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    <head><title>Protective CO2 and aging</title></head>
    <body>
        <h1>
            Protective CO2 and aging
        </h1>

        <p></p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            In ancient China the Taoists were concerned with longevity, and according to Joseph Needham (<em>Science and
                Civilization in China</em>) 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.
        </p>
        <p>
            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.
        </p>

        <p>
            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).
        </p>
        <p>
            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. 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.
        </p>
        <p>
            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.
        </p>
        <p>
            With aging, DNA methylation is increased (Bork, et al., 2009). <strong>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).
            </strong>

            Hibernation (Morin and Storey, 2009) and sporulation (Ruiz-Herrera, 1994; Clancy, et al., 2002) appear to
            use methylation protectively.
        </p>
        <p>
            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.
        </p>
        <p>
            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). <strong> </strong>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.)
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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).
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p><h3>REFERENCES</h3></p>
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        <p>
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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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        </p>

        <p>
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        </p>
        <p>
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        </p>
        <p>
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        </p>

        <p>
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            </strong>
            Boutilier RG, Randall DJ, Shelton G, Toews DP.
        </p>
        <p>
            Acta Neurobiol Exp (Wars). 2007;67(2):197-206. <strong>Role of hypercapnia in brain oxygenation in
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            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.
        </p>
        <p>
            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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        </p>

        <p>
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        <p>
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        </p>
        <p>
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        </p>

        <p>
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        </p>
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            </strong>

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        <p>
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        <p>
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        </p>

        <p>
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            </strong>
            Kogan AKh, Grachev SV, Eliseeva SV, Bolevich S.
        </p>
        <p>
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        </p>
        <p>
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            </strong>Kogan AKh, Grachev SV, Bolevich S, Eliseeva SV.
        </p>

        <p>
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        </p>
        <p>
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        </p>
        <p>
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        </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>
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            Li Y, Cohenford MA, Dutta U, Dain JA.
        </p>

        <p>
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        </p>
        <p>
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        <p>
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            </strong>

            Pikulev AT, Dzhugurian NA, Zyrianova TN, Lavrova VM, Mostovnikov VA.
        </p>
        <p>
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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.
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            Sano H.
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            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>

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                Mammals.</strong> Studier EM and Fresquez AA.
        </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>
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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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            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
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