To understand the current state of the alternative health universe, you have to understand where Kurt Harris fits in. Kurt was one of the first intelligent people I came across in my health journey, and at the time, similar to Matt Stone, had a large effect on me. While some people think his synthesis propelled him into the territory of a Masterjohn or a Guyenet, I think his rise to stardom was mostly due to his humor.
Kurt wasn't afraid to be himself and speak his mind, and he consistently cracked me up when he publicly dismantled dissenting opinions. In 2012, armed with my newfound knowledge of Ray Peat's writings, I decided to engage in a battle of mental chess with Kurt who had brushed off Peat's ideas without ever addressing what was wrong with them. In addition to belittling me at every opportunity, one of Kurt's main points was that "theories of everything" lived and bathed in the realm of pseudoscience. And in classical MD fashion, Kurt believed that different problems had different starting points, needed different treatments, and presumably (because he never addressed it when I asked) had little to do with biological energy.
When I read Kurt's thoughts at the time, I realized that I was, and always had been attracted to thinkers progressing "theories of everything." Although subbing "theories of everything" for Erwin Schrödinger's big question, might be more fitting:
I'm not yet prepared to answer Schrödinger's big question, although Gilbert Ling has in his excellent book, What is Life Answered. However, I am prepared to talk about cellular growth and differentiation, how the cell maintains a balance between the two states, what happens when things lean too far in the wrong direction — and how this all relates to my realization that I'm a walking aquarium.
I: A SELF-ORGANIZING VESSEL
Ray Peat and Albert Szent-Györgyi were the first people to bring the cellular processes of growth and differentiation to my attention. They explained that primitive life could be characterized by growth, while an evolutionarily advanced feature of life was the ability to restrain growth, and redirect energy to specialized functions.[1,2]
More specifically, cellular energy produced from glycolysis or fermentation supported primitive structures and functions, while our evolutionarily advanced ability to make energy with oxygen (mitochondrial respiration or oxidative metabolism) helped produce complex structures and functions. Another way of thinking about it is that the more energy an organism is able to produce, the more organization present.
Apparently, the interdependence between energy and organization is not only evident in our own cells, but is central in the origins of life. In Vladimir Vernadsky's book, The Biosphere, he explains that life was the inevitable consequence of the earth being energized from two sources: the core and the sun. In this sense, organized life was not an accident, it was "purposeful," in that organized life on earth is the fruit of extended, complex processes — an inevitable result of the earth's high rate of metabolism. As Ray mentioned in an episode of politics and science, this has implications for every plant and animal having an essential role in the whole — with dire consequences of their removal from the system.
The young human animal has a high rate of metabolism, and the ability to quickly regenerate is often said to be a defining characteristic of youth. This 'regenerative advantage' tends to noticeably fade in mid-age, but the physiological realization that you're Mr. Glass from Shyamalan's masterpiece, Unbreakable, probably occurs much earlier. For example, Cynthia Illingworth found that children under eleven were able to perfectly recover from the amputation of a fingertip by regenerating the lost third of their finger, while children over eleven could not. Recorded currents emitted by children with the ability were remarkably similar to those obtained by Borgens et al. on salamanders. Similarly, in 1969, a group found that aortic fatty streaks (the beginnings of atherosclerosis) were present in many children under the age of three, and were nearly always present after age 20, suggesting that the youthful regenerative advantage is short lived in our current environment. A possible explanation for the enhanced regenerative powers of youth is more robust thyroid function.
II: THE VESSEL'S MOTHER AND MATRIX
Thyroid hormone is responsible for coordinating the delicate balance between growth and differentiation of an organism. For example, administering thyroid hormone to a tadpole inhibits normal growth, and produces a small fully differentiated miniature frog. In this sense, the small fully differentiated frog would be in a highly oxidized state with few free electrons. Thyroid hormone shifts cell's reduction oxidation (redox) balance, or the balance between electron acceptors and donors, towards oxidation (a higher ratio of NAD+ to NADH).
- Oxidation - The loss of electrons.
- Reduction - The gain of electrons.
