The problem of Alzheimer's disease as a clue to immortality
- Part 1
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
The problem of Alzheimer's disease as a clue to immortality
- Part 2
痴呆难题-永生线索（第二部分）
by Raymond Peat
V. HORMONE IMBALANCE, LEADING TO FAILURE OF PROTECTIVE INHIBITION AND ALZHEIMER'S DISEASE
五、荷尔蒙失衡，导致保护性抑制失效及阿尔茨海默病
“All cell death is characterized by an increase of intracellular calcium….” “Increase of cytoplasmic free calcium may therefore be called 'the final common path' of cell disease and cell death. Aging as a background of diseases is also characterized by an increase of intracellular calcium. Diseases typically associated with aging include hypertension, arteriosclerosis, diabetes mellitus and dementia.”
所有细胞死亡的特征是细胞内钙的增加….因此，细胞质游离钙的增加可被称为细胞疾病和细胞死亡的'最终共同途径'。作为疾病背景的衰老也以细胞内钙的增加为特征。通常与衰老相关的疾病包括高血压、动脉硬化、糖尿病和痴呆。”
T. Fujita, “Calcium, parathyroids and aging,” in Calcium-Regulating Hormones. 1. Role in Disease and Aging, H. Morii, editor, Contrib. Nephrol. Basel, Karger, 1991, vol. 90, pp. 206-211.
THE FUNCTION OF ENERGY
能量的作用
Most people are slightly demented now and then, when they are very sleepy or tired, or sick, or drunk, or having a hormone imbalance or extreme anxiety state. Sometimes physicians have described people as demented, implying that the condition would never improve, when the person was depressed or hypothyroid. If the person has a history of epilepsy, or is very old, the physician is more likely to diagnose dementia than if the same loss of mental function occurs in a younger person without a history of a nervous disorder. Even people with less education are at increased risk of being diagnosed as “demented.”
大多数人偶尔会有轻微的精神错乱，当他们非常困倦或疲劳，或生病，或醉酒，或有激素失衡或极端焦虑状态时。有时，当病人抑郁或甲状腺机能减退时，医生会把病人描述为精神错乱，暗示病情永远不会好转。如果一个人有癫痫史，或者年纪很大，医生更有可能诊断出痴呆，而不是一个没有神经疾病史的年轻人出现同样的精神功能丧失。即使受教育程度较低的人被诊断为“精神错乱”的风险也在增加。
In 1976, I saw a 52 year-old woman who had the diagnosis of epileptic dementia. After 3 or 4 days of taking progesterone, her mental function returned to the extent that she could find her way around town by herself, and could work. A few months later, she returned to graduate school, got straight As and a master's degree. A few years later, a man in his 80s showed the classical signs of senile dementia, with childishness, confusion, self-centeredness, and unstable emotions. A few days after getting a mixture of thyroid, pregnenolone, and progesterone, his mind was again clear, and he was able to work on a research project he had set aside years before.
1976年，我见到一位52岁的妇女，她被诊断为癫痫性痴呆。服用黄体酮3到4天后，她的精神功能恢复到可以自己在城里找路，可以工作的程度。几个月后，她回到了研究生院，成绩全优并获得了硕士学位。几年后，一位80多岁的老人表现出典型的老年性痴呆症状，孩子气、困惑、以自我为中心，情绪不稳定。在服用了甲状腺、孕烯酮和孕酮的混合物几天后，他的头脑又恢复了清醒，能够从事多年前搁置的一个研究项目。
When the body temperature is very much below normal, mental functioning is seriously limited. I think the first question that should be asked about a demented person is “is this the cold brain syndrome, or is something else involved?” When it is known that the brain has shrunken drastically, and filled up with plaques and developed gliosis, we know that something more than a “cold brain” is involved, but we don't know how much function could be regained if the hormones were normalized. Every moment of malfunction probably leaves its structural mark. Early or late, it is good to prevent the functional errors that lead to further damage, and to give the regenerative systems an opportunity to work. Before the final “calcium death” described (above) by Fujita, there are many opportunities for intervening to stop or reverse the process. The older the person is, the more emphasis should be put on protective inhibition, rather than immediately increasing energy production. Magnesium, carbon dioxide, sleep, red light, and naloxone might be appropriate at the beginning of therapy.
当体温远远低于正常水平时，大脑功能就会受到严重限制。我认为关于一个精神错乱的人应该问的第一个问题是“这是冷脑综合症，还是其他的原因?”当我们知道大脑已经急剧萎缩，并且充满了斑块和神经胶质增生，我们知道这不仅仅是一个“冷大脑”的问题，但我们不知道如果激素恢复正常，能恢复多少功能。每一次故障都可能会留下结构性的痕迹。无论是早是晚，都能很好地防止导致进一步破坏的功能错误，并给再生系统一个工作的机会。在藤田(Fujita)所描述的最后“钙死亡”之前，有很多干预的机会来阻止或逆转这一过程。人越老，越应该强调保护性抑制，而不是立即增加能量的产生。镁、二氧化碳、睡眠、红光和纳洛酮可能在治疗开始时是合适的。
The resting state of a cell is a highly energized state. To the old Pavlovians, the resting state existed at two energy levels, and they applied the term “protective inhibition” generally to the depleted state (parabiosis) that occurs in exhaustion or coma, but I am using the phrase in a more general sense, that seems reasonable now that the concept of “excitotoxic” injury has become current. I mean it to include everything which protects against excitotoxic injury. This definition therefore has the virtue of being biochemically and physiologically very specific, while retaining the functional and therapeutic significance that it had for the Pavlovians. (My book, Mind and Tissue, and the chapter “A unifying principle” in Generative Energy, discussed the idea of the resting state and protective inhibition.)
