Also see: Protective Altitude Protect the Mitochondria Lactate Paradox: High Altitude and Exercise Altitude Improves T3 LevelsProtective Carbon Dioxide, Exercise, and PerformanceSynergistic Effect of Creatine and Baking Soda on Performance Altitude Improves T3 Levels Altitude Sickness: Therapeutic Effects of Acetazolamide and Carbon Dioxide Comparison: Carbon Dioxide v. Lactic Acid Carbon Dioxide Basics Universal Principle of Cellular Energy Carbon Dioxide as an Antioxidant Comparison: Oxidative Metabolism v. Glycolytic Metabolic
Over the oxygen supply of the body carbon dioxide spreads its protecting wings. Friedrich Miescher, Swiss physiologist, 1885
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People who live at very high altitudes live significantly longer; they have a lower incidence of cancer (Weinberg, et al., 1987) and heart disease (Mortimer, et al., 1977), and other degenerative conditions, than people who live near sea level. As I have written earlier, I think the lower energy transfer from cosmic radiation is likely to be a factor in their longevity, but several kinds of evidence indicate that it is the lower oxygen pressure itself that makes the biggest contribution to their longevity.
The end product of respiration is carbon dioxide, and it is an essential component of the life process. The ability to produce and retain enough carbon dioxide is as important for longevity as the ability to conserve enough heat to allow chemical reactions to occur as needed.
Carbon dioxide protects cells in many ways. By bonding to amino groups, it can inhibit the glycation of proteins during oxidative stress, and it can limit the formation of free radicals in the blood; inhibition of xanthine oxidase is one mechanism (Shibata, et al., 1998). It can reduce inflammation caused by endotoxin/LPS, by lowering the formation of tumor necrosis factor, IL-8 and other promoters of inflammation (Shimotakahara, et al., 2008). It protects mitochondria (Lavani, et al., 2007), maintaining (or even increasing) their ability to respire during stress.
The replicative lifespan of a cell can be shortened by factors like resveratrol or estrogen that interfere with mitochondrial production of carbon dioxide. Both of those chemicals cause skin cells, keratinocytes, to stop dividing, to take up calcium, and to begin producing the horny material keratin, that allows superficial skin cells to form an effective barrier. This process normally occurs as these cells differentiate from the basal (stem) cells and, by multiplying, move farther outward away from the underlying blood vessels that provide the nutrients that are oxidized to form carbon dioxide, and as they get farther from the blood supply, they get closer to the external air, which contains less than 1% as much CO2 as the blood. This normally causes their eventual hardening into the keratin cells, but when conditions are optimal, numerous layers of moist, translucent cells that give the skin the characteristic appearance of youth, will be retained between the basal cells and the condensed surface layers. (Wilke, et al., 1988)
In other types of tissue, a high level of carbon dioxide has a similar stabilizing effect on cells, preserving stem cells, limiting stress and preventing loss of function. In the lining of the mouth, where the oxygen tension is lower, and carbon dioxide higher, the cells dont form as much keratin as the skin cells do. In the uterus, the lining cells would behave similarly, except that estrogen stimulates keratinization. A vitamin A deficiency mimics an estrogen excess, and can cause excessive keratinization of membrane cells.
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 mothers 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.
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 havent 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 toads 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).
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.
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 thats 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.
I think of high altitude as analogous to theprotected gestational state. (Both progesteroneand carbon dioxide are increased in peopleadapted to high altitude.) Respiratory acidosis,meaning the retention of carbon dioxide, is veryprotective, and is an outstanding feature of life inthe uterus. Even at the time that an embryo isimplanting in the uterus, adequate carbon dioxideis crucial. Many of the mysteries of embryologyand developmental biology have been explained by the presence of a high level of carbon dioxideduring gestation. For example, an injury to the fetus heals without scarring, that is, with completeregeneration instead of the formation of a sort ofcollagenous plug. Over the last fifty years, severalpeople have discovered that simply enclosing awound (for example an amputated finger tip) in anair-tight compartment allows remarkably complete regeneration, even in adults, who supposedly have lost the power of regeneration.(Exposure of tissues to air causes them to losecarbon dioxide.)
