Protective CO2 and aging

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 (Science and Civilization in China) their methods included the use of herbs, minerals, and steroids extracted from the urine of children. Some of those who claimed extreme longevity practiced controlled breathing and tai chi (involving imagery, movement, and breating), typically in the early morning hours, when stress reduction is most important. As far as I know, there are no studies of carbon dioxide levels in practitioners of tai chi, but the sensation of warmth they typically report suggests that it involves hypoventilation.

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). I suggest that methylation stabilizes and protects cells when growth and regeneration aren’t possible (and that it’s likely to increase when CO2 isn’t available). Hibernation (Morin and Storey, 2009) and sporulation (Ruiz-Herrera, 1994; Clancy, et al., 2002) appear to use methylation protectively.
Parental stress, prenatal stress, early life stress, and even stress in adulthood contribute to “imprinting of the genes,” partly through methylation of DNA and the histones.

Methionine and choline are the main dietary sources of methyl donors. Restriction of methionine has many protective effects, including increased average (42%) and maximum (44%) longevity in rats (Richie, et al., 1994). Restriction of methyl donors causes demethylation of DNA (Epner, 2001). The age accelerating effect of methionine might be related to disturbing the methylation balance, inappropriately suppressing cellular activity. Besides its effect on the methyl pool, methionine inhibits thyroid function and damages mitochondria.

The local concentration of carbon dioxide in specific tissues and organs can be adjusted by nervous and hormonal activation or inhibition of the carbonic anhydrase enzymes, that accelerate the oonversion of CO2 to carbonic acid, H2CO3. The activity of carbonic anhydrase can determine the density and strength of the skeleton, the excitability of nerves, the accumulation of water, and can regulate the structure and function of the tissues and organs.
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.
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Sci Signal. 2009 Mar 31;2(64): pe17. Reversing DNA methylation: new insights from neuronal activity-induced Gadd45b in adult neurogenesis. Wu H, Sun YE. Neurogenesis in the adult mammalian brain involves activity-dependent expression of genes critical for the proliferation of progenitors and for neuronal maturation. A recent study suggests that the stress response gene Gadd45b (growth arrest and DNA-damage-inducible protein 45 beta) can be transiently induced by neuronal activity and may promote adult neurogenesis through dynamic DNA demethylation of specific gene promoters in adult hippocampus. These results provide evidence supporting the provocative ideas that active DNA demethylation may occur in postmitotic neurons and that DNA methylation-mediated dynamic epigenetic regulation is involved in regulating long-lasting changes in neural plasticity in mammalian brains.
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Sci. Signal., 31 March 2009 Vol. 2, Issue 64, p. pe17, Reversing DNA Methylation: New Insights from Neuronal Activity-Induced Gadd45b in Adult Neurogenesis Wu H, Sun YI

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