细胞的静息状态是一个高能量状态。老巴甫洛夫,静息状态存在于两个能级,它们“保护性抑制”一词,通常适用于枯竭状态(异种共生)发生在疲惫或昏迷,但我使用这个短语从更一般的意义上说,这似乎是合理的,现在“兴奋性毒素”伤害的概念已成为当前。我指的是所有能防止兴奋性损伤的东西。因此，这一定义具有生物化学和生理上非常具体的优点，同时保留了巴普洛夫氏菌的功能和治疗意义。(我的书《心灵与组织》和《生成能量》中的“统一原则”一章讨论了静息状态和保护性抑制的概念。)
Ordinary healthy sleep is an example of restorative, protective inhibition. The energy charge, including levels of ATP, creatine phosphate, and glycogen storage, regulates many restorative enzyme systems. I have suggested (1975, J. Orthomol. Psychiatry) how the entropy-sensitivity or cold-inactivation of an enzyme could be involved in shifting the brain toward a state of inhibition. A recent publication (J. H. Benington and H. C. Heller, “Restoration of brain energy metabolism as the function of sleep,” Progress in Neurobiol. 45, 347-360, 1995) has proposed that reduction of energy charge and depolarization of cells act through adenosine secretion to restore glycogen stores. Since glycogen stores decrease with aging, this work supports the idea that protective inhibition is weakened with aging. (L. N. Simanovskiy and Zh. A. Chotoyev, “The effect of hypoxia on glycogenolysis and glycolysis rates in the rat brain,” Zhurnal Evolyutsionnoy Biokhimii i Fiziologii 6(5), 577-579, 1970.)
普通的健康睡眠就是恢复和保护性抑制的一个例子。能量充电，包括ATP、磷酸肌酸和糖原储存的水平，调节许多恢复酶系统。我建议(1975,J. Orthomol。(精神病学)一种酶的熵敏感性或冷灭活如何使大脑转向抑制状态。最近发表的一篇文章(J. H. Benington和H. C. Heller，“恢复大脑能量代谢作为睡眠的功能，”Neurobiol进展。45,347 -360,1995)提出，减少能量电荷和细胞去极化通过腺苷分泌来恢复糖原储存。由于糖原储存随着年龄的增长而减少，这项工作支持了保护性抑制随着年龄的增长而减弱的观点。Simanovskiy和Zh。A. Chotoyev，“缺氧对大鼠脑糖原分解和糖酵解率的影响”，journal Evolyutsionnoy Biokhimii i Fiziologii 6(5)， 577-579, 1970。
J. H. Benington and H. C. Heller, “Restoration of brain energy metabolism as the function of sleep,” Prog. in Neurobiology 45, 347-360, 1995. “…the conditions that have been demonstrated to stimulate adenosine release from neural tissue represent either increases in metabolic demand (…activation of excitatory receptors) or decreases in metabolic supply (hypoxia, ischaemia, hypoglycemia)….” “In the brain, adenosine-stimulated increases in potassium conductance produce hyperpolarization, thereby reducing neuronal responsiveness….” “Adenosine release is triggered globally in response to changes in cerebral energy homeostasis.” “A number of findings provide indirect support for the hypothesis that glycogen stores are depleted during waking and restored during sleep.” “Reduced availability of glycogen to astrocytes must…increase adenosine release….” “Because ATP concentration is 100-fold greater than AMP concentration, a minute decrease in cellular energy charge…is translated into a large proportional increase in extracellular adenosine cencentration….”
J. H. Benington和H. C. Heller，“恢复大脑能量代谢作为睡眠的功能”，Prog。在神经生物学45,347-360,1995。＂…已经被证明能够刺激神经组织释放腺苷的条件要么表现为代谢需求的增加(…兴奋性受体的激活)或代谢供给的减少(缺氧、缺血、低血糖)….”“在大脑中，受腺苷刺激的钾电导增加产生超极化，从而降低神经元的反应性….”“腺苷释放是对大脑能量稳态变化的全球反应。”“许多研究结果为糖原储存在清醒时被消耗，在睡眠时被恢复的假设提供了间接支持。”“减少糖原对星形胶质细胞的可用性必须……提高腺苷释放……”“因为ATP浓度是AMP浓度的100倍，细胞能量电荷每减少一分钟……转化为细胞外腺苷浓度的大比例增加….”
The terms “functional quiescence” and “G0 quiescence” are similar in meaning to the resting state; I think of cells in the state of “G0 quiescence” as being stem cells, waiting for use in regeneration, but I don't subscribe to the idea that they can't be reconstituted from functioning, differentiated cells. In plants, dedifferentiation is achieved fairly easily, and in the study of animal cells the trend in that direction seems very obvious, though many people keep saying that it just isn't possible. In general, the things such as lipid peroxidation or calcium influx which cause cell replication at one level, cause cell death at a higher level.
术语“功能性静止”和“G0静止”在意义上与静止状态相似;我认为处于“G0静止”状态的细胞是干细胞，等待着被用于再生，但我不同意这种观点，即它们不能从功能良好的分化细胞中重建。在植物中，去分化相当容易，在动物细胞的研究中，这个方向的趋势似乎非常明显，尽管许多人一直说这是不可能的。一般来说，脂质过氧化或钙内流在一个水平上引起细胞复制，在更高水平上引起细胞死亡。
Energy to resist stress makes quiescence possible, and prevents the deterioration of cells, of the sort that occurs in aging. O. Toussaint, et al., “Cellular aging and energetic factors,” Exp. Gerontology 30(1), 1-22, 1995. “Experiments performed with endothelial cells in the context of the ischemia-reperfusion toxicity of free radicals, also offer good examples of the impact of cell energy on cell resistance to these toxic molecules.” “…if a supplement of energy is given…the toxic effect of the free radicals is much reduced….”
