When Ya-Chieh Hsu, professor of stem cell and regenerative biology at Harvard University and the Harvard Stem Cell Institute, wanted to figure out exactly what makes hair turn grey, she started with an obvious, albeit anecdotal, culprit: stress. There are well-known historical examples of the connection between stress and hair greying—Marie Antoinette’s coif reportedly blanched after she was captured during the French Revolution—and studies have even linked stress in animals to greying hair. But for the first time, Hsu and her colleagues figured out the biological reason why stress saps the pigment out of hair.

In a study published in Nature, Hsu and her team report that the process starts with the sympathetic nervous system, which orchestrates all of the critical body processes that we never have to think about—our heart rate, our breathing, as well as things like digesting food and fighting off germs. It is also responsible for the fight-or-flight response—the auto-pilot behavior system that helps us to recognize and respond to threats before we really have time to think about and process them. The sympathetic nervous system is intimately linked to our stress response, so in that respect it’s not entirely surprising it might have something to do with greying hair.

But the sympathetic nervous system’s response to stress is generally one of last resort, activated only in a dire emergency when other systems are too slow or have failed. It’s not called into action when you’re behind on a project at work, for example, or are anxious about making an upcoming public presentation. Because of the energy required to turn on the fight-or-flight response, it wouldn’t make sense to rely on it for those situations. For those non-emergency stressors, there are other processes at work.

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And that’s where Hsu focused her attention at first. She suspected that if stress were indeed turning hair grey, then it was probably working through something like the immune system, which might be releasing cells to attack color-producing cells in the hair follicle; or by triggering the release of stress hormones like cortisol from the adrenal glands. But neither seemed to be the case. She chemically induced stress in mice by injecting them with a compound called resiniferatoxin, which boosted the animals’ stress hormone levels; this method provided a reliable way of inducing the stress response over other strategies that the team explored, including using restraints, tilting the animals’ cages, wetting their bedding and changing their lighting conditions. Mice lacking immune cells and mice without adrenal glands both continued to show premature greying after getting these stress-mimicking injections.

That’s when Hsu turned to the sympathetic nervous system, and found that it could do permanent damage to a population of cells responsible for coloring hair. “We were really surprised,” she says. “The sympathetic nervous system would have been the last system we thought about. We know it’s activated under stress but you normally think about it as an emergency system, for fight-or-flight responses that are at the very least transient and reversible once the threat is gone. But here, we found that the sympathetic nervous system can permanently deplete an entire stem cell population.”

The cells that are targeted by the sympathetic nervous system under stress are a group of color-generating stem cells found deep in the so-called bulge of the hair follicle from which all new hair grows. Called melanocyte stem cells, these cells become active when a new hair begins to sprout in the follicle; the melanocyte stem cell then starts to divide and produce pigment-producing cells that color the shaft of the hair as it grows.

Hsu found that even during normal stress (not the fight-or-flight kind), the sympathetic nervous system is active, and produces the chemical norepinephrine, which leads to increased muscle contraction, including in the heart. In response to the norepinephrine, the melanocyte stem cells start churning out more than the usual allotment of pigment, misreading the stress-induced cue for the one that signals new hair growth. Eventually, their color reservoir runs dry and they can’t produce pigment any more. “Melanocyte stem cells are important in maintaining the pigment-producing cells in the hair follicle, and they are the only ones that can do so. Once they are gone, they are gone for good,” says Hsu. “ The result: hair stripped of color, turned grey.

The connection between stress and the nervous system and pigment-producing cells may be an evolutionarily conserved association among different species—cephalopods, including squid and octopi, also change color when under stress. Whether something similar (but in reverse) is at work in mammals and greying hair isn’t clear yet, but these findings are a reminder that stress has widespread effects on the body, and may be working in ways that doctors still don’t fully understand. Understanding how stress affects stem cell populations, which seed all of the cells in the body, from skin cells to blood cells and hair cells, could provide clues about how to cope better under stress and perhaps even age in a more healthy way. “Stress is an inevitable part of modern life, but we understand very little about how it affects stem cell biology and tissue turnover,” says Hsu. “Hair color is an excellent starting point because hair is so visible and easily accessible. But different stem cells and different organs may respond to the signals of the sympathetic nervous system very differently, and we don’t know exactly how yet.”

Based on these findings, it’s possible that there may eventually be a way to either preserve the melanocyte stem cells, or control the effect that the sympathetic nervous system has on their number. But for now, Hsu says, “There is no treatment available at this very moment. There is still a lot of work to do in this area.”

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