Protective CO2 and aging
具有保护性的二氧化碳和老化
by Raymond Peat
The therapeutic effects of increasing carbon dioxide are being more widely recognized in recent years. Even Jane Brody, the NY Times writer on health topics, has favorably mentioned the use of the Buteyko method for asthma, and the idea of “permissive hypercapnia” during mechanical ventilation, to prevent lung damage from excess oxygen, has been discussed in medical journals. But still very few biologists recognize its role as a fundamental, universal protective factor. I think it will be helpful to consider some of the ways carbon dioxide might be controlling situations that otherwise are poorly understood.
The brain has a high rate of oxidative metabolism, and so it forms a very large proportion of the carbon dioxide produced by an organism. It also governs, to a great extent, the metabolism of other tissues, including their consumption of oxygen and production of carbon dioxide or lactic acid. Within a particular species, the rate of oxygen consumption increases in proportion to brain size, rather than body weight. Between very different species, the role of the brain in metabolism is even more obvious, since the resting metabolic rate corresponds to the size of the brain. For example, a cat's brain is about the size of a crocodile's, and their oxygen consumption at rest is similar, despite their tremendous difference in body size.
近年来，越来越多的二氧化碳的治疗效果得到了更广泛的认识。就连《纽约时报》健康话题的作者简·布罗迪(Jane Brody)也积极地提到了用Buteyko方法治疗哮喘，医学期刊上也讨论了机械通气过程中“允许性高碳酸血症”的想法，以防止氧气过量对肺造成损害。但仍然很少有生物学家认识到它作为一种基本的、普遍的保护因素的作用。我认为，考虑一下二氧化碳控制情况的一些方式是有帮助的，否则我们对这些情况的了解就会很差。
大脑有很高的氧化代谢率，因此它形成了有机物产生的很大一部分二氧化碳。在很大程度上，它还控制着其他组织的新陈代谢，包括它们对氧气的消耗和二氧化碳或乳酸的产生。在一个特定的物种中，氧气消耗的速度与大脑的大小成比例，而不是与体重成比例。在非常不同的物种之间，大脑在新陈代谢中的作用更加明显，因为静止代谢率与大脑的大小相对应。例如，猫的大脑和鳄鱼的差不多大，它们休息时的耗氧量也差不多，尽管它们的体型有很大的不同。
Stress has to be understood as a process that develops in time, and the brain (especially the neocortex and the frontal lobes) organizes the adaptive and developmental processes in both the spatial and temporal dimensions. The meaning of a situation influences the way the organism responds. For example, the stress of being restrained for a long time can cause major gastrointestinal bleeding and ulcerization, but if the animal has the opportunity to bite something during the stress (signifying its ability to fight back, and the possibility of escape) it can avoid the stress ulcers.
The patterning of the nervous activity throughout the body governs the local ability to produce carbon dioxide. When the cortex of the brain is damaged or removed, an animal becomes rigid, so the cortex is considered to have a “tonic inhibitory action” on the body. But when the nerves are removed from a muscle (for example, by disease or accident), the muscle goes into a state of constant activity, and its ability to oxidize glucose and produce carbon dioxide is reduced, while its oxidation of fatty acids persists, increasing the production of toxic oxidative fragments of the fatty acids, which contributes to the muscle's atrophy.
压力必须被理解为一个在时间上发展的过程，大脑(尤其是新皮层和额叶)在空间和时间两个维度组织了适应和发展过程。情境的意义会影响机体的反应方式。例如，长时间受到约束的压力会导致严重的胃肠道出血和溃疡，但如果动物在压力期间有机会咬东西(表明它有反击的能力和逃跑的可能性)，它可以避免压力溃疡。
全身神经活动的模式控制着局部产生二氧化碳的能力。当大脑皮层受损或被移除时，动物就会变得僵硬，因此大脑皮层被认为对身体有“强直性抑制作用”。但当神经从肌肉(例如,通过疾病或事故),肌肉进入状态持续活动,及其氧化葡萄糖和产生二氧化碳的能力降低,而其脂肪酸氧化,增加生产有毒的氧化脂肪酸的片段,导致肌肉萎缩。
The organism's intentions, expectations, or plans, are represented in the nervous system as a greater readiness for action, and in the organs and tissues controlled by the nerves, as an increase or decrease of oxidative efficiency, analogous to the differences between innervated and denervated muscles. This pattern in the nervous system has been called “the acceptor of action,” because it is continually being compared with the actual situation, and being refined as the situation is evaluated. The state of the organism, under the influence of a particular acceptor of action, is called a “functional system,” including all the components of the organism that participate most directly in realizing the intended adaptive action.
The actions of nerves can be considered anabolic, because during a stressful situation in which the catabolic hormones of adaption, e.g., cortisol, increase, the tissues of the functional system are protected, and while idle tissues may undergo autophagy or other form of involution, the needs of the active tissues are supplied with nutrients from their breakdown, allowing them to change and, when necessary, grow in size or complexity.
The brain's role in protecting against injury by stress, when it sees a course of action, has a parallel in the differences between concentric (positive, muscle shortening) and eccentric (negative, lengthening under tension) exercise, and also with the differences between innervated and denervated muscles. In eccentric exercise and denervation, less oxygen is used and less carbon dioxide is produced, while lactic acid increases, displacing carbon dioxide, and more fat is oxidized. Prolonged stress similarly decreases carbon dioxide and increases lactate, while increasing the use of fat.