抵抗压力的能量使安静成为可能，并防止细胞老化的发生。杜桑等，“细胞老化与活力因子”，《老年医学》30(1)，1-22,1995。“在自由基的缺血-再灌注毒性背景下进行的内皮细胞实验，也提供了细胞能量影响细胞抵抗这些有毒分子的良好例子。”＂…如果补充能量…自由基的毒性作用大大降低….“
The specific approaches of this orientation –to energize but quiet the brain–are diametrically opposed to some of the “therapies” for Alzheimer's disease that have been promoted recently by the drug industries: Things to increase stimulation, especially to increase cholinergic excitation; even the excitotoxic amino acids themselves and their analogs; and estrogen, which is a multiple brain excitant, proconvulsant, excitotoxic promoter, and anti-memory agent. Those product-centered publications stand out distinctly from the actual research.
这一方向的具体方法——激活但使大脑安静——与制药行业最近推广的一些治疗阿尔茨海默病的“疗法”截然相反:增加刺激，尤其是增加胆碱能兴奋;甚至兴奋毒性氨基酸本身及其类似物;还有雌激素，它是一种多种大脑兴奋剂、促惊厥剂、兴奋毒性促进剂和抗记忆剂。这些以产品为中心的出版物从实际研究中脱颖而出。
There are many energy-related vicious circles associated with aging, but the central one seems to be the fat-thyroid-estrogen-free-radical-calcium sequence, in which the ability to produce stabilizing substances including carbon dioxide and progesterone is progressively lost, increasing susceptibility to the unstable unsaturated fats.
衰老有许多与能量相关的恶性循环，但最主要的似乎是脂肪-甲状腺-雌激素-自由基-钙序列，在这个序列中，产生稳定物质(包括二氧化碳和孕酮)的能力逐渐丧失，增加了对不稳定不饱和脂肪的敏感性。
EFFECTS OF ESTROGEN AND UNSATURATED FATTY ACIDS
雌激素和不饱和脂肪酸的作用
Estrogen production is facilitated when tissue is cooler, and it lowers body temperature. Estrogen and the endorphins act together in many ways (including the behavior of estrus), and naloxone (the antagonist of morphine and the endorphins) raises body temperature and in other ways opposes estrogen. Naloxone has been found to improve the symptoms of demented people, and I have seen it quickly, and dramatically, improve the mental clarity of a 60 year old woman who had used estrogen. It, like clonidine (the anti-adrenaline drug), is a good candidate for controlling the hot flashes and other symptoms of menopause.
当组织温度较低时，雌激素的分泌就会加快，从而降低体温。雌激素和内啡肽在许多方面共同作用(包括发情行为)，纳洛酮(吗啡和内啡肽的拮抗剂)提高体温，并以其他方式对抗雌激素。人们发现纳洛酮能改善精神错乱患者的症状，我发现它能迅速、显著地改善一位使用雌激素的60岁妇女的思维清晰度。它和可乐定(一种抗肾上腺素的药物)一样，是控制潮热和其他更年期症状的好方法。
In various degenerative brain conditions, blood clotting has been implicated either as a cause or a complication. Many people are promoting unsaturated oils for their “anti-clotting” value, in spite of the older literature showing that they inhibit proteolytic enzymes and slow clot removal. Several newer publications have revealed other aspects of their involvement in thrombus formation. A. J. Honour, et al., “The effects of changes in diet on lipid levels and platelet thrombus formation in living blood vessels,” Br. J. Expt. Pathol. 59(4), 390-394, 1978–corn oil caused platelets to be more sensitive to ADP.
在各种退行性脑疾病中，血凝被认为是一个原因或并发症。许多人提倡不饱和油的“抗凝血”价值，尽管较早的文献表明它们抑制蛋白水解酶和减缓凝血清除。一些较新的出版物揭示了它们参与血栓形成的其他方面。A. J. Honour等，“饮食变化对活血管中血脂水平和血小板血栓形成的影响”，Br。[J. Expt. Pathol. 59(4)， 390- 394,1978—玉米油使血小板对ADP更敏感。
Although there is a lot of talk about “membrane fluidity,” as a desirable thing, and the loss of unsaturated lipids in the aged brain, there are some interesting observations related to “viscosity” in Alzheimer's disease. The platelets of Alzheimer's patients are less viscous, and lipids extracted from the brain are more fluid, and contain 30% less cholesterol than normal (on a molar basis, in relation to phospholipids). (G. S. Roth, et al., 1995.) In general, lipid peroxidation causes cellular viscosity to increase, apparently by causing cross-linking of proteins, but I think the significance of the decreased cholesterol relates to its significance as precursor to pregnenolone and progesterone, and to the known association with Alzheimer's disease of a variant form of the cholesterol transporter protein, ApoE, which I suppose is a slightly less stable molecular form that is more susceptible to malfunction in stress.
虽然有很多关于“膜流动性”的讨论，作为一种可取的东西，以及老年大脑中不饱和脂质的损失，但有一些关于阿尔茨海默病的“黏度”的有趣观察。阿尔茨海默氏症患者的血小板粘性更小，从大脑中提取的脂质更流质，胆固醇含量比正常水平低30%(以摩尔为基础，相对于磷脂)。(G. S. Roth等，1995年)。一般来说，脂质过氧化导致细胞黏度增加，显然是通过引起蛋白质的交联，但我认为胆固醇降低的重要性与它作为孕烯醇酮和孕酮的前体的重要性有关，以及已知的与阿尔茨海默病有关的胆固醇转运蛋白的变体，载脂蛋白e，我认为这是一种稍微不稳定的分子形式，更容易在压力下发生故障。
The extracellular matrix is a major factor in the function and stability of brain cells. (L. F. Agnati, et al., “The concept of trophic units in the central nervous system,” Prog. in Neurobiol. 46, 561-574, 1995. Any factor producing edema tends to disrupt the extracellular matrix (Chan and Fishman, 1978, 1980, and L. Loeb, 1948.)
