In most cases, hair starts to gray in the thirties, and becomes pronounced in the fifties, at which time the head is typically crowned with a thatch of white, gray and perhaps some hair of the original color. A new study published January 2020 in the journal Nature, shows that this process is speeded up significantly by acute stress persisting over a period, or by severe trauma.
Historically, the French queen Marie Antoinette is said to turned gray in one single night, developing a pure white head after she heard of her projected end under the guillotine, when the French Revolution was at its peak in 1793.
Scientists call this phenomenon canities or achromotrichia. The contribution of stress to this graying has been a matter of commonly accepted but not medically proven fact so far. The researchers say, “Our study proved that the phenomenon does indeed occur, and we identified the mechanisms involved. In addition, we discovered a way of interrupting the process of hair color loss due to stress.”
Image comparing mice submitted to pain-inducing experiment, which resulted in loss of pigmentation [bottom], to dark-colored mice in the control group. Image Credit: William A. Gonçalves
How the study came about
Researcher Thiago Mattar Cunha explains, “We were conducting a study on pain using black C57 mice, a dark-furred laboratory strain. In this model, we administered a substance called resiniferatoxin to activate a receptor expressed by sensory nerve fibers and induce intense pain. Some four weeks after systemic injection of the toxin, a PhD student observed that the animals' fur had turned completely white.”
This was followed up several times but finally it became evident that the gray hair was a consequence of the application of resiniferatoxin. This chemical is sourced from nature, being found abundantly in the resin spurge (Euphorbia resinifera), which is a native Moroccan cactus-like plant.
The study and its findings
The experimental setup for the current study was simple and designed to evaluate just one thing: does the stress of something painful cause the fur to change color? Says Cunha, “"We designed a very simple experiment to see if the phenomenon was dependent on activation of sympathetic nerve fibers.” The sympathetic nervous system is part of the autonomic nervous system from where most of the control of involuntary and visceral action takes place. It is made up of spinal ganglia, or knots of nerve cells, from where fibers branch out to travel all over the country.
The sympathetic system is well known, because it controls the level of epinephrine that directly influences the body. It regulates the well-known “fight or flight” response when the body is faced with a very risky situation, through both epinephrine and cortisol release. Sympathetic stimulation means an increasing heartbeat, a higher blood pressure, faster breathing and a dilated pupil, and other systemic effects.
Sympathetic blockage and preserved hair color
The mice were first administered resiniferatoxin, and then they were treated with guanethidine, a drug that inhibits the neural sympathetic fibers and so can arrest the expression and transmission of sympathetic nerve signals. They found that guanethidine prevented the loss of hair color over the weeks following the induction of stress, by blocking sympathetic inputs following the pain-inducing injection.
Another experiment involved the removal of sympathetic fibers surgically, following the induction of pain. When the sympathetic system was blocked, fur color was preserved.
The researchers concluded that signal transmission through the sympathetic nerve system is a powerful role-player in achromotrichia. Next, they turned their attention to the why of this finding.
Why stress causes graying of hair
Skipping ahead a few years, it was Cunha who, during a scholarship stint at Harward, heard of and later joined a group there which had discovered something similar, partly by a lucky observation. They focused on their new discovery that stress due to pain was speeding up the maturation of the melanocyte stem cells within the bulb of the hair follicle beyond normal limits. Only young cells, which are undifferentiated, produce melanin. As the cell matures, it differentiates and melanin release stops. The researcher explains, “We used various methodologies to show that intense sympathetic activity speeds up differentiation significantly. In our model, therefore, pain accelerated the aging of the stem cells that produce melanin.”
Professor Ya-Chieh Hsu, who leads the group, chimes in: “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. 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."
Another researcher, Bing Zhang, describes it as a permanent depletion of stem cells due to acute stress. Thus, instead of the fight-or-flight response benefiting the animal by helping it to survive, it is causing long-term harm to the animal.
Such effects are probably affecting other regions of the body too. Cunha says, “I'm currently working with other researchers on an investigation of the effects of sympathetic activity in other stem cell subpopulations."
Gene expression and hair graying
Using RNA sequencing as a tool, the researchers also examined the processes which enhance the differentiation of melanocyte stem cells, and compared how genes were expressed in mice that were injected with resiniferatoxin and thereafter showed signs of pain, stress and loss of hair color, with the way they were expressed in control mice injected with a placebo.
Their goal was to find genes that were expressed at very different levels after the animal developed stress. They were arrested by one gene that encodes an important enzyme called CDK, or cyclin-dependent kinase, which helps the cell divide.
When a CDK inhibitor was given to the mice after inducing pain, the result was a blockage in the differentiation of melanocyte stem cells, and in color loss. Cunha explains: “This finding shows that CDK participates in the process and could, therefore, be a therapeutic target. It's too soon to know whether it will actually become a target someday in clinical practice, but it's worth exploring further.”
In another experiment, a strong sympathetic stimulus was used. As a result, the scientists found that the nerve fibers to the hair follicle bulbs secreted noradrenaline close to the melanocyte stem cells, causing them to differentiate. Cunha describes the findings: “We showed that melanocyte stem cells express the protein ADRB2 [beta-2 adrenergic receptor], which is activated by noradrenaline, and we discovered that the stem cells differentiate when this receptor is activated by noradrenaline.”
They then repeated the experiment with mice that could not express ADBR2, and thus could not pass on sympathetic signals. These mice remained their original color even after a resiniferatoxin injection was given.
The final test was to treat human melanocytes in culture, which they had taken from the volunteers, with noradrenaline. This mimicked the effects of sympathetic stimulation and produced a rise in the expression of CDK like that which occurred in the whole mice.
About the applications
The researchers are not yet sure whether these findings will be useful for actual aesthetic purposes, such as developing a new drug to preserve the original hair color. They could use CDK inhibitors for this, but they need to look for side effects, and whether these outweigh the benefits. However, they are confident that they have found how and why pain-induced acute stress causes our hair to turn white.
Zhang, B., Ma, S., Rachmin, I. et al. Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells. Nature (2020). https://doi.org/10.1038/s41586-020-1935-3