有机体的意图、期望或计划，在神经系统中表现为更大的行动准备，在神经控制的器官和组织中表现为氧化效率的增加或降低，类似于有神经支配的肌肉和去神经支配的肌肉之间的差异。神经系统中的这种模式被称为“行动的接受者”，因为它不断地与实际情况进行比较，并在对情况进行评估时加以改进。有机体的状态，在特定的行为受体的影响下，被称为“功能系统”，包括最直接参与实现预期的适应行为的有机体的所有组成部分。
神经的作用可以被认为是合成代谢的，因为在应激情况下，适应的分解代谢激素，如皮质醇，增加，功能系统的组织受到保护，而闲置的组织可能经历自噬或其他形式的退化，活性组织的需要从它们的分解中获得营养，使它们能够改变，并在必要时增长大小或复杂性。
当大脑看到一个动作过程时，它在保护免受压力伤害方面的作用，与同心圆运动(积极的，肌肉缩短)和偏心运动(消极的，在张力下延长)之间的差异，以及有神经支配的肌肉和去神经支配的肌肉之间的差异，是相似的。在偏心运动和去神经运动中，使用的氧气少，产生的二氧化碳少，乳酸增加，取代二氧化碳，更多的脂肪被氧化。同样，长时间的压力会减少二氧化碳，增加乳酸，同时增加脂肪的消耗。
Darkness is stressful and catabolic. For example, in aging people, the morning urine contains nearly all of the calcium lost during the 24 hour period, and mitochondria are especially sensitive to the destructive effects of darkness. Sleep reduces the destructive catabolic effects of darkness. During the rapid-eye-movement (dreaming) phase of sleep, breathing is inhibited, and the level of carbon dioxide in the tissues accumulates. In restful sleep, the oxygen tension is frequently low enough, and the carbon dioxide tension high enough, to trigger the multiplication of stem cells and mitochondria.
Dreams represent the “acceptor of action” operating independently of the sensory information that it normally interacts with. During dreams, the brain (using a system called the Ascending Reticular Activating System) disconnects itself from the sensory systems. I think this is the nervous equivalent of concentric/positive muscle activity, in the sense that the brain is in control of its actions. The active, dreaming phase of sleep occurs more frequently in the later part of the night, as morning approaches. This is the more stressful part of the night, with cortisol and some other stress hormones reaching a peak at dawn, so it would be reasonable for the brain's defensive processes to be most active at that time. The dreaming process in the brain is associated with deep muscle relaxation, which is probably associated with the trophic (restorative) actions of the nerves.
In ancient China the Taoists were concerned with longevity, and according to Joseph Needham (Science and Civilization in China) their methods included the use of herbs, minerals, and steroids extracted from the urine of children. Some of those who claimed extreme longevity practiced controlled breathing and tai chi (involving imagery, movement, and breating), typically in the early morning hours, when stress reduction is most important. As far as I know, there are no studies of carbon dioxide levels in practitioners of tai chi, but the sensation of warmth they typically report suggests that it involves hypoventilation.
黑暗是压力和分解代谢的。例如，对于老年人来说，早晨的尿液几乎包含了他们在24小时内失去的所有钙，线粒体对黑暗的破坏性影响特别敏感。睡眠可以减少黑暗对分解代谢的破坏性影响。在睡眠的快速眼动(做梦)阶段，呼吸被抑制，组织中的二氧化碳水平会累积。在宁静的睡眠中，氧张力经常很低，而二氧化碳张力很高，从而触发干细胞和线粒体的增殖。
梦代表着“行动的接受者”独立于它通常与之相互作用的感官信息而运作。在做梦时，大脑(使用一种叫做升天网状激活系统的系统)断开了自己与感觉系统的连接。我认为这是一种神经等效的同心同德/积极的肌肉活动，在某种意义上，大脑控制着它的行为。随着清晨的临近，活跃的、做梦的睡眠阶段在深夜更频繁地出现。这是晚上压力最大的时候，皮质醇和其他压力荷尔蒙在黎明达到顶峰，所以大脑的防御过程在那个时候最活跃是合理的。在大脑中做梦的过程与深层肌肉放松有关，这可能与神经的营养(恢复)活动有关。
在中国古代，道家注重长寿，据李约瑟(中国科学与文明)说，他们的方法包括使用草药、矿物质和从儿童尿液中提取的类固醇。一些声称能长寿的人练习了有控制的呼吸和太极(包括想象、运动和呼吸)，通常是在清晨，此时减压是最重要的。据我所知，目前还没有关于太极拳练习者体内二氧化碳水平的研究，但他们通常报告的温暖感觉表明，这与通气不足有关。
In the 1960s, a Russian researcher examined hospital records of measurements of newborn babies, and found that for several decades the size of their heads had been increasing. He suggested that it might be the result of increasing atmospheric carbon dioxide.
The experiences and nutrition of a pregnant animal are known to affect the expression of genes in the offspring, affecting such things as allergies, metabolic rate, brain size, and intelligence. Miles Storfer (1999) has reviewed the evidence for epigenetic environmental control of brain size and intelligence. The main mechanisms of epigenetic effects or “imprinting” are now known to involve methylation and acetylation of the chromosomes (DNA and histones).
Certain kinds of behavior, as well as nutrition and other environmental factors, increase the production and retention of carbon dioxide. The normal intrauterine level of carbon dioxide is high, and it can be increased or decreased by changes in the mother's physiology. The effects of carbon dioxide on many biological processes involving methylation and acetylation of the genetic material suggest that the concentration of carbon dioxide during gestation might regulate the degree to which parental imprinting will persist in the developing fetus.