During gestation, after organs have differentiated,nerve cells extend their fibers from the brain to innervate muscles and other tissues. The specialconditions of life in the uterus support thisprocess, but something similar can happen duringadult life, when damaged nerves regenerate. Amajor difference between injury to the fetus, andinjury to an adult, is that the wound regeneratesperfectly without a scar in the fetus, but in theadult, regeneration is often impaired, and aconnective tissue scar replaces normally functioningtissue.
In childhood, wounds heal quickly, and inflammation is quickly resolved; in extreme old age, or during extreme stress or starvation, wound healing is much slower, and the nature of the inflammation and wound closure is different. In the fetus, healing can be regenerative and scarless, for example allowing a cleft palate to be surgically corrected without scars (Weinzweig, et al., 2002).
The amount of disorganized fibrous material formed in injured tissue is variable, and it depends on the state of the individual, and on the particular situation of the tissue. For example, the membranes lining the mouth, and the bones and bone marrow, and the thymus gland are able to regenerate without scarring. What they have in common with each other is a relatively high ratio of carbon dioxide to oxygen. Salamanders, which are able to regenerate legs, jaw, spinal cord, retina and parts of the brain (Winklemann & Winklemann, 1970), spend most of their time under cover in burrows, which besides preventing drying of their moist skin, keeps the ratio of carbon dioxide to oxygen fairly high.
The regeneration of finger tips, including a well-formed nail if some of the base remained, will occur if the wounded end of the finger is kept enclosed, for example by putting a metal or plastic tube over the finger. The humidity keeps the wound from forming a dry scab, and the cells near the surface will consume oxygen and produce carbon dioxide, keeping the ratio of carbon dioxide to oxygen much higher than in normal uninjured tissue.
Carbon dioxide is being used increasingly to prevent inflammation and edema. For example, it can be used to prevent adhesions during abdominal surgery, and to protect the lungs during mechanical ventilation. It inhibits the formation of inflammatory cytokines and prostaglandins (Peltekova, et al., 2010, Peng, et al., 2009, Persson & van den Linden, 2009), and reduces the leakiness of the intestine (Morisaki, et al., 2009). Some experiments show that as it decreases the production of some inflammatory materials by macrophages (TNF: Lang, et al., 2005), including lactate, it causes macrophages to activate phagocytic neutrophils, and to increase their number and activity (Billert, et al., 2003, Baev & Kuprava, 1997).
Factors that are associated with a decreased level of carbon dioxide, such as excess estrogen and lactate, promote fibrosis. Adaptation to living at high altitude, which is protective against degenerative disease, involves reduced lactate formation, and increased carbon dioxide. It has been suggested that keloid formation (over-growth of scar tissue) is less frequent at high altitudes (Ranganathan, 1961), though this hasnt been carefully studied. Putting an injured arm or leg into a bag of pure carbon dioxide reduces pain and accelerates healing.
In the fetus, especially before the fats from the mothers diet begin to accumulate, signals from injured tissue produce the changes that lead quickly to repair of the damage, but during subsequent life, similar signals produce incomplete repairs, and as they are ineffective they tend to be intensified and repeated, and eventually the faulty repair processes become the main problem. Although this is an ecological problem, it is possible to decrease the damage by avoiding the polyunsaturated fats and the many toxins that synergize with them, while increasing glucose, niacinamide, carbon dioxide, and other factors that support high energy metabolism, including adequate exposure to long wavelength light and avoidance of harmful radiation. As long as the toxic factors are present, increased amounts of protective factors such as progesterone, thyroid, sugar, niacinamide, and carbon dioxide can be used therapeutically and preventively.
For hundreds or thousands of years, the therapeutic value of carbonated mineral springs has been known. The belief that it was the waters lively gas content that made it therapeutic led Joseph Priestley to investigate ways to make artificially carbonated water, and in the process he discovered oxygen. Carbonated water had its medical vogue in the 19th century, but the modern medical establishment has chosen to define itself in a way that glorifies dangerous, powerful treatments, and ridicules natural and mild approaches. The motivation is obviousto maintain a monopoly, there must be some reason to exclude the general public from the practice of medicine. Witch doctors maintained their monopoly by working with frightening ghost-powers, and modern medicine uses its technical mystifications to the same purpose.vAlthough the medical profession hasnt lost its legal monopoly on health care, corporate interests have come to control the way medicine is practiced, and the way research is done in all the fields related to medicine.