The shift in redox balance is largely due to thyroid's role in stimulating the production of carbon dioxide — which enhance the use of oxygen by cells, tissues, and organs. Without carbon dioxide, the electrons cannot be sufficiently donated to oxygen, can become "jammed" in the mitochondria, and can participate in harmful oxidation processes leading to oxidative stress and lipid peroxidation. The "jammed" electrons also shift the cell's redox balance towards reduction (too many electrons), or a state of growth, rearranging the cell's water economy.
In his book, The Living State, Albert Szent-Györgyi describes life as having originated from water, that it was "part in parcel" of living machinery, if not the hub of life. Dr. Gilbert Ling and Dr. Gerald Pollack have both expanded on Szent-Györgyi's original exploration into the nature of cell water, and the topic will be covered in Brad Abraham's and Jeremy Stuart's upcoming documentary film, On The Back of a Tiger:
When a cell is stressed and isn't getting everything it needs, it's water content increases, and at least in cancer, can become disordered. The increased reliance on glycolysis (or fermentation) to meet energy requirements, and the hypoxic conditions it creates (due to a lack of carbon dioxide), can increase the intracellular accumulation of calcium, which has been called the "final common path" in cell aging and death. However, increasing the production of carbon dioxide inhibits processes leading to the accumulation of intracellular calcium, and can restore the balance between NAD+ and NADH.[14,15]
III: MAINTAINING THE CHARGE
If Cynthia Illingworth's regenerative-salamander-kids were demonstrating the benefits of robust thyroid function, I think the phenomenon offers some clues about maintaining the core elements of what makes us human. Perhaps the same regenerative capacities she noticed can be maintained into old age by adopting a lifestyle that supports rate of metabolism rather than inhibiting it.
Considering the factors we've talked about in this short article (thyroid hormone, carbon dioxide, stress, redox balance, and water economy), a good starting place might be the rate-limiting enzyme in mitochondrial respiration, cytochrome c oxidase. The activity of cytochrome c oxidase is supported by the unique phospholipid found exclusively in the mitochondria called cardiolipin. The fatty acid composition of cardiolipin changes with aging, “specifically [by] an increase in highly unsaturated fatty acids,” and these changes decrease the activity of cytochrome c oxidase.[16-19] In addition to minimizing the unsaturated fats to a comfortable level, and replacing them with saturated fats, thyroid hormone increases the activity cytochrome c oxidase.
In 2009, Landsberg et al. found that sufficient heat generation was a thyroid dependent process through the mitochondria. In the 1940 Merck Manual, low thyroid function was corrected with a supplement until a "feeling of warmth, increased pulse rate, [and] quicker mental reaction" was observed. A glass of milk with 2 or 3 tablespoons of white sugar and some salt can sometimes provide results similar to a few micrograms of active thyroid hormone, triiodothyronine or T3 (personal observation). Other metabolically stimulating diet considerations include a high ratio of calcium to phosphate, which limits the need for the anti-respiratory substances parathyroid hormone and prolactin, salting liquids and food to taste, and regular exposure to red light. [Red Light Video]
This article began with a simple argument between Kurt Harris and I three years ago about "theories of everything" in health and disease. I don't think supplementing thyroid hormone is a panacea, however, I think it's useful to see health problems as "disorders of energy metabolism," as Ray Peat has been writing about for the last several decades. This tends to annoy people with specialized knowledge (Kurt was a radiologist), but I think the elegant simplicity of the idea enables people that might not be scientifically inclined to take their health into their own hands, and become their own experts.
- Szent-Györgyi, A. The Living State: With Observations on Cancer. (1972). [Book]
- Peat, R. Generative Energy. (1994). [Book]
- Vernadsky, V. The Biosphere. (1926). "The biosphere is at least as much a creation of the sun as a result of terrestrial processes. Ancient religious intuitions that considered terrestrial creatures, especially man, to be children of the sun were far nearer the truth than is thought by those who see earthly beings simply as ephemeral creations arising from blind and accidental interplay of matter and forces. Creatures on Earth are the fruit of extended, complex processes, and are an essential part of a harmonious1o cosmic mechanism, in which it is known that fixed laws apply and chance does not exist." "The action of solar radiation on earth-processes provides a precise basis for viewing the biosphere as both a terrestrial and a cosmic mechanism. The sun has completely transformed the face of the Earth by penetrating the biosphere, which has changed the history and destiny of our planet by converting rays from the sun into new and varied forms of energy. At the same time, the biosphere is largely the product of this radiation. The important roles played by ultraviolet, infrared, and visible wavelengths are now well-recognized. We can also identify the parts of the biosphere that transform these three systems of solar vibration, but the mechanism of this transformation presents a challenge which our minds have only begun to comprehend. The mechanism is disguised in an infinite variety of nat- ural colors, forms and movements, of which we, ourselves, form an integral part. It has taken thousands of centuries for human thought to discern the outlines of a single and complete mecha- nism in the apparently chaotic appearance of nature."
