"This leads us to the first rule of electrobiology: the living state is the electronically desaturated state of molecules, and the degree of development and differentiation is a function of the degree of electronic desaturation."
—The Living State by Albert Szent-Györgyi (1972)
In his book, The Living State, Albert Szent-Györgyi defined the complexity of life by the degree of "electronic desaturation" or the mobility of electrons. An electron itself has no energy, but by dropping from a higher to a lower level, can give off energy.
The reduction-oxidation (redox) balance of the living cell is an example of Szent-Györgyi's electron level jumping. By reducing a molecule, we add an electron to it, increasing its energy, by oxidizing, or by losing an electron, we decrease it.
A redox balance in favor of reduction is a feature of primitive life forms; electrons are "tightly held" and mobility through cells is poor. The redox balance in organized life favors oxidation; electrons are "loosely held" and "flow" through cells liberally. However, some structures in the organized animal still rely on an overly reduced environment for their energy needs.
The hair follicle is one such structure. In fact, it has one of the fastest rates of cell division in the entire body. Adopting the same "inefficient" metabolism as cancer, aerobic glycolysis, hair follicles are in a perpetual state of renewal, constantly drawing upon their resources.[1,2]
Oxidative metabolism is active in hair follicles, but they derive a majority of their energy from glucose through fermentation and the pentose phosphate pathway. I think interference in these energy systems, over time, provides an explanation for the changes in hair growth that are typically seen in aging.
I: WHEN HAIR ENERGY FAILS: OXIDATIVE STRESS
"There is circumstantial evidence that oxidative stress may be a pivotal mechanism contributing to hair graying and hair loss. New insights into the role and prevention of oxidative stress could open new strategies for intervention and reversal of the hair graying process and age-dependent alopecia." —Oxidative Stress in Ageing Hair (2009)
Energy-hungry hair follicles get their electrons from molecules such as sugar, fat, and protein. Some of the electrons will "flow" through the cell to meet up with oxygen ("the ultimate electron acceptor"), but most of them will be disposed of using the cell's reductive systems: fermentation and the pentose phosphate pathway.
- Fermentation (Basics): Glycolysis breaks down glucose into a small amount of energy and reduced NADH. Due to the deficiency of oxygen, electrons from NADH are donated to pyruvate, generating lactic acid.
- Pentose Phosphate Pathway (Basics): Glucose is converted to glucose-6-phosphate, and along with glucose-6-phosphate dehydrogenase and oxidized NADP+, generates reduced NADPH. NADPH provides "reducing power" for a variety of functions in the cell (including the synthesis of the "youth-associated" substances).
Typically, a healthy cell has a high ratio of NADPH to NADP+, however, in environmental stress, NADPH is consumed at an accelerated rate.
To keep up, the activity of the rate-limiting enzyme of the pentose phosphate pathway, glucose-6-phosphate dehydrogenase, which is needed produce NADPH, increases.
However, in pattern baldness, the activity of glucose-6-phosphate dehydrogenase—and the pentose phosphate pathway in general—is impaired. While the subject is far from clear, this impairment may be due to the replacement of fatty acids for glucose as a source of fuel.
Like the brain, hair follicles are strongly dependent on glucose to fulfill their high-energy requirements. While the hair follicles can oxidize fatty acids and ketones, they appear to inhibit the pentose phosphate pathway, and are energetically unfavorable for hair growth:
"Although fatty acids and ketone bodies were oxidized by the hair follicle, they are poor energetic substitutes for glucose. Nor will fatty acids or ketone bodies sustain hair growth in vitro." —Metabolism of freshly isolated human hair follicles capable of hair elongation (1993)
“Although we have shown that the contribution of the pentose phosphate pathway to the overall glucose metabolism in isolated hair follicles is small, this value does account for 32% of the total glucose oxidized by the hair follicle, and is, moreover, significantly inhibited by both palmitate and B-hydroxybutyrate.” —Metabolism of freshly isolated human hair follicles capable of hair elongation (1993)
"Thus, although our ATP measurements indicate that fats will maintain hair follicle viability, it appears that they are poor hair follicle fuels." —Metabolic studies on isolated hair follicles (1991)
The inhibition of the pentose phosphate pathway majorly interferes with the synthesis of NADPH, which provides "reducing power" to recycle oxidized glutathione (GSSG) back into reduced glutathione (GSH). Decreased levels of reduced glutathione in the hair follicle appear to be associated with aging.
