565 lines
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565 lines
39 KiB
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<head><title>Protective CO2 and aging</title></head>
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<body>
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<h1>
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Protective CO2 and aging
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</h1>
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<p></p>
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<p>
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The therapeutic effects of increasing carbon dioxide are being more widely recognized in recent years. Even
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Jane Brody, the NY Times writer on health topics, has favorably mentioned the use of the Buteyko method for
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asthma, and the idea of "permissive hypercapnia" during mechanical ventilation, to prevent lung damage from
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excess oxygen, has been discussed in medical journals. But still very few biologists recognize its role as a
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fundamental, universal protective factor. I think it will be helpful to consider some of the ways carbon
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dioxide might be controlling situations that otherwise are poorly understood.
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</p>
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<p>
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The brain has a high rate of oxidative metabolism, and so it forms a very large proportion of the carbon
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dioxide produced by an organism. It also governs, to a great extent, the metabolism of other tissues,
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including their consumption of oxygen and production of carbon dioxide or lactic acid. Within a particular
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species, the rate of oxygen consumption increases in proportion to brain size, rather than body weight.
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Between very different species, the role of the brain in metabolism is even more obvious, since the resting
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metabolic rate corresponds to the size of the brain. For example, a cat's brain is about the size of a
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crocodile's, and their oxygen consumption at rest is similar, despite their tremendous difference in body
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size.
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</p>
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<p>
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Stress has to be understood as a process that develops in time, and the brain (especially the neocortex and
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the frontal lobes) organizes the adaptive and developmental processes in both the spatial and temporal
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dimensions. The meaning of a situation influences the way the organism responds. For example, the stress of
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being restrained for a long time can cause major gastrointestinal bleeding and ulcerization, but if the
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animal has the opportunity to bite something during the stress (signifying its ability to fight back, and
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the possibility of escape) it can avoid the stress ulcers.
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</p>
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<p>
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The patterning of the nervous activity throughout the body governs the local ability to produce carbon
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dioxide. When the cortex of the brain is damaged or removed, an animal becomes rigid, so the cortex is
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considered to have a "tonic inhibitory action" on the body. But when the nerves are removed from a muscle
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(for example, by disease or accident), the muscle goes into a state of constant activity, and its ability to
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oxidize glucose and produce carbon dioxide is reduced, while its oxidation of fatty acids persists,
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increasing the production of toxic oxidative fragments of the fatty acids, which contributes to the muscle's
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atrophy.
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</p>
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<p>
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The organism's intentions, expectations, or plans, are represented in the nervous system as a greater
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readiness for action, and in the organs and tissues controlled by the nerves, as an increase or decrease of
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oxidative efficiency, analogous to the differences between innervated and denervated muscles. This pattern
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in the nervous system has been called "the acceptor of action," because it is continually being compared
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with the actual situation, and being refined as the situation is evaluated. The state of the organism, under
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the influence of a particular acceptor of action, is called a "functional system," including all the
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components of the organism that participate most directly in realizing the intended adaptive action.
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</p>
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<p>
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The actions of nerves can be considered anabolic, because during a stressful situation in which the
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catabolic hormones of adaption, e.g., cortisol, increase, the tissues of the functional system are
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protected, and while idle tissues may undergo autophagy or other form of involution, the needs of the active
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tissues are supplied with nutrients from their breakdown, allowing them to change and, when necessary, grow
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in size or complexity.
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</p>
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<p>
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The brain's role in protecting against injury by stress, when it sees a course of action, has a parallel in
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the differences between concentric (positive, muscle shortening) and eccentric (negative, lengthening under
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tension) exercise, and also with the differences between innervated and denervated muscles. In eccentric
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exercise and denervation, less oxygen is used and less carbon dioxide is produced, while lactic acid
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increases, displacing carbon dioxide, and more fat is oxidized. Prolonged stress similarly decreases carbon
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dioxide and increases lactate, while increasing the use of fat.
