The problem of Alzheimer's disease as a clue to immortality
痴呆难题-永生线索（第一部分）
by Raymond Peat
I. INTRODUCTION引言
II. COMMON FACTORS IN INJURY DURING GROWTH AND AGING
生长和衰老过程中常见的损伤因素
III. A VIEW OF ENTROPY–RENEWAL OF THE BRAIN
熵-大脑的更新
IV. FALSE SIGNALS FROM THE ENVIRONMENT
来自环境的错误信号
A. EDUCATION, DIET AND MEDICINE INTERACT
教育、饮食和医学相互作用
B. SIGNALS IN THE ABSTRACT
摘要中的信号
V. HORMONE IMBALANCE, LEADING TO FAILURE OF PROTECTIVE INHIBITION AND ALZHEIMER'S DISEASE
荷尔蒙失衡，导致保护性抑制失效及阿尔茨海默病
A. THE FUNCTION OF ENERGY
能量的作用
B. EFFECTS OF ESTROGEN AND UNSATURATED FATTY ACIDS
雌激素和不饱和脂肪酸的影响
C. VITAMIN A AND STEROIDS
维生素A和类固醇
D. THE NATURE OF ALZHEIMER'S DISEASE痴的本质
E. AN EXAMPLE; DIET AFFECTS HORMONES WHICH AFFECT STRUCTURE AND LEAD TO APPARENT SELF- DESTRUCTION
一个例子;饮食影响荷尔蒙，荷尔蒙影响身体结构，导致明显的自我毁灭
VI. STRUCTURE AS A REGULATORY SYSTEM–AN EMERGING VISION OF PERVASIVE EPIGENESIS
结构作为一个调节系统——普遍的后生作用的一个新兴观点
I. INTRODUCTION
引言
The toxicity of estrogen and of the unsaturated fats has been known for most of the twentieth century, and much has been learned about their interactions in the aging process. The body, during this time, has been understood as a dynamic interaction of cellular trophic influences which govern both form and function. My argument here will be that some of our adaptive, protective regulatory processes are overridden by the excessive supply of unsaturated fats–supported by a few other toxins–in our diet, acting as a false-signal system, and that cholesterol, pregnenolone, and progesterone which are our main long-range defenses, are overcome by the effects of the unsaturated fats, and that the resulting cascade of ineffective and defective reactions (including various estrogen-stimulated processes) leads to lower and lower energy production, reduced function, and death. At certain times, especially childhood and old age, iron (which also has important regulatory roles) accumulates to the point that its signal functions may be inappropriate.
雌激素和不饱和脂肪的毒性在二十世纪的大部分时间里都已为人所知，而且对它们在衰老过程中的相互作用也有了很多了解。在此期间，身体被理解为控制形态和功能的细胞营养影响的动态相互作用。我的观点是，我们的一些适应性、保护性调节过程被过度供应的不饱和脂肪——由一些其他毒素支持——所取代，作为一个虚假信号系统，而胆固醇、孕烯醇酮和孕酮是我们主要的长期防御，被不饱和脂肪的影响所克服，并由此产生的一系列无效和缺陷反应(包括各种雌激素刺激的过程)导致能量产量越来越低，功能下降，甚至死亡。在某些时候，特别是童年和老年时期，铁元素(它也有重要的调节作用)积累到一定程度，其信号功能可能不合适。
It interacts with estrogen and unsaturated fats in ways that can change restraint and adaptation into sudden self-destruction, apoptotic cell death. If we look at the human organism from one perspective, it seems coherent and intelligible, but from the perspective of established academic biological doctrine, it seems appallingly complex, lacking any visible integrating principle, and as a result simplistic mechanical, pharmaceutical, or religious ideas are increasingly offered to fill the gap. But experimental data can be taken out of the muddle, and put to coherent human use. In what follows, I am acting as though the doctrines of genetic determination and regulation by membranes were mere historical relics. The emerging control systems are now clear enough that we can begin to use them to reverse the degenerative diseases: Alzheimer's dementia, epileptic dementia, arthritis, osteoporosis, depression, hypertension, hardening of the heart and blood vessels, diabetes, and some types of tumor, immunodeficiencies, reflex problems, and special atrophic problems, including clearing of amyloid and mucoid deposits. I think many people experience regenerative age-regressing when many circumstances are just right; for example, taking a trip to the mountains in the spring with friends can optimize several basic regulatory systems.
它与雌激素和不饱和脂肪相互作用的方式可以改变约束和适应突然自我毁灭，凋亡细胞死亡。如果我们看人类有机体从一个角度来看,似乎一致的和可理解的,但从生物学说建立了学术的角度来看,似乎令人毛骨悚然地复杂,没有任何可见的整合原则,因此简单机械、制药、或宗教思想越来越来填补这一缺口。但实验数据可以从混乱中提取出来，并用于连贯的人类使用。在接下来的事情中，我的行为就好像基因决定和膜调控的理论仅仅是历史遗迹。新出现的控制系统现在已经足够清晰，我们可以开始使用它们来逆转退化性疾病:阿尔茨海默氏症，癫痫性痴呆，关节炎，骨质疏松，抑郁症，高血压，心脏和血管硬化，糖尿病，和某些类型的肿瘤，免疫缺陷，反射问题，和特殊的萎缩性问题，包括清除淀粉样和粘液样沉积物。我想很多人经历再生衰老的时候，很多情况都是合适的;例如，春天和朋友去爬山可以优化几个基本的调节系统。
II. COMMON FACTORS IN BRAIN INJURY DURING GROWTH AND AGING
生长和衰老过程中脑损伤的常见因素
Most people are surprised by the number of cells in the prenatal brain, and in the very old brain: In the human fetus at 6 months of development, there are about twice as many brain cells as there are at the time of birth, and in old age the number of cells in the brain keeps increasing with age, so that at the age of 90 the amount of DNA in the brain (36.94 grams) is about 50%.greater than at the age of 16-20 (23.04 grams). In the aged brain, glial cells multiply while neurons die. In the fetus, the cells that die are apparently nerve cells that haven't yet matured. The factors that are known to reduce the brain size at birth are also factors that are involved in the degenerating brain in old age or Alzheimer's disease: lack of oxygen, excess unsaturated fats or deficiency of saturated fats, estrogen excess, progesterone deficiency, and lack of glucose. A lack of carbon dioxide is probably harmful in both. Inflammation and blood clots may be factors in the aging brain, and bleeding with vascular spasm is sometimes a contributing factor to brain damage in both the old and the fetal brain. Endotoxemia may be a factor in nerve degeneration only during adult life, but it is sometimes present during pregnancy.