I have been using aging (menopause and the ovaries) and cancer (carbon monoxide as a hormone of cellular immortality) to explore the issue of cell renewal and tissue regeneration. Yesterday, Lita Lee sent me an article about K. P. Buteyko, describing his approach to the role of carbon dioxide in physiology and medicine. Buteyko devoted his career to showing that sufficient carbon dioxide is important in preventing an exaggerated and maladaptive stress response. He advocated training in intentional regulation of respiration (avoiding habitual hyperventilation) to improve oxygenation of the tissues by retaining carbon dioxide. He showed that a deficiency of carbon dioxide (such as can be produced by hyperventilation, or by the presence of lactic acid in the blood) decreases cellular energy (as ATP and creatine phosphate) and interferes with the synthesis of proteins (including antibodies) and other cellular materials.
When I first heard of Buteykos ideas, I saw the systemic importance of carbon dioxide, but I wasnt much impressed by his idea of intentionally breathing less. If the hyperventilation is produced by anxiety, then a deliberate focussing on respiration can help to quiet the nerves. Knowing that hyperventilation can make a person faint, because loss of carbon dioxide causes blood vessels in the brain to constrict, I saw that additional carbon dioxide would increase circulation to the brain. This seemed like a neat system for directing the blood supply to the part of the brain that was more active, since that would be the part producing the most carbon dioxide.
In a nutrition class, in the late 70s, I described the way metabolically produced carbon dioxide opens blood vessels in the brain, and mentioned that carbonated water, or soda water, should improve circulation to the brain when the brains production of carbon dioxide wasnt adequate. A week later, a student said she had gone home that night and (interpreting soda water as bicarbonate of soda in water) given her stroke-paralyzed mother a glass of water with a spoonful of baking soda in it. Her mother had been hemiplegic for 6 months following a stroke, but 15 minutes after drinking the bicarbonate, the paralysis lifted, and she remained normal. Later, a man who had stroke-like symptoms when he drank alcohol late at night, found that drinking a glass of carbonated water caused the symptoms to stop within a few minutes.
Realizing that low thyroid people produce little carbon dioxide, it seemed to me that there might be a point at which the circulatory shut-down of unstimulated parts of the brain would become self-sustaining, with less circulation to an area decreasing the CO2 produced in that area, which would cause further vasoconstriction. Carbon dioxide (breathing in a bag, or drinking carbonated water, or bathing in water with baking soda) followed by thyroid supplementation, would be the appropriate therapy for this type of functional ischemia of the brain.
I have been concerned about the probable effects on the fetus of the silly panting respiration that is being taught to so many pregnant women, to use during labor. Panting blows out so much carbon dioxide that it causes vasoconstriction. Possibly the uterus is protected against this, and possibly the fetus produces enough carbon dioxide that it is protected, but this isnt known. Especially if the mother is hypothyroid, it seems that this could interfere with the delivery of oxygen to the fetus. Besides vasoconstriction, Buteyko points out that the Bohr effect, in which CO2 causes hemoglobin to release oxygen, means that a low level of carbon dioxide decreases the availability of oxygen. If the Bohr effect applies to fetal hemoglobin, then this suggests that the mothers panting will deprive the fetal tissues of oxygen.
It is normal for the fetus to be exposed to a high concentration of carbon dioxide. Recent experiments with week-old rats show that carbon dioxide, at the very high concentration of 6% powerfully protects against the brain damage caused by oxygen deprivation (tying a carotid artery and administering 8% oxygen). (R. C. Vannucci, et al., 1995.)