Without the protection reduced glutathione provides, the delicate mini-organ is more exposed to highly reactive unpaired electrons, which in a series of events can damage the hair follicle's structure in a phenomenon known as oxidative stress.[6,7] Unsurprisingly, oxidative stress has long been associated with both so-called "male-pattern baldness" and general hair aging.[8,9]
II: Thyroid, Carbon Dioxide, and PUFA
In the 2013 study that I reference incessantly, Vidali et al. hypothesized that the increased oxidative stress characteristic of aging hair follicles would be made worse by the addition of thyroid hormone. However, they were surprised to find that thyroid hormone reduced levels of oxidative stress. Carbon dioxide, which is produced under the direction of thyroid hormone, inhibits the enzyme that consumes NADPH, and might provide a more in-depth answer for why Vidali et al. called thyroid hormones, "mitochondrial hair medicine".
Working in the opposite direction of thyroid hormone, the "essential" polyunsaturated fats require NADPH for their oxidation, possibly contributing to the cumulative stress the hair follicle is experiencing in pattern baldness. Moreover, the synthesis of prostaglandins from the polyunsaturated fat, arachidonic acid, is apparently sensitive to an overly reduced cellular environment. Perhaps this "reductive stress" is involved in the accumulation of prostaglandin D2 in the scalps of balding men discovered by Garza et al. in 2012.
What's happening at the local level in the hair follicle appears to be an outgrowth of a systemic unfavorable adaptive phenomenon that is influencing the vitality of the entire organism.
- Kenji, A., et al. Human Hair Follicles: Metabolism and Control Mechanisms. J. Soc. Cosmet. Chem., 21, 901-924 Dec. 9, 1970. “In 1958, Bullough and Laurence reported that mitosis in the hair bulb requires adequate supplies of oxygen and energy sources, such as glucose, fructose, and pyruvate.” “It was found that all of these inhibitors [e.g., cyanide, etc.] decreased CO2 production, and indication that the Krebs cycle is operative in the hair follicles…” “The activity of the Krebs cycle increases about 35% during the growth stage of the hair follicle…” “Thus, in the growing follicles, glucose assimilation produces not only sufficient, energy for the follicles function but also essential substances for the follicle to metabolism fatty acid, nucleic acid, and steroid hormones.”
- Philpott, M.P. and Kealey, T. Metabolic studies on isolated hair follicles: hair follicles engage in aerobic glycolysis and do not demonstrate the glucose fatty acid cycle. J Invest Dermatol. 1991 Jun;96(6):875-9. “The matrix cell of the hair follicle have one of the highest rates of cell division in the mammalian body, but their fuel metabolism is poorly understood.” “In this study we have shown that the hair follicle exhibits aerobic glycolysis, that of the total glucose utilized by the hair follicle, only 10% is oxidized to Co2.” “Although we have shown that the contribution of the pentose phosphate pathway to the overall glucose metabolism in isolated hair follicles is small, this value does account for 32% of the total glucose oxidized by the hair follicle, and is, moreover, significantly inhibited by both palmitate and B-hydroxybutyrate.”
- Patra, K.C., and Hay, N. The pentose phosphate pathway and cancer. Trends Biochem Sci. 2014 Aug;39(8):347-54. “…but also provides NADPH, which is required for both the synthesis of fatty acids and cell survival under stress conditions.”
- Adachi, K., et al. Activity of glucose-6-phosphate 1-dehydrogenase in hair follicles with male-pattern alopecia. Biosci Biotechnol Biochem. 1999 Dec;63(12):2219-21. “Activity of glucose-6-phosphate 1-dehydrogenase (G6PDH) in human hair follicles was measured. A good relationship has been demonstrated between the activity and the ratio of the number of the anagen hairs to that of all the plucked hairs in the frontal-parietal region of the scalp with male-pattern alopecia. As the ratio becomes lower so that the advancing degree of alopecia is higher, the G6PDH activity becomes lower.” "“In other words, it was made sure that the G6PDH activity decreases when the ratio of the anagen hairs decreases so that the advancing degree of alopecia increases. The energy metabolism done by G6PDH in hair follicles of male-pattern alopecia may be related to the hair growth, and activation of the energy metabolism may be a new strategy to prevent and cure male-pattern alopecia. G6PDH could be a suitable marker for diagnosis of alopecia, and enzyme immunoassay of G6PDG might be applicable for this purpose with higher sensitivity and more convenience than the G6PDH activity assay used in this study""
- Pruche, F., et al. Changes in glutathione content in human hair follicle keratinocytes as a function of age of donor: relation with glutathione dependent enzymes. Int J Cosmet Sci. 1991 Jun;13(3):117-24. “A reduction of 88% was observed in glutathione reductase activity and of 78% in the activity of glutathione-S-transferase from group A to group B. The glutathione peroxidase activity remains relatively constant. The decrease in the GSH concentration and the constancy of the glutathione peroxidase suggest that the capacity of the cell to protect itself from peroxides remains unchanged but that the GSH concentration may become the limiting factor.”