大多数人对产前大脑和老年大脑中的细胞数量感到惊讶:在人类胎儿在6个月的发展,大约有两倍的大脑细胞在出生的时候就有,在老年大脑细胞的数量随着年龄的不断增加,这90岁的大脑中的DNA(36.94克)约为50%。大于16-20岁时(23.04克)。在衰老的大脑中，神经胶质细胞繁殖，而神经元死亡。在胎儿中，死亡的细胞显然是尚未成熟的神经细胞。已知的在出生时缩小大脑大小的因素也与老年或阿尔茨海默病时大脑退化有关:缺氧、过多的不饱和脂肪或饱和脂肪缺乏、雌激素过多、黄体酮缺乏和葡萄糖缺乏。缺乏二氧化碳可能对两者都有害。炎症和血凝块可能是大脑老化的因素，而血管痉挛出血有时是老年人和胎儿脑损伤的一个促成因素。内毒素血症可能是神经退行性变的一个因素，但它有时出现在怀孕期间。
M. C. Diamond, Enriching Heredity: The Importance of the Environment on the Anatomy of the Brain. Free Press, N.Y., 1988. C. Finch and L. Hayflick, Handbook of the Biology of Aging. Van Nostrand Reinhold, N.Y., 1977.
III. A VIEW OF ENTROPY: RENEWAL OF THE BRAIN
熵:大脑的更新
When a fertilized egg is developing into a person, each cell division creates a new environment for the daughter cells, to which they adapt. They may run into limits and resistances (sometimes a certain gene doesn't meet the need of the situation, or toxins are present, or nutrients and hormones are imperfectly supplied), but the process is flexible, and a way is normally found to get around the limitation. The embryo's brain development is my favorite example of the ways genes interact with the environment. We might think of the “optimal brain development” of a person, or a rat, or a chicken, as something which is clearly limited by “the genes.” But if rats are given a stimulating environment, each generation gets a slightly bigger, slightly more intelligent brain. If rats are treated during pregnancy to increase the amount of progesterone, the offspring have bigger brains and learn more efficiently. Still, that might just be restoring a condition that was natural for rats in some perfect environment. Chickens develop inside an egg shell, and so the nutrients needed for their development are all present when the egg is laid.
当受精卵发育成人的时候，每次细胞分裂都会为子细胞创造一个新的适应环境。它们可能会遇到限制和阻力(有时某个基因不能满足情况的需要，或有毒素存在，或营养和激素供应不完美)，但这个过程是灵活的，通常会找到绕过限制的方法。胚胎的大脑发育是我最喜欢的基因与环境相互作用的例子。我们可能会认为，一个人、一只老鼠或一只鸡的“最佳大脑发育”显然受到了“基因”的限制。但如果给老鼠一个刺激的环境，每一代老鼠的大脑都会变得更大，更聪明。如果老鼠在怀孕期间增加孕激素的含量，其后代的大脑就会更大，学习效率也更高。不过，这可能只是在某种完美环境下恢复老鼠的自然状态。鸡是在蛋壳里发育的，所以它们发育所需的营养物质都是在下蛋时就存在的。
The brain, like the other organs, stops growing when the food supply is used up. But an experimenter (Zamenhof) opened the egg shells at the stage of development when the brain normally stops growing, and added glucose, and found that the brain continued growing, producing chickens with bigger brains. The “genes” of a chicken, as part of a system, have something to do with the development of that system, but the environment existing in and around the organism is able to guide and support the way the system develops. The size, complexity, and intelligence of the brain represents a very large part of the “information” contained in the organism, and Zamenhof's experiment showed that the ability to realize this potential, to create this complexity, comes from the support of the environment, and that the “genetic nature of the chicken” didn't constitute a limit to the development of its brain.
大脑和其他器官一样，在食物供应耗尽时停止生长。但是一名实验者(Zamenhof)在正常情况下大脑停止生长的发育阶段打开蛋壳，添加葡萄糖，发现大脑继续生长，使鸡的大脑更大。作为一个系统的一部分，鸡的“基因”与系统的发展有关，但存在于有机体内部和周围的环境能够指导和支持系统的发展。大脑的大小、复杂性和智力代表了生物体中包含的“信息”的很大一部分，而扎门霍夫的实验表明，实现这种潜力、创造这种复杂性的能力，来自环境的支持，“鸡的遗传特性”并没有限制其大脑的发育。
I am going to argue that Alzheimer's disease is analogous to the situation confronted by the developing chicken embryo or the rat or human fetus, when the environment is unable to meet the needs of the highly energetic, demanding and sensitive brain cells, and the brain cells begin to die, instead of developing into a more complex state, passing beyond various barriers and limitations. There are two stereotypes that are in conflict with this view: (1) That the structure of the brain is determined at an early point in life, sometimes explicitly stated as the age of 12 or 16, and (2) that the structure of the brain goes into an “entropic” deterioration during the process of aging. My position is that the brain cells are in a vital developmental process at all times, and that the same things that injure the brain of a fetus also injure the brain of an aging person.
我将认为阿尔茨海默病是类似于现状面临的发展鸡胚胎或胎儿大鼠或人类,当环境无法满足高能的需要,要求和敏感的脑细胞,脑细胞开始死亡,而不是发展成一个更复杂的状态,超越各种障碍和限制。有两个相冲突的刻板印象这一观点:(1)大脑的结构确定早期的时候在生活中,有时显式声明为12或16岁,大脑的结构(2)进入一个“的”恶化过程中老化。我的观点是，脑细胞在任何时候都处于一个至关重要的发育过程中，伤害胎儿大脑的东西也会伤害老年人的大脑。
If novelty is really appearing during development, then it is hard to maintain that “entropy increases” during the development of an individual. Isn't a child a richer organization than a fertilized egg? Isn't an adult more individualized or realized than an infant? Seen from the inside, our known world gets richer with experience. Learning is certainly anti-entropic. Where does the idea of “increasing entropy with living” come from? Many things contribute, including a doctrine of genetic determinism, the old Platonic idea of the imperfection of the concrete, the unreality of the existent, and the medieval idea of the “corruption of the body.” These philosophies still motivate some people in aging research. The astrophysicist, N. A. Kozyrev, showed that the idea of an “entropic cosmos” derived simply from the assumptions of 19th century deism, “God set the clockwork universe in motion, and left it to run down.” Early in this century, Raymond Pearl argued that the “rate of living” governed the life-span, so that “fast living” meant a short life. He based his argument on cantaloupe seeds: the faster they grew, the sooner they died. This was because he didn't give them anything but water, so they had to live on their stored energy; if they grew quickly, obviously they ran out of stored energy sooner. I have never heard that described as a stupid idea, but I think politeness is sometimes carried too far. In the clock analogy, or the seed analogy, the available energy is used up.