在20世纪60年代，一名俄罗斯研究人员检查了新生儿的医院测量记录，发现几十年来他们的头一直在变大。他认为这可能是大气中二氧化碳含量增加的结果。
众所周知，怀孕动物的经历和营养会影响后代的基因表达，影响过敏、代谢率、大脑大小和智力等因素。Miles Storfer(1999)回顾了表观遗传环境控制大脑大小和智力的证据。表观遗传效应或“印迹”的主要机制目前已知涉及染色体(DNA和组蛋白)的甲基化和乙酰化。
某些行为，以及营养和其他环境因素，增加了二氧化碳的产生和保留。正常情况下，子宫内的二氧化碳水平是高的，它可以通过母亲的生理变化而增加或减少。二氧化碳对包括遗传物质甲基化和乙酰化在内的许多生物过程的影响表明，妊娠期间二氧化碳的浓度可能会调节发育中的胎儿对亲代印记的持续程度。
There is some evidence of increased demethylation associated with the low level of oxygen in the uterus (Wellman, et al., 2008). A high metabolic rate and production of carbon dioxide would increase the adaptability of the new organism, by decreasing the limiting genetic imprints.
A quick reduction of carbon dioxide caused by hyperventilation can provoke an epileptic seizure, and can increase muscle spasms and vascular leakiness, and (by releasing serotonin and histamine) contribute to inflammation and clotting disorders. On a slightly longer time scale, a reduction of carbon dioxide can increase the production of lactic acid, which is a promoter of inflammation and fibrosis. A prolonged decrease in carbon dioxide can increase the susceptibility of proteins to glycation (the addition of aldehydes, from polyunsaturated fat peroxidation or methylglyoxal from lactate metabolism, to amino groups), and a similar process is likely to contribute to the methylation of histones, a process that increases with aging. Histones regulate genetic activity.
With aging, DNA methylation is increased (Bork, et al., 2009). I suggest that methylation stabilizes and protects cells when growth and regeneration aren't possible (and that it's likely to increase when CO2 isn't available). Hibernation (Morin and Storey, 2009) and sporulation (Ruiz-Herrera, 1994; Clancy, et al., 2002) appear to use methylation protectively.
有一些证据表明，子宫内的低氧水平会增加去甲基化(Wellman等，2008)。高代谢率和二氧化碳的产生将增加新生物的适应性，减少限制性遗传印记。
由过度通气引起的二氧化碳的快速减少会引发癫痫发作，并会增加肌肉痉挛和血管渗漏，(通过释放血清素和组胺)会导致炎症和凝血障碍。在稍微长一点的时间尺度上，二氧化碳的减少会增加乳酸的产生，乳酸是炎症和纤维化的促进剂。长期减少二氧化碳可以增加蛋白质的敏感性糖化(醛、从多元不饱和脂肪过氧化反应或甲基乙二醛乳酸代谢,氨基酸组),和一个类似的过程可能会导致组蛋白的甲基化,一个随衰老的过程。组蛋白调节遗传活性。
随着年龄的增长，DNA甲基化也会增加(Bork等，2009)。我认为，当细胞无法生长和再生时，甲基化可以稳定和保护细胞(当没有二氧化碳时，它很可能会增加)。冬眠(Morin and Storey, 2009)和产孢(Ruiz-Herrera, 1994;克兰西等人，2002)似乎是保护性地使用甲基化。
Parental stress, prenatal stress, early life stress, and even stress in adulthood contribute to “imprinting of the genes,” partly through methylation of DNA and the histones.
Methionine and choline are the main dietary sources of methyl donors. Restriction of methionine has many protective effects, including increased average (42%) and maximum (44%) longevity in rats (Richie, et al., 1994). Restriction of methyl donors causes demethylation of DNA (Epner, 2001). The age accelerating effect of methionine might be related to disturbing the methylation balance, inappropriately suppressing cellular activity. Besides its effect on the methyl pool, methionine inhibits thyroid function and damages mitochondria.
The local concentration of carbon dioxide in specific tissues and organs can be adjusted by nervous and hormonal activation or inhibition of the carbonic anhydrase enzymes, that accelerate the oonversion of CO2 to carbonic acid, H2CO3. The activity of carbonic anhydrase can determine the density and strength of the skeleton, the excitability of nerves, the accumulation of water, and can regulate the structure and function of the tissues and organs.
父母的压力，产前的压力，早期生活的压力，甚至成年后的压力都会导致“基因印记”，部分是通过DNA和组蛋白的甲基化。
蛋氨酸和胆碱是甲基供体的主要膳食来源。限制蛋氨酸有许多保护作用，包括提高大鼠的平均寿命(42%)和最大寿命(44%)(Richie等，1994)。限制甲基供体会导致DNA去甲基化(Epner, 2001)。蛋氨酸的加速衰老作用可能与扰乱甲基化平衡、不适当地抑制细胞活性有关。除了对甲基池的影响外，蛋氨酸还抑制甲状腺功能，损害线粒体。
特定组织和器官中二氧化碳的局部浓度可以通过神经和激素的激活或碳酸酐酶的抑制来调节，碳酸酐酶能加速二氧化碳转化为碳酸，H2CO3。碳酸酐酶的活性可以决定骨骼的密度和强度，神经的兴奋性，水分的积累，并可以调节组织器官的结构和功能。
Ordinarily, carbon dioxide and bicarbonate are thought of only in relation to the regulation of pH, and only in a very general way. Because of the importance of keeping the pH of the blood within a narrow range, carbon dioxide is commonly thought of as a toxin, because an excess can cause unconsciousness and acidosis. But increasing carbon dioxide doesn't necessarily cause acidosis, and acidosis caused by carbon dioxide isn't as harmful as lactic acidosis.