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</p>
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<p>
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Darkness is stressful and catabolic. For example, in aging people, the morning urine contains nearly all of
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the calcium lost during the 24 hour period, and mitochondria are especially sensitive to the destructive
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effects of darkness. Sleep reduces the destructive catabolic effects of darkness. During the
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rapid-eye-movement (dreaming) phase of sleep, breathing is inhibited, and the level of carbon dioxide in the
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tissues accumulates. In restful sleep, the oxygen tension is frequently low enough, and the carbon dioxide
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tension high enough, to trigger the multiplication of stem cells and mitochondria.
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</p>
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<p>
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Dreams represent the "acceptor of action" operating independently of the sensory information that it
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normally interacts with. During dreams, the brain (using a system called the Ascending Reticular Activating
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System) disconnects itself from the sensory systems. I think this is the nervous equivalent of
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concentric/positive muscle activity, in the sense that the brain is in control of its actions. The active,
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dreaming phase of sleep occurs more frequently in the later part of the night, as morning approaches. This
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is the more stressful part of the night, with cortisol and some other stress hormones reaching a peak at
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dawn, so it would be reasonable for the brain's defensive processes to be most active at that time. The
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dreaming process in the brain is associated with deep muscle relaxation, which is probably associated with
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the trophic (restorative) actions of the nerves.
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</p>
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<p>
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In ancient China the Taoists were concerned with longevity, and according to Joseph Needham (<em>Science and
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Civilization in China</em>) their methods included the use of herbs, minerals, and steroids extracted
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from the urine of children. Some of those who claimed extreme longevity practiced controlled breathing and
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tai chi (involving imagery, movement, and breating), typically in the early morning hours, when stress
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reduction is most important. As far as I know, there are no studies of carbon dioxide levels in
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practitioners of tai chi, but the sensation of warmth they typically report suggests that it involves
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hypoventilation.
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</p>
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<p>
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In the 1960s, a Russian researcher examined hospital records of measurements of newborn babies, and found
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that for several decades the size of their heads had been increasing. He suggested that it might be the
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result of increasing atmospheric carbon dioxide.
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</p>
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<p>
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The experiences and nutrition of a pregnant animal are known to affect the expression of genes in the
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offspring, affecting such things as allergies, metabolic rate, brain size, and intelligence. Miles Storfer
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(1999) has reviewed the evidence for epigenetic environmental control of brain size and intelligence. The
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main mechanisms of epigenetic effects or "imprinting" are now known to involve methylation and acetylation
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of the chromosomes (DNA and histones).
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</p>
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<p>
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Certain kinds of behavior, as well as nutrition and other environmental factors, increase the production and
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retention of carbon dioxide. The normal intrauterine level of carbon dioxide is high, and it can be
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increased or decreased by changes in the mother's physiology. The effects of carbon dioxide on many
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biological processes involving methylation and acetylation of the genetic material suggest that the
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concentration of carbon dioxide during gestation might regulate the degree to which parental imprinting will
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persist in the developing fetus. There is some evidence of increased demethylation associated with the low
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level of oxygen in the uterus (Wellman, et al., 2008). A high metabolic rate and production of carbon
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dioxide would increase the adaptability of the new organism, by decreasing the limiting genetic imprints.
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</p>
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<p>
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A quick reduction of carbon dioxide caused by hyperventilation can provoke an epileptic seizure, and can
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increase muscle spasms and vascular leakiness, and (by releasing serotonin and histamine) contribute to
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inflammation and clotting disorders. On a slightly longer time scale, a reduction of carbon dioxide can
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increase the production of lactic acid, which is a promoter of inflammation and fibrosis. A prolonged
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decrease in carbon dioxide can increase the susceptibility of proteins to glycation (the addition of
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aldehydes, from polyunsaturated fat peroxidation or methylglyoxal from lactate metabolism, to amino groups),
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and a similar process is likely to contribute to the methylation of histones, a process that increases with
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aging. Histones regulate genetic activity.