如果新颖性真的是在发展过程中出现的，那么就很难坚持“熵增加”是在个体发展过程中出现的。一个孩子不是比一个受精卵更富有的组织吗?难道一个成年人不比一个婴儿更有个性和觉悟吗?从内心看，我们的已知世界因经验而丰富。学习当然是反熵的。“随着生活而增加熵”的想法从何而来?很多东西都有贡献，包括遗传决定论的学说，关于具体事物不完美的旧柏拉图思想，存在者的不现实性，以及中世纪的“身体腐败”思想。这些理念仍然激励着一些人进行衰老研究。天体物理学家n·a·科济列夫(n.a. Kozyrev)指出，“熵宇宙”的概念仅仅源自19世纪自然神论的假设，“上帝让发条般的宇宙运转起来，然后让它运行下去。”在本世纪初，雷蒙德•珀尔(Raymond Pearl)提出，“生活速度”决定了寿命，因此“快节奏的生活”意味着短暂的生命。他的论点基于哈密瓜种子:它们生长得越快，就死得越早。这是因为他除了水什么都不给它们，所以它们必须靠储存的能量生活;如果它们长得快，储存的能量就会很快耗尽。我从来没听人说这是个愚蠢的想法，但我觉得礼貌有时太过分了。在时钟或种子的类比中，可用的能量被消耗殆尽。
The clock with its wound-up spring and the seed in a dish of water may be considered as closed systems, and we can understand their fate. But if it is foolish to argue from a confined seed to free-living organisms, then it is just as foolish to argue from a clock to a cosmos. Unfortunately, these inferences about closed systems are often applied to real situations that aren't energetically closed.
发条上的时钟和盛在一盘水里的种子可以被认为是封闭的系统，我们可以了解它们的命运。但是，如果说从一颗封闭的种子争论到自由的生物体是愚蠢的，那么从时钟争论到一个宇宙也是愚蠢的。不幸的是，这些关于封闭系统的推论经常被应用于实际情况，而这些情况并不是能量封闭的。
The “rate of living” theory of aging picked up the idea of aging as a natural physical property of time, and gave it expression in mathematical form, arguing (Hershey, “Entropy, basal metabolism and life expectancy,” Gerontologia 7, 245-250, 1963) that “the total lifetime entropy production” could be calculated, to give insight into “life expectancy and evolutional development.” Unfortunately, the equation Hershey used assumed that the flow of heat out of the body into the surroundings is reversible. This suggests an image of Dr. Frankenstein vivifying his monster with lightning, putting the heat back into the body. If heat is to be “put back into the body,” it is necessary to make sure that it is appropriate for the structure as it exists.
衰老的“活率”理论将衰老作为时间的一种自然物理属性，并将其以数学形式表达出来，认为(好时，“熵，基础代谢和预期寿命，”老年学7,245 -250,1963)，“总寿命熵产生”可以计算，以提供对“预期寿命和进化发展”的洞察。不幸的是，好时使用的方程假设了热量从身体流向周围环境是可逆的。这让人联想到弗兰肯斯坦博士用闪电使他的怪物活灵活现，把热量放回身体。如果要把热“放回体内”，就必须确保它适合当前存在的结构。
Actually, it is just the directed flow of energy which generates the structures. If any biological argument can be made from the idea of entropy, it is that it would be extremely difficult to regenerate food, by putting heat into a person. In a few situations, it is possible to show that living structures can directly absorb heat from their environment (causing the temperature to fall)–“negative heat production”–but the exact meaning of this isn't clear. (B. C. Abbott, et al., “The positive and negative heat production associated with a nerve impulse,” Proc. R. Soc. B 148, 149, 1958; R. D. Keynes and J. M. Ritchie, “The initial heat production of amphibian myelinated nerve fibres,” Proc. Physiol. Soc., June 1970, page 29P-30P: “It is now clear that in both crustacean…and mammalian (Howarth, et al., 1968) non-myelinated fibres there is an initial production of heat during (or soon after) the action potential, 80% of which is rapidly reabsorbed.”) A. I. Zotin (“Aging and rejuvenation from the standpoint of the thermodynamics of irreversible processes,” Priroda, No. 9, 49-55, 1970), citing the theory of Prigogine-Wiame, argued that the aging process involves both a decrease in entropy and a decrease in the rate of heat production.
实际上，正是能量的定向流动产生了这些结构。如果从熵的概念中可以得出任何生物学上的论点，那就是通过给人加热来再生食物是极其困难的。在少数情况下，有可能证明生物结构可以直接从环境中吸收热量(导致温度下降)——“负产热”——但这一说法的确切含义尚不清楚。(B. C. Abbott等，“与神经冲动相关的正和负热产生”Proc. R. Soc。b148, 149, 1958;凯恩斯(r.d. Keynes)和里奇(j.m. Ritchie)，《两栖类有髓神经纤维最初的热产生》，刊于《生理学》。Soc。1970年6月，第29P-30P页:“现在很清楚，甲壳类动物……和哺乳动物(Howarth, et al.， 1968)的无髓鞘纤维，在动作电位期间(或不久之后)会产生最初的热量，其中80%会被迅速地重新吸收。”Priroda, No. 9, 49-55, 1970)，引用Prigogine-Wiame的理论，认为老化过程涉及熵的下降和产热率的下降。
Regeneration involves a production of entropy, as when an egg is formed. (The temperature fluctuation at the time of ovulation might make a contribution to the construction of the entropic egg.) The argument that aging of the animal (like aging of the cosmos) is governed by “the tendency of entropy to increase” has led people to say that rejuvenation would be like unscrambling an egg. Zotin's argument is interesting, because he says that an egg is a “scrambled animal.” This view is very much like Warburg's and Szent-Gyorgyi's theory of cancer, that it is like a reversion to a simpler state of life. To sketch out what I have argued in different contexts, water is the part of the living substance that we can most meaningfully discuss in terms of entropy. In fact, much of the concept of entropy has derived from the study of water, as it changed state in steam engines, etc. Cancer cells, like egg cells, have a higher water content than the differentiated, functioning cells of an adult, and the water is less rigidly ordered by the cellular molecules. This different, more mobile state of the water, can be measured by the NMR (nuclear magnetic resonance) machines which are used for MRI (magnetic resonance imaging).
再生涉及到熵的产生，就像鸡蛋形成时一样。(排卵时的温度波动可能对熵卵的形成有贡献。)动物的衰老(就像宇宙的衰老)是由“熵增加的趋势”决定的，这一观点让人们认为，恢复活力就像整理鸡蛋。Zotin的观点很有趣，因为他说鸡蛋是“炒动物”。这个观点很像Warburg和Szent-Gyorgyi关于癌症的理论，它就像是回归到一种更简单的生活状态。概括一下我在不同情况下的观点，水是我们可以从熵的角度最有意义地讨论的生命物质的一部分。事实上，熵的很多概念来自于对水的研究，因为水在蒸汽机中改变了状态，等等。和卵细胞一样，癌细胞的含水量比分化的、正常的成人细胞要高，而且细胞分子对水的排列也不那么严格。水的这种不同的、更可移动的状态，可以通过核磁共振仪来测量，而核磁共振仪就是用于核磁共振成像的。
Estrogen has a special place in relation to the water in an organism. It is intimately involved with the formation of the egg cell, and wherever it operates, it increases both the quantity of water and, apparently, the disorder of the water. Its function, I believe, is to promote regeneration, as in Zotin's scheme, by increasing entropy, or “scrambling the animal.” The way it promotes regeneration is by promoting water uptake, stimulating cell division, and erasing the differentiated state to one degree or another, providing a new supply of “stem cells,” or cells at the beginning of a certain sequence of differentiation. These more numerous cells then must find a hospitable environment in which to develop and adapt. If the proper support can't be found, then they will be recycled, like the unfed cells in the brain of a fetus. If we imagine the course of development as a summary of evolution (“ontogeny recapitulating phylogeny”), then the egg, as it “unscrambles” itself in embryonic development, passing through stages resembling jelly fish, worm, fish, reptile, bird, baboon, keeps finding that the available energy allows it to, in effect, say “I want this, I don't want that,” until it emerges as a human baby, saying “I want,” and begins eating and learning, and with luck continues the unscrambling, or self-actualization.. Degenerative aging, rather than being “physically derived from the properties of time,” seems to be produced situationally, by various types of contamination of our energy supply. Unsaturated fats, interacting with an excess of iron and a deficiency of oxygen or usable energy, redirect our developmental path.