Frogs and toads, being amphibians, are especially dependent on water, and in deserts or areas with a dry season they can survive a prolonged dry period by burrowing into mud or sand. Since they may be buried 10 or 11 inches below the surface, they are rarely found, and so haven't been extensively studied. In species that live in the California desert, they have been known to survive 5 years of burial without rainfall, despite a moderately warm average temperature of their surroundings.
One of their known adaptations is to produce a high level of urea, allowing them to osmotically absorb and retain water. (Very old people sometimes have extremely high urea and osmotic tension.)
Some laboratory studies show that as a toad burrows into mud, the amount of carbon dioxide in its tissues increases. Their skin normally functions like a lung, exchanging oxygen for carbon dioxide. If the toad's nostrils are at the surface of the mud, as dormancy begins its breathing will gradually slow, increasing the carbon dioxide even more. Despite the increasing carbon dioxide, the pH is kept stable by an increase of bicarbonate (Boutilier, et al., 1979). A similar increase of bicarbonate has been observed in hibernating hamsters and doormice.
通常，二氧化碳和碳酸氢盐只被认为与pH值的调节有关，而且只是以一种非常普遍的方式。由于保持血液pH值在一个狭窄范围内的重要性，二氧化碳通常被认为是一种毒素，因为过量会导致昏迷和酸中毒。但是增加二氧化碳并不一定会引起酸中毒，而且由二氧化碳引起的酸中毒也没有乳酸酸中毒那么有害。
青蛙和蟾蜍是两栖动物，特别依赖水，在沙漠或旱季的地区，它们可以通过在泥土或沙子里挖洞来度过长时间的干旱期。由于它们可能被埋在地表以下10或11英寸，它们很少被发现，因此没有被广泛研究。在生活在加利福尼亚沙漠的物种中，他们已经被知道可以在没有降雨的情况下存活5年，尽管他们周围的平均温度是温和的。
它们已知的适应性之一是产生高水平的尿素，允许它们渗透吸收和保留水分。(老年人有时尿素和渗透压极高。)
一些实验室研究表明，蟾蜍钻进泥土时，其组织中的二氧化碳含量会增加。它们的皮肤正常功能就像肺一样，将氧气交换为二氧化碳。如果蟾蜍的鼻孔位于泥的表面，当冬眠开始时，它的呼吸会逐渐变慢，从而增加更多的二氧化碳。尽管二氧化碳在增加，但碳酸氢盐的增加使pH值保持稳定(Boutilier等人，1979)。在冬眠的仓鼠和门鼠中也观察到类似的碳酸氢盐增加。
Thinking about the long dormancy of frogs reminded me of a newspaper story I read in the 1950s. Workers breaking up an old concrete structure found a dormant toad enclosed in the concrete, and it revived soon after being released. The concrete had been poured decades earlier.
Although systematic study of frogs or toads during their natural buried estivation has been very limited, there have been many reports of accidental discoveries that suggest that the dormant state might be extended indefinitely if conditions are favorable. Carbon dioxide has antioxidant effects, and many other stabilizing actions, including protection against hypoxia and the excitatory effects of intracellular calcium and inflammation (Baev, et al., 1978, 1995; Bari, et al., 1996; Brzecka, 2007; Kogan, et al., 1994; Malyshev, et al., 1995).
When mitochondria are “uncoupled,” they produce more carbon dioxide than normal, and the mitochondria produce fewer free radicals. Animals with uncoupled mitochondria live longer than animals with the ordinary, more efficient mitochondria, that produce more reactive oxidative fragments. One effect of the high rate of oxidation of the uncoupled mitochondria is that they can eliminate polyunsatured fatty acids that might otherwise be integrated into tissue structures, or function as inappropriate regulatory signals.
Birds have a higher metabolic rate than mammals of the same size, and live longer. Their tissues contain fewer of the highly unsaturated fatty acids. Queen bees, which live many times longer than worker bees, have mainly monounsaturated fats in their tissues, while the tissues of the short-lived worker bees, receiving a different diet, within a couple of weeks of hatching will contain highly unsaturated fats.
想到青蛙的长时间休眠让我想起了我在20世纪50年代读到的一篇报纸报道。工人们在拆除一座旧混凝土建筑时发现了一只潜伏在混凝土中的蟾蜍，它在被释放后不久就复活了。混凝土早在几十年前就已经浇筑好了。
虽然对青蛙或蟾蜍在自然埋藏下休眠期间的系统研究非常有限，但已有许多偶然发现的报告表明，如果条件有利，休眠状态可能会无限期延长。二氧化碳具有抗氧化作用和许多其他稳定作用，包括防止缺氧和细胞内钙和炎症的兴奋效应(Baev等，1978,1995;巴里等人，1996;Brzecka, 2007;Kogan等，1994;Malyshev等，1995)。
当线粒体“分离”时，它们产生的二氧化碳比正常情况下更多，而线粒体产生的自由基更少。拥有分离线粒体的动物比拥有能产生更多活性氧化碎片的普通线粒体的动物寿命更长。解耦线粒体的高氧化率的一个影响是，它们可以消除多不饱和脂肪酸，否则这些脂肪酸可能会被整合到组织结构中，或作为不适当的调节信号发挥作用。
鸟类的代谢率比同等体型的哺乳动物高，寿命也更长。它们的组织含有较少的高不饱和脂肪酸。蜂王的寿命是工蜂的好几倍，它们的组织中主要含有单一不饱和脂肪，而寿命较短的工蜂，由于饮食不同，在孵化后的几周内，其组织中会含有高度不饱和脂肪。
Bats have a very high metabolic rate, and an extremely long lifespan for an animal of their size. While most animals of their small size live only a few years, many bats live a few decades. Bat caves usually have slightly more carbon dioxide than the outside atmosphere, but they usually contain a large amount of ammonia, and bats maintain a high serum level of carbon dioxide, which protects them from the otherwise toxic effects of the ammonia.