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</p>
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<p>
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With aging, DNA methylation is increased (Bork, et al., 2009). <strong>I suggest that methylation stabilizes
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and protects cells when growth and regeneration aren't possible (and that it's likely to increase when
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CO2 isn't available).
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</strong>
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Hibernation (Morin and Storey, 2009) and sporulation (Ruiz-Herrera, 1994; Clancy, et al., 2002) appear to
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use methylation protectively.
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</p>
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<p>
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Parental stress, prenatal stress, early life stress, and even stress in adulthood contribute to "imprinting
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of the genes," partly through methylation of DNA and the histones.
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</p>
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<p>
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Methionine and choline are the main dietary sources of methyl donors. Restriction of methionine has many
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protective effects, including increased average (42%) and maximum (44%) longevity in rats (Richie, et al.,
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1994). Restriction of methyl donors causes demethylation of DNA (Epner, 2001). <strong> </strong>
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The age accelerating effect of methionine might be related to disturbing the methylation balance,
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inappropriately suppressing cellular activity. Besides its effect on the methyl pool, methionine inhibits
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thyroid function and damages mitochondria.
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</p>
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<p>
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The local concentration of carbon dioxide in specific tissues and organs can be adjusted by nervous and
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hormonal activation or inhibition of the carbonic anhydrase enzymes, that accelerate the oonversion of CO2
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to carbonic acid, H2CO3. The activity of carbonic anhydrase can determine the density and strength of the
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skeleton, the excitability of nerves, the accumulation of water, and can regulate the structure and function
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of the tissues and organs.
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</p>
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<p>
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Ordinarily, carbon dioxide and bicarbonate are thought of only in relation to the regulation of pH, and only
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in a very general way. Because of the importance of keeping the pH of the blood within a narrow range,
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carbon dioxide is commonly thought of as a toxin, because an excess can cause unconsciousness and acidosis.
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But increasing carbon dioxide doesn't necessarily cause acidosis, and acidosis caused by carbon dioxide
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isn't as harmful as lactic acidosis.
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</p>
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<p>
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Frogs and toads, being amphibians, are especially dependent on water, and in deserts or areas with a dry
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season they can survive a prolonged dry period by burrowing into mud or sand. Since they may be buried 10 or
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11 inches below the surface, they are rarely found, and so haven't been extensively studied. In species that
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live in the California desert, they have been known to survive 5 years of burial without rainfall, despite a
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moderately warm average temperature of their surroundings. One of their known adaptations is to produce a
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high level of urea, allowing them to osmotically absorb and retain water. (Very old people sometimes have
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extremely high urea and osmotic tension.)
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</p>
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<p>
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Some laboratory studies show that as a toad burrows into mud, the amount of carbon dioxide in its tissues
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increases. Their skin normally functions like a lung, exchanging oxygen for carbon dioxide. If the toad's
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nostrils are at the surface of the mud, as dormancy begins its breathing will gradually slow, increasing the
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carbon dioxide even more. Despite the increasing carbon dioxide, the pH is kept stable by an increase of
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bicarbonate (Boutilier, et al., 1979). A similar increase of bicarbonate has been observed in hibernating
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hamsters and doormice.
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</p>
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<p>
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Thinking about the long dormancy of frogs reminded me of a newspaper story I read in the 1950s. Workers
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breaking up an old concrete structure found a dormant toad enclosed in the concrete, and it revived soon
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after being released. The concrete had been poured decades earlier.
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</p>
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<p>
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Although systematic study of frogs or toads during their natural buried estivation has been very limited,
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there have been many reports of accidental discoveries that suggest that the dormant state might be extended
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indefinitely if conditions are favorable. Carbon dioxide has antioxidant effects, and many other stabilizing
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actions, including protection against hypoxia and the excitatory effects of intracellular calcium and
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inflammation (Baev, et al., 1978, 1995; Bari, et al., 1996; Brzecka, 2007; Kogan, et al., 1994; Malyshev, et
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al., 1995).
