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.
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