The naked mole rat, another small animal with an extremely long lifespan (in captivity they have lived up to 30 years, 9 or 10 times longer than mice of the same size) has a low basal metabolic rate, but I think measurements made in laboratories might not represent their metabolic rate in their natural habitat. They live in burrows that are kept closed, so the percentage of oxygen is lower than in the outside air, and the percentage of carbon dioxide ranges from 0.2% to 5% (atmospheric CO2 is about 0.038). The temperature and humidity in their burrows can be extremely high, and to be very meaningful their metabolic rate would have to be measured when their body temperature is raised by the heat in the burrow.
When they have been studied in Europe and the US, there has been no investigation of the effect of altitude on their metabolism, and these animals are native to the high plains of Kenya and Ethiopia, where the low atmospheric pressure would be likely to increase the level of carbon dioxide in their tissues. Consequently, I doubt that the longevity seen in laboratory situations accurately reflects the longevity of the animals in their normal habitat.
蝙蝠有非常高的代谢率，对于它们这种体型的动物来说，寿命也非常长。虽然大多数体型较小的动物只能活几年，但许多蝙蝠可以活几十年。蝙蝠洞穴里的二氧化碳含量通常比外面的大气略高，但它们通常含有大量的氨，而蝙蝠的血清中二氧化碳含量很高，这可以保护它们免受氨的毒性影响。
裸鼢鼠,另一个小动物一个超长的寿命(被囚禁他们活了30年,9或10倍的时间比相同大小的老鼠)基础代谢率低,但我想在实验室测量可能不代表他们的代谢率在自然栖息地。它们生活在封闭的洞穴里，所以氧气的百分比比外面的空气低，二氧化碳的百分比在0.2%到5%之间(大气中的二氧化碳大约是0.038)。它们洞穴里的温度和湿度可能非常高，要想有意义，就必须测量它们的代谢率，因为洞穴里的热量会提高它们的体温。
当他们研究了在欧洲和美国,没有调查的高度对新陈代谢的影响,和这些动物原产于肯尼亚和埃塞俄比亚的高地平原,那里的大气压力低会增加二氧化碳的水平在他们的组织。因此，我怀疑在实验室中看到的寿命是否准确地反映了动物在正常栖息地的寿命。
Besides living in a closed space with a high carbon dioxide content, mole rats have another similarity to bees. In each colony, there is only one female that reproduces, the queen, and, like a queen bee, she is the largest individual in the colony. In beehives, the workers carefully regulate the carbon dioxide concentration, which varies from about 0.2% to 6%, similar to that of the mole rat colony. A high carbon dioxide content activates the ovaries of a queen bee, increasing her fertility.
Since queen bees and mole rats live in the dark, I think their high carbon dioxide compensates for the lack of light. (Both light and CO2 help to maintain oxidative metabolism and inhibit lactic acid formation.) Mole rats are believed to sleep very little. During the night, normal people tolerate more CO2, and so breathe less, especially near morning, with increased active dreaming sleep.
A mole rat has never been known to develop cancer. Their serum C-reactive protein is extremely low, indicating that they are resistant to inflammation. In humans and other animals that are susceptible to cancer, one of the genes that is likely to be silenced by stress, aging, and methylation is p53, a tumor-suppressor gene.
If the intrauterine experience, with low oxygen and high carbon dioxide, serves to “reprogram” cells to remove the accumulated effects of age and stress, and so to maximize the developmental potential of the new organism, a life that's lived with nearly those levels of oxygen and carbon dioxide might be able to avoid the progressive silencing of genes and loss of function that cause aging and degenerative diseases.
除了生活在一个二氧化碳含量高的封闭空间外，鼹鼠和蜜蜂还有另一个相似之处。在每个蜂群中，只有一只雌性蜂王在繁殖，就像蜂王一样，她是蜂群中最大的个体。在蜂箱里，工蜂小心地调节二氧化碳的浓度，大约在0.2%到6%之间变化，与鼹鼠群体的浓度相似。高浓度的二氧化碳会激活蜂王的卵巢，增加其生育能力。
由于蜂王和鼹鼠生活在黑暗中，我认为他们的高二氧化碳补偿了缺乏光。(光和二氧化碳都有助于维持氧化代谢和抑制乳酸的形成。)人们认为鼹鼠睡得很少。在夜间，正常人可以忍受更多的二氧化碳，因此呼吸更少，特别是在接近早晨的时候，活跃的做梦睡眠会增加。
目前还不知道鼹鼠会得癌症。他们的血清c反应蛋白极低，表明他们能抵抗炎症。在人类和其他易患癌症的动物中，有一种基因很可能因压力、衰老和甲基化而沉默，它是p53，一种肿瘤抑制基因。
如果子宫内低氧高二氧化碳的经历有助于“重新编程”细胞，以消除年龄和压力累积的影响，从而最大限度地发挥新生物的发育潜力，一个生活在氧气和二氧化碳水平附近的人，也许能够避免基因的逐渐沉默和功能的丧失，这些都会导致衰老和退化性疾病。
Several diseases and syndromes are now thought to involve abnormal methylation of genes. Prader-Willi sydrome, Angelman's syndrome, and various “autistic spectrum disorders,” as well as post-traumatic stress disorder and several kinds of cancer seem to involve excess methylation.
