The problem of Alzheimer's disease as a clue to immortality
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:
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:
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
http://raypeat.com/articles/articles/alzheimers2.shtml
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Accumulation of the mentioned metabolites, as well as abnormalities in signal transduction owing to stimulation of lipases and phospholipases, may be involved in the pathogenesis of the neurodegeneration in AD.” Leo Loeb, V. Suntzeff, and E. L. Burns, “Changes in the nature of the stroma in vagina, cervix and uterus of the mouse produced by long-continued injections of estrogen and by advancing age,” The American Journal of Cancer 35(2), 159-174, 1939. Loeb, et al., speak of collagenous deposits as fibrous-hyaline tissue, varying from a fibrillar to a homogeneous appearance, and varying in consistency from very dense and glassy in appearance, to the softer gelatinous substance between cells and around arteries and glands. This material increases with aging and eventually appears between cells in the muscular part of the uterus. With the injection of moderate amounts of estrogen, the quantity of the material is increased. When large amounts of estrogen are injected, “The connective tissue and muscle appear rarefied, almost as though they were perforated by a large number of small holes.” ”…this condition is presumably due to a deposit of a mixture of hyaline material and edematous fluid….“ “This process of hyalinization…is counteracted by invasion by connective tissue.” In this way there may take place in many areas a substitution and organization of the hyaline material by connective tissue, in which dilated capillaries may also be visible.” “There is a second process which in many cases accompanies the invasion and organization of hyaline substance by connective tissue, namely a formation, at the margin of the hyaline material, of epithelioid and of small giant cells possessing more than one nucleus.” “As a rule, the epithelioid cells are seen alone; giant cells are more rare.” “…the connective-tissue fibrils may in places appear somewhat separated, perhaps by edematous fluid.” “The first changes consist very likely in the transudation of fluid from the vessels into the connective tissue.” “It seems, then, that at a very early stage after the beginning of the injections of effective doses of estrogen, a liquid substance which separates the connective-tissue elements makes its appearance, and that this represents one of the earliest changes induced by the hormone. It may be accompanied, or soon followed, by the deposit of a hyaline substance which occurs first between the connective-tissue cells, but may extend also to the muscle fibers.” “…the deposit of hyaline which progressively becomes more and more devoid of connective-tissue cells and blood vessels, is so marked that the material acts like a foreign body….” “While it may be found also around blood vessels, such deposits are less conspicuous than in other organs in mice, such as the mammary gland…. There is a tendency for the hyaline substance to form sheaths around various organs and it is more prominent at the border separating different tissues and organs.” “In its appearance and in the foreign body reactions which it initiates this substance somewhat resembles amyloid, which is readily produced in mice in various groups. The application of stains differentiating amyloid from other hyaline material, however, gave negative results.” Leo Loeb, V. Suntzeff, and E. L. Burns, “The effects of age and estrogen on the stroma of vagina, cervix and uterus in the mouse,” Science 88(22, Nov. 4), 1938. “…large amounts of a hyaline substance are deposited, which act as foreign bodies and cause the formation of epithelioid and giant cells and an ingrowth of connective tissue. Thus an organization of this substance is attempted, which is interrupted, however, by renewed deposition of this hyaline material.” “No definite statement can be made at present as to the chemical nature of this substance and its possible relation to a plasma constituent, except that it is not amyloid.” “…a very intense fibrosis and hyalinization of the stroma which may induce abnormal reactions in the surrounding tissue. In this way it seems to be possible to accelerate and intensify very much some of the old age changes in certain organs.” P. 