Hair Graying? Relax in the COLD 🥶

At least, if you have the R402Q tyrosinase polymorphism.

My mom got her first gray hair when she was 14, and I got my first gray hair when I was in my mid 20s.

I long suspected that she was homozygous and I was heterozygous for an impairment in copper handling, since copper is the cofactor of the tyrosinase enzyme that initiates the conversion of the amino acid tyrosine to the primary body pigment melanin.

However, I never felt like varying my copper status had any impact on my hair graying, and it was obvious that most increases in hair graying took place during high-stress periods that were punctuated by stability in hair color.

For example, I got my first gray hair during grad school, which was a high-stress period.

It turns out that my mom is homozygous for the A allele of the rs1126809 R402Q allele of tyrosinase (TYR), and I am heterozygous for it.

Functional studies (here, here, and here) indicate that this allele produces an enzyme that has totally normal activity at 31 C (87.8 F), but at 37 C (98.6 F) it loses 75% of its copper-binding activity and at least 75% if not all of its enzymatic activity.

This indicates that the allele confers thermolability on the enzyme, making it intolerant to heat to the extent that normal body temperature impairs it. This is a common theme in enzymatic impairments.

31C is cold enough for hypothermia, and maintaining body temperature at that point is not a viable strategy to prevent hair graying.

Indeed, high body temperature helps all enzymatic reactions occur more effectively if the enzymes do not have impairments that make them thermolabile. For example, the wild-type allele for tyrosinase operates more effectively at 43 C (109.4 F) than at body temperature, but this is above the threshold of fever (41-42 C, 105.9-10.7.6F) that can cause brain damage and become life-threatening.

Maintaining supraphysiological copper concentrations is also not a viable strategy for preventing hair graying because high concentrations of free copper are toxic. In fact, they cause oxidative stress, which can lead to hydrogen peroxide production, which can destroy hair pigment and cause graying.

This allele is part of a grouping that is dose-dependently associated with lighter pigmentation of the hair, skin, and eyes.

Whether it can contribute to albinism is controversial, but it appears that it cannot cause albinism on its own but it can contribute to it when combined with rare mutations.

This SNP is very common in people with European ancestry, where just under 40% of people are heterozygous and 7.6% are homozygous. It is not found in many Asians. It is found in American Blacks and Latin Americans, but not in African pygmies or Australian Aborigines, leading to speculation that it arose in Caucasians and spread to other groups through admixture.

While toxic levels of copper and deliberate hypothermia are not viable strategies to optimize around the polymorphism, it does make sense to not worsen it by avoiding copper deficiency (manage copper status using the Comprehensive Nutritional Screening and the Cheat Sheet).

In the case of heterozygosity the temperature implications are difficult to predict, but if you are homozygous for this it may help to err on the side of maintaining cooler ambient temperatures.

The properties of the R402Q enzyme have only been measured at 31 and 37 C and not in between. However, most likely the loss of function begins to occur at some threshold temperature higher than 31 and then progresses linearly as the temperature increases toward body temperature, and gets worse at temperatures above that, which would occur transiently during fever, sauna, and exercise.

In theory we are warm blooded animals and regulate our body temperature tightly. However, the ability to compensate for ambient temperatures differs based on genetics and nutritional status, and is likely never complete. For example, Japanese, whose genetics were shaped in temperate environments, develop about double the elevation in body temperature during heat stress as Malaysians, whose genetics were shaped in tropical environments. When comparing 60 hours spent at 16C/60.8F to the same time spent at 22C/71.6F, core temperature is about a half degree lower.

None of this is to say you want a lower metabolic rate. In a colder ambient temperature, you increase your food intake and metabolic rate to stay warm as an adaptation.

It seems, moreover, that the R402Q polymorphism began as a mutation in the colder environments of northern Europe, so this all might be to say that your hair may gray a little faster if you are genetically adapted for the cold but spend way too much of your time in the heat.

That said, we know what stress does to hair color:

This principle is probably more universal, more actionable, and not dependent on genetics.

It was known in the early 20th century that Addison’s disease, which causes adrenal insufficiency, causes excessive skin pigmentation, and that adrenocorticotropic hormone (ACTH), a pituitary hormone that elicits the production of hormones by the adrenals, does the same. These two findings made sense together, because the adrenal insufficiency of Addison’s disease elicits a compensatory increase in pituitary secretion of ACTH. However, why ACTH would increase skin pigmentation remained a mystery through the 1950s because everything known about the production of melanin indicated that the copper-dependent enzyme tyrosinase made melanin from the amino acid tyrosine after ultraviolet light decreased the concentrations of antioxidant inhibitors of the enzyme like vitamin C and glutathione in the skin. Researchers tried to show that ACTH modified the status of copper, vitamin C, or glutathione but results were extremely conflicting and no consensus could be reached.

Fast forward to the 21st century and there is now a rich body of evidence showing ACTH regulation of melanin synthesis. ACTH and melanocyte-stimulating hormone (MSH) are both derived from processing of the precursor protein proopiomelanocortin (POMC). They both act primarily on the melanocortin-1 (MC1) receptor to increase skin pigmentation, and UV light sensitizes skin cells to their effects by increasing the density of receptors and also increases their production. The action of ACTH and MSH on these receptors activates melanin synthesis in cellular compartments known as melanosomes. A second melanocortin receptor known as the MC2 receptor also responds to ACTH. It is primarily expressed in the adrenals and is thought to be much more important in regulating adrenal hormone production, but it is also present in human skin cells and plays a subsidiary role in ACTH stimulation of melanin production.

ACTH most strongly elicits the production of cortisol by the adrenals, but it also elicits adrenal production of testosterone and aldosterone. It has a likely indirect ability to stimulate the release of epinephrine and norepinephrine, but it has little effect on total circulating concentrations of norepinephrine because most norepinephrine is made in the nervous system. The primary determinants of ACTH levels are the diurnal rhythm that bottoms at night and peaks in the morning, and anything that would elicit a rise in cortisol, such as psychological or emotional stress or low blood sugar.

Cortisol, however, will exert negative feedback control on POMC.

So, if your stress response results in your cortisol being elevated beyond what is good for the body, the negative feedback on POMC will suppress the ACTH and MSH involved in pigmentation.

MSH, which also suppresses food intake and stimulates sexual arousal, is one of many brain peptides that require vitamin C, copper, zinc, and glycine for their activation, so using the Comprehensive Nutritional Screening and the Cheat Sheet to optimize these nutrients could also be helpful.

The clearest thing, though, is you want to manage stress properly.

And if you are homozygous for the R402Q (rs1126809 A/A) of the tyrosinase (TYR) gene, you may want to err on the side of staying cool.