细胞外基质是影响脑细胞功能和稳定性的重要因素。(L. F. Agnati等，“中枢神经系统营养单位的概念”，Prog。Neurobiol. 46, 561-574, 1995。任何引起水肿的因素都倾向于破坏细胞外基质(Chan和Fishman, 1978, 1980, L. Loeb, 1948)。
Seizures are known to be promoted by estrogen, by unsaturated fats, and by lipid peroxidation, and to cause an increase in the size of the free fatty acid pool in the brain. Prolonged seizures cause nerve damage in certain areas, especially the hippocampus, thalamus, and neocortex (Siesjo, et al., 1989). Dementia is known to be produced by prolonged seizures.
已知，雌激素、不饱和脂肪和脂质过氧化会促进癫痫发作，并导致大脑中游离脂肪酸池的大小增加。长时间的癫痫发作会导致某些区域的神经损伤，特别是海马体、丘脑和新皮层(Siesjo等，1989)。众所周知，痴呆是由长期癫痫发作引起的。
Prenatal exposure to estrogen, to oxygen deficiency, or to unsaturated fats decreases the size of the brain at birth. There is apparently a requirement for saturated fats during development (J. M. Bourre, N. Gozlan-Devillierre, O. Morand, and N. Baumann, “Importance of exogenous saturated fatty acids during brain development and myelination in mice,” Ann. Biol. Anim., Biochim., Biophys. 19(1B), 172-180, 1979.
产前暴露于雌激素、缺氧或不饱和脂肪会降低出生时大脑的大小。显然，在发育过程中需要饱和脂肪(J. M. Bourre, N. Gozlan-Devillierre, O. Morand, N. Baumann，“外源性饱和脂肪酸在小鼠大脑发育和髓鞘形成过程中的重要性，”Ann。医学杂志。动画。, Biochim。生物物理学报。19(1B)， 172-180, 1979。
Under the influence of estrogen, or unsaturated fats, brain cells swell, and their shape and interactions are altered. Memory is impaired by an excess of estrogen. Estrogen and unsaturated fat and excess iron kill cells by lipid peroxidation, and this process is promoted by oxygen deficiency. The fetus and the very old have high levels of iron in the cells. Estrogen increases iron uptake. Estrogen treatment produces elevation of free fatty acids in the blood, and lipid peroxidation in tissues. This tends to accelerate the accumulation of lipofuscin, age-pigment. Lactic acid, the production of which is promoted by estrogen, lowers the availability of carbon dioxide, leading to impairment of blood supply to the brain.
在雌激素或不饱和脂肪的影响下，脑细胞膨胀，它们的形状和相互作用被改变。记忆力因雌激素过多而受损。雌激素、不饱和脂肪和过量的铁通过脂质过氧化作用杀死细胞，而缺氧促进了这一过程。胎儿和老人的细胞中铁含量很高。雌激素会增加铁的摄取。雌激素治疗可使血液中的游离脂肪酸升高，并使组织中的脂质过氧化。这倾向于加速脂褐素和年龄色素的积累。由雌激素促进产生的乳酸会降低二氧化碳的可得性，导致大脑血液供应的损害。
Estrogen stimulates cell division, but can also increase the rate of cell death. Unsaturated fatty acids can also stimulate or kill.
雌激素会刺激细胞分裂，但也会增加细胞的死亡率。不饱和脂肪酸也能刺激或杀死人。
Both estrogen and unsaturated fats promote the formation of age-pigment. Besides increasing the free fatty acid concentration, estrogen possibly depresses the level of cholesterol, both of which are changes seen in the senile brain.
雌激素和不饱和脂肪都能促进衰老色素的形成。除了增加游离脂肪酸的浓度，雌激素还可能降低胆固醇的水平，这两种变化都可以在老年大脑中看到。
Estrogen causes massive alterations of extracellular matrix, and seems to promote dissolution of microtubules (Nemetschek-Gannsler), as calcium does. Unsaturated fats increase calcium uptake by at least some brain cells (H. Katsuki and S. Okuda, 1995.) Unsaturated fats, like estrogen, increase the permeability of blood vessels. The unsaturated fat causes edema of the brain, inhibits choline uptake, blocking acetylcholine production.
雌激素引起细胞外基质的大量改变，似乎促进微管的溶解(Nemetschek-Gannsler)，就像钙一样。不饱和脂肪至少会增加某些脑细胞对钙的吸收(H. Katsuki和S. Okuda, 1995)。不饱和脂肪，如雌激素，增加血管的渗透性。不饱和脂肪会导致大脑水肿，抑制胆碱的吸收，阻止乙酰胆碱的产生。
Progesterone is a nerve growth factor, produced by glial cells (oligodendrocytes). It promotes the production of myelin, protects against seizures, and protects cells against free radicals. It protects before conception, during gestation, during growth and puberty, and during aging. It promotes regeneration. Its production is blocked by stress, lipid peroxidation, and an excess of estrogen and iron.