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</p>
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<p>
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When mitochondria are "uncoupled," they produce more carbon dioxide than normal, and the mitochondria
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produce fewer free radicals. Animals with uncoupled mitochondria live longer than animals with the ordinary,
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more efficient mitochondria, that produce more reactive oxidative fragments. One effect of the high rate of
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oxidation of the uncoupled mitochondria is that they can eliminate polyunsatured fatty acids that might
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otherwise be integrated into tissue structures, or function as inappropriate regulatory signals.
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</p>
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<p>
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Birds have a higher metabolic rate than mammals of the same size, and live longer. Their tissues contain
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fewer of the highly unsaturated fatty acids. Queen bees, which live many times longer than worker bees, have
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mainly monounsaturated fats in their tissues, while the tissues of the short-lived worker bees, receiving a
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different diet, within a couple of weeks of hatching will contain highly unsaturated fats.
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</p>
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<p>
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Bats have a very high metabolic rate, and an extremely long lifespan for an animal of their size. While most
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animals of their small size live only a few years, many bats live a few decades. Bat caves usually have
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slightly more carbon dioxide than the outside atmosphere, but they usually contain a large amount of
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ammonia, and bats maintain a high serum level of carbon dioxide, which protects them from the otherwise
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toxic effects of the ammonia.
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</p>
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<p>
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The naked mole rat, another small animal with an extremely long lifespan (in captivity they have lived up to
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30 years, 9 or 10 times longer than mice of the same size) has a low basal metabolic rate, but I think
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measurements made in laboratories might not represent their metabolic rate in their natural habitat. They
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live in burrows that are kept closed, so the percentage of oxygen is lower than in the outside air, and the
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percentage of carbon dioxide ranges from 0.2% to 5% (atmospheric CO2 is about 0.038). The temperature and
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humidity in their burrows can be extremely high, and to be very meaningful their metabolic rate would have
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to be measured when their body temperature is raised by the heat in the burrow.
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</p>
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<p>
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When they have been studied in Europe and the US, there has been no investigation of the effect of altitude
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on their metabolism, and these animals are native to the high plains of Kenya and Ethiopia, where the low
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atmospheric pressure would be likely to increase the level of carbon dioxide in their tissues. Consequently,
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I doubt that the longevity seen in laboratory situations accurately reflects the longevity of the animals in
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their normal habitat.
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</p>
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<p>
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Besides living in a closed space with a high carbon dioxide content, mole rats have another similarity to
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bees. In each colony, there is only one female that reproduces, the queen, and, like a queen bee, she is the
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largest individual in the colony. In beehives, the workers carefully regulate the carbon dioxide
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concentration, which varies from about 0.2% to 6%, similar to that of the mole rat colony. A high carbon
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dioxide content activates the ovaries of a queen bee, increasing her fertility.
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</p>
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<p>
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Since queen bees and mole rats live in the dark, I think their high carbon dioxide compensates for the lack
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of light. (Both light and CO2 help to maintain oxidative metabolism and inhibit lactic acid formation.) Mole
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rats are believed to sleep very little. During the night, normal people tolerate more CO2, and so breathe
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less, especially near morning, with increased active dreaming sleep.
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</p>
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<p>
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A mole rat has never been known to develop cancer. Their serum C-reactive protein is extremely low,
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indicating that they are resistant to inflammation. In humans and other animals that are susceptible to
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cancer, one of the genes that is likely to be silenced by stress, aging, and methylation is p53, a
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tumor-suppressor gene.
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</p>
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<p>
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If the intrauterine experience, with low oxygen and high carbon dioxide, serves to "reprogram" cells to
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remove the accumulated effects of age and stress, and so to maximize the developmental potential of the new
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organism, a life that's lived with nearly those levels of oxygen and carbon dioxide might be able to avoid
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the progressive silencing of genes and loss of function that cause aging and degenerative diseases.