雌性激素在生物体中与水有特殊的关系。它与卵细胞的形成密切相关，在它活动的地方，它增加了水的数量，显然，也增加了水的无序性。我认为，它的功能是促进再生，就像Zotin的计划一样，通过增加熵，或“扰乱动物”。它促进再生的方式是通过促进水的吸收，刺激细胞分裂，并在某种程度上消除分化状态，提供新的“干细胞”，或在某个特定序列分化的开始细胞。这些数量更多的细胞必须找到一个适宜的环境来发展和适应。如果找不到合适的支持，它们就会被循环利用，就像胎儿大脑中未被喂养的细胞一样。如果我们想象的发展进化的摘要(“个体发生学概括发展史”),鸡蛋,胚胎发育的“整理”本身,通过阶段像水母,虫,鱼,爬行动物,鸟类,狒狒,不断发现可用的能量使得它,实际上,说“我想要这个,直到它变成人类婴儿，说“我想要”，并开始进食和学习，如果幸运的话，继续整理，或自我实现。退化性衰老不是“从时间的物理特性中衍生出来的”，似乎是由我们的能源供应受到各种类型的污染而产生的。不饱和脂肪与铁的过量和氧气或可用能量的缺乏相互作用，改变了我们的发展道路。
The saturated fats, in themselves, seem to have no “signalling” functions, and when they are naturally modified by our desaturating enzymes, the substances produced behave very differently from the plant-derived “eicosanoids.” As far as their effects have been observed, it seems that they are adaptive, rather than dysadaptive. All of the factors that affect the brain of a fetus should be examined in relation to the aging brain. Besides estrogen and fats, I am thinking of oxygen and carbon dioxide, glucose, iron and calcium, cholesterol, progesterone, pregnenolone, DHEA, the endorphins, GABA, thyroid, and vitamin A. An additional factor, endotoxin poisoning, eventually tends to intervene during stress and aging, exacerbating the trend begun under the influence of the other factors.
饱和脂肪本身似乎没有“信号”功能，当它们被我们的去饱和酶自然改变时，产生的物质的行为与植物衍生的“二十烷类物质”非常不同。就观察到的影响而言，它们似乎是有适应性的，而不是无适应性的。所有影响胎儿大脑的因素都应该与大脑衰老相关。除了雌激素和脂肪，我还想到了氧气和二氧化碳、葡萄糖、铁和钙、胆固醇、孕酮、孕烯醇酮、DHEA、内啡肽、GABA、甲状腺和维生素A。另外一个因素，内毒素中毒，最终倾向于干预压力和衰老，这一趋势在其他因素的影响下开始恶化。
IV. FALSE SIGNALS FROM THE ENVIRONMENT
来自环境的错误信号
The environment can be supportive, but it can also divert development from an optimal course.
环境可能是有利的，但它也可能使发展偏离最佳路线。
Passively taking whatever you are given, by history and nature, is entropic; choosing intelligently from possible diets, selecting courses of action, will create pattern and reduce entropy. If education contains an element of choice and self-actualization, then the results seen in several Alzheimer's studies could have a significance larger than what has been suggested by the investigators. A diagnostic bias has been reported to result from the use of standardized tests based on vocabulary, because education increases vocabulary, and tends to cover up the loss of vocabulary that occurs in dementia. In the Framingham study, it was concluded that there was a real association of lower educational level with dementia, but the suggestion was made that self-destructive practices such as smoking were more common among the less educated.
被动地接受历史和自然给予你的一切，是熵;从可能的饮食中明智地选择，选择行动路线，将创造模式并减少熵。如果教育包含选择和自我实现的元素，那么在几项阿尔茨海默氏症研究中所看到的结果可能比研究者们所建议的更有意义。据报道，使用基于词汇的标准化测试产生了诊断偏差，因为教育增加了词汇量，并往往掩盖了痴呆症中词汇量的减少。在弗雷明汉的研究中，研究人员得出结论，受教育程度较低确实与痴呆症有关联，但也有人提出，吸烟等自我毁灭行为在受教育程度较低的人群中更为常见。
The Seattle study of the patients in a health maintenance organization showed a very distinct difference in educational level between the demented and the non-demented, both of whom had roughly similar frequency of prescriptions for estrogen. The features that seemed important to me, that weren't discussed by the authors, were that the demented women had a much lower rate of progestogen use, and a much higher incidence of hysterectomy, which interferes with natural progesterone production. Although Brenner, et al., in the Seattle study concluded that “this study provides no evidence that estrogen replacement therapy has an effect on the risk of Alzheimer's disease in postmenopausal women,” they reported that “Current estrogen use of both the oral and the vaginal routes had odds ratios below 1, while former use of both types yielded odds ratios above 1….” (They seem to neglect the fact that Alzheimer's-type disease in old people has a long developmental history, so it is precisely the “former” use that is relevent. 31% of the demented women had formerly used estrogen, and only 20% of the control group. Since estrogen is a brain excitant, present use creates exactly the same sort of effect on verbal fluency and other signs of awareness of the environment that a little cocaine does. Anyone who neglects this effect is probably deliberately constructing a propaganda study.)
西雅图的一项健康维护组织对病人的研究表明，精神错乱和非精神错乱患者的受教育程度有非常明显的差异，两个人开雌激素处方的频率大致相同。对我来说似乎很重要，但作者们没有讨论的特征是，精神错乱的女性使用孕激素的比例要低得多，子宫切除术的发生率要高得多，这干扰了自然孕激素的生成。尽管Brenner等人在西雅图的研究中得出结论，“这项研究没有提供证据表明雌激素替代疗法对绝经后妇女患阿尔茨海默病的风险有影响，”他们报告说:“目前口服和阴道注射雌激素的比值比低于1，而以前两种方式使用雌激素的比值比高于1….。”(他们似乎忽略了一个事实，那就是老年痴呆症在老年人中有很长的发展历史，所以这正是“前”的使用是相关的。31%的精神错乱女性曾经使用过雌激素，而对照组只有20%。因为雌性激素是一种大脑兴奋剂，现在使用它对语言流利程度和其他环境意识的影响与少量可卡因完全相同。任何忽视这一效应的人可能是在故意构建一项宣传研究。)
This observation, that the demented had 155% as much former estrogen use as the normal group, as well as the difference in rates of progestogen use (normal patients had 50% more progestogen use than demented) and hysterectomy (demented had 44.1% vs. 17% in the normals, i.e., 259% as many; the incidence of hysterectomies after the age of 55, which is a strong indication of a natural excess of estrogen, in the demented was 374% of the incidence in the non-demented), should call for a larger study to clarify these observatons, which tend to indicate that exposure to estrogen in middle-age increases the risk of Alzheimer's disease in old age, and that even medical progestogens offer some protection against it..
