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<strong>Protective CO2 and aging</strong>
</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. 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.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.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.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 (<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.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. 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). <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.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). <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. 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. 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.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.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.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.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.<span
style="white-space: pre-wrap"
>
</span>
<h3>REFERENCES</h3>Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E621-7. <strong>Uncoupling protein-2 regulates
lifespan in mice.</strong> Andrews ZB, Horvath TL. Fiziol Zh SSSR 1978 Oct;64(10):1456-62. <strong>[Role of
CO2 fixation in increasing the body's resistance to acute hypoxia].</strong> 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.<strong>
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[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. <strong>Differential effects of short-term hypoxia
and hypercapnia on N-methyl-D-aspartate-induced cerebral vasodilatation in piglets.</strong> Bari F, Errico
RA, Louis TM, Busija DW.Vojnosanit Pregl. 1996 Jul-Aug;53(4):261-74. <strong>[Carbon dioxide inhibits the
generation of active forms of oxygen in human and animal cells and the significance of the phenomenon in
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</strong>Boutilier RG, Randall DJ, Shelton G, Toews DP.Acta Neurobiol Exp (Wars). 2007;67(2):197-206. <strong
>Role of hypercapnia in brain oxygenation in sleep-disordered breathing.</strong> 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.
<strong>The role of epigenetics in aging and age-related diseases.</strong> Calvanese V, Lara E, Kahn A, Fraga
MF.Rev Esp Geriatr Gerontol. 2009 Jul-Aug;44(4):194-9. Epub 2009 Jul 3. <strong>[Effect of restricting amino
acids except methionine on mitochondrial oxidative stress.]
</strong>[Article in Spanish] Caro P, G"mez J, S"nchez I, L"pez-Torres M, Barja G.Cell Metab. 2007
Jan;5(1):21-33. <strong>A central thermogenic-like mechanism in feeding regulation: an interplay between arcuate
nucleus T3 and UCP2.</strong> 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. <strong>[Changes in the sensitivity of
leukocytes to the inhibiting effect of CO2 on their generation of active forms of oxygen in bronchial asthma
patients]</strong> Daniliak IG, Kogan AKh, Sumarokov AV, Bolevich S.Cell Metab. 2007 Dec;6(6):497-505.
<strong>Respiratory uncoupling in skeletal muscle delays death and diminishes age-related disease.</strong>
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.<strong>
Fibrotic Appearance of Lungs in Severe Hypothyroidism is Reversible with Thyroxine Replacement.</strong>
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25. <strong>Effect of methionine dietary supplementation on mitochondrial oxygen radical generation and
oxidative DNA damage in rat liver and heart.
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</strong>Kogan AKh, Grachev SV, Eliseeva SV, Bolevich S.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
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low minute ventilation in a patient with severe hypothyroidism.</strong> Lee HT, Levine M.Tl128@columbia.edu
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
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</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
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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.
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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+
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