A Ray Peat newsletter, 1999-12.

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Ray Peat's Newsletter What is now proved was once only imagin 'd.

Copyright Raymond Peat 1999 PO Box 5764, Eugene OR 97405 December, 1999 Homeostasis and Aging Thyroid mysteries and minerals: Cramps, excitotoxicity, dementia, and C02 Blood perfusion of the brain and heart and muscles is increased by carbon dioxide, which is logical, considering that carbon dioxide ordinarily rises during metabolic activation. But the kidneys don't have this simple response to carbon dioxide, and this seems to be because of the special role of carbon dioxide In homeostasis and kidney function.

Blood flow to the kidneys is regulated by nerves and hormones. Parathyroid hormone and growth hormone cause vasodilation in the kidney, and increase its blood flow. The increased flow tends to produce a more dilute, hypotonic urine. In the kidneys, carbon dioxide's effects are much more complex than just regulating blood flow, and the kidneys maintain a remarkably high concentra-tion of CO2, causing some people to argue that they concentrate it from About 88 years ago, J :1. (who is known for his cancer therapy) studied the parafuy-roid hormone and its relation to tetany (prolonged . muscle contraction) and convulsIons, and was able to demonstrate that the major minerals, sodium, potassium, magnesium, and c.ill£lum are fOSOme extentinterchangeable in alleviating the tetany and convulsions produced by removal of the parathyroid gland, though was the most effective. This work was ignored by those who wanted to establish a simple relationship between "one gland, one hormone, one mecha-nism, one symptom or disease." A. L Carlson's group promoted the idea that the parathyroid hormone's function was simply to increase the amount of calcium in the blood, and that it was calcium which prevented tetany. This doctrine has had far-reaching consequences.

The view which has come to dominate twenti-eth century biology is that organisms were assem-bled by a simple-minded watchmaker named Natural Selection, and that they can be understood by reducing them to their simple parts, the way we understand a watch or a motor. A polar opposite to that view would be that nature is infinite, but knowable. To understand Koch's step from tetany to cancer isn't possible within the conven-tions of ordinary "medical endocrinology," but Koch assumed that nature hadn't learned its methods in medical school. KQch postulated, early in the century, that electrons and free Books by William Frederick Koch: Cancer and its Allied Diseases, 1926. Natural Immunity, 1934.

'-.- The Chemistry of Natural Immunity, 1939.-The Survival Factor in Cancer and Viral Infections, 1955, 1958.

radicals were involved in the most important biological processes-respiration, movement, immunity, regeneration, etc. He was probably the first person to apply the subtleties of organic chemistry (such as the activation of chemical groups by nearb rou s to biology. (Electronic induction.) bert Szent-Gyorgyi a Hungarian aristocrat, recognized t e complexity of nature and tried to work out a detailed scientific explana-tion for the ideas postulated by Koch. Szent-Gyorgyi, following Koch's interest in free radical color changes and fluorescence, underst.Jod that certain biological pigments represented special interactions of 'itectrons:J and \.photons] with proteins, and that muscle contraction wasn't just "a mechanical process," but probably involved all of the processes that distinguish life from .death.

A 1. Carlson, incidentally, had a prominent role in the conspiracy against Ivy.)

For both Koch and Szent-Gyorgyi, contraction, respiration, and life processes that required understanding the interac-tions offWateBLelectron]] andlproteins.] Practically all other biologists ridiculed their interest in water and electrons.

(One of Szent-Gyorgyi's major projects in studying the role of respiratory energy in muscle contraction involved a strain of goat that suffers from chronic and generalized exces-,gve muscle tension. I suspect that Koch's work with tetany led him in this direction.)

of receptors and effectors, and ..J!lQ1Q.rs an.£! pumps, all built up arbitrarily by natural selection, the coherent view of the organ-ism is that the fundamental properties of matter are used and amplified and focussed by processes of tuning and balancing. It is the "subtle reactivity" of the living system which maintains the adaptive organization of energy and structure. Part of the reactivity of the organism is the flexibly interactive metabolism, which adaptively distributes substance and energy. Ordinary metabolism, by acljusting the affinities of the cell substance, can account more rationally for the processes that are called "homeostatic" than the hypothetical apparatus of "pumps" and "channels," which are biology's deus ex machina, proposed whenever needed.