Moderate methionine restriction (for example, using gelatin regularly in the diet) might be practical, but if increased carbon dioxide can activate the demethylase enzymes in a controlled way, it might be a useful treatment for the degenerative diseases and for aging itself.
The low carbon dioxide production of hypothyroidism (e.g., Lee and Levine, 1999), and the respiratory alkalosis of estrogen excess, are often overlooked. An adequate supply of calcium, and sometimes supplementation of salt and baking soda, can increase the tissue content of CO2.
一些疾病和综合征现在被认为与基因的异常甲基化有关。普瑞德-威利综合症、安格尔曼综合症和各种“自闭症谱系障碍”，以及创伤后应激障碍和几种癌症似乎都与过度甲基化有关。
适度限制蛋氨酸(例如，在饮食中定期使用明胶)可能是可行的，但如果增加二氧化碳可以以可控的方式激活去甲基化酶，它可能是一种有效的治疗退行性疾病和衰老本身的方法。
甲状腺功能减退症(例如，Lee和Levine, 1999)产生的低二氧化碳，以及雌激素过量引起的呼吸性碱中毒，常常被忽视。充足的钙供应，有时补充盐和小苏打，可以增加组织中的二氧化碳含量。
REFERENCES
Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E621-7. Uncoupling protein-2 regulates lifespan in mice. Andrews ZB, Horvath TL.
Fiziol Zh SSSR 1978 Oct;64(10):1456-62. [Role of CO2 fixation in increasing the body's resistance to acute hypoxia]. Baev VI, Vasil'ev VV, Nikolaeva EN. In rats, the phenomenon of considerable increase in resistance to acute hypoxia observed after 2-hour stay under conditions of gradually increasing concentration of CO2, decreasing concentration of O2, and external cooling at 2--3 degrees seems to be based mainly on changes in concentration of CO2 (ACCORDINGLY, PCO2 and other forms of CO2 in the blood). The high resistance to acute hypoxia develops as well after subcutaneous or i.v. administration of 1.0 ml of water solution (169.2 mg/200 g) NaHCO2, (NH4)2SO4, MgSO4, MnSO4, and ZnSO4 (in proportion: 35 : 5 : 2 : 0.15 : 0.15, resp.) or after 1-hour effect of increased hypercapnia and hypoxia without cooling.
Fiziol Zh Im I M Sechenova 1995 Feb;81(2):47-52. [The unknown physiological role of carbon dioxide]. Baev VI, Vasil'eva IV, L'vov SN, Shugalei IV [The data suggests that carbon dioxide is a natural element of the organism antioxidant defence system. ion poisoning].
Stroke. 1996 Sep;27(9):1634-9; discussion 1639-40. Differential effects of short-term hypoxia and hypercapnia on N-methyl-D-aspartate-induced cerebral vasodilatation in piglets. Bari F, Errico RA, Louis TM, Busija DW.
Vojnosanit Pregl. 1996 Jul-Aug;53(4):261-74. [Carbon dioxide inhibits the generation of active forms of oxygen in human and animal cells and the significance of the phenomenon in biology and medicine] [Article in Serbian] Boljevic S, Kogan AH, Gracev SV, Jelisejeva SV, Daniljak IG.
J Exp Biol. 1979 Oct;82:357-65. Acid-base relationships in the blood of the toad, Bufo marinus. III. The effects of burrowing. Boutilier RG, Randall DJ, Shelton G, Toews DP.
Acta Neurobiol Exp (Wars). 2007;67(2):197-206. Role of hypercapnia in brain oxygenation in sleep-disordered breathing. Brzecka A. Adaptive mechanisms may diminish the detrimental effects of recurrent nocturnal hypoxia in obstructive sleep apnea (OSA). The potential role of elevated carbon dioxide (CO2) in improving brain oxygenation in the patients with severe OSA syndrome is discussed. CO2 increases oxygen uptake by its influence on the regulation of alveolar ventilation and ventilation-perfusion matching, facilitates oxygen delivery to the tissues by changing the affinity of oxygen to hemoglobin, and increases cerebral blood flow by effects on arterial blood pressure and on cerebral vessels. Recent clinical studies show improved brain oxygenation when hypoxia is combined with hypercapnia. Anti-inflammatory and protective against organ injury properties of CO2 may also have therapeutic importance. These biological effects of hypercapnia may improve brain oxygenation under hypoxic conditions. This may be especially important in patients with severe OSA syndrome.
Ageing Res Rev. 2009 Oct;8(4):268-76. Epub 2009 Apr 1. The role of epigenetics in aging and age-related diseases. Calvanese V, Lara E, Kahn A, Fraga MF.
Rev Esp Geriatr Gerontol. 2009 Jul-Aug;44(4):194-9. Epub 2009 Jul 3. [Effect of restricting amino acids except methionine on mitochondrial oxidative stress.] [Article in Spanish] Caro P, Gómez J, Sánchez I, López-Torres M, Barja G.
Cell Metab. 2007 Jan;5(1):21-33. A central thermogenic-like mechanism in feeding regulation: an interplay between arcuate nucleus T3 and UCP2. Coppola A, Liu ZW, Andrews ZB, Paradis E, Roy MC, Friedman JM, Ricquier D, Richard D, Horvath TL, Gao XB, Diano S.
Ter Arkh. 1995;67(3):23-6. [Changes in the sensitivity of leukocytes to the inhibiting effect of CO2 on their generation of active forms of oxygen in bronchial asthma patients] Daniliak IG, Kogan AKh, Sumarokov AV, Bolevich S.