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</p>
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<p>
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Several diseases and syndromes are now thought to involve abnormal methylation of genes. Prader-Willi
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sydrome, Angelman's syndrome, and various "autistic spectrum disorders," as well as post-traumatic stress
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disorder and several kinds of cancer seem to involve excess methylation.
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</p>
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<p>
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Moderate methionine restriction (for example, using gelatin regularly in the diet) might be practical, but
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if increased carbon dioxide can activate the demethylase enzymes in a controlled way, it might be a useful
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treatment for the degenerative diseases and for aging itself.
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</p>
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<p>
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The low carbon dioxide production of hypothyroidism (e.g., Lee and Levine, 1999), and the respiratory
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alkalosis of estrogen excess, are often overlooked. An adequate supply of calcium, and sometimes
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supplementation of salt and baking soda, can increase the tissue content of CO2.
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</p>
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<p><h3>REFERENCES</h3></p>
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<p>
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Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E621-7. <strong>Uncoupling protein-2 regulates lifespan in
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mice.</strong> Andrews ZB, Horvath TL.
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</p>
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<p>
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Fiziol Zh SSSR 1978 Oct;64(10):1456-62. <strong>[Role of CO2 fixation in increasing the body's resistance to
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acute hypoxia].</strong> Baev VI, Vasil'ev VV, Nikolaeva EN. In rats, the phenomenon of considerable
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increase in resistance to acute hypoxia observed after 2-hour stay under conditions of gradually increasing
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concentration of CO2, decreasing concentration of O2, and external cooling at 2--3 degrees seems to be based
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mainly on changes in concentration of CO2 (ACCORDINGLY, PCO2 and other forms of CO2 in the blood). The high
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resistance to acute hypoxia develops as well after subcutaneous or i.v. administration of 1.0 ml of water
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solution (169.2 mg/200 g) NaHCO2, (NH4)2SO4, MgSO4, MnSO4, and ZnSO4 (in proportion: 35 : 5 : 2 : 0.15 :
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0.15, resp.) or after 1-hour effect of increased hypercapnia and hypoxia without cooling.
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</p>
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<p>
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Fiziol Zh Im I M Sechenova 1995 Feb;81(2):47-52.<strong>
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[The unknown physiological role of carbon dioxide].</strong> Baev VI, Vasil'eva IV, L'vov SN, Shugalei
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IV [The data suggests that carbon dioxide is a natural element of the organism antioxidant defence system.
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ion poisoning].
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</p>
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<p>
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Stroke. 1996 Sep;27(9):1634-9; discussion 1639-40. <strong>Differential effects of short-term hypoxia and
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hypercapnia on N-methyl-D-aspartate-induced cerebral vasodilatation in piglets.</strong> Bari F, Errico
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RA, Louis TM, Busija DW.
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</p>
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<p>
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Vojnosanit Pregl. 1996 Jul-Aug;53(4):261-74. <strong>[Carbon dioxide inhibits the generation of active forms
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of oxygen in human and animal cells and the significance of the phenomenon in biology and
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medicine]</strong> [Article in Serbian] Boljevic S, Kogan AH, Gracev SV, Jelisejeva SV, Daniljak IG.
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</p>
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<p>
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J Exp Biol. 1979 Oct;82:357-65. <strong>Acid-base relationships in the blood of the toad, Bufo marinus. III.
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The effects of burrowing.
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</strong>
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Boutilier RG, Randall DJ, Shelton G, Toews DP.