In general, lactic acid in the blood can be takenas a sign of defective respiration, since the breakdownof glucose to lactic acid increases to makeup for deficient oxidative energy production. Normalaging seems to involve a tendency toward excesslactic acid -production, and age-pigment isknown to activate the process. Eliminating respiratorytoxins (such as unsaturated oils, estrogenicand antithyroid substances, lead, and excess iron)is the most obvious first step to take when there isexcess lactic acid formation. Carbon dioxide supplementshave been shown experimentally to reduceresidual lactate production. Many peopleexperience exhilaration when they go to very highaltitudes, and it is known that people generallybum calories faster at high altitude. It has beenfound that, during intense exercise (which alwaysproduces a lactic acid accumulation inthe blood), a lower peak accumulation of lactate occurs at high altitude, and this seems tobe caused by a reduction in the rate of glycolysis,or glucose consumption. (B.Grassi, et aI.)Since there is less oxygen at high elevation, andsince oxygen is used to consume lactic acid, thiseffect is the opposite of what many people expected.In some sense, respiration becomes moreefficient at high altitude. Youth and increased times supported the process by helping to stabilize the high energy metabolism of the brain, and evenby stabilizing the energized state of water thatsupports brain efficiency. Roman Schmitt has proposedthat, 66 million years ago when dinosaursbecame extinct and mammals began their rapidevolution, at that time hydrothermal venting wentwild, releasing huge volumes of carbon dioxideand other substances into the atmosphere.
Antarctic ice cores show there were large increasesin atmospheric carbon dioxide in relativelyrecent times: 10,200, 11,600, and 12,900 yearsago, and two broad peaks in carbon dioxide releaseoccurred just 4,200 and 7,700 years ago(Figge and White.) Local or regional increases incarbon dioxide from volcanism could have morecontinuous effects on brain development.
In times of lower atmospheric carbon dioxide,our Krebs cycle still produces it internally, and therapid development of the brain during gestationtakes advantage of the high concentration of carbon dioxide in the uterus.(These ideas make me doubt the safety of the rapid breathing encouragedby some obstetricians.)
We know that glucose can be metabolized into pyruvic acid, which, in the presence of oxygen, can be metabolized into carbon dioxide. Without oxygen, pyruvic acid can be converted into lactic acid. The production of lactic acid tends to increase the pH inside the cell, and its excretion can lower the pH outside the cell.
The decrease of carbon dioxide that generally accompanies increased lactic acid, corresponds to increased intracellular pH. Carbon dioxide binds to many types of protein, for example by forming carbamino groups, changing the protein conformation, as well as its electrical properties, such as its isoelectric point. With increased pH, cell proteins become more strongly ionized, tending to separate, allowing water to enter the spaces, in the same way a gel swells in an alkaline solution.
The Bohr-Haldane effect describes the fact that hemoglobin releases oxygen in the presence of carbon dioxide, and releases carbon dioxide in the presence of oxygen. When oxygen is too abundant, it makes breathing more difficult, and one of its effects is to cause carbon dioxide to be lost rapidly. At high altitude, more carbon dioxide is retained, and this makes cellular respiration more efficient.
The importance of carbon dioxide to cell control process, and to the structure of the cell and the structure of proteins in general suggested that degenerative diseases would be less common at high altitude. Wounds and broken bones heal faster at high altitude, but the available statistics are especially impressive in two of the major degenerative conditions, cancer and cataracts.
The two biggest studies of altitude and cataracts (involving 12,217 patients in one study, and 30,565 lifelong residents in a national survey in Nepal) showed a negative correlation between altitude and the incidence of cataract. At high altitude, cataracts appeared at a later age. In Nepal, an increase of a few thousand feet in elevation decreased the incidence of cataracts by 2.7 times. At the same time, it was found that exposure to sunlight increased the incidence of cataracts, and since the intensity of ultraviolet radiation is increased with altitude, this makes the decreased incidence of cataracts even more important.
All of the typical causes of cataracts, aging, poisons, and radiation, decrease the formation of carbon dioxide, and tend to increase the formation of lactic acid. Lactic acid excess is typically found in eyes with cataracts.
The electrical charge on the structural proteins will tend to increase in the presence of lactic acid or the deficiency of carbon dioxide, and the increase of charge will tend to increase the absorption of water.
The lens can survive for a considerable length of time in vitro (since it has its own circulatory system), so it has been possible to demonstrate that changes in the composition of the fluid can cause opacities to form, or to disappear.
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Ray Peat, PhD on Carbon Dioxide, Longevity, and ...