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.” C. LarssonBackstrom, et al., “Effects of dietary alpha- and gamma-linolenic acids on liver fatty acids, lipid metabolism, and survival in sepsis,” Shock 4(1), 11-20, 1995. “Dietary GLA reduced survival from sepsis.” D. Chemla, et al., “Influence of dietary polyunsaturated fatty acids on contractility, inotropy and compliance of isolated rat myocardium, J mol Cell Cardiol 27(8), 1745-1755, 1995. “There was a trend towards a lower peak lengthening velocity at preload in the LC (n-3) group…together with an unchanged peak rate of isometric force decline. This resulted in a significant impairment of the two mechanical indexes testing the load dependence of myocardial relaxation.” See B. Pieske, Circul. 92(5), 1169-78 R. Lerner, et al., “Development and characterization of essential fatty acid deficiency in human endothelial cells in culture,” Proc Natl Acad Sci USA 92(4), 1147-1151, 1995. Oleic acid derivative 5,8,11-eicosatrienoic acid (20:3 omega 9) (5,8,11,14,17 eicosapentaenoic, 20-5 omega 3)); 20:3 omega 9 impaired the Ca2(i) response, indicating a suppressive effect of it. (Agonist-induced increases in concentrations of prostacycline PGI 2, and cytosolic Ca2+ were reduced in efad cells.) K. Imaizumi, et al., “Dissociation of protein kinase C activities and diacylglycerol levels in liver plasma membranes of rats on coconut oil and safflower oil diets,” J. Nutr Biochem 6(10), 528-533, 1995. “The activation of PKC is affected differently in vitro by different fatty acids.” “Rats on coconut oil…had a markedly lower PKC activity in liver plasma membranes with slight but significant reduction of the activity in the cytosol than did rats fed safflower oil….” ”…coconut oil resulted in a higher content of diacylglycerols in these membranes than did ingestion of safflower oil, whereas the proportions of saturated fatty acids and phospholipids and membrane fluidity were similar between rats ingesting different fats.“ “It seems likely that saturated fats exert various physiological effects on lipid and lipoprotein metabolism, in part through PKC pathways.” V. Boutard, et al., “Fish oil supplementation and essential fatty acid deficiency reduce nitric oxide synthesis by rat macrophages,” Kidney Int. 46(5), 1280-1286, 1994. “Both…have been shown to exert anti-inflammatory effects….” A A Farooqui, K Wells, L A Horrocks, “Breakdown of membrane phospholipids in Alzheimer disease–involvement of excitatory amino acid receptors,” Mol Chem Neuropathol 25(2-3) 155-173, 1995. “The release of arachidonate from the sn-2 position of glycerophospholipids is catalyzed by phospholipases and lipases. These enzymes are coupled to EAA receptors. Overstimulation of these receptors may be involved in abnormal calcium homeostasis, degradation of membrane phospholipids, and the accumulation of free fatty acids, prostaglandins, and lipid peroxides. Accumulation of the mentioned metabolites, as well as abnormalities in signal transduction owing to stimulation of lipases and phospholipases, may be involved in the pathogenesis of the neurodegeneration in AD.” P. H. Chan and R. A. Fishman, “Transient formation of superoxide radicals in polyunsaturated fatty acid-induced brain swelling,” J. of Neurochemistry 35, 1004-1007, 1980. J. S. Jensen, et al., “Microalbuminuria reflects a generalized transvascular albumin leakiness in clinically healthy subjects,” Clin Sci 88(6), 629-633, 1995. “In epidemiological studies microalbuminuria, i.e., slightly elevated urinary albumin excretion rate, predicts increased atherosclerotic vascular morbidity and mortality.” “In animal experiments the outflux of albumin and lipids to the arterial wall are highly correlated, and both are elevated in atherosclerosis.” ”…microalbuminuria is an independent marker of systemic transvascular albumin leakiness in clinically healthy subjects.