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</p>
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<p>
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Acta Neurobiol Exp (Wars). 2007;67(2):197-206. <strong>Role of hypercapnia in brain oxygenation in
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sleep-disordered breathing.</strong> Brzecka A. Adaptive mechanisms may diminish the detrimental effects
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of recurrent nocturnal hypoxia in obstructive sleep apnea (OSA). The potential role of elevated carbon
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dioxide (CO2) in improving brain oxygenation in the patients with severe OSA syndrome is discussed. CO2
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increases oxygen uptake by its influence on the regulation of alveolar ventilation and ventilation-perfusion
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matching, facilitates oxygen delivery to the tissues by changing the affinity of oxygen to hemoglobin, and
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increases cerebral blood flow by effects on arterial blood pressure and on cerebral vessels. Recent clinical
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studies show improved brain oxygenation when hypoxia is combined with hypercapnia. Anti-inflammatory and
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protective against organ injury properties of CO2 may also have therapeutic importance. These biological
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effects of hypercapnia may improve brain oxygenation under hypoxic conditions. This may be especially
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important in patients with severe OSA syndrome.
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</p>
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<p>
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Ageing Res Rev. 2009 Oct;8(4):268-76. Epub 2009 Apr 1. <strong>The role of epigenetics in aging and
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age-related diseases.</strong> Calvanese V, Lara E, Kahn A, Fraga MF.
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</p>
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<p>
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Rev Esp Geriatr Gerontol. 2009 Jul-Aug;44(4):194-9. Epub 2009 Jul 3. <strong>
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[Effect of restricting amino acids except methionine on mitochondrial oxidative stress.]
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</strong>[Article in Spanish] Caro P, G"mez J, S"nchez I, L"pez-Torres M, Barja G.
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</p>
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Coppola A, Liu ZW, Andrews ZB, Paradis E, Roy MC, Friedman JM, Ricquier D, Richard D, Horvath TL, Gao XB,
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Diano S.
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</p>
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<p>
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Ter Arkh. 1995;67(3):23-6. <strong>[Changes in the sensitivity of leukocytes to the inhibiting effect of CO2
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on their generation of active forms of oxygen in bronchial asthma patients]</strong> Daniliak IG, Kogan
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AKh, Sumarokov AV, Bolevich S.
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</p>
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<p>
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Cell Metab. 2007 Dec;6(6):497-505. <strong>Respiratory uncoupling in skeletal muscle delays death and
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diminishes age-related disease.</strong> Gates AC, Bernal-Mizrachi C, Chinault SL, Feng C, Schneider JG,
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Coleman T, Malone JP, Townsend RR, Chakravarthy MV, Semenkovich CF.
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</p>
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<p>
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Endocr Pract. 2009 Jun 2:1-13.<strong>
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Fibrotic Appearance of Lungs in Severe Hypothyroidism is Reversible with Thyroxine Replacement.</strong>
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George JT, Thow JC, Rodger KA, Mannion R, Jayagopal V.
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</p>
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<p>
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J Bioenerg Biomembr. 2009 Jun;41(3):309-21. Epub 2009 Jul 25. <strong>Effect of methionine dietary
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supplementation on mitochondrial oxygen radical generation and oxidative DNA damage in rat liver and
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heart.
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</strong>
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Gomez J, Caro P, Sanchez I, Naudi A, Jove M, Portero-Otin M, Lopez-Torres M, Pamplona R, Barja G.
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</p>
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<p>
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Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7612-7. <strong>Increased tricarboxylic acid cycle flux in rat
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brain during forepaw stimulation detected with 1H[13C]NMR.
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</strong>Hyder F, Chase JR, Behar KL, Mason GF, Siddeek M, Rothman DL, Shulman RG.
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</p>
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<p>
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Can J Neurol Sci. 1979 May;6(2):105-12. <strong>The effects of partial chronic denervation on forearm
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metabolism.</strong> Karpati G, Klassen G, Tanser P.