该观察发现，痴呆患者使用前雌激素的数量是正常组的155%，以及孕激素使用率(正常患者孕激素使用率比痴呆患者多50%)和子宫切除术(痴呆患者为44.1%，正常人为17%，即259%;55岁以后的子宫切除术的发生率，这是一个强烈的迹象，自然过量的雌激素，在痴呆的发生率是374%的非痴呆)，应该呼吁更大的研究来澄清这些观察，这表明，中年时接触雌激素会增加老年时患阿尔茨海默病的风险，甚至医学上的黄体酮也能提供一定的保护。
(Although this study might have been bigger and better, it is far better than the junk-studies that have been promoted by the pharmaceutical publicity machine. I have seen or heard roughly 100 mentions of the pro-estrogen anti-scientific “studies,” and none mentioning this one.)
(尽管这项研究的规模可能更大，效果也更好，但它比那些由制药宣传机器推动的垃圾研究要好得多。我已经看到或听到了大约100个关于支持雌激素的反科学的“研究”，但没有一个提到这个。)
D. E. Brenner, et al., Postmenopausal estrogen replacement therapy and the risk of Alzheimer's disease: A population-based case-control study, 绝经后雌激素替代疗法与阿尔茨海默病的风险:一项基于人群的病例对照研究
“ Am. J. Epidemiol. 140, 262-267, 1994. “Women tend to have higher age-specific prevalence and incidence rates of Alzheimer's disease than do men.” 与男性相比，女性的老年痴呆症的患病率和发病率在年龄上往往更高。
A.F. Jorm, The Epidemiology of Alzheimer's disease and related disorders, Chapman and Hall, London, 1990, and W. A. Rocca, et al., Ann. Neurol. 30, 381-190, 1991.
H. C. Liu, et al., “Performance on a dementia screening test in relation to demographic variables–study of 5297 community residents in Taiwan,”痴呆筛查测试与人口统计学变量的关系——对台湾5297名社区居民的研究
Arch. Neurol. 51(9), 910-915, 1994. “Commonly used dementia screening tests may be unfair to poorly educated individuals, especially women and rural residents.”
“通常使用的痴呆症筛查测试可能对教育程度低的人不公平，尤其是女性和农村居民。”
SIGNALS IN THE ABSTRACT
摘要中的信号
When I taught endocrinology, I annoyed my tidy-minded students by urging them to consider the potential hormone-like action of everything in the body, and to think of layers of control, ranging from sugar, salt, and carbon dioxide, through the “official hormones,” to complex nervous system actions such as expectancy, and biorhythms. Certain things that are active in very important processes deserve special attention as “signals,” but they still have to be understood in context. In this sense, we can think of Ca2+ as a signal substance, in its many contexts; it is strongly regulated by the cell's energy charge. Magnesium and sodium antagonize it in certain situations. Linoleic acid, linolenic acid, arachidonic acid: Their toxicity is potentially prevented by the Mead acids, and their eicosanoid derivatives, which behave very differently from the familiar prostaglandins, as far as they have been compared; can be drastically reduced by dietary changes. Prostaglandins, prostacyclin, thromboxane: Formation is blocked by aspirin and other antiinflammatory drugs.
当我教内分泌学,惹恼了我缜密的学生通过敦促他们考虑的潜在种行动在体内的一切,和认为层控制,从糖,盐,和二氧化碳,通过“官方激素”等复杂神经系统的行为预期,和生物节律。在非常重要的过程中，某些活跃的东西作为“信号”值得特别注意，但它们仍然需要在上下文中理解。在这个意义上，我们可以把Ca2+看作是一种信号物质，在很多情况下;它受到细胞能量电荷的强烈调节。镁和钠在某些情况下可以拮抗它。亚油酸、亚麻酸、花生四烯酸:它们的毒性可以被米德酸和它们的二十烷类衍生物所预防，这些衍生物的性能与我们熟悉的前列腺素非常不同，就它们的比较而言;可以通过改变饮食来大幅减少前列腺素、前列环素、血栓素:阿司匹林和其他抗炎药物可阻止其形成。
Adenosine: Sleep inducing protective effect. Adenosine is structurally very similar to inosine, another natural substance (found in meat, for example) which is a component of “inosiplex,” an antiviral drug (Brown and Gordon, Fed. Proc. 29, 684, 1970, and Can. J. Microbiol. 18, 1463, 1972) or immunostimulant which has also been found to have an anti-senility effect (Doty and Gordon, Fed. Proc. 29). Adenosine is a free radical scavenger, and protects against calcium and glutamate excitotoxicity. (I. Yokoi, et al., “Adenosines scavenged hydroxyl radicals and prevented posttraumatic epilepsy,” Free Radical Biol. Med. 19(4), 473-479, 1995; M. P. Abbracchio, et al., “Adenosine A(1) receptors in rat brain synaptosomes: Transductional mechanisms, efects on glutamate release, and preservation after metabolic inhibition,” Drug Develop. Res. 35(3), 119-129, 1995.) It also appears to protect against the relative hyperventilation that wastes carbon dioxide, and endotoxin can interfere with its protective action. Guanosine, in this same group of substances, might have some similar properties. Thymidine and cytidine, which are pyrimidine-based, are endogenous analogs of the barbiturates, and like them, they might be regulators of the cytochrome P450 enzymes. Uridine, in this group, promotes glycogen synthesis, and is released from bacteria in the presence of penicillin.
腺苷:有睡眠保护作用。腺苷在结构上与肌苷非常相似，肌苷是另一种天然物质(例如，存在于肉类中)，是抗病毒药物“肌苷复合体”的组成部分(Brown and Gordon, Fed. Proc. 29,684, 1970, Can.)。J. Microbiol. 18, 1463, 1972)或免疫刺激剂，也被发现有抗衰老的作用(Doty和Gordon, Fed. Proc. 29)。腺苷是一种自由基清除剂，保护钙和谷氨酸的兴奋毒性。(I. Yokoi等，“腺苷清除羟自由基和预防创伤后癫痫，”Free Radical Biol。医学19(4)，473-479,1995;“大鼠脑突触小体中的腺苷A受体:转导机制、对谷氨酸释放的影响和代谢抑制后的保存”，《药物开发》。参考文献(3)，199 - 199,1995。它似乎还能防止相对过度通气(过度通气会浪费二氧化碳)，而内毒素会干扰它的保护作用。鸟苷，在同一组物质中，可能有一些相似的性质。基于嘧啶的胸腺嘧啶和胞嘧啶是巴比妥酸盐的内源性类似物，与它们一样，它们可能是细胞色素P450酶的调控因子。尿苷促进糖原合成，并在青霉素存在的细菌中释放出来。
Iron: Regulator of mRNA stability, heme synthesis; reacts with reductants and unsaturated oils, to produce free radicals and lipid peroxides; its absorption is increased by estrogen, hypothyroidism, anemia or lack of oxygen. Glutamate and aspartate, excitotoxins, and GABA, an inhibitory transmitter.