Cell Metab. 2007 Dec;6(6):497-505. Respiratory uncoupling in skeletal muscle delays death and diminishes age-related disease. Gates AC, Bernal-Mizrachi C, Chinault SL, Feng C, Schneider JG, Coleman T, Malone JP, Townsend RR, Chakravarthy MV, Semenkovich CF.
Endocr Pract. 2009 Jun 2:1-13. Fibrotic Appearance of Lungs in Severe Hypothyroidism is Reversible with Thyroxine Replacement. George JT, Thow JC, Rodger KA, Mannion R, Jayagopal V.
J Bioenerg Biomembr. 2009 Jun;41(3):309-21. Epub 2009 Jul 25. Effect of methionine dietary supplementation on mitochondrial oxygen radical generation and oxidative DNA damage in rat liver and heart. Gomez J, Caro P, Sanchez I, Naudi A, Jove M, Portero-Otin M, Lopez-Torres M, Pamplona R, Barja G.
Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7612-7. Increased tricarboxylic acid cycle flux in rat brain during forepaw stimulation detected with 1H[13C]NMR. Hyder F, Chase JR, Behar KL, Mason GF, Siddeek M, Rothman DL, Shulman RG.
Can J Neurol Sci. 1979 May;6(2):105-12. The effects of partial chronic denervation on forearm metabolism. Karpati G, Klassen G, Tanser P.
Biull Eksp Biol Med. 1994 Oct;118(10):395-8. [CO2--a natural inhibitor of active oxygen form generation by phagocytes] Kogan AKh, Manuilov BM, Grachev SV, Bolevich S, Tsypin AB, Daniliak IG.
Izv Akad Nauk Ser Biol. 1997 Mar-Apr;(2):204-17. [Carbon dioxide--a universal inhibitor of the generation of active oxygen forms by cells (deciphering one enigma of evolution)] Kogan AKh, Grachev SV, Eliseeva SV, Bolevich S.
Vopr Med Khim. 1996 Jul-Sep;42(3):193-202. [Ability of carbon dioxide to inhibit generation of superoxide anion radical in cells and its biomedical role] Kogan AKh, Grachev SV, Eliseeva SV, Bolevich S.
Dokl Akad Nauk. 1996 May;348(3):413-6. [New evidence for the inhibitory action of CO2 on generation of superoxide anion radicals by phagocytes in various tissues. (Mechanism of bio- and eco-effects of CO2)] Kogan AKh, Grachev SV, Bolevich S, Eliseeva SV.
Biull Eksp Biol Med. 1996 Apr;121(4):407-10. [Carbon dioxide gas inhibition of active forms of oxygen generation by cells in the internal organs and its biological significance] Kogan AKh, Grachev SV, Eliseeva SV.
Fiziol Cheloveka. 1995 Jul-Aug;21(4):128-36. [CO2--a natural inhibitor of the generation of active species of oxygen in phagocytes] Kogan AKh, Manuilov BM, Grachev SV, Bolevich S, Tsypin AB, Daniliak IG.
Patol Fiziol Eksp Ter. 1995 Jul-Sep;(3):34-40. [Comparative study of the effect of carbon dioxide on the generation of active forms of oxygen by leukocytes in health and in bronchial asthma] Kogan AKh, Bolevich S, Daniliak IG.
Can J Anaesth. 1999 Feb;46(2):185-9. Acute respiratory alkalosis associated with low minute ventilation in a patient with severe hypothyroidism. Lee HT, Levine M. [email protected] PURPOSE: Patients with severe hypothyroidism present unique challenges to anesthesiologists and demonstrate much increased perioperative risks. Overall, they display increased sensitivity to anesthetics, higher incidence of perioperative cardiovascular morbidity, increased risks for postoperative ventilatory failure and other physiological derangements. The previously described physiological basis for the increased incidence of postoperative ventilatory failure in hypothyroid patients includes decreased central and peripheral ventilatory responses to hypercarbia and hypoxia, muscle weakness, depressed central respiratory drive, and resultant alveolar hypoventilation. These ventilatory failures are associated most frequently with severe hypoxia and carbon dioxide (CO2) retention. The purpose of this clinical report is to discuss an interesting and unique anesthetic presentation of a patient with severe hypothyroidism. CLINICAL FEATURES: We describe an unique presentation of ventilatory failure in a 58 yr old man with severe hypothyroidism. He had exceedingly low perioperative respiratory rate (3-4 bpm) and minute ventilation volume, and at the same time developed primary acute respiratory alkalosis and associated hypocarbia (P(ET)CO2 approximately 320-22 mmHg). CONCLUSION: Our patient's ventilatory failure was based on unacceptably low minute ventilation and respiratory rate that was unable to sustain adequate oxygenation. His profoundly lowered basal metabolic rate and decreased CO2 production, resulting probably from severe hypothyroidism, may have resulted in development of acute respiratory alkalosis in spite of concurrently diminished minute ventilation.
Anal Bioanal Chem. 2008 Jan;390(2):679-88. Epub 2007 Oct 27. The structural modification of DNA nucleosides by nonenzymatic glycation: an in vitro study based on the reactions of glyoxal and methylglyoxal with 2'-deoxyguanosine. Li Y, Cohenford MA, Dutta U, Dain JA.
Biull Eksp Biol Med. 1995 Jun;119(6):590-3. [Adaptation to high altitude hypoxia facilitates a limitation of lipid peroxidation activation in inflammation and stress] [Article in Russian] Malyshev VV, Vasil'eva LS, Belogorov SB, Nefedova TV.
Am J Physiol Regul Integr Comp Physiol. 2007 Sep;293(3):R1159-68. Epub 2007 Jun 20. Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production. Muller FL, Song W, Jang YC, Liu Y, Sabia M, Richardson A, Van Remmen H.