“ 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.” F. Laszlo, et al., “Association of microvascular leakage with induction of nitric oxide synthase: Effects of nitric oxide synthase inhibitors in various organs,” Eur. J. Pharmacol. 283(1-3), 47-53, 1995. ”…assessed by the vascular leakage of … albumin.“ “Endotoxin…induced the expression of a calcium-independent nitric oxide synthase….” 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. S. Capsoni, et al., “Reduction of regional cerebral blood flow by melatonin in young rats,” Neuroreport 6(9), 1346-1348, 1995. ”…reduced in the cerebral areas supplied by circle of Willis and the basilar arteries. [Also to the] …choroid plexuses.“ A. C. Bowling and M. F. Beal, “Bioenergetic and oxidative stress in neurodegenerative diseases,” Life Sci. 56(14), 1151-1171, 1995. “Defects in energy metabolism and increased cortical lactate levels have been detected in Huntington's disease patients. Studies of Alzheimer's disease patients have identified decreased [mitochondrial]complex IV activity….” “The age-related onset and progressive course of these neurodegenerative diseases may be due to a cycling process betwen impaired energy metabolism and oxidative stress.” K. Nakai, et al., “Regeneration of norepinephrine-containing fibers in occipital cortex of adult cats,” Brain Res. Bull. 35(5-6), 409-412, 1994. “The present results indicate that the regenerative ability of the central NE neurons is universal, not limited to the immature brain. …equipped with a transmitter-specific repair mechanism throughout life.” A. Bhatnagar, “Biochemical mechanism, of irreversible cell injury caused by free radical-initiated reactions,” Mol. Cell. Biochem. 137(1), 9-16, 1994. ”…free radical-induced irreversible cell injury results from a loss of protein thiols.“ L. Balazs and M. Leon, “Evidence of an oxidative challenge in the Alzheimer's brain,” Neurochem. Res. 19(9), 1131-1137, 1994. “These data suggest that the entire Alzheimer's brain may be subject to an oxidative challenge, but that some brain areas may be more vulnerable than others to the consequent neural damage that characterizes the disease.” J. A. Court and E. K. Perry, “CNS nicotinic receptors–possible therapeutic targets in neurodegenerative disorders,” CNS Drugs 2(3), 216-233, 1994. ”…epidemiological evidence suggests that later in life tobacco smoking may offer some protection against Parkinson's and Alzheimer's diseases.“ N. A. Simonian and B. T. Hyman, “Functional alterations in Alzheimer's disease: Selective loss of mitochondrial-encoded cytochrome oxidase mRNA in the hippocampal formation,” J. Neuropathol. Exp. Neurol. 53(5), 508-512, 1994. A. M. Proenze, et al., “Estrogen effects on blood amino acid compartmentation,” Life Sci. 57(17), 1589-1587, 1995. S. S. Smith, “Sensorimotor-correlated discharge recorded from ensembles of cerebellar Purkinje cells varies across the estrous cycle of the rat,” J. Neurophysiol. 74(3), 1095-1108, 1995. ”…estradiol augments excitatory responses of cerebellar Purkinje cells to…glutamate….“ C. F. Lim, et al., “Influence of nonesterified fatty acid and lysolecithins on thyroxine binding to thyroxine-binding globulin and transthyretin,” Thyroid 5(4), 319-324, 1995. “Unsaturated nonesterified fatty acids…inhibited T4 binding to TBG.” “Saturated NEFAs…were inactive.” O. V. Sviridov, “Specific binding of thyroid hormones by human plasma apolipoproteins: A new property of known proteins,” Biochemistry (Engl. translation) 59(5), 457-466, 1884. T. Parasassi, et al., “Cholesterol protects the phospholipid bilayer from oxidative damage,” Free Radical Biology & Medicine 19(4), 511-516, 1995. A. G. Herzog, “Progesterone therapy in women with complex partial and secondary generalized seizures,” Neurology 45(9), 1660-1662, 1995. Z. Q. Ma, et al., Estrogenic control of monoamine oxidase A activity in human neuroblastoma cells expressing physiological concentrations of estrogen receptor,” Eur. J. Pharmacol. 