铁:mRNA稳定性的调节因子，血红素合成;与还原剂和不饱和油反应，产生自由基和脂质过氧化物;雌激素、甲状腺机能减退、贫血或缺氧会增加其吸收。谷氨酸和天冬氨酸，兴奋毒素，GABA，一种抑制性递质。
These have metabolic links with each other, with ammonia, and with stress and energy metabolism.
它们之间有代谢联系，与氨、压力和能量代谢有关。
Estrogen and acetylcholine, excitotoxins; see Savolainen, et al., 1994. The information on this is overwhelmingly clear, and the publicity to the contrary is a horrifying example of the corruption of the mass media by the drug industry.
雌激素和乙酰胆碱，兴奋性毒素;见Savolainen等，1994。这方面的信息是非常清楚的，而相反的宣传是一个令人震惊的例子，说明了大众媒体被制药业所腐化。
Endorphins: Stress induced, laterally specific, involved in estrogen action, antagonized by naloxone and similar anti-opiate drugs. I have proposed that the endorphins can cause or sustain some of the symptoms of aging. Naloxone appears to be a useful treatment for senility. E. Roberts, Ann. N. Y. Acad. Sci. 396, 165, 1982; B. Reisberg, et al., N. Engl. J. Med. 308, 721, 1983.
内啡肽:应激诱导，侧特异性，参与雌激素作用，可被纳洛酮和类似的抗阿片类药物拮抗。我已经提出内啡肽可以引起或维持衰老的一些症状。纳洛酮似乎是治疗衰老的有效药物
Endotoxin: Antimitochondrial action, causes elevation of estrogen. It synergizes with unsaturated fats, and naloxone opposes some of its toxic effects.
内毒素:抗线粒体作用，引起雌激素升高。它与不饱和脂肪协同作用，纳洛酮对抗它的一些毒性作用。
Urea, cholesterol: Structural stability of proteins and lipid-protein complexes.
尿素、胆固醇:蛋白质和脂蛋白复合物的结构稳定性。
Things that act directly on the water structure: I think all of the natural regulators have an effect on the structure of water, but some unusual substances seem to act primarily on the water. Noble gases, for example, have no chemical effects, but they tend to form “cages” of water molecules around themselves. Camphor, adamantane, and the antiviral drug amantadine, probably have a similar water-structuring effect, and amantadine, which is widely used as a therapy in Parkinson's disease, has an anti-excitotoxic action.
直接作用于水结构的东西:我认为所有的自然调节物都对水的结构有影响，但一些不寻常的物质似乎主要作用于水。例如，稀有气体没有化学效应，但它们倾向于在自身周围形成水分子的“笼子”。樟脑、金刚烷和抗病毒药物金刚烷胺可能具有类似的水结构作用，而金刚烷胺被广泛用于治疗帕金森病，具有抗兴奋毒性作用。
Raymond Peat, Ph.D.
Copyright 1997
SELECTED REFERENCES
S. Rose, “Genuine genetics or conceited convenience?” Trends in Neuro. Sci. 17(3), 105, 1994. F. P. Monnet, et al., “Neurosteroids, via sigma receptors, modulate the [H3]norepinephrine release evoked by N-methyl-D-aspartate in the rat hippocampus,” P.N.A.S. (USA) 92(9), 3773-3778, 1995. ”…progesterone may act as a sigma antagonist.“ J. L. Sanne and K. E. Krueger, “Expression of cytochrome P450 side-chain cleavage enzyme and 3 beta-hydroxysteroid dehydrogenase in the rat central nervous system: A study by polymerase chain reaction and in situ hybridization,” J. of Neurochemistry 65(2), 528-536, 1995. V. V. Zakusov and R. U. Ostrovskaya, “Increased resistance of mice to hypoxia under the influence of tranquilizers of the benzodiazepine series,” Byulletan Eksperimentalnoy Biologii i Meditsiny 71(2), 45-47, 1971. [The protection was not from the sedative effects, “Rather, the protective effect of these compounds is attributed to some specific intervention in the metabolism whereby the sensitivity of the tissues to oxygen insufficiency is reduced. …the cortical structures of the brain especially appear to derive enhanced resistance to oxygen deficiency.”] A. I. Zotin, “Aging and rejuvenation from the standpoint of the thermodynamics of irreversible processes,” Priroda 9, 49-55, 1970. [The process of aging ”…is manifested by a decrease in entropy and…also by a continuous decrease in the rate of heat production.. The organism exhibits two types of approaches to a steady state: (i) constitutive movement of the system to the final steady state and (ii) inducible return of the system to the current steady state after deviating under the influence of internal or external factors. Oogenesis represents a constitutive deviation from the steady state; entropy reaches a level sufficient for the start of development and passage of the living system into the state of constitutive approach to the final steady state. From the standpoint of the thermodynamic theory of development, oogenesis reflects the process of regeneration of the system. In all other stages of life there is only the aging process accompanied by a decrease in entropy.“ M. M. Tikhomirova, et al., “Mechanisms underlying the resistance of genetic material of the animal cell to stress treatment,” Genetika 30(8), 1092-1104, 1994. ”…these studies prove that the formation of a mutation is a multistage process involving many cell and organism systems…which are affected by environmental factors…. They can hinder or accelerate the mutational process, in this way providing both a superadditive effect and adaptive response. Recent studies deal with a universal system of heat shock proteins, which is involved in the maintenance of resistance of genetic material and genetic processes in the cell.“ Gross, “Reproductive cycle biochemistry,” Fertility & Sterility 12(3), 245-260, 1961. “The maintenance of an environment conducive to anaerobic metabolism–which may involve the maintenance of an adequate supply of the substances that permit anaerobiosis…seems to depend primarily upon the action of estrogen.” “Glycolytic metabolism gradually increases throughout the proliferative phases of the cycle, reaching a maximum coincident with the ovulation phase, when estrogen is at a peak. Following this, glycolysis decreases, the respiratory mechanisms being more active during the secretory phase. Eschbach and Negelein showed the metabolism of the infantile mouse uterus to be less anaerobic than that of the adult. If estrogen is administered, however, there is a 98 per cent increase in glycolytic mechanisms.”“The effect of the progestational steroids may be such as to interfere with the biochemical pattern required for support of this anaerobic environment.” M. A. G. Sissan, et al., “Effects of low-dose oral contraceptive oestrogen and progestin on lipid peroxidation in rats,” J. of International Med. Res. 23(4), 272-278, 1995. “The levels of lipid peroxides, free fatty acids and glutathione in the liver, and of serum ceruloplasmin increased significantly with oestrogen treatment. Lipid peroxides (in the liver only), and serum ceruloplasmin decreased significantly when progestin was administered. The activities of superoxide dismutase and catalase decreased significantly in the oestrogen group…but increased in the progestin group.” A. Jendryczko, et al., “Effects of two low-dose oral contraceptives on erythrocyte superoxide dismutase, catalase and glutathione peroxidase activities,” Zentralbl. Gynakol. (Germany) 115(11), 469-472, 1993. “These data suggest that low-dose oral contraceptives, by decreasing the activities of antioxidant enzymes and by enhancing the lipid peroxidation, increase the risk of cardiovascular disease.” J. W. Olney, “Excitotoxins in foods,” Neurotoxicology 15(3), 535-544, 