- Illingworth, C. Trapped Fingers and Amputated Finger Tips in Children. J Pediatr Surg. 1974 Dec;9(6):853-58. “In The Accident and Emergency Department of the Children’s Hospital, Sheffield, we see each year between 300 and 350 trapped fingers. The management of this injury has been modified with experience. We now know that spontaneous regeneration and excellent cosmetic and functional results can be obtained in guillotine amputations of finger tips in young children.” “Electrical field charges have been demonstrated in experimental animals during the healing process. Becker5and Becker and Spadaro showed that partial limb regeneration could be induced in rats by applying appropriate levels of electrical stimulation to simulate the ‘current of injury’ which occurs in forms which can regenerate.” “We do not know the upper age limit for the successful application of this method. The oldest child treated in this way was 11 yr old, but we see com- paratively few older children with trapped fingers.” “We have developed a simple, relatively painless and very effective method of treating trapped fingers in small children. When a finger tip of a small child has been amputated, there is a remarkable capacity for the tip to regenerate if given a chance and if the injury is treated by a nonintervention technique.”
- Borgens, et al. Bioelectricity and regeneration: large currents leave the stumps of regenerating newt limbs. Proc Natl Acad Sci U S A. 1977 Oct;74(10):4528-32. “Electrical currents near regenerating newt limbs were measured with a recently developed vibrating probe. Steady currents with local surface densities of 10 to 100 muA/cm2 or more leave the end of the stump during the first 5-10 days after amputation and are balanced by currents with densities of only 1-3 muA/cm2 that enter the intact skin around the stump. They are immediately dependent upon the entry of sodium ions into this skin and are therefore inferred to be skin-driven. The outward currents are comparable in direction, density, duration, and position to artificially imposed currents previously found sufficient to induce significant regeneration of amputated adult frog limbs. This comparison suggests that the endogenous stump currents play some causal role in initiating regeneration.”
- Strong, J.P., and McGill, H.C. The pediatric aspects of atherosclerosis. Volume 9, Issue 3, 6 May 1969, Pages 251–265. “From data on more than 1600 autopsied persons, we have found that aortic fatty streaks are present in many children under age 3, and in all children over age 3. Later, we found that coronary artery fatty streaks are rare before age 10, but become much more frequent in the second decade of lile and are nearly always present after age 20.”
- Callergy, E.M., and Elinson, R. P. Thyroid hormone-dependent metamorphosis in a direct developing frog. Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2615-20.
- Lee, H.T., and Levine, M. Acute respiratory alkalosis associated with low minute ventilation in a patient with severe hypothyroidism. Can J Anaesth. 1999 Feb;46(2):185-9. “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 alkalosis in spite of concurrently diminished minute ventilation.”
- Kenneth, M.S., et al. Water structure differences between healthy and cancerous tissues. (2009). “Water in cancer cells exhibits different response to MRI than water in healthy cells. The contrast image differences, which represent longer relaxation times for cancer versus healthy cells, suggest that the water in healthy cells is more ordered than that in cancer cells, or conversely, water in cancer cells is more ‘bulk-like’ than the structured water in normal cells.”