284(1-2), 171-176, 1995. J. G. Belasco and G. Brawerman, Control of Messenger RNA Stability, Academic Press, NY, 1994. Leo Loeb, V. Suntzeff, and E. L. Burns, “Changes in the nature of the stroma in vagina, cervix and uterus of the mouse produced by long-continued injections of estrogen and by advancing age,” The American Journal of Cancer 35(2), 159-174, 1939. Loeb, et al., speak of collagenous deposits as fibrous-hyaline tissue, varying from a fibrillar to a homogeneous appearance, and varying in consistency from very dense and glassy in appearance, to the softer gelatinous substance between cells and around arteries and glands. This material increases with aging and eventually appears between cells in the muscular part of the uterus. With the injection of moderate amounts of estrogen, the quantity of the material is increased. When large amounts of estrogen are injected, “The connective tissue and muscle appear rarefied, almost as though they were perforated by a large number of small holes.” “…this condition is presumably due to a deposit of a mixture of hyaline material and edematous fluid….” “This process of hyalinization…is counteracted by invasion by connective tissue.” In this way there may take place in many areas a substitution and organization of the hyaline material by connective tissue, in which dilated capillaries may also be visible.“ “There is a second process which in many cases accompanies the invasion and organization of hyaline substance by connective tissue, namely a formation, at the margin of the hyaline material, of epithelioid and of small giant cells possessing more than one nucleus.” “As a rule, the epithelioid cells are seen alone; giant cells are more rare.” ”…the connective-tissue fibrils may in places appear somewhat separated, perhaps by edematous fluid.“ “The first changes consist very likely in the transudation of fluid from the vessels into the connective tissue.” “It seems, then, that at a very early stage after the beginning of the injections of effective doses of estrogen, a liquid substance which separates the connective-tissue elements makes its appearance, and that this represents one of the earliest changes induced by the hormone. It may be accompanied, or soon followed, by the deposit of a hyaline substance which occurs first between the connective-tissue cells, but may extend also to the muscle fibers.” ”…the deposit of hyaline which progressively becomes more and more devoid of connective-tissue cells and blood vessels, is so marked that the material acts like a foreign body….“ “While it may be found also around blood vessels, such deposits are less conspicuous than in other organs in mice, such as the mammary gland…. There is a tendency for the hyaline substance to form sheaths around various organs and it is more prominent at the border separating different tissues and organs.” “In its appearance and in the foreign body reactions which it initiates this substance somewhat resembles amyloid, which is readily produced in mice in various groups. The application of stains differentiating amyloid from other hyaline material, however, gave negative results.” Leo Loeb, V. Suntzeff, and E. L. Burns, “The effects of age and estrogen on the stroma of vagina, cervix and uterus in the mouse,” Science 88(22, Nov. 4), 1938. ”…large amounts of a hyaline substance are deposited, which act as foreign bodies and cause the formation of epithelioed and giant cells and an ingrowth of connective tissue. Thus an organization of this substance is attempted, which is interrupted, however, by renewed deposition of this hyaline material.“ “No definite statement can be made at present as to the chemical nature of this substance and its possible relation to a plasma constituent, except that it is not amyloid.” ”…a very intense fibrosis and hyalinization of the stroma which may induce abnormal reactions in the surrounding tissue. In this way it seems to be possible to accelerate and intensify very much some of the old age changes in certain organs.“ Winfried G. Rossmanith, “Gonadotropin secretion during aging in women: Review article,” Exp. Gerontology 30(3/4) 369-381, 1995. ”…major functional derangements, primarily at a hypothalamic rather than a pituitary site, have been determined as concomitants of aging in women.“ ”…aging may impair the negative feedback sensitivity to ovarian sex steroids….