孕酮是一种神经生长因子，由胶质细胞(少突细胞)产生。它促进髓磷脂的生成，防止癫痫发作，保护细胞免受自由基的伤害。它在怀孕前、怀孕期间、生长和青春期以及衰老期间起到保护作用。它促进再生。它的产生受到压力、脂质过氧化、雌激素和铁过量的阻碍。
Aspirin protects against iron toxicity, clot formation, and reduces lipid peroxidation while blocking prostaglandin formation. Aspirin and other antiinflammatory drugs, taken for arthritis, have been clearly associated with a reduced incidence of Alzheimer's disease. Aspirin reduces the formation of prostaglandins from arachidonic acid.
阿司匹林可以防止铁中毒，血栓形成，减少脂质过氧化，同时阻断前列腺素的形成。阿司匹林和其他用于治疗关节炎的抗炎药物显然与降低阿尔茨海默病的发病率有关。阿司匹林可以减少花生四烯酸产生的前列腺素。
Unsaturated fatty acids, but not saturated fatty acids, are signals which activate cell systems.
不饱和脂肪酸，不是饱和脂肪酸，是激活细胞系统的信号。
Many different stimuli can induce cell activity, cell death, or change to another cell type. (J. Niquet, et al., “Glial reaction after seizure induced hippocampal lesion: Immunohistochemical characterization of proliferating glial cells,” J. Neurocytol. 23(10), 641-656, 1994: ”…hippocampal astrocytes from kainate-treated rats experess A2B5 immunoreactivity, a marker of type-2 astrocytes.“ “This suggests that in the CNS, normal resident astrocytes acquire the phenotypic properties of type-2 astrocytes.”)
许多不同的刺激可以诱导细胞活动、细胞死亡或转变为另一种细胞类型。(J. Niquet等，“癫痫诱发海马损伤后的神经胶质反应:增殖的神经胶质细胞的免疫组化特征”，J. Neurocytol. 23(10)， 641-656, 1994:“…红藻酸盐处理的大鼠海马星形胶质细胞表达A2B5免疫反应性，这是2型星形胶质细胞的标志。”“这表明，在中枢神经系统中，正常的驻留星形胶质细胞获得了2型星形胶质细胞的表型特性。”)
A “deficiency” of polyunsaturated fatty acids leads to altered rates of cellular regeneration and differentiation, a larger brain at birth, improved function of the immune system, decreased inflammation, decreased mortality from endotoxin poisoining, lower susceptibility to lipid peroxidation, increased basal metabolic rate and respiration, increased thyroid function, later puberty and decreases other signs of estrogen dominance. When dietary PUFA are not available, the body produces a small amount of unsaturated fatty acid (Mead acids), but these do not activate cell systems in the same way that plant-derived PUFAs do, and they are the precursors for an entirely different group of prostaglandins.
“缺乏”多不饱和脂肪酸会导致细胞再生和分化率的改变，出生时大脑更大，免疫系统功能改善，炎症减少，内毒素中毒死亡率降低，对脂质过氧化的敏感性降低，基础代谢率和呼吸增加，甲状腺功能增强，青春期推迟，雌激素占优势的其他迹象减少。当饮食中没有多不饱和脂肪酸时，身体会产生少量的不饱和脂肪酸(米德酸)，但这些不饱和脂肪酸不能像植物源的多不饱和脂肪酸那样激活细胞系统，它们是一组完全不同的前列腺素的前体。
VITAMIN A AND THE STEROIDS
维生素A和类固醇
In a variety of cell types, vitamin A functions as an estrogen antagonist, inhibiting cell division and promoting or maintaining the functioning state. It promotes protein synthesis, regulates lysosomes, and protects against lipid peroxidation. Just as stress and estrogen-toxicity resemble aging, so does a vitamin A deficiency. While its known functions are varied, I think the largest use of vitamin A is for the production of pregnenolone, progesterone, and the other youth-associated steroids. One of vitamin E's important functions is protecting vitamin A from destructive oxidation. Although little attention has been given to the effects of unsaturated fats on vitamin A, their destruction of vitamin E will necessarily lead to the destruction of vitamin A. The increased lipid peroxidation of old age represents a vicious circle, in which the loss of the antioxidants and vitamin A leads to their further destruction.
在多种细胞类型中，维生素A作为雌激素拮抗剂，抑制细胞分裂，促进或维持功能状态。它促进蛋白质合成，调节溶酶体，防止脂质过氧化。正如压力和雌激素毒性与衰老相似，维生素A缺乏也是如此。虽然它的已知功能是多种多样的，但我认为维生素A最大的用途是生产孕烯醇酮、孕酮和其他与青少年相关的类固醇。维生素E的重要功能之一就是防止维生素A被氧化。虽然很少注意已经给不饱和脂肪的影响维生素A,维生素E的毁灭必然导致的破坏维生素A。老年脂质过氧化作用的增加代表一个恶性循环,其中的抗氧化剂和维生素的损失会导致他们的进一步破坏。
To produce pregnenolone, thyroid, vitamin A, and cholesterol have to be delivered to the mitochondria in the right proportion and sufficient quantity. Normally, stress is balanced by increased synthesis of pregnenolone, which improves the ability to cope with stress. Lipid peroxidation, resulting from the accumulation of unsaturated fatty acids, iron, and energy deficiency, damages the mitochondrias' ability to produce pregnenolone. When pregnenolone is inadequate, cortisol is over-produced. When progesterone is deficient, estrogen's effect is largely unopposed. When both thyroid and progesterone are deficient, even fat cells synthesize estrogen.