Szent-Gyorgyi found that progesterone and estrogen have antagonistic effects on the heart, and explained progesterone' similarity to digitalis by suggesting t at It .e ps the cells to "build struc-!!llf." The \structur€Jthat he referred to in the muscle cell was the structure made up of "strus-tured water" and -protems }and stances. Carbon dioxide's concentration affects the structural energy content ofthe protein-water system, and this effect can nicely account for many of the mysteries of cellular heat produc-tion, including the negative heat observed in certain stages of nerve and muscle activity. [Szent- a variety of cal interactions to demonstrate that intracellular water has special structural properties. This line of thinking led him to a view of ionic regulation (1957) similar to Gilbert Ling's, and probably contributed to Linus Pauling's similar ideas (1960). (Szent-Gyorgyi never-publicly acknowl- his respect for Koch's work, since he was obviously aware of the great dangers from the coalition of the medical-pharmaceutical establish-ment, and organized crime, which.Jlrove Koch out of the United States. During the decade in which Koch operated his clinic in it was the only large city in the U.S. in which cancer mortality declined; while cancer mortality in Los Angeles was rising by 30%, in Detroit it was declining by. 20%. Immediately after the Koch episode, the same alliance conspired against Andrew Ivy and the Durovic others to steal the anticancer drug they called Krebiozen but in , Koch's case, they couldn't figure out Just what to steal, so they tried to kill him or put him in jail.

The doctrine of"one gland-one action" caused people to focus on the low blood calcium which occurs in the tetany which is brought on by removal of the parathyroid gland (which sometimes killed patients when their thyroids were removed, along with the associated parathy-roids). By the 1920s, surgeons were careful about avoiding damage to the parathyroids to avoid tetany, but tetany kept occurring. They began leaving part of the thyroid gland, too, but tetany still occurred in a significant portion of patients. In fact, tetany is a risk following other operations, such as removal ofthe gall bladder. A new expla-nation for ost-thyroidectomy tetany was invented, "the hun bone syn rom 'based on the idea that hyperthyroi Ism ro s the bones of calcium, and that the bones begin stealing calcium from the rest of the body when the gland is removed. However, animal experiments show that it is only synthetic thyroxin which causes bone to lose calcium, and that the natural thyroid hormone, T3, stimulates bone growth; also, euthy-roid patients can experience tetany foHowing removal oftheir thyroid.

