Marco Kaltofen was 11 when he noticed his first white hairs. As his hair grew whiter, his middle-school friends started calling him “the professor.” By his mid-30s, it was completely white, as it had been for three of his grandparents. His parents went white in their 40s, “so I had no chance of avoiding this,” Kaltofen says.
Now 61, he is a civil engineer who lives in Boston. He wears his white hair in a ponytail. “White hair is part of my identity, and I am completely at peace with it,” he says.
Then there is Joe Rees, 75, a retired customs attache who lives in Washington. He is balding, but the hair that remains – on the sides and in the back – is the same dark brown it always has been. He jokingly attributes this to “clean living and a pure heart,” although, like Kaltofen, it probably is genetic. His mother’s black hair didn’t start to go gray until she was in her 70s, and was “50/50” when she died at 88, he says.
Still, “I’d rather be gray than bald,” he says. “That way, I wouldn’t have to worry about wearing a hat all the time.”
To be sure, Rees and Kaltofen are exceptions, since most people start graying in their 50s and 60s. Nevertheless, their experiences are among the many mysteries of gray, white or silver-looking hair that scientists are exploring to learn more about aging. They want to know why some people turn gray early and others late – or not at all – and what this might signal about their health. They also want to understand the factors that hasten graying, and even whether gray hair is reversible – which could be a boon to those allergic to hair dye, or who hate spending money to keep the gray away.
Most important, studying gray hair could point to new approaches in promoting healthier aging, says Candace Kerr, health scientist administrator in the National Institute on Aging’s Division of Aging Biology.
“While graying is one of the markers of aging – aging is the ultimate risk factor for why hair goes gray – it highlights the need for better understanding of the mechanisms that drive aging and age-related diseases,” she says. “To be able to target these pathways will be critically important for our aging population to live longer and happier lives.”
Hair that looks gray, white or silver actually is colorless. Hair color comes from melanin, a pigment produced by cells in the hair follicles. Over time, these cells suffer damage and become depleted, losing their ability to make melanin. This results in new hair without pigment – meaning, no color.
People use “gray,” “white” and “silver” interchangeably to describe hair that is turning or has turned. Its appearance – whether it looks, gray, white or silver – depends on how much natural color, or pigment, remains, experts say. Hair that has lost all its color typically appears white.
Studies have identified a number of factors that also may speed up gray hair, including smoking, diet, stress and genetics.
“Our hair color depends on a set of specialized stem cells called melanocyte stem cells, and every time a new hair grows, these melanocyte stem cells have to divide in two and make a new melanocyte, [or] pigment cells,” explains Melissa Harris, assistant professor of biology at the University of Alabama at Birmingham. “These pigment cells stay in the base of your hair and their job is to produce pigment. These melanocytes reach out skinny arms, called dendritic processes, that shuttle the pigment to the hair shaft as it grows. So if all your melanocyte stem cells disappear, so do your melanocytes and so does your hair pigment. Thus – gray hair.”
Because stem cells directly influence hair color, studying gray hair can provide insights about why stem cells age and ultimately fail, offering important clues about the workings of other stem cells in the body – for example, those found in muscles, bones and organs. In turn, these ultimately could point to whether gray hair could be a marker for disease, or the opposite, a longer life. Previous studies have not shown a relationship between life span and gray hair, including whether late onset of gray hair predicts longevity. Some research, however, indicates that gray or white hair can be a sign of early heart disease, regardless of age.
“In some people, gray hair could potentially serve as indication of their health – for instance when caused by stress, or a signal for those who may be developing cardiovascular disease,” Kerr says. “We still need to learn more about whether – and, if so, how – late onset of gray hair can signal better health and longevity in some people under certain circumstances,” as well as whether early graying means stem cells might be aging.
“There are many different stem cells in our body which may or may not age by different means,” she says. “How stem cells mark aging overall and how they could interact to promote aging is an important question.”
This is why scientists who study gray hair regard it as a valuable research tool.
“As gray hair researchers, we often have to defend why we study a cosmetic characteristic, rather than a life-threatening disease,” Harris says. “But what is very cool about gray hair from a scientific point of view is that we can see it with our own eyes, meaning we don’t have to take invasive biopsies, and it doesn’t kill you. We have asked a lot of important and interesting questions about stem cells by studying gray hair in mice. And, we are constantly on the lookout for gray-haired mice so we can use our scientific skills to find out what makes them gray.”