为了产生孕烯醇酮，甲状腺、维生素A和胆固醇必须以适当的比例和足够的数量输送到线粒体。正常情况下，通过增加孕烯醇酮的合成来平衡压力，从而提高应对压力的能力。由不饱和脂肪酸、铁和能量不足引起的脂质过氧化损伤了线粒体产生孕烯醇酮的能力。当孕烯酮不足时，皮质醇产生过多。当黄体酮缺乏时，雌激素的作用在很大程度上是不可抗拒的。当甲状腺和黄体酮都缺乏时，甚至脂肪细胞也会合成雌激素。
THE NATURE OF ALZHEIMER'S DISEASE
阿尔茨海默症的本质
Although Alzheimer's disease until recently referred to a certain type of organic dementia occuring in people in their thirties, forties and fifties (presenile dementia), structural similarities seen in senile dementia have caused the term to lose its original meaning. Alzheimer's sclerosis of blood vessels, and even the death of nerve cells, are sometimes neglected in favor of the more stylish ideas, emphasizing certain proteins that cause the tangles and plaques. Until recently, the “tangles” were commonly interpreted as the debris left after the death of a cell, rather than as one of the processes causing the death of the cell.
虽然阿尔茨海默氏病直到最近还指的是发生在30多岁、40多岁和50多岁人群中的某种器质性痴呆(早老性痴呆)，但老年性痴呆的结构相似性已经使这个词失去了原来的含义。阿尔茨海默氏症的血管硬化，甚至是神经细胞的死亡，有时都被忽视了，取而代之的是更时髦的观点，强调了引起缠结和斑块的特定蛋白质。直到最近，“缠结”通常被解释为细胞死亡后留下的碎片，而不是导致细胞死亡的过程之一。
Alzheimer-type dementia is different from other dementias, but it overlaps with them, and with age-related and stress-related changes in other organs.
阿尔茨海默型痴呆症不同于其他痴呆症，但它与它们重叠，并与年龄和压力相关的其他器官的变化。
Physical signs (seen at autopsy) of AD:
1) Death of neurons (increase of glial cells),
2) Amyloid plaques (extracellular), associated with a particular variant of apolipoprotein E, the epsilon 4 allele,
3) Fibrillary tangles (intracellular, or remaining after the rest of the cell has disappeared),
4) Amyloid in blood vessels.
AD的体征(尸检):
1)神经元死亡(胶质细胞增多);
2)淀粉样斑块(细胞外)，与载脂蛋白E的一种特殊变体，epsilon 4等位基因，
3)纤维缠结(细胞内，或其余细胞消失后仍存在)，
4)血管淀粉样蛋白。
Functional and biochemical observations:
1) The mitochondrial energy problem, cytochrome oxidase and its regulation; body temperature/pulse-rate cycle disturbance; lipid peroxidation; respiratory defect; altered amino acid uptake; memory impairment; dominance of the excitatory systems vs. the inhibitory adenosine/GABA/progesterone/pregnenolone system. Increased calcium uptake, which is associated with lipid peroxidation and cell death. Increased cortisol and DHEA.
2) Deposit of abnormal proteins, such as transthyretin-amyloid; albumin binding of PUFA, vs. transport of thyroid and retinol. Beta-glucuronidase increases, depositing estrogen in cells. (A. J. Cross, et al., “Cortical neurochemistry in Alzheimer-type dementia,” Chapter 10, pages 153-170 in Aging of the Brain and Alzheimer's Disease, Prog. in Brain Res. 70, edited by D. F. Swaab, et al., Elsevier, N.Y., 1986.)
3) Abnormally phosphorylated (tau) proteins; association with the variant form of Apo E; tau microtubule organizing proteins, microtubules are involved in transporting cholesterol; phosphorylation, by the kinase systems, regulated by PUFA; the intermediate filaments are generally stress-associated.
4) ApoE, in cytoplasm, involved in cholesterol delivery for pregnenolone synthesis, as in the adrenal; its expression regulated by thyroid. Regulation of the side-chain cleaving enzymes; regulation of the cholesterol intake and conversion to pregnenolone by the endozepine receptor/GABA receptor, modified by progesterone.
功能及生化观察:
1)线粒体能量问题、细胞色素氧化酶及其调控;体温/脉搏周期干扰;脂质过氧化作用;呼吸系统缺陷;氨基酸摄取改变;记忆障碍;兴奋性系统vs.抑制性腺苷/GABA/孕酮/孕烯酮系统。钙摄取增加，这与脂质过氧化和细胞死亡有关。皮质醇和脱氢表雄酮增加。
2)异常蛋白沉积，如转甲状腺淀粉样蛋白;多不饱和脂肪酸的白蛋白结合，对甲状腺和视黄醇的转运。-葡糖醛酸酶增加，使雌激素沉积在细胞内。(A. J. Cross, et al.，“阿尔茨海默型痴呆症的皮层神经化学”，第10章，153-170页，《大脑老化与阿尔茨海默病》，Prog。D. F. Swaab等人编辑的Brain Res. 70, Elsevier，纽约，1986。)
3)异常磷酸化(tau)蛋白;与Apo E变异型结合;Tau微管组织蛋白，微管参与胆固醇运输;磷酸化，由激酶系统，由PUFA调控;中间细丝通常与应力有关。
4)胞浆中的载脂蛋白e参与孕烯醇酮合成的胆固醇传递，如肾上腺;其表达受甲状腺调节。侧链切割酶的调控;通过内啡肽受体/伽马氨基丁酸受体(经孕酮修饰)调节胆固醇摄入和转化为孕烯醇。
AN EXAMPLE OF A REGULATORY PROBLEM
一个管理问题的例子
Vegetable oil suppresses the thyroid, increasing estrogen. Estrogen and calcium depolymerize microtubules. Microtubule transport for Apo E, transthyretin, thyroid, and cholesterol for pregnenolone synthesis is disrupted.