- Wei, Y.H., et al. Respiratory function decline and DNA mutation in mitochondria, oxidative stress and altered gene expression during aging. Chang Gung Med J. 2009 Mar-Apr;32(2):113-32. “Aging is a biological process that is characterized by the gradual loss of physiological function and increases in the susceptibility to disease of an individual. During the aging process, a wide spectrum of alterations in mitochondria and mitochondrial DNA (mtDNA) has been observed in somatic tissues of humans and animals. This is associated with the decline in mitochondrial respiratory function; excess production of the reactive oxygen species (ROS); increase in the oxidative damage to mtDNA, lipids and proteins in mitochondria; accumulation of point mutations and large-scale deletions of mtDNA; and altered expression of genes involved in intermediary metabolism. It has been demonstrated that the ROS may cause oxidative damage and mutations of mtDNA and alterations of the expression of several clusters of genes in aging tissues and senescent cells. We found that intracellular levels of hydrogen peroxide (H2O2) and oxidative damage to DNA in the tissue cells and skin fibroblasts of old donors were higher than those of young donors. In H2O2-induced senescent skin fibroblasts, we observed an increase in the protein expression and activity levels of manganese-dependent superoxide dismutase and a concurrent decrease in the activity of cytochrome c oxidase and the rate of oxygen consumption. Moreover, the mRNA and protein expression levels of pyruvate dehydrogenase (PDH) were decreased but those of PDH kinase and lactate dehydrogenase were increased in senescent skin fibroblasts. The changes in the expression of these enzymes suggest a metabolic shift from mitochondrial respiration to glycolysis as a major supply of ATP in aging human cells. On the other hand, recent studies on mitochondrial mutant mice, which carry a proofreading deficient subunit of DNA polymerase gamma, revealed that mtDNA mutations accumulated in somatic tissues in the mice that displayed prominent features of aging. Taken together, we suggest that the respiratory function decline and increase in the production of the ROS in mitochondria, accumulation of mtDNA mutation and oxidative damage, and altered expression of a few clusters of genes that culminated in the metabolic shift from mitochondrial respiration to glycolysis for major supply of ATP were key contributory factors in the aging process in the human and animals.”
- Smith, I.F., et al. Effects of chronic hypoxia on CA2+ stores and capacitive CA2+ entry in human neuroblastoma cells. Journal of Neurochemistry, 2001, 79, 877-884. “Our results indicate that chronic hypoxia causes increased ®lling of intracellular Ca2I stores, suppressed expression or activity of NaI/Ca2I exchange and reduced capacitative Ca2I entry. These effects are not attributable to increased amyloid b peptide or presenilin-1 levels, but are likely to be important in adaptive cellular remodelling in response to prolonged hypoxic or ischemic episodes.”
- T. Fujita, “Calcium, parathyroids and aging.” in Calcium-Regulating Hormones. 1. Role in Disease and Aging, H. Morii, editor, Contrib. Nephrol. Basel, Karger, 1991, vol. 90, pp. 206-211. “All cell death is characterized by an increase of intracellular calcium….” “Increase of cytoplasmic free calcium may therefore be called ‘the final common path’ of cell disease and cell death. Aging as a background of diseases is also characterized by an increase of intracellular calcium. Diseases typically associated with aging include hypertension, arteriosclerosis, diabetes mellitus and dementia.”
- Richalet, J.P., et al. Effects of high-altitude hypoxia on the hormonal response to hypothalamic factors. Am J Physiol Regul Integr Comp Physiol. 2010 Dec;299(6):R1685-92. "Thyroid hormones were elevated at altitude (+16 to +21%), while TSH levels were unchanged, and follicle-stimulating hormone and prolactin decreased, while leutinizing hormone was unchanged."
- Gyulai, L., et al. NAD/NADH: redox state changes on cat brain cortex during stimulation and hypercapnia. Am J Physiol. 1982 Oct;243(4):H619-27. “Hypercapnic acidosis led to NADH oxidation.”
- Boljevic, S., et al. [Carbon dioxide inhibits the generation of active forms of oxygen in human and animal cells and the significance of the phenomenon in biology and medicine]. Vojnosanit Pregl. 1996 Jul-Aug;53(4):261-74. “Finally, it was established that CO2 led to the better coordination of oxidation and phosphorylation and increased the phosphorylation velocity in liver mitochondria.”