A 2018 mouse study by “Team Hair-Us” (Harris’ nickname for her lab colleagues) found a connection between MITF (microphthalmia), a transcription factor (a protein involved in gene expression) important in managing pigment production, and the innate immune system, suggesting that some people’s hair may turn gray in response to serious illness or chronic stress. They discovered a relationship between genes involved in hair color and those that trigger an immune response to a viral infection, suggesting this interaction could increase the chances of developing gray hair.
“MITF, in a sense, shields melanocyte stem cells from our own immune system,” she says. “Normally our immune system protects our bodies from infection. But for melanocyte stem cells, too much immune response is bad for their health, and this leads to their loss and to gray hair. Why melanocyte stem cells are so sensitive to our own natural means for protection, we still don’t know.
“I’m very curious to see whether we see an uptick in individuals with gray hair due to coronavirus infection,” she says. “Unfortunately, we probably won’t know because gray hair is rarely documented clinically, unless it is very extreme.”
Scientists still don’t know why some people turn gray early, late, or not at all, although they suspect genes, nutrients and possibly the immune system play a role in depleting melanocyte stem cells.
“There is still much to learn about what regulates these stem cells and what may contribute to their loss,” says Ya-Chieh Hsu, associate professor of stem cell and regenerative biology at Harvard University and principal faculty member of the Harvard Stem Cell Institute.
Among other things, Hsu studies the effect of stress on graying. Most of us are familiar with those “before-and-after” photographs of U.S. presidents – most recently Barack Obama – showing a striking increase in gray hair during their terms, even in relatively young presidents. It’s known as the “Marie Antoinette Syndrome,” after the 18th-century French queen whose hair allegedly turned white overnight before she went to the guillotine and her death at age 38 during the French Revolution.
“With the aging process, we gradually lose melanocyte stem cells one-by-one over a very long period of time,” Hsu says. “What we found in our research was that the stress can accelerate that process.”
Hsu and her colleagues found that stress stimulates the same nerves that trigger the “fight-or-flight” response, which in turn causes permanent damage to the pigment-producing cells in hair follicles. The fight or flight response “is thought to be a good thing in stressful situations because it can drive us and other organisms to respond to danger rapidly,” Hsu says. This activation “causes a spike in the neurotransmitter norepinephrine. Norepinephrine raises our heartbeat and allows us to react quickly to danger without having to think about it.”
But norepinephrine also tells melanocyte stem cells to pump up their activity and proliferate, “and too much norepinephrine, in this case triggered by stress, causes the melanocyte stem cells to burst into so much activity it leads to rapid depletion of the stem cell reservoir,” she says. “If all the stem cells are depleted, no more pigment-producing cells can be produced anymore, and the hair turns gray.”
Other stress hormones, ACTH (adrenocorticotropic hormone) for example, can cause melanocyte stem cells to migrate away from the hair follicle before they can produce the melanocytes needed for hair and skin color, according to research. “Such hormones are known to increase in the body after stress, and may have the potential to promote the loss of these cells, regardless of age,” says study author Mayumi Ito, associate professor in the departments of cell biology and dermatology at the New York University Grossman School of Medicine.
Hsu believes the connection between stress and hair color could reveal additional information about how stress affects other biological processes. “How stress affects our tissues is still poorly understood, and one of the powerful aspects about the melanocyte is that it provides a visible and highly trackable system to study stress,” she says.
Ito also found that certain cell signaling proteins called endothelins (substances known to constrict blood vessels and raise blood pressure) bind to melanocyte stem cells and, in doing so, keep them healthy. Interrupting the process causes cell loss and early graying in mice. They are studying whether the same happens in human hair follicles, hoping to find ways to preserve or regenerate the key stem cells that give hair its color.
All of this raises the intriguing possibility that scientists could discover ways to prevent or reverse gray hair.
They’re working on it.
“Team Hair-Us” recently published a paper describing a topical drug combination that increased melanocyte stem cells in gray mice, ridding them of their gray and restoring their original fur color – perhaps for good. Because the treatment – originally developed to regrow hair – replenished pigment-producing stem cells, the effects could be long-lasting, Harris says.
“We didn’t keep the mice forever so we don’t know,” says Harris, who plans more studies. “This has made us very interested in whether gray hair really is permanent, and if we can do something about it. We really want to know – and so does everyone else we talk to – is whether and when we can bring this to humans.”