Radiobiologiia. 1984 Jan-Feb;24(1):29-34. [Enzyme activity of glutamic acid metabolism and the Krebs cycle in the brain of rats laser-irradiated against a background of altered adrenoreceptor function] [Article in Russian] Pikulev AT, Dzhugurian NA, Zyrianova TN, Lavrova VM, Mostovnikov VA.
Rejuvenation Res.2007 Dec12; :18072884, Exploring Overlooked Natural Mitochondria-Rejuvenative Intervention: The Puzzle of Bowhead Whales and Naked Mole Rats. Prokopov A.F.
Proceedings of the Japan Academy. Ser. B: Physical and Biological Sciences Vol.78, No.10(2002)pp.293-298. DNA methylation and Lamarckian inheritance, Sano H.
Biol Chem. 2009 Nov;390(11):1145-53. The epigenetic bottleneck of neurodegenerative and psychiatric diseases. Sananbenesi F, Fischer A. The orchestrated expression of genes is essential for the development and survival of every organism. In addition to the role of transcription factors, the availability of genes for transcription is controlled by a series of proteins that regulate epigenetic chromatin remodeling. The two most studied epigenetic phenomena are DNA methylation and histone-tail modifications. Although a large body of literature implicates the deregulation of histone acetylation and DNA methylation with the pathogenesis of cancer, recently epigenetic mechanisms have also gained much attention in the neuroscientific community. In fact, a new field of research is rapidly emerging and there is now accumulating evidence that the molecular machinery that regulates histone acetylation and DNA methylation is intimately involved in synaptic plasticity and is essential for learning and memory. Importantly, dysfunction of epigenetic gene expression in the brain might be involved in neurodegenerative and psychiatric diseases. In particular, it was found that inhibition of histone deacetylases attenuates synaptic and neuronal loss in animal models for various neurodegenerative diseases and improves cognitive function. In this article, we will summarize recent data in the novel field of neuroepigenetics and discuss the question why epigenetic strategies are suitable therapeutic approaches for the treatment of brain diseases.
Ukr Biokhim Zh 1994 Jan-Feb;66(1):109-12. [Protective effect of sodium bicarbonate in nitrite ion poisoning]. Shugalei IV, L'vov SN, Baev VI, Tselinskii IV
Am J Respir Crit Care Med. 2000 Mar;161(3 Pt 1):891-8. Modulation of release of reactive oxygen species by the contracting diaphragm. Stofan DA, Callahan LA, DiMarco AF, Nethery DE, Supinski GS.
Ecology: Vol. 50, No. 3, pp. 492-494. Carbon Dioxide Retention: A Mechanism of Ammonia Tolerance in Mammals. Studier EM and Fresquez AA.
Sci Signal. 2009 Mar 31;2(64): pe17. Reversing DNA methylation: new insights from neuronal activity-induced Gadd45b in adult neurogenesis. Wu H, Sun YE. Neurogenesis in the adult mammalian brain involves activity-dependent expression of genes critical for the proliferation of progenitors and for neuronal maturation. A recent study suggests that the stress response gene Gadd45b (growth arrest and DNA-damage-inducible protein 45 beta) can be transiently induced by neuronal activity and may promote adult neurogenesis through dynamic DNA demethylation of specific gene promoters in adult hippocampus. These results provide evidence supporting the provocative ideas that active DNA demethylation may occur in postmitotic neurons and that DNA methylation-mediated dynamic epigenetic regulation is involved in regulating long-lasting changes in neural plasticity in mammalian brains.
Patol Fiziol Eksp Ter. 2005 Apr-Jun;(2):13-5. [The effect of the NMDA-receptor blocker MK-801 on sensitivity of the respiratory system to carbon dioxide] Tarakanov IA, Dymetska A, Tarasova NN.
Life Sci. 1997;61(5):523-35. Effect of acidotic challenges on local depolarizations evoked by N-methyl-D-aspartate in the rat striatum. Urenjak J, Zilkha E, Gotoh M, Obrenovitch TP. “Hypercapnia reduced NMDA-evoked responses in a concentration-dependent manner, with 7.5 and 15 % CO2 in the breathing mixture reducing the depolarization amplitude to 74 % and 64 % of that of the initial stimuli, respectively. Application of 50 mM NH4+ progressively reduced dialysate pH, and a further acidification was observed when NH4+ was discontinued. Perfusion of NMDA after NH4+ application evoked smaller depolarizations (56 % of the corresponding control, 5 min after NH4+ removal), and this effect persisted for over 1 h.” “Together, these results demonstrate that extracellular acidosis, such as that associated with excessive neuronal activation or ischemia, inhibits NMDA-evoked responses in vivo.”
Arch Int Physiol Biochim. 1977 Apr;85(2):295-304. Glutamate and glutamine in the brain of the neonatal rat during hypercapnia. Van Leuven F, Weyne J, Leusen I.
Pediatrics 1995 Jun;95(6):868-874. Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: an experimental study in the immature rat. Vannucci RC, Towfighi J, Heitjan DF, Brucklacher RM
Pediatr Res 1997 Jul;42(1):24-29. Effect of carbon dioxide on cerebral metabolism during hypoxia-ischemia in the immature rat. Vannucci RC, Brucklacher RM, Vannucci SJ
Sci. Signal., 31 March 2009 Vol. 2, Issue 64, p. pe17, Reversing DNA Methylation: New Insights from Neuronal Activity-Induced Gadd45b in Adult Neurogenesis Wu H, Sun YI
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