One need only compare photos of US presidents on inauguration day and then four or eight years later to be struck by the dramatic effect stress has on the graying of hair. And while some might view gray hair as a rite of passage, perusing the hair dye aisle of a neighborhood drug store reveals that covering up graying hair is a booming industry for both women and men. Recent research has uncovered new findings about the roots (no pun intended) of this inevitable change. For some people, seeing their hair turn gray over time can be stressful, and in fact, stress might be what’s responsible for the graying itself.

Most people know that psychological stress has a negative impact on their physical and mental health. Stress is well known to trigger a flareup in irritable bowel disorders and autoimmune conditions and may even be a causal factor in the latter. Constantly high stress levels affect insulin sensitivity and blood glucose regulation, making stress a risk factor for metabolic syndrome and type 2 diabetes. With so many different parts of the body negatively affected by high stress, perhaps it shouldn’t be surprising that melanocytes responsible for producing hair pigment are not immune. This is what was found by Harvard researchers and published in Nature. The title says it all: Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells.

The research was performed in mice, but it may still offer insights into what happens in humans. Cortisol is an obvious first candidate as a culprit in the connection between stress and undesired outcomes. Researchers ruled out cortisol as the causal factor after using adrenalectomized mice and witnessing the graying of hair in the absence of cortisol. They were also able to rule out graying as an immune-mediated attack on melanocytes because mice lacking immune cells continued to gray as well. Then they set their sights on the sympathetic nervous system.

Hair follicles contain sympathetic nerves and the stem cells that regenerate hair pigment are sensitive to norepinephrine (NE):

“Secretion of NE resulting from stress causes differentiation of most hair pigment melanocyte stem cells (MeSCs) into melanocytes, rapidly depleting the hair follicle of pigment-producing cells as mature melanocytes undergo apoptosis and MeSCs are eventually eliminated.” (Mendelsohn & Larrick, 2020)

In a press release from Harvard about the findings, the study’s senior author, Ya-Chieh Hsu, Associate Professor of Stem Cell and Regenerative Biology, said, “I expected that stress was bad for the body -- but the detrimental impact of stress that we discovered was beyond what I imagined. After just a few days, all of the pigment-regenerating stem cells were lost. Once they’re gone, you can’t regenerate pigment anymore. The damage is permanent.”

This may come as a disappointment to those who lament their gray hair despite the feelings of others who may see it as debonair, distinguished, or at the very least, hard-earned. Older individuals can build muscle and regain bone mass, but it seems that once the hair pigment stem cells are lost, gray is the way.

Stress isn’t the only thing that contributes to the graying of hair. Various nutrient deficiencies have been implicated in the process, particularly with regard to premature graying. For example, zinc is a key nutrient for skin and hair: “Skin contains approximately 6% of total body zinc. At the subcellular level, melanosomes act as a storehouse for zinc, and its concentration in human hair melanosomes is the highest zinc concentration attained in a structural element of the human body.” This comes from a case report of an infant with graying hair who was found to be zinc deficient. (He showed other signs and symptoms, such as skin lesions and chronic diarrhea.) Fortunately for this 5-month old, a full head of darkly pigmented hair grew in  within three months of starting zinc supplementation.

Other nutrient deficiencies implicated in premature graying of hair include vitamin B12, copper, and iron. Malnutrition from protein inadequacy may also be a contributing factor. (Unlike the effects of sympathetic nervous system activation on hair melanocytes, however, these deficiencies are associated with reversible graying—pigmentation may return upon nutritional repletion.) Suboptimal thyroid hormones may also affect hair pigmentation, as T3 and/or T4 increase melanogenesis and help modulate pigmentation. As if we needed another nail in the coffin for smoking, smoking accelerates hair graying. The mechanism is believed to be increased damage to hair follicle melanocytes from reactive oxygen species generated from smoking. (This tidbit might be especially helpful for preventing young people from picking up the habit: among smokers, premature graying may occur even before age 30!)

Both smoking and psycho-emotional stress may contribute to the “free radical theory of graying,” which implicates oxidative stress-induced damage as a cause of melanocyte apoptosis. The authors of the Nature paper noted that neuronal activity induced by acute stress “can drive a rapid and permanent loss of somatic stem cells.” Premature graying of hair is the change we can see on the outside. What may be more worrisome are the changes on the inside that we can’t see.