1994. “The most frequently encountered food excitotoxin is glutamate which is commercially added to many foods despite evidence that it can freely penetrate certain brain regions and rapidly destroy neurons by hyperactivating the NMDA subtype of glutamate receptor.” K. Savolainen, et al., “Phosphoinositide second messengers in cholinergic excitotoxicity,” Neurotoxicology 15(3), 493-502, 1994. “Acetylcholine is a powerful excitotoxic neurotransmitter in the brain. By stimulating calcium-mobilizing receptors, acetylcholine, through G-proteins, stimulates phospholipase C and cause the hydrolysis of a membrane phospholipid….” “Inositol-1,4,5-triphosphate is important in cholinergic neuronal stimulation, and injury. Cholinergic agonists cause tonic-clonic convulsions which may be either transient or persistent. Even short-term cholinergic convusions may be associated with neuronal injury, especially in the basal forebrain and the hippocampus. Cholinergic-induced convulsions also elevate levels of brain calcium which precede neuronal injury. Female sex and senescence increase the sensitivity of rats to cholinergic excitotoxicity.” “Furthermore, glutamate increases neuronal oxidative stress….” L. N. Simanovskiy and Zh. A. Chotoyev, “The effect of hypoxia on glycogenolysis and glycolysis rates in the rat brain,” Zhurnal Evolyutsionnoy Biokhimii i Fiziologii 6(5), 577-579, 1970. “Glycogenolysis and glycolysis in the whole brain of young and old rats were studied at sea level and under hypoxic conditions in a low-pressure chamber or at an altitude of 3,200 meters. The rate of carbohydrate metabolism increaased during postnatal development. In the absence of hypoxia, the rate of accumulation of lactate from either glycogen or glucose increases with maturation of the animals. The brain of young rats consumes primarily glycogen, particularly under anaerobic conditions.” “Adaptation of mature rats to intermittent hypoxia is related to an increase in glycolysis, whereas adaptation of rats to high altitudes results in an increase in glycogenolysis. The type of carbohydrate metabolism is thus similar to the metabolism characteristic of the early stages of ontogenesis.” Ye. Sadovskiy, “For the prolongation of human life,” Sovetskaya Belorussiya 23, page 4, Dec. 1970. ”…the accumulation of metals in the organism with age is one of the most important factors in the development of the aging process.“ Cerebral ischemia (and several other imbalances, relating to steroid regulation, shock) might be relieved by naloxone: D. S. Baskin and Y. Hosobuchi, Lancet ii, 272-275, 1981. V. Reynolds, et al., “Heart rate variation, age, and behavior in subjects with senile dementia of Alzheimer type,” Chronobiol. Int. 12(1), 37-45, 1995. ”…circadian rhythm of SDAT may be more often unimodal than that of normal subjects of similar age, and that phase shift of the endogenous, clock-mediated component of the rhythm (with higher heart rate at night) is to be expected in a proportion of individuals with SDAT.“ 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.“ 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.” G. C. Ness and Z. H. Zhao, “Thyroid hormone rapidly induces hepatic LDL receptor mRNA levels in hypophysectomized rats,” Arch. Biochem. Biophys. 315(1), 199-202, 1994. E. M. Mutisya, et al., “Cortical cytochrome oxidase activity is reduced in Alzheimer's disease,” J. Neurochem. 63(6), 2170-2184, 1994. “These results provide further evidence of a cytochrome oxidase defect in Alzheimer's disease postmortem brain tissue. A deficiency in this key energy-metabolizing enzyme could lead to a reduction in energy stores and thereby contribute to the neurodegenerative process.” G. J. Bu, et al., “Subcellular localization and endocytic function of low density lipoprotein receptor-related protein in human glioblastoma cells,” J. Biol. Chem. 269(47), 29874-29882, 1994. “Our results thus strongly suggest several potential roles for LRP in brain protein and lipoprotein metabolism, as well as control of extracellular protease activity.” V. Vandenbrouck, et al., “The modulation of apolipoprotein E gene expression by 3,3'-5-triiodothyronine in HepG(2) cells occurs at transcriptional and post-transcriptional levels,” Eur. J. Biochem. 224(2), 463-471, 1994. ”…thyroid hormone stimulated apoE gene transcription threefold in 24 hours.“ T. Yamada, et al., “Apolipoprotein E mRNA in the brains of patients with Alzheimer's disease,” J. Neurol. Sci. 129(1), 56-61, 1995. In A.D. Apo E “was decreased in relation to the apoE-epsilon 4 gene dosage.” “AD patients who had long survival times showed high expression of apoE and low expression of GFAP [glial fibrillary acidic protein]. These results suggest that apoE suppresses the progression of AD, including gliosis, in the brain.” G. P. Jarvik, et al., “Genetic influences on age-related change in total cholesterol, low density lipoprotein-cholesterol, and triglyceride levels: Longitudinal apolipoprotein E genotype effects,” Genet. Epidemiol. 11(4), 375-384, 1994. “Apo E is a component of LDL, is a ligand for the LDL receptor, and apo E genotype has been consistently associated with variation in mean levels of total cholesterol and LDL-C….” With aging, total cholesterol and LDL-C became significantly lower in the “epsilon 4 genotype” group; this is the group at risk for AD. S. Miller and J. M. Wehner, “Cholesterol treatment facilitates spatial learning performance in DBA/2Ibg mice,” Pharmacology Biochemistry and Behavior 49(1) 257-261, 1994. “Our results suggest that subchronic treatment with the steroid hormone precursor, cholesterol, enhances spatial learning performance in DBA mice.” A. D. Roses, “Apolipoprotein E affects the rate of Alzheimer disease expression: beta-amyloid burden is a secondary consequence dependent on ApoE genotype and duration of disease,” J. Neuropathol. Exp. Neurol. 53(5), 429-437, 1994. T. Gunther and V. Hollriegl, “Increased protein oxidation by magnesium deficiency and vitamin E depletion,” Magnesium-Bull. 16(3), 101-103, 1994. F. Oyama, et al., “Apolipoprotein E genotype, Alzheimer's pathologies and related gene expression in the aged population,” Mol. Brain Res. 29(1), 92-98, 1995. ”…ApoE4/4 accelerates and ApoE2/3 decelerates the development of the AD pathologies in the aged brain….“ M. L. C. Maatschieman, et al., “Microglia in diffuse plaques in hereditary cerebral hemorrhage with amyloidosis (Dutch). An immunohistochemical study,” J. Neuropathol. Exp. Neurol. 53(5), 483-491, 1994. “Microglia are intimately associated with congophilic plaques in Alzheimer's disease….” “Intensely immunoreactive microglia with enlarged cell bodies and short, thick processes clustered in congophilic plaques.” J. Poirier, “Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease,” Trends Neurosci. 