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</p>
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<p>
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|
Biull Eksp Biol Med. 1994 Oct;118(10):395-8. <strong>
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|
[CO2--a natural inhibitor of active oxygen form generation by phagocytes]</strong> Kogan AKh, Manuilov
|
|
BM, Grachev SV, Bolevich S, Tsypin AB, Daniliak IG.
|
|
</p>
|
|
|
|
<p>
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Izv Akad Nauk Ser Biol. 1997 Mar-Apr;(2):204-17.<strong>
|
|
[Carbon dioxide--a universal inhibitor of the generation of active oxygen forms by cells (deciphering
|
|
one enigma of evolution)]
|
|
</strong>
|
|
Kogan AKh, Grachev SV, Eliseeva SV, Bolevich S.
|
|
</p>
|
|
<p>
|
|
Vopr Med Khim. 1996 Jul-Sep;42(3):193-202.<strong>
|
|
[Ability of carbon dioxide to inhibit generation of superoxide anion radical in cells and its biomedical
|
|
role]</strong> Kogan AKh, Grachev SV, Eliseeva SV, Bolevich S.
|
|
</p>
|
|
<p>
|
|
Dokl Akad Nauk. 1996 May;348(3):413-6. <strong>[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)]
|
|
</strong>Kogan AKh, Grachev SV, Bolevich S, Eliseeva SV.
|
|
</p>
|
|
|
|
<p>
|
|
Biull Eksp Biol Med. 1996 Apr;121(4):407-10. <strong>[Carbon dioxide gas inhibition of active forms of
|
|
oxygen generation by cells in the internal organs and its biological significance]</strong> Kogan AKh,
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|
Grachev SV, Eliseeva SV.
|
|
</p>
|
|
<p>
|
|
Fiziol Cheloveka. 1995 Jul-Aug;21(4):128-36. <strong>[CO2--a natural inhibitor of the generation of active
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|
species of oxygen in phagocytes]</strong> Kogan AKh, Manuilov BM, Grachev SV, Bolevich S, Tsypin AB,
|
|
Daniliak IG.
|
|
</p>
|
|
<p>
|
|
<strong>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]</strong> Kogan
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|
AKh, Bolevich S, Daniliak IG.
|
|
</p>
|
|
|
|
<p>
|
|
Can J Anaesth. 1999 Feb;46(2):185-9. <strong>Acute respiratory alkalosis associated with low minute
|
|
ventilation in a patient with severe hypothyroidism.</strong>
|
|
Lee HT, Levine M. <a href="mailto:Tl128@columbia.edu" target="_blank">Tl128@columbia.edu</a> 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.
|
|
</p>
|
|
<p>
|
|
Anal Bioanal Chem. 2008 Jan;390(2):679-88. Epub 2007 Oct 27. <strong>The structural modification of DNA
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|
nucleosides by nonenzymatic glycation: an in vitro study based on the reactions of glyoxal and
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|
methylglyoxal with 2'-deoxyguanosine.</strong>
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|
Li Y, Cohenford MA, Dutta U, Dain JA.
|
|
</p>
|
|
|
|
<p>
|
|
Biull Eksp Biol Med. 1995 Jun;119(6):590-3. <strong>[Adaptation to high altitude hypoxia facilitates a
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|
limitation of lipid peroxidation activation in inflammation and stress] [Article in Russian]
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</strong>
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Malyshev VV, Vasil'eva LS, Belogorov SB, Nefedova TV.
|
|
</p>
|
|
<p>
|
|
Am J Physiol Regul Integr Comp Physiol. 2007 Sep;293(3):R1159-68. Epub 2007 Jun 20. <strong
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|
>Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS
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|
production.</strong> Muller FL, Song W, Jang YC, Liu Y, Sabia M, Richardson A, Van Remmen H.
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</p>
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<p>
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Radiobiologiia. 1984 Jan-Feb;24(1):29-34. <strong>[Enzyme activity of glutamic acid metabolism and the Krebs
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|
cycle in the brain of rats laser-irradiated against a background of altered adrenoreceptor function]
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[Article in Russian]
|
|
</strong>
|
|
|
|
Pikulev AT, Dzhugurian NA, Zyrianova TN, Lavrova VM, Mostovnikov VA.
|
|
</p>
|
|
<p>
|
|
Rejuvenation Res.2007 Dec12; :18072884, <strong>Exploring Overlooked Natural Mitochondria-Rejuvenative
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|
Intervention: The Puzzle of Bowhead Whales and Naked Mole Rats.