Practically any kind of poisoning causes cells to take up calcium from the blood, so e finding of hypocalcemia in association with te_ might permit people to confuse effect with caus en 0 i Vi Ii f" VI 'U The doctrine of hypocalcemic tetany led to the interfering with respiration at the same time that it practice of treating tetany with intravenous produces th excitatory glutamic acid. Ammonia, calcium solutions; for example, veterinarians in chronic po' . g, rat er producing often treat cows' "grass tetany" with large intrave-convulsions, produces stupor and coma, and at nous doses of calcium. The treatment works, but this point, its combination witt gliltamic aci{f to the tetany is now attributed to a magnesium produce glutamine is· probably Important ris a deficiency (since magnesium supplementation defense against seizures, eliminating both works better, as Koch discovered), and excessive ammonia and glutamic acid. ammonia produced in the cow's rumen can Hyperventilation, in which too much carbon contribute to the magnesium deficiency. The facts dioxl e is "blown off," causes fetanYJ and in that have grown up in veterinary research have a susceptible people, can cause convulsions. strong parallel to Koch's ideas presented around Hyperventilation causes constnctlOn) of the 1912. bronchial muscles and thickening of Koch found that the convulsions produced by producing symptoms of asthma. It causes removal of the parathyroid glands were associ-contraction of blood vessels in weaken-ated with the development of nephritis and the ing the pumping action, while blood vessels in the appearance of the toxic substances, guanidine general circulation also constrict, raisin.E blood and mefhylguanidine. \ These compounds, an and reducing circulation. Hyperventila-Iammonia" are now known to roduce convulsions tion commonly causes and thickens by actrng on the "«(xcitato amino acid receptors" the blood. The loss of carbon dioxide reduces These excitatory receptors release c into the brain circulation, creating complex paresthesias cytoplasm, many cell processes, includ-and stroke symptoms. "Hyperventilation" is a ing the liberation ofratty the breakdown relative term, and refers to the amount of carbon of proteins. When these "receptors" are activated, dioxide which is lost from the blood. Heavy, e ce s energy requirement increases, and rapid breathing at high altitude or in the presence glucose is consumed rr.cre rapidly. Whenever of a carbon dioxide-rich atmosphere, doesn't these "receptors" are activated, €nesiumYill necessarily constitute hyperventilation. protect the cell from the "toxic" excitation. Effec-Water, proteins, oxygen, and minerals, are all tive antidotes to the excitotoxins have been based crucially re lated b car on dioxide. The on their. blocking of these "receptors." enzyme, carbonic anhydraseJ which is regulated is now known for its neuroprotective by hormones (including the parathyroid hormone) actIvity, as well as its anticholinergic and antiviral and nerves, accelerates the interchange between effects. In the 1950s, toxins based on the carbon dioxide and bicarbonate, each of which guanidine group (e.g., lPfieriforrrunl were intro-has special functions. Bicarbonate is more duced to treat diabetes, because they can lower soluble in water, but carbon dioxide is more blood sugar, but they were later withdrawn soluble in living substance and fats. Carbonic because they killed the patients too quickly. anydrase is active in regions which regulate fluids, dlOXldfl produced by respiratory use s as the kidn e eye, and the of glucose, suppresses glycolysis, and so spares bular a aratus of the inner ear. sugar. Carbon dioxide is also with Carbon dioXl e IrrutS t e electrical -.ammonia, drtoxifying it into urea. Although it zation of nerves and muscles, a phenomenon first hasn't been determined, I suspect that Koch's discovered by Gilbert Ling. This .prevents the "toxic arnines" are detoxified by their 'direct over-excitation and exhaustion of brain cells and combination with c",bon dioxide, muscle cells, including the heart. The pmence of neously reacts with amines to form carbarnmo carbon dioxide limits the formation of lactic acid. groups. When there isn't enough carbon dioxi e This explains the "lactate paradox" of high to combine with ammonia, the ammonia can altitude exertion (lactic acid isn't produced during combine wit ketoglutarate from the Krebs cycle, hypoxic exercise, since carbon dioxide is retained r S (. I".,. c by the Haldane effect, in which the low oxygen pressure fails to displace all of the carbon dioxide carried in the blood cells), and it eX,I?lains why lactic acid tends to be alwavs present in the blond in hypothyrOIdism, and obesity-insuffi-cient carbon dioxide is and lactic acid is produced even with()lIt ()XVQ'en deprivation or stress. This glycolySIS) the production of lactic acid in the presence of oxygen, was defined by Otto Warburg as the characteristic cancer J!l.etaboli§11l. The "respiratory'defect" in which the I Pasteur ettecy (suppression of lactic acid forma- tion in the presence of oxygen) fails to operate, consists largely of the failure to produce carbon dioxide in the mitochondria.

Simple hyperventilation causes muscle spasms and paresthesia (prickling of the skin), in an experiment anyone can perform in a few minutes. When a large amount of carbon dioxide is blown off, the blood's pH increases very slightly, because of systemic adjustments. The "calcium deficiency" theory of tetany would suggest that increased alkalinity of the blood decreases the "availability" of ionized CalCiUID, and that (somehow) the "decreased availability of ionized calcium" interrupts a relaxed state of the nerves and muscles. At least, that's the explanation that I have heard many times, though I am stating it in a way that makes it sound fairly crazy. (See Stadler, et al., 1995.) But, in fact, everywhere calcium is studied, it is an activator, an excitant, a goad to activity, when it enters the cytoplasm. The evidence is that hyperventilation, which changes the serum concentration of bicarbonate, magne-sium, potassium, chloride, and phosphate, does not change the serum calcium concentration, while it does increase the intracellular calcium content. (Fujimoto, et al., 1987; Stadler, et al., 1995.)