- Lee, H.J., et al. Selective remodeling of cardiolipin fatty acids in the aged rat heart. Lipids Health Dis. 2006; 5: 2. “The concentration (nmol/g) of linoleic acid was decreased in 24 month old rats (3965 ± 617, mean ± SD) vs 4 month old rats (5525 ± 656), while the concentrations of arachidonic and docosahexaenoic acid were increased in 24 month old rats (79 ± 9 vs 178 ± 27 and 104 ± 16 vs 307 ± 68 for arachidonic and docosahexaenoic acids, 4 months vs 24 months, respectively). Similar changes were not observed in ethanol amine glycerophospholipids or plasma unesterified fatty acids, suggesting specificity of these effects to cardiolipin.” “These results demonstrate that cardiolipin remodeling occurs with aging, specifically an increase in highly unsaturated fatty acids.”
- Paradies, G., et al. Age-dependent decline in the cytochrome c oxidase activity in rat heart mitochondria: role of cardiolipin. FEBS Lett. 1997 Apr 7;406(1-2):136-8. “Cardiolipin is a major mitochondrial membrane lipid and plays a pivotal role in mitochondrial function. We have recently suggested a possible involvement of this phospholipid in the age-linked decline of cytochrome c oxidase activity in rat heart mitochondria [G. Paradies et al. (1993) Arch. Gerontol. Geriatr. 16, 263-272]. The aim of this work was to test our earlier proposal. We have investigated whether addition of exogenous cardiolipin to mitochondria is able to reverse, in situ, the age-linked decrease in the cytochrome oxidase activity.“ “We demonstrate that the lower cytochrome c oxidase activity in heart mitochondria from aged rats can be fully restored to the level of young control rats by exogenously added cardiolipin. No restoration was obtained with other phospholipids or with peroxidized cardiolipin. Our data support a key role for cardiolipin in the age-linked decline of rat heart mitochondrial cytochrome c oxidase activity.”
- Kunkel, H.O., et al. The effects of fat deficiency upon enzyme activity in the rat. J Biol Chem. 1951 Apr;189(2):755-61. “The activity of the cytochrome oxidase, however, is markedly increased in fat deficiency…” “This is particularly interesting in view of the observation of Burr and Beeber (8) and Wesson and Burr (9) that fat-deficient rats had a markedly increased metabolic rate. The latter authors reported that the basal and assimilatory metabolic rates of fat-deficient animals were 25 per cent greater than the rates of the control animals. Thus the liver cytochrome oxidase activity appears to parallel the met,abolic rate in fat deficiency. This increased cytochrome oxidase activity in liver and perhaps other tissues may account in a large part for the increased metabolic rate.” “Supplementation with 100 mg. of methyl linoleate per rat per day reduced the cytochrome oxidase to the level of that produced by a 5 percent corn oil diet.”
- Yamaoka, S., et al. Mitochondrial function in rats is affected by modification of membrane phospholipids with dietary sardine oil. J Nutr. 1988 Mar;118(3):290-6. “Phospholipids of heart and liver of rats fed a diet containing sardine oil had more omega 3 polyunsaturated fatty acids and less omega 6 polyunsaturated fatty acids than those of rats fed corn oil, whereas there was little difference in the fatty acid composition of brain phospholipids. The mass of phospholipid classes in rat heart mitochondria was not changed, but their fatty acid compositions were altered. Modification of the fatty acid compositions of mitochondrial phosphatidylcholine and phosphatidylethanolamine reached a plateau after 10 d of feeding, but that of cardiolipin continued for 30 d. The O2 consumption rate of rat heart mitochondria decreased as the fatty acid composition of the phospholipids changed. This may be due to the reduction of the activity of cytochrome c oxidase, which requires cardiolipin for its activity.”