|
|
</strong>
|
|
Prokopov A.F.
|
|
</p>
|
|
<p>
|
|
Proceedings of the Japan Academy. Ser. B: Physical and Biological Sciences Vol.78, No.10(2002)pp.293-298.
|
|
<strong>DNA methylation and Lamarckian inheritance, </strong>
|
|
Sano H.
|
|
</p>
|
|
<p>
|
|
Biol Chem. 2009 Nov;390(11):1145-53. <strong>The epigenetic bottleneck of neurodegenerative and psychiatric
|
|
diseases.
|
|
</strong>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.
|
|
</p>
|
|
|
|
<p>
|
|
Ukr Biokhim Zh 1994 Jan-Feb;66(1):109-12. <strong>[Protective effect of sodium bicarbonate in nitrite ion
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poisoning].</strong> Shugalei IV, L'vov SN, Baev VI, Tselinskii IV
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</p>
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<p>
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|
Am J Respir Crit Care Med. 2000 Mar;161(3 Pt 1):891-8. <strong>
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|
Modulation of release of reactive oxygen species by the contracting diaphragm.</strong>
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|
Stofan DA, Callahan LA, DiMarco AF, Nethery DE, Supinski GS.
|
|
</p>
|
|
<p>
|
|
Ecology: Vol. 50, No. 3, pp. 492-494. <strong>Carbon Dioxide Retention: A Mechanism of Ammonia Tolerance in
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|
Mammals.</strong> Studier EM and Fresquez AA.
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|
</p>
|
|
|
|
<p>
|
|
Sci Signal. 2009 Mar 31;2(64): pe17. <strong>Reversing DNA methylation: new insights from neuronal
|
|
activity-induced Gadd45b in adult neurogenesis.
|
|
</strong>
|
|
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.
|
|
</p>
|
|
<p>
|
|
Patol Fiziol Eksp Ter. 2005 Apr-Jun;(2):13-5. <strong>[The effect of the NMDA-receptor blocker MK-801 on
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|
sensitivity of the respiratory system to carbon dioxide]</strong>
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|
Tarakanov IA, Dymetska A, Tarasova NN.
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|
</p>
|
|
<p>
|
|
Life Sci. 1997;61(5):523-35. <strong>Effect of acidotic challenges on local depolarizations evoked by
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|
N-methyl-D-aspartate in the rat striatum.</strong> 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."
|
|
</p>
|
|
|
|
<p>
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|
Arch Int Physiol Biochim. 1977 Apr;85(2):295-304. <strong>Glutamate and glutamine in the brain of the
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|
neonatal rat during hypercapnia.</strong> Van Leuven F, Weyne J, Leusen I.
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</p>
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<p>
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|
<strong>Pediatrics 1995 Jun;95(6):868-874. Carbon dioxide protects the perinatal brain from hypoxic-ischemic
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|
damage: an experimental study in the immature rat.</strong> Vannucci RC, Towfighi J, Heitjan DF,
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|
Brucklacher RM
|
|
</p>
|
|
<p>
|
|
Pediatr Res 1997 Jul;42(1):24-29. <strong>Effect of carbon dioxide on cerebral metabolism during
|
|
hypoxia-ischemia in the immature rat.
|
|
</strong>
|
|
Vannucci RC, Brucklacher RM, Vannucci SJ
|
|
</p>
|
|
|
|
<p>
|
|
Sci. Signal., 31 March 2009 Vol. 2, Issue 64, p. pe17, <strong>Reversing DNA Methylation: New Insights from
|
|
Neuronal Activity-Induced Gadd45b in Adult Neurogenesis</strong>
|
|
Wu H, Sun YI
|
|
</p>
|
|
|
|
Copyright 2011. Raymond Peat, P.O. Box 5764, Eugene OR 97405. All Rights Reserved. www.RayPeat.comNot for
|
|
republication without written permission.
|
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