- Zago, E.B., et al. The redox state of endogenous pyridine nucleotides can determine both the degree of mitochondrial oxidative stress and the solute selectivity of the permeability transition pore. FEBS Lett. 2000 Jul 28;478(1-2):29-33. “We propose that the shift from a low to a high conductance state of the PTP can be promoted by the oxidation of NADPH. This impairs the antioxidant function of the glutathione reductase/peroxidase system, strongly strengthening the state of mitochondrial oxidative stress.”
- Ying, W. NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid Redox Signal. 2008 Feb;10(2):179-206. “Accumulating evidence has suggested that NAD (including NAD+ and NADH) and NADP (including NADP+ and NADPH) could belong to the fundamental common mediators of various biological processes, including energy metabolism, mitochondrial functions, calcium homeostasis, antioxidation/generation of oxidative stress, gene expression, immunological functions, aging, and cell death.” “Future investigation into the metabolism and biological functions of NAD and NADP may expose fundamental properties of life, and suggest new strategies for treating diseases and slowing the aging process.”
- Upton, J.H., et al. Oxidative stress-associated senescence in dermal papilla cells of men with androgenetic alopecia. J Invest Dermatol. 2015 May;135(5):1244-52. “Balding DPCs had higher levels of catalase and total glutathione but appear to be less able to handle oxidative stress compared with occipital DPCs. These in vitro findings suggest that there may be a role for oxidative stress in the pathogenesis of AGA both in relation to cell senescence and migration but also secretion of known hair follicle inhibitory factors.”
- Trüeb, R. Oxidative stress in ageing of hair. Int J Trichology. 2009 Jan;1(1):6-14. “There is circumstantial evidence that oxidative stress may be a pivotal mechanism contributing to hair graying and hair loss. New insights into the role and prevention of oxidative stress could open new strategies for intervention and reversal of the hair graying process and age-dependent alopecia.”
- Vidali, S., et al. Hypothalamic-Pituitary-Thyroid Axis Hormones Stimulate Mitochondrial Function and Biogenesis in Human Hair Follicles. J Invest Dermatol. 2013 Jun 27. “HPT-axis hormones did not increase reactive oxygen species (ROS) production. Rather, T3 and T4 reduced ROS formation, and all tested HPT-axis hormones increased the transcription of ROS scavengers (catalase, superoxide dismutase 2) in HF keratinocytes. Thus, mitochondrial biology, energy metabolism, and redox state of human HFs are subject to profound (neuro-)endocrine regulation by HPT-axis hormones. The neuroendocrine control of mitochondrial biology in a complex human mini-organ revealed here may be therapeutically exploitable.“ “The current data also provide clinically relevant pointers to how HF aging and disease correlated with declining mitochondrial function might be effectively counteracted in the future by endogenous neurohormones produced in the human epithelium, e.g., TRH and TSH. This also applies to THs [thyroid hormones], which have long been known to modulate hair shaft quality and/or pigmentation. Both TRH and T4 are administered routinely in thyroid medicine and are FDA-approved agents with a well-known toxicity profile. Therefore, regulatory hurdles to reposition these hormones for novel ‘mitochondrial hair medicine’ approaches are relatively low.”
- Kogan, A.K., et al. [Carbon dioxide--a universal inhibitor of the generation of active oxygen forms by cells (deciphering one enigma of evolution)]. Izv Akad Nauk Ser Biol. 1997 Mar-Apr;(2):204-17. “The results obtained suggest that CO2 at a tension close to that observed in the blood (37.0 mm Hg) and high tensions (60 or 146 mm Hg) is a potent inhibitor of generation of the active oxygen forms by the cells and mitochondria of the human and tissues. The mechanism of CO2 effect appears to be realized, partially, through inhibition of the NADPH-oxidase activity.”
- Clejan, S. and Schulz, H. Effect of growth hormone on fatty acid oxidation: growth hormone increases the activity of 2,4-dienoyl-CoA reductase in mitochondria. Arch Biochem Biophys. 1986 May 1;246(2):820-8. “…energy is required for the effective oxidation of polyunsaturated fatty acids…” “All data together lead to the conclusion that the mitochondrial oxidation of highly polyunsaturated fatty acids is limited by the availability of NADPH…”
- Rathaus, M. Clin Chim Acta. NADH-dependent prostaglandin E2-9-ketoreductase activity and prostaglandin synthesis in the Brattleboro rat kidney. 1986 Oct 31;160(2):205-10.