植物油抑制甲状腺，增加雌激素。雌激素和钙能解聚微管。载脂蛋白E、转甲状腺素、甲状腺和胆固醇的微管运输为孕烯醇酮合成中断。
Transthyretin and Apo E accumulate unused, and deposit in blood vessels, around nerves, and in cytoplasm. Pregnenolone and progesterone deficiency (aggravating thyroid deficiency) causes memory loss, destabilization of nerve cells, failure of myelin formation, and excess cortisol synthesis. Free radicals and calcium cause multiple cell injuries including nerve-death. Estrogen is released by elevated beta-glucuronidase. Imbalances of other steroids, including cortisol and DHEA, develop as cells compensate for pregnenolone deficiency, causing shifts in balance of glial cells.
转甲状腺素和载脂蛋白E在血管、神经周围和细胞质中积累和沉积。孕烯酮和孕酮缺乏(加重甲状腺缺乏)会导致记忆丧失、神经细胞不稳定、髓鞘形成失败和皮质醇合成过剩。自由基和钙会导致多种细胞损伤，包括神经死亡。雌激素是由升高的-葡醛酸酶释放的。当细胞弥补孕烯醇酮缺乏时，包括皮质醇和脱氢表雄酮在内的其他类固醇激素失衡，导致胶质细胞平衡发生变化。
Hypothyroidism, estrogen excess, free unsaturated fats cause increased vascular permeability and brain edema, protein leakage, and alteration of the matrix..
甲状腺功能减退、雌激素过量、游离不饱和脂肪会导致血管通透性增加、脑水肿、蛋白质渗漏和基质改变。
VIII: STRUCTURE AS A REGULATORY SYSTEM–AN EMERGING VISION OF PERVASIVE EPIGENESIS
作为调节系统的结构——普遍后生作用的新兴观点
In the introduction I mentioned that membranous regulation and genetic determination should be considered as defunct theories. What I have been saying about self-actualizing systems and the factors that disrupt them derives from a view of cell function that has been developing since the 1920s.
在引言中，我提到膜调控和遗传决定应该被认为是不存在的理论。我一直在说的自我实现的系统和破坏它们的因素来自自20世纪20年代以来一直在发展的细胞功能的观点。
Around 1940, a Russian biochemist (Oparin, I think) proposed that the enzymes of glycolysis were bound to the structure of the cell when they were not in use, and that they were “desorbed” under the conditions that required abundant glycolysis. Knowing that concept, in 1970 I proposed that the cell water itself underwent a transition under such conditions (which could include increased temperature, reduced oxygen, or nervous or hormonal stimulation). Activation of glycolysis is usually explained by the availability of regulatory substances such as ammonia, phosphate, and NAD, and many biochemists were content to understand cells in terms of test-tube models. But in the last few years, it has become clear that some of these basic regulatory molecules do bind to structural components of the cell. (T. Henics, “Thoughts over cell biology: A commentary,” Physiol. Chem. Phys. & Med. NMR 27, 139-140, 1995.) Although the details aren't clear, it is known that hormones and other factors stabilize or destabilize RNA, and that during some of these events relevant enzymes bind to the RNA. When these facts are combined with the information that is accumulating on splicing and modification of RNA, and the copying of RNA back into DNA, the hereditary system is seen to be much more flexible than it was believed to be.
大约在1940年，一个俄罗斯生物化学家(我想是Oparin)提出糖酵解的酶在不使用的时候被绑定在细胞的结构上，并且在需要大量糖酵解的条件下被“解吸”。知道了这个概念后，我在1970年提出，细胞中的水本身在这样的条件下经历了一个转变(这可能包括温度升高，氧气减少，或神经或激素刺激)。糖酵解的激活通常由调节物质如氨、磷酸盐和NAD的可用性来解释，许多生物化学家满足于从试管模型的角度来理解细胞。但在过去几年里，一些基本的调控分子确实与细胞的结构成分结合，这一点已经变得很清楚。(T. Henics，“关于细胞生物学的思考:评论”，Physiol。化学。理论物理。核磁共振27,139-140,1995。虽然具体细节尚不清楚，但已知的是，激素和其他因素稳定或不稳定RNA，在某些事件中，相关酶与RNA结合。当这些事实与RNA的剪接和修饰以及将RNA复制回DNA所积累的信息结合在一起时，遗传系统看起来比人们想象的要灵活得多。
A global change of state is able to steer each part of the process, continuously. In this way, the cell resembles an analog, rather than a digital, control system: each part is momentarily guided, rather than waiting for “feedback.”
全球状态的变化能够持续地引导过程的每一部分。这样，电池就像一个模拟控制系统，而不是一个数字控制系统:每个部分都有暂时的引导，而不是等待“反馈”。
Where before, cellular “regulatory mechanisms” referred to certain feedback mechanisms based on interactions of randomly diffusing molecules, the new understanding of the cell sees a highly structured system in which very little is random, and the cell's adaptive possibilities, instead of being limited to a certain number of genetic switches, are shaped by every imaginable environmental influence. The cell's structure, far from being “read out of the genome,” is sensitively reshaped constantly by processes that incorporate some of the environment in establishing each new stability. The old-model-geneticists have been forced to admit that the genes can't specify everything in the organism's structure, and it was the brain's complexity that forced this recognition that certain things are developed “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.”
之前,细胞“监管机制”指某些基于交互反馈机制的随机扩散分子,细胞的新的理解很少看到一个高度结构化的系统是随机的,和细胞的自适应的可能性,而不是局限于一定数量的基因开关,都受到各种环境的影响细胞的结构远不是“从基因组中读出”，而是在建立每一种新的稳定性时，通过吸收某些环境因素的过程，敏感地不断重塑。旧模式的遗传学家不得不承认，基因并不能指定生物体结构中的所有东西，是大脑的复杂性迫使他们承认某些东西是“表观遗传”发展的。但是，大多数生物学家不愿意接受的一个新事实是，细胞本身的结构很大程度上是基于从环境中接收到的信息而形成的，也就是“表观遗传”。
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.”