The combination of the calcium ion, Ca2+, with the bicarbonate ion, HC03-, forms a very soluble complex ion with a single positive charge. In the saliva, there is more carbon dioxide than in the mouth, and this situation is believed to explain the fact that calcium which is dissolved in the saliva tends to be deposited in an insoluble form as it loses its solublizing bicarbonate, and the insoluble form contributes to dental plaque.

..

(Presumably, this physical principle would account for the deposition of calcium in the walls of blood vessels or in any tissue which is relatively deficient in carbon dioxide.) Similarly, when serum bicarbonate decreases, the calcium escapes from its soluble complex, and in effect the available calcium-the forms of calcium which are not bound to bicarbonate--has increased, exactly the opposite of what the Carlson school has argued. . Calcium, which is released into the cytoplasm by the excitotoxins, triggers the release of fatty acids, the activation of nerve and muscle, and the release of a variety of transmitter substances, in a cascade of excitatory processes, but at the same time, it tends to impair mitochondrial metabolism, and progressively tends to accumulate in mitochondria, leading to their calcification death, which is also promoted by the antirespiratory effects of the unsaturated fatty acids and the lipid peroxidation they promote. Iron and calcium both tend to accumulate with aging or stress, and both promote excitatory damage; bicarbonate contrib-utes to keeping iron in its inactive state, and probably has a similar effect against a broad spectrum of excitatory substances. Histamine release, nitric oxide, and carbon monoxide are broadly involved in excitotoxic damage, and carbon dioxide tends to be protective against these, too.

Besides the simple excitotoxic killing of nerve cells, the processes which impair carbon dioxide production set in motion the long degenerative process that ranges from diabetic lacticacidemia to dementia. In Alzheimer's disease, brain respi-ratory metabolism is inhibited, creating a carbon dioxide deficiency with an excess of lactic acid and ammonia. Both Alzheimer's disease ·and multiple sclerosis involve depressed brain metabolism combined with an inflammatory process. In any inflamed tissue, the enzyme beta-glucuronidase is activated, and this enzyme releases estrogen within the irritated cell, activat-ing another sequence ofneurotoxic processes.

In Alzheimer's disease, two other outstanding features are the tangles of microtubular material left where cells have disintegrated, and the amyloid plaques, which often form ill extracellular spaces and around blood vessels. One of the forms of amyloid (amyloid is named for its "starchy" appearance in stained slides) is produced from the normal protein, transthyretin, which carries vitamin A and thyroid hormone, when this protein is "glycosylated," by the addition of sugar molecules. In this glycosylated form, it resembles a mutant protein, and binds to the extracellular matrix. This glycosylation can occur spontaneously and quickly, in the absence of enzymes to catalyze it, when there is too much glucose present, and when the protein's amino groups (usually Iysines) are not protected by being combined with carbon dioxide (as carbamino groups). The carbamino groups form rapidly when there is an abundance of carbon dioxide, but also rapidly decompose in the absence of carbon dioxide, allowing the protein to be structurally degraded by the addition of sugar molecules.

Reactions very similar to these occur when the products oflipid peroxidation attach themselves to proteins.

Similar reactions, reflecting metabolic and energetic conditions, can alter the structure and organization of the neurotubules, leading to cell death and the formation of the characteristic neurofibrillary tangles.

W. F. Koch also found that excessive coagula-tion was produced in the toxic antirespiratory state. Carbon dioxide, probably by controlling the availability of calcium, is an important protection against abnormal clotting. The prevention of clotting by carbon dioxide is thought to be part of the explanation for its protective effect against oxygen deprivation. (pak and Sverchkova, 1987.) Hyperventilation causes increased vascular perme-ability, leading to hemoconcentration when a large portion of the blood's water escapes into the tissues. Vascular spasm, increased viscosity of the concentrated blood, and disturbed coagulation processes undoubtedly contribute to a wide range of health problems, including stroke, heart attack, and multiple sclerosis.

Since permanent high altitude residents chronically retain a larger amount of carbon dioxide in their tissue, I have looked for data on the incidence of degenerative brain disease among high altitude populations. In Kashmir, a house-to-house study of more than 66,000 people found that nearly one percent of the population suffered from some neurological impairment, such. as cerebral palsy, epilepsy, mental retarda-tion or stroke. But no cases of Alzheimer's disease or multiple sclerosis were found. In India, the incidence of these diseases is much lower than in the U.S., but their absence in Kashmir IS remarkable.