“ Hormonal changes at menopause “may represent the sum of functional aberrations that were initiated much earlier in life….” ”…prolonged estrogen exposure facilitates the loss of hypothalamic neurons….“ J. R. Brawer, et al., “Ovary-dependent degeneration in the hypothalamic arcuate nucleus,” Endocrinology 107, 274-279, 1980. G. C. Desjardins, “Estrogen-induced hypothalamic beta-endorphin neuron loss: A possible model of hypothalamic aging,” Exp. Gerontology 30(3/4), 253-267, 1995. “This loss of opioid neurons is prevented by treatment with antioxidants indicating that it results from estradiol-induced formation of free radicals.” ”…this beta-endorphin cell loss is followed by a compensatory upregulation of mu opioid receptors in the vicinity of LHRH cell bodies.“ Resulting supersensitivity of the cells results “in chronic opioid suppression of the pattern of LHRH release, and subsequently that of LH.” The neurotoxic effects of estradiol causes a “cascade of neuroendocrine aberrations resulting in anovulatory acyclicity.” Treatment with an opiod antagonist “reversed the cystic morphology of ovaries and restored normal ovarian cycles” in estrogen-treated rats. G. B. Melis, et al., “Evidence that estrogens inhibit LH secretion through opioids in postmenopausal women using naloxone,” Neuroendocrinology 39, 60-63, 1984. H. J. Sipe, et al., “The metabolism of 17 beta-estradiol by lactoperoxidase: A possible source of oxidative stress in breast cancer,” Carcinogenesis 15(11), 2637-2643, 1994. ”…molecular oxygen is consumed by a sequence of reactions initiated by the glutathione thiyl radical. …the estradiol phenoxyl radical abstracts hydrogen from…NADH to generate the NAD radical.“ ”…the futile metabolism of micromolar quantities of estradiol catalyzes the oxidation of much greater concentrations of biochemical reducing cofactors, such as glutathione and NADH, with hydrogen peroxide produced as a consequence.“ S. Santagati, et al., “Estrogen receptor is expressed in different types of glial cells in culture,” J. Neurochem. 63(6), 2058-2064, 1994. ”…in all three types of glial cell analyzed in almost equal amounts…“ D. X. Liu and L. P. Li, “Prostaglandin F-2 alpha rises in response to hydroxyl radical generated in vivo,” Free Radical Biol. Med. 18(3), 571-576, 1995. “Free radicals and some free fatty acids, such as arachidonic acid metabolites…may form a feedback loop in which generation of one type leads to formation of the other.” “Prostaglandin F-2 alpha dramatically increased in response to hydroxyl radical generation….” J. Owens and P. A. Schwartzkroin, “Suppression of evoked IPSPs by arachidonic acid and prostaglandin F-2 alpha,” Brain Res. 691(1-2), 223-228, 1995. “These findings suggest that high levels of AA and its metabolites may bias neurons towards excitation.” E. A. Quail and G. C. T. Yeoh, “The effect of iron status on glyceraldehyde 3-phosphate dehydrogenase expression in rat liver,” FEBS Lett. 359(2-3), 126-128, 1995. ”…the overexpression of GAPDH mRNA in iron deficiency is probably due to increased message stability.“ [This is one of the points discussed by Henics. Estrogen, which increases iron retention, also modifies mRNA stability.] J. G. Liehr, et al., “4-hydroxylation of estradiol by human uterine myometrium and myoma microsomes: Implications for the mechanism of uterine tumorigenesis,” Proc Natl Acad Sci USA 92(20), 9220-9224, 1995. ”… elicits biological activities distinct from estradiol, most notably an oxidant stress response induced by free radicals generated by metabolic redox cycling reactions.“ J. G. Liehr and D. Roy, “Free radical generation by redox cycling of estrogens,” Free Rad. Biol. Med. 8, 415-423, 1990. F. Fourrier, Circ. Shock 43(4), 171-178, 1994, “High estrogen levels were specifically observed in patients with sepsis and septic shock, either males or females.” “Circulating T levels were decreased in all male patients.” J. A. Jarvis, et al., “H-1 NMR analysis of fibril-forming peptide fragments of transthyretin,” Int. J. Pept. Protein Res. 44(4), 388-398, 1994. ”…fragments of the protein transthyretin, previously shown to form cross beta-sheet amyloid-like fibrils in vitro, were investigated….“
