
|
30(3/4) 369-381, 1995. "...major functional derangements, primarily at a hypothalamic rather than a
|
|
pituitary site, have been determined as concomitants of aging in women." "...aging may impair the negative
|
|
feedback sensitivity to ovarian sex steroids...." Hormonal changes at menopause "may represent the sum of
|
|
functional aberrations that were initiated much earlier in life...." "...prolonged estrogen exposure
|
|
facilitates the loss of hypothalamic neurons...."
|
|
</p>
|
|
<p>
|
|
J. R. Brawer, et al., "Ovary-dependent degeneration in the hypothalamic arcuate nucleus," Endocrinology 107,
|
|
274-279, 1980.
|
|
</p>
|
|
|
|
<p>
|
|
G. C. Desjardins, "Estrogen-induced hypothalamic beta-endorphin neuron loss: A possible model of
|
|
hypothalamic aging," Exp. Gerontology 30(3/4), 253-267, 1995. "This loss of opioid neurons is prevented by
|
|
treatment with antioxidants indicating that it results from estradiol-induced formation of free radicals."
|
|
"...this beta-endorphin cell loss is followed by a compensatory upregulation of mu opioid receptors in the
|
|
vicinity of LHRH cell bodies." Resulting supersensitivity of the cells results "in chronic opioid
|
|
suppression of the pattern of LHRH release, and subsequently that of LH." The neurotoxic effects of
|
|
estradiol causes a "cascade of neuroendocrine aberrations resulting in anovulatory acyclicity." Treatment
|
|
with an opiod antagonist "reversed the cystic morphology of ovaries and restored normal ovarian cycles" in
|
|
estrogen-treated rats.
|
|
</p>
|
|
|
|
<p>
|
|
G. B. Melis, et al., "Evidence that estrogens inhibit LH secretion through opioids in postmenopausal women
|
|
using naloxone," Neuroendocrinology 39, 60-63, 1984.
|
|
</p>
|
|
<p>
|
|
H. J. Sipe, et al., "The metabolism of 17 beta-estradiol by lactoperoxidase: A possible source of oxidative
|
|
stress in breast cancer," Carcinogenesis 15(11), 2637-2643, 1994. "...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." "...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."
|
|
</p>
|
|
<p>
|
|
S. Santagati, et al., "Estrogen receptor is expressed in different types of glial cells in culture," J.
|
|
Neurochem. 63(6), 2058-2064, 1994. "...in all three types of glial cell analyzed in almost equal amounts..."
|
|
</p>
|
|
|
|
<p>
|
|
D. X. Liu and L. P. Li, "Prostaglandin F-2 alpha rises in response to hydroxyl radical generated in vivo,"
|
|
Free Radical Biol. Med. 18(3), 571-576, 1995. "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." "Prostaglandin F-2 alpha dramatically increased in response to hydroxyl radical generation...."
|
|
</p>
|
|
<p>
|
|
J. Owens and P. A. Schwartzkroin, "Suppression of evoked IPSPs by arachidonic acid and prostaglandin F-2
|
|
alpha," Brain Res. 691(1-2), 223-228, 1995. "These findings suggest that high levels of AA and its
|
|
metabolites may bias neurons towards excitation."
|
|
</p>
|
|
<p>
|
|
E. A. Quail and G. C. T. Yeoh, "The effect of iron status on glyceraldehyde 3-phosphate dehydrogenase
|
|
expression in rat liver," FEBS Lett. 359(2-3), 126-128, 1995. "...the overexpression of GAPDH mRNA in iron
|
|
deficiency is probably due to increased message stability." [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., "4-hydroxylation of estradiol by human uterine myometrium and myoma microsomes:
|
|
Implications for the mechanism of uterine tumorigenesis," Proc Natl Acad Sci USA 92(20), 9220-9224, 1995.
|
|
"... elicits biological activities distinct from estradiol, most notably an oxidant stress response induced
|
|
by free radicals generated by metabolic redox cycling reactions."
|
|
</p>
|
|
<p>
|
|
J. G. Liehr and D. Roy, "Free radical generation by redox cycling of estrogens," Free Rad. Biol. Med. 8,
|
|
415-423, 1990.
|
|
</p>
|
|
<p>
|
|
F. Fourrier, Circ. Shock 43(4), 171-178, 1994, "High estrogen levels were specifically observed in patients
|
|
with sepsis and septic shock, either males or females." "Circulating T levels were decreased in all male
|
|
patients."
|
|
</p>
|
|
|
|
<p>
|
|
J. A. Jarvis, et al., "H-1 NMR analysis of fibril-forming peptide fragments of transthyretin," Int. J. Pept.
|
|
Protein Res. 44(4), 388-398, 1994. "...fragments of the protein transthyretin, previously shown to form
|
|
cross beta-sheet amyloid-like fibrils in vitro, were investigated...."
|
|
</p>
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<p>
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© Ray Peat 2006. All Rights Reserved. www.RayPeat.com
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