If excess lactic acid in the brain tissue is characteristic of Alzheimer's disease and multiple sclerosis, then the "lactate paradox" suggests that a slightly higher retention of carbon dioxide in the brain of Kashmir residents would counteract chronic excitotoxic effects, suppressing the stress metabolism which leads to the degenera-tive brain diseases. Experimentally increased carbon dioxide tends to decrease intracellular calcium, and to decrease brain excitability.

Cancer, the classical disease of extreme "aerobic glycolysis," is also negatively associated with increased altitude. Mortality from heart disease, too, decreases with increasing altitude, and the role of carbon dioxide in heart function is very clear.

The neuroprotective steroids, progesterone and pregnenolone, and magnesium a:ld carbo;l dioxide all protect against excitoxicity and the related excess of intracellular calcium, while promoting normal calcification. The thyroid hormone happens to promote the production of these steroids and carbon dioxide, and the reten-tion of magnesium. By the simple process of avoiding the antithyroid substances, especially the polyunsatured fatty acids, the degenerative processes discussed here will be minimized. Cyanide, another common component of foods (usually in the bound form as cyanogenic glycosides, in seeds, sprouts, nuts, and grains), has specific antagonisms to carbon dioxide, thyroid, and respiration.

REFERENCES Kosm BioI Aviakosm Med 1987 Nov-Dec;2I(6):43-7. [Role of carbon dioxide in the correction of coagulation hemostasis during hypoxial. [Article in Russian] Pak GD, Sverchkova VS. In acute animal experiments coagulation hemostasis reactions and blood acid-base state were investigated when dogs were breathing hypoxic (10% 02) or hypoxic-hypercapnic (10% 02, 5% C02) gas mixtures.

given the hypoxic mixture, activation of blood coagu-latIon was accompanied by depression of anti-coagulatory and fibrinolytic properties. These changes developed together with distinct hypoxemia, respiratory alkalosis and secondary metabolic acidosis. When given the hypoxic-hypercapnic mixture, no hypercoagulation occurred which can be explained by higher (than on the hypoxic mixture) pa02, lack of disorders in acid-base equilibrium and in oxygen supply. It is believed that the ability of carbon dioxide to maintain relative normocoagulation when added to the hypoxic mixture is one of the factors that increase tolerance to hypoxia.

lAMA 1980 lui 4;244(1):61-2. The effects of bicarbonate on blood coagulation. Wong DW, Mishkin FS, Tanaka IT. The anticoagulant effects of sodium and potassium bicarbonate were investigated with use of fresh human whole blood obtained from normal healthy volunteers. Results from prothrombin and thrombin clotting time determinations demonstrated that bicarbonate can interfere with the clotting process. Clinical data obtained from patients who received intravenous administration of sodium bicarbonate supported these fmdings.

Nippon Geka Gakkai Zasshi 1987 lul;88(7):864-71. [Eryth-rocyte calcium and pH levels during postoperative tetany following radical operations for thyroid cancer]. Fujimoto M, Mizuno S. To investigate the mechanism of postoperative tetany, erythrocyte calcium and pH were consecutively measured in IS patients who underwent total removal and subsequent autotransplantation of parathyroid glands at the surgery for thyroid cancer. Of these, 8 patients presented tetany signs, but the other 7 patients had no symptoms. In the non-tetanized group, the concentration of erythrocyte calcium decreased by 33.2% and 46.0% on the 3rd and 5th postopera-tive day, respectively. On the other hand, it increased by 49.8% and 34.6%, respectively, in the tetanized group, showing a significantly different concentration between two groups. No significant differences were observed, however, in the serum calcium level at any time between two groups. The erythrocyte pH as as the plasma pH in the tetanized group was signifi-cantly higher on the 3rd postoperative day, than that in the non-tetanized group. These results suggest the possibility that the elevated cellular calcium content is more closely linked with postoperative tetany than the serum calcium level, and that the elevated cellular pH as well as plasma pH is another causative factor in evoking tetany.