传统上，后生意味着胚胎或有机体的形式不预先存在，或不完全由基因指定。也就是说，它与细胞之间的关系有关。它包括一种认识，即“细胞足够聪明，能够设计一个有机体。”这是一个重要的一步，超越了认识到“细胞足够聪明，能够重新设计自己，以满足从未见过的情况。”
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.
研究细菌和酵母的生物学家发现它们以非随机的方式适应新环境。根据教科书和大多数生物学教授支持的“中心教条”，“定向突变”是不可能的，但它们确实发生在那些单细胞生物中。芭芭拉·麦克林托克表明，在玉米中，她的可移动基因被胁迫所调动。尽管这并不完全是“定向突变”，但它是在需要适应时增加适应的机制的一个例子。有一种酶能在DNA链上产生特定的切割。生物技术专家发现，它们的存在对他们的目的很方便，但它们的存在可能在所有生物体中都是出于生理目的，就像麦克林托克在玉米中描述的那样。在产生一种被称为凋亡的特殊细胞死亡的终极压力中，这些酶会把基因组变成五彩纸屑。
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.
毒素，如雌激素、不饱和脂肪酸，甚至辐射，在不同剂量下产生不同的影响。低剂量通常刺激细胞分裂，大剂量产生细胞类型的改变和分化状态的改变，最后，足够剂量产生凋亡细胞死亡。关于细胞凋亡有一种特殊的意识形态，认为它是“基因决定的”，这意味着无论何时它在大脑中发生，它注定迟早会发生。但事实上，各种各样的“生长因素”都可以预防它。越来越清楚的是，它代表着过度的压力和不足的资源。遗传器官参与分化和根本适应，表明细胞(表观遗传)资源是无限的。
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.
已知的变化是由我们习惯性接触的有毒物质所产生的，而这些变化恰恰发生在衰老的大脑中。当我浏览了数百个定义雌激素、不饱和脂肪、过量铁和脂质过氧化作用的研究时，我的观点似乎很普通，甚至微不足道，除了我知道它明显与大多数退化性疾病的治疗有关，这个伟大的文化机器在几个方面传播着不同的观点，这些观点对我的论点至关重要。
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.
他们在提出一个关于人性的神话，所以我要提出一个反神话。在人类大脑发育的时候，他们生活在热带地区。我认为，在以谷物为基础的农业发展之前，他们的饮食是相对不饱和脂肪和低铁的——以热带水果为基础。我认为乞力马扎罗山的博斯科人头骨是当时人类的代表，根据我们目前对大脑大小与寿命关系的了解，他们——正如各种“黄金时代”神话所宣称的那样——一定有很长的寿命。随着人们向北方迁移并发展出新的生活方式，他们对不饱和脂肪的消耗增加了，大脑体积缩小了，他们迅速衰老。尼安德特人的遗物表明亚麻籽是他们的主食。
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.
即使生活在热带地区，也有很多可能的饮食富含干扰信号的物质，包括铁，而在高纬度地区，我们有机会减少与它们的接触。作为蛋白质的来源，牛奶的铁含量非常低。土豆由于蛋白质的高质量，可能相对来说不含有毒的信号物质。许多热带水果除了含有相对饱和的脂肪外，铁的含量也很低，通常还含有大量的氨基酸和蛋白质。在这样的背景下，Jeanne Calment一生中每天对巧克力的消费就会出现在脑海中:当她接近121岁生日时，她仍然在吃巧克力，尽管她已经戒烟戒酒了。巧克力中的饱和脂肪已被发现可以阻止富含亚油酸的油的毒性，其奇怪的蛋白质似乎具有合成代谢作用。
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.
如果我们真的认真对待传统的表观演化，特别是如果我们接受更深层次的细胞结构和功能的表观演化，我们就必须把生物体看作一种“细胞旋风”，由原子旋风组成(用沃尔纳德斯基的话说)，我们的生活方式设定了界限，我们的细胞将在其中自我重组。
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.
自由基的随机产生，不仅仅是通过基因损伤或蛋白质交联的方式，也可以作为一种信号传递过程，也就是说，在严格的生理水平上。过量的不饱和脂肪酸本身就构成了调节系统的巨大扭曲，但它也导致了“二十烷”系统的扭曲和越来越不受控制的自由基的产生，以及能量、甲状腺活性和类固醇平衡的变化。衰老的身体不像一辆需要不断修理直到简单磨损而崩溃的汽车，而更像一辆行驶在越来越崎岖泥泞的道路上的汽车，直到道路变成无法通行的沼泽。
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.
建议的治疗方法是对信号传导过程的纠正，而不是“遗传手术”、移植等，这是对氧化损伤只是一个“磨损”、“体细胞突变”和“交联”问题这一学说的悲观暗示。这些问题是可以修复的，我们的重点应该放在能源的生产和避免使不良信号积累的条件上。
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.
缺乏不饱和脂肪的饮食没有癌症，新陈代谢速度加快，自由基产生减少，对压力和铁、酒精、内毒素、四氧嘧啶和链脲霉素等的中毒有抵抗力，大脑结构和功能改善，对血凝块的敏感性降低，肥胖和老年斑节食和缺乏使用椰子油而不是不饱和脂肪,表明可以做一些非常简单的减少主要的退化性疾病,而且它很有可能代理通过降低衰老过程本身的生理上的核心。
Copyright: Raymond Peat, PhD 1997
PO Box 5764 Eugene, OR 97405
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