- Paradies, G., et al. Cardiolipin-dependent decrease of cytochrome c oxidase activity in heart mitochondria from hypothyroid rats. Biochim Biophys Acta. 1997 Mar 28;1319(1):5-8. “The thyroid hormones are known as one of the major factors involved in the regulation of cardiac function. Mitochondria are considered to be likely subcellular targets of thyroid hormone action in view of their crucial role in the energy metabolism. Thy- roid hormones regulate mitochondrial respiration with increased rates in hyperthyroidism and decreased rates in hypothyroidism. Changes in membrane lipid con- tent, lipid composition and lipid-proteins interactions do occur in mitochondria isolated from hypo- and hyperthyroid animals. These changes have been considered at least in part, respon- sible for the changes in the activity of certain mito- chondrial anion carrier proteins and electron transport systems. Cardiolipin is a phospholipid of unusual structure, found almost exclusively at the level of the inner mitochondrial membrane where it is biosynthesized. The biosynthesis of this phospholipid in hepatic and cardiac mitochondria has been shown to be under thyroid hormone regulation. Cardiolipin plays an important role in mitochondrial membrane structure and function. This phospholipid interacts with various proteins of the inner mitochondrial membrane including several anion carrier systems and certain electron transport complexes. Among these, the interaction of cardiolipin with cytochrome oxidase, the terminal enzyme complex of the electron transport chain, has been best characterised. A large number of studies indicate a specific and tight association between cytochrome oxidase and cardiolipin that is functionally important for maximal activity of this enzyme.
- Landsberg, L., et al. Is obesity associated with lower body temperatures? Core temperature: a forgotten variable in energy balance. Metabolism. 2009 Jun;58(6):871-6. “The underlying physiological basis for these differences have remained poorly understood. The energetic requirements of homeothermy, the maintenance of a constant core temperature in the face of widely divergent external temperatures, accounts for a major portion of daily energy expenditure. Changes in body temperature are associated with significant changes in metabolic rate.” “This metabolic energy required for homeothermy is thyroid dependent and apparently generated principally in mitochondria throughout the body of warm-blooded animals.” “A decrease in body temperature, in fact, occurs at night in relation to the sleep cycle in human populations. A fall in body temperature occurs duringstarvation, as noted above, and in hypoglycemia, an acute state of energy deprivation.” “Recent evidence implicating fibroblast growth factor in the metabolic response to fasting supports the important adaptive role that temperature plays in the adaptation to starvation.” “Individuals with the 1°C lower core temperature, thus, would have a thermogenic handicap of about 100 to 130 kcal/d or about 3000 to 4000 kcal/mo. In 1 month, this would account for 1 lb of fat, 12 lb in 1 year, and about 120 lb in a decade, all else being equal. In the normally active example described above where RMR constitutes 37% of total energy expenditure, the impact is less but still impressive. Under these circumstances, the thermogenic handicap of a 1°C lower core temperature might approximate 74 to 96 kcal/d or about 2200 to 2900 kcal/mo. Greater falls in temperature, perhaps during sleep or in response to low-energy diets, would have correspondingly greater effects.”
- The Merck Manual Seventh Edition. 1940. “Hypothyroidism. Gradual onset of apathy, gain in weight, and development of nonpittng edema, especially of hands, feet and face. Skin dry and scaly. Hair becomes brittle and thin, nails rough, striated and break easily. There are lassitude, fatiguability, drowsiness, imperfect cerebration, even psychosis; poor appetite and constipation; pulse slow, blood pressure low, temperature subnormal; menstruation irregular; may cease or become excessive. Anemia in majority of cases.” “Causes: A disease in middle life, 6 times more common in women than in men, especially liable to occur with menstrual disturbances. Diagnoses: Gradual onset of apathy, gain in weight, and development of nonpitting edema, especially of hands, feet and face (“full moon-like” face and coarse features). Skin dry and scaly (scales best seen in stockings. Hair becomes brittle and thin, nails rough, striated and break easily. There are lassitude, fatiguability, drowsiness, imperfect cerebration, even psychosis; poor appetite and constipation; pulse slow, blood pressure low, temperature subnormal; menstruation irregular; may cease or become excessive. Anemia in majority of cases. Tests: Basal metabolism low, hypercholesteremia, alimentary tolerance for dextrose greatly increased, diminished sensitivity to epinephrine and pilocarpine. Therapy: The administration of desiccated thyroid which may have to be continued throughout life is best divided into two periods: 1. Initial Dose: One usually may commence with 1 grain of thyroid 3 times a day; and increased dose by 1 grain a week until 3 grains is taken three times a day or until there is feeling of warmth, increased pulse rate, quicker mental reaction. These symptoms are followed by elevation of temperature, sharp loss of body weight, sweating and increased metabolic rate… Exercise should be very constricted until improvement is well advanced.”