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Stress and Stuck Stem Cells Contribute to Gray Hair

A person with gray hair.
Credit: Gabriel Silvério / Unsplash.
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If we notice silvery locks sprouting through our luscious manes, we might be compelled (with a grimace) to say that we’re “turning gray”. However, hair strands do not suddenly “turn” a different color.

Hair color is programmed by melanocyte stem cells (McSCs), a type of stem cell that can be found in the hair follicle bulge and germ area. When a strand of hair falls out, these stem cells receive a signal that causes them to mature into melanocytes, which move into the hair bulb and inject pigment into the hair shaft as a new strand grows. The outcome? A colored strand of hair.

A growing area of research is working to understand what factors might contribute to a loss of McSCs and consequently more gray hairs.

Stress and gray hair – Old Wives’ Tale, or scientific fact?

The notion that stress can cause gray hair is often interpreted as an Old Wives’ Tale, but a study by researchers at Harvard University suggests there is scientific evidence behind the theory.

Nerves that make up the sympathetic nervous system – commonly referred to as the “fight or flight”, or “stress” response – also innervate hair follicles. Alongside colleagues, Dr. Ya-Chieh Hsu, the Alvin and Esta Star Associate Professor of Stem Cell and Regenerative Biology at Harvard University, sought to understand how the release of norepinephrine by these nerves might impact the hair follicle.

What is norepinephrine?

Norepinephrine is both a hormone and a neurotransmitter belonging to the catecholamine family. When we experience states of stress, norepinephrine and epinephrine are released and bind to adrenergic receptors in the body.

Using a variety of techniques in mouse models, Hsu and colleagues found that stress causes sympathetic nerve activation, leading to a burst release of norepinephrine that drives McSCs into rapid proliferation. The stem cells rapidly differentiate and migrate out of the hair follicle, from which they cannot return. A loss in the reserve of McSCs – which would eventually differentiate into pigment-producing melanocytes – reduces the number of cells capable of producing colored hair.

“When we started to study this, I expected that stress was bad for the body – but the detrimental impact of stress that we discovered was beyond what I imagined,” says Hsu. “After just a few days, all of the melanocyte stem cells were lost. Once they’re gone, you can’t regenerate pigments anymore. The damage is permanent.”

Jammed stem cells lead to gray hair

A recent study by New York University (NYU) Langone scientists revealed that McSCs are plastic. Depending on their spatial location within the hair follicle – and therefore what protein signals they are exposed to – McSCs can adapt their phenotype or state of differentiation from a primitive state to the next phase of maturity, known as the transit-amplifying state.

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The research, led by Dr. Mayumi Ito, a professor in the Ronald O. Perelman Department of Dermatology and the Department of Cell Biology at NYU Langone Health, used a combination of microscopy and single-cell RNA sequencing to follow McSCs in mice as they aged.

Ito and colleagues physically plucked the hair of mice to model aging and observed how McScs moved around in response. They found that a growing number of McSCs became “stuck” in the bulge of the hair follicle – the number of cells in this region increased to 50% after plucking, compared to 15% prior to plucking. In the bulge, McSCs find themselves in a sort of no man’s land; they’re incapable of maturing into the transit-amplifying state, but they also cannot return to the germ compartment, where proteins might have instigated their regeneration into pigment cells. “It is the loss of chameleon-like function in melanocyte stem cells that may be responsible for graying and loss of hair color,” says Ito. “These findings suggest that melanocyte stem cell motility and reversible differentiation are key to keeping hair healthy and colored.”

“Our study adds to our basic understanding of how melanocyte stem cells work to color hair,” says Dr. Qi Sun, a postdoctoral researcher at NYU Langone Health and co-author of the paper. If this fixed positioning of McSCs also occurs in humans, it may present new opportunities to explore treatments for gray hair reversal. While considered a natural part of the aging process – which we are frequently encouraged to embrace – gray hair can be a source of insecurity for some people, particularly in cases when it happens prematurely.

Prematurely graying hair, or PGH, occurs in certain illnesses and can be a sign of nutritional deficiencies, such as a lack of iron, copper or vitamin B12. Currently, a medical treatment to encourage hair repigmentation does not exist. While some drugs and nutritional supplements have been reported to induce repigmentation, a 2020 systematic review found the evidence behind these claims to be of low quality. Continued efforts to understand the molecular processes underpinning a loss or depletion of McSCs could support efforts to reverse graying hair. However, research confirming that these processes, first identified in animal models, also translate to humans, is paramount.