Schweiz Rundsch Med Prax 1995, Mar 21;84(12):328-34.

changes during and after voluntary hyperventila-tion). Stadler G, Steurer 1, Dur P, Binswanger U, Vetter W. Paresthesia and tetanic finger cramps during hyperventilation-induced respiratory alkalosis are believed to derive from a pH-dependent decrease of ionized serum calcium. In the study reported here, ionized serum calcium, total calcium and total protein were measured during a three-minute hyperventilation period in ten volunteers. During hyperventilation finger pares-thesias appeared in all probands without proof of any sianifi-cant change in ionized serum calcium (1.26 +/- 0.05 mmo b 1ll at the of the three-minute hyperventilation period). Total protem mcreased as a consequence of hyperventilation-induced transient hemo-concentration. Paresthesias and tetanic finger cramps during the three-minute hyperventilation could not be related to changes of ionized serum calcium; however the other electrolytes, i.e. .sodium, magnesium, potassium, chloride, phosphate and bicarbonate, showed, with the exception of sodium, significant changes.

Dtsch Med Wochenschr 1997 lui 11;122(28-29):887-9 [The effect ,of short-term hyperventilation on the concentration of ionized serum calcium]. [Article in German) Steurer 1 Pei P Vetter, W. " " 1 Clin Invest 1975 lan;55(1):149-56. Inhibition of carbonic anhydrase by parathyroid hormone and cyclic AMP in rat renal cortex in \;tro. Beck N, Kim KS, Wolak M, Davis BB.

N Engil Med 1973 lui 19;289(3):141-6. Guanidine deriva-tives in medicine. Davidoff, F.

Dan Med Bull 19731un;20(3):65-79 Biguanides and lactate metabolism: a review. Hermarm, L.S.

J Clin Invest 1968 Oct;47(10):2331-43. Effects of d.erivati:ves on mitochondrial function. 1 Phenethyl-blguaDide Inhibition of respiration in mitochondria from guinea pig and rat tissues. Davidoff F.

Neurosci Lett 1993 lui 23;157(2):123-6. N-methyl-D-aspartate receptors contribute to guanidinosuccinate-induced convulsions in mice. DRooge R, Pei YQ, De Deyn PP.

1 Neurosci 1996 Feb /;16(3):1193-202. Potentiation of neuronal NMDA response induced by dehydroepiandrosterone and its suppression by progesterone: effects mediated .;a sigma receptors. Bergeron R, de Montigny C, DebonneJ G.

Am 1 Hypertens 1998 Oct;I 1(10):1 199-207. Renal perfusion pressure is an important determinant of sodium and calcium excretion in DOC-salt hypertension. Brands MW, HalIJE.

Am 1 Med Sci 1998 Nov;316(5):321-8. Recent insights the coordinate regulation of body water and divalent mineral ion metabolism. Baurn MA, Harris HW.

1 Neurosci 1993 Nov;13(II):4861-71.Intracellular calcium levels and calcium fluxes in the CAl region of the rat hippo-campal slice during in vitro ischemia: relationship to electro-physiological cell damage. Lobner D, Lipton P.

Biochem Soc Trans 1994 NoV;22(4):398S. Histamine release from mast cells by polyamines: an NMDA receptor-mediated event? Purcell WM, Doyle KM, Bagga L, Derks M.

1 Am Coli Nutr 1998 Aug;17(4):401-3. Parenteral calcium gluconate supplementation: efficacious or potentially disastrous? Canada T, Albrecht 1.

1 Neurosci Res 1998 lan 15;51(2):133-8. Roles of neuroac-tiye amino acids in ammonia neurotoxicity. Albrecht 1..

Neurochem Int 1994 Ontogenetic differ-ences in connl1sive action and cerebral uptake of uremic guanidino compounds in juvenile mice. DRooge R, Pei YQ, Marescau B, De Deyn PP.

Pediatr Res 1997 lul;42(1 ):24-9. Effect of carbon dioxide on cerebral metabolism during hypoxia-ischemia in the immature rat Vannucci RC, Brucklacher RM, Vannucci S1.

Baird, S.L. lr., Karreman, G., Mueller, H., Szent-Gyorgyi, A., "Ionic semipermeability as a bulk property," Proc. Nat. Acad. Sci. 43, 705-708, 1957.