17(12), 525-530, 1994. “The coordinated expression of ApoE and its receptor…[low density lipoprotein (LDL)] receptor, appears to regulate the transport of cholesterol and phospholipids during the early and intermediate phases of the reinnervation process.” ”…a dysfunction of the lipid-transport system associated with compensatory sprouting and synaptic remodeling could be central to the AD process.“ P. H. Chan and R. A. Fishman, “Brain edema: Induction in cortical slices by polyunsaturated fatty acids,” Science 201, 358-369, 1978. “This cellular edema was specific, since neither saturated fatty acids nor a fatty acid containing a single double bond had such effect.” R. Nogues, et al., “Influence of nutrition, thyroid hormones, and rectal temperature on in-hospital mortality of elderly patients with acut illness,” Am J Clin Nutr 61(3), 597-602, 1995. “Serum albumin, body weight, and total T3 concentration were higher in survivors than in nonsurvivors.” “Mild hypothermia was a good predictor of death. Hypoalbuminemia and hypothermia were associated with low T3 and high rT3 values.” R. C. Vannucci, et al., “Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: An experimental study in the immature rat,” Pediatrics 95(6), 868-874, 1995. 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.” J. S. Jensen, et al., “Microalbuminuria reflects a generalized transvascular albumin leakiness in clinically healthy subjects,” Clin. Sci. 88(6), 629-633, 1995. “It is suggested that the observed transvascular leakiness, in addition,may cause increased lipid insudation to the arterial walls.” C. Nilsson, et al., “The nocturnal increase in human cerebrospinal fluid production is inhibited by a beta(1)-receptor antagonist,” Amer. J. Physiol.-Regul. Integr. C 36(6), R1445-R1448, 1994. D. L. Williams, et al., “Cell surface 'blanket' of apolipoprotein E on rat adrenocortical cells,” J. Lipid Res. 36(4), 745-758, 1995. ”…the zona fasciculata cell is encircled or covered with apoE on all faces of the cell. …this cell surface 'blanket' of apoE participates in the uptake of lipoprotein cholesterol by either the endocytic or selective uptake pathways.“ C. A. Frye and J. D. Sturgis, “Neurosteroids affect spatial reference, working, and long-term memory of female rats,” Neurobiol. Learn. Memory 64(1), 83-96, 1995. [Female rats take longer to acquire a spatial task during behavioral estrus.)] 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. Robel, et al., “Biosynthesis and assay of neurosteroids in rats and mice: Functional correlates,” J. Steroid Biochem. Mol. Biol. 53(1-6), 355-360, 1995. [Discusses the effects of pregnenolone and progesterone on aggression and learning. The animals which learned most easily had the highest levels of pregnenolone sulfate.] K. W. Lange and P. Riederer, “Glutamatergic drugs in Parkinson's disease,” Life Sci. 55(25-26, 2067-2075, 1994. ”…excitatory amino acids such as glutamate are involved in the pathophysiological cascade of MPTP…-induced neuronal cell death.“ “The 1-amino-adamantanes amantadine and memantine have recently been shown to be non-competitive NMDA antagonists and are widely used in Europe as antiparkinsonian agents.” R. A. Wallis, et al., “Glycine-induced CA1 excitotoxicity in the rat hippocampal slice,” Brain Res. 664(1-2) 115-125, 1994. K. Ossawska, “The role of excitatory amino acids in experimental models of Parkinson's disease,” J. Neural Transm.-Parkinsons 8(1-2_, 39-71, 1994. G. S. Roth, et al., “Membrane alterations as causes of impaired signal transduction in Alzheimer's disease and aging,” Trends Neurosci. 18, 203-206, 1995. “Reconstituted lipid membranes from cortical gray matter of AD brain samples were significantly thinner (that is, had less microviscosity) than corresponding age-matched controls.” “This change in membrane width correlated with a 30% decrease in the moles of cholesterol:phospholipid.” “Addition of cholesterol restored the membrane width to that of the age-matched control samples.” T. Reed, et al., “Lower cognitive performance in normal older adult male twins carrying the apolipoprotein E epsilon 4 allele,” Arch. Neurol. 51(12), 1189-1182, 1994. S.Y. Tan and M. B. Pepys, “Amyloidosis,” Histopathology 25(5), 403-414, 1994. ”…abnormal protein fibrils which are derived from different proteins in different forms of the disease. Asymptomatic amyloid deposition in a variety of tissues is a universal accompaniment of ageing, and clinical amyloidosis is not rare. Intracerebral and cerebrovascular beta-protein amyloid deposits are a hallmark of the pathology of … Alzheimer's disease….“ “Amyloid deposits are in a state of dynamic turnover and can regress if new fibril formation is halted.” A. V. Sirotkin, “Direct influence of melatonin on steroid, nonapeptide hormones, and cyclic nucleotide secretion by granulosa cells isolated from porcine ovaries,” J. Pineal Res. 17(3), 112-117, 1994. “It was found that melatonin is able to inhibit progesterone and stimulate estradiol secretion.” “Some inhibition of vasopressin and cAMP and significant stimulation of cGMP also resulted from melatonin treatment.” R. M. Sapolsky, “Glucocorticoid toxicity in the hippocampus: Reversal with supplementation with brain fuels,” J. Neurosci. 6, 2240-2245, 1986. R. M. Sapolsky, “Glucocorticoids, hippocampal damage and the glutaminergic synapse,” Prog. Brain Res. 86, 13-23, 1990. M. Schwartz, et al., “Growth-associated triggering factors and central nervous system regeneration,” p. 47 in Trophic Factors and the Nervous System, edited by L. A. Horrocks, et al., Raven Press, NY, 1990. R. W. Ordway, et al., “Direct regulation of ion channels by fatty acids,” Trends Neurosci. 14, 96-100, 1991. H. G. P. Swarts, et al., “Binding of unsaturated fatty acids to Na+,K+-ATPase leading to inhibition and inactivation,” Biochim. Biophys. Acta 1024, 32-40, 1990. G. Autore, et al., “Essential fatty acid-deficient diet modifies PAF levels in stomach and duodenum of endotoxin-treated rats,” J. Lipid Mediators Cell Signalling 9, 145-153, 1994. J. Rafael, et al., “The effect of essential fatty acid deficiency on basal respiration and function of liver mitochondria in rats,” J. Nutr. 114, 255-262, 1984. A. M. Weiner, et al., “Nonviral retroposons, genes, pseudogenes, and transposable elements generated by the reverse flow of genetic information,” Ann. Rev. Biochem. 55, 631-661, 1986. I. Zs.-Nagy, “Semiconduction of proteins as an attribute of the living state: The ideas of Albert Szent-Gyorgyi revisited in light of the recent knowledge regarding oxygen free radicals,” Exp. Gerontology 30(3-4), 327-335, 1995. “In this assumption, the continuous radical flux is as important for the maintenance of the living state, as the voltage power supply is essential for the functioning of the computer.”