Every single silver strand of hair represents the successful elimination of DNA-damaged cells. (Credit: Halfpoint on Shutterstock)

In A Nutshell

• Gray hair in mice signals successful cancer defense: When stem cells that produce hair pigment get DNA damage, the body forces them to mature and exit, leaving gray hair behind as evidence that potentially dangerous cells were eliminated.
• Carcinogens hijack the system: Cancer-causing chemicals like UV radiation override this protective response by flooding stem cells with survival signals, allowing damaged cells to persist and potentially form melanoma instead of causing gray hair.
• Your hair follicle niche makes life-or-death decisions: Surrounding support cells produce a protein called KIT ligand that determines whether damaged stem cells get eliminated (causing gray hair) or allowed to survive and multiply (risking cancer).
• Mouse findings show support in human tissue: While the protective mechanism was demonstrated in mice, researchers found elevated KIT ligand in several human melanoma samples, suggesting similar processes may occur in people, though more research is needed.

Those silver strands sprouting on your head might be doing more than announcing your age. Research from the University of Tokyo shows that gray hair in mice reflects a built-in cleanup program in which the body hunts down and eliminates damaged cells capable of becoming cancer. Importantly, there are supporting signs this same mechanism is present in human skin tissue samples.

Scientists tracked what happens to the stem cells responsible for hair color when they get damaged. This led to a surprising discovery in mice. Their bodies force these damaged cells to mature and then kick them out, leaving behind gray hair.

It’s a biological trade-off that may be happening in humans too. In other words, accept some gray hairs, or allow damaged cells to persist.

Gray Hair 101: How Follicles Clear Cells Tied To Skin Cancer

The stem cells in your hair follicles act as tiny factories that produce pigment. When everything works correctly, these cells wake up during each hair growth cycle, make copies of themselves, and send some of their offspring down the hair shaft to add color. Then they go back to sleep until the next cycle.

But what happens when radiation, sun damage, or other environmental stressors break the DNA in these stem cells? Researchers Yasuaki Mohri and Emi K. Nishimura discovered something unexpected. The damaged cells don’t just die quietly. Instead, they get forced into an unusual double state: they stop dividing forever (that’s the safety brake) while simultaneously maturing into regular pigment cells (that’s the exit strategy).

The cells essentially get a one-way ticket out of the follicle. They complete one last job making pigment, then leave the protected stem cell area and get cleared away naturally. The hair follicle loses its color-making factory, and you get a gray hair. Each silver strand represents a successful elimination of cells carrying DNA damage.

The study, published in Nature Cell Biology, confirmed this in mice by studying animals lacking p53, a protein that acts as the body’s chief DNA damage detector. These mice kept their dark fur even after radiation exposure that would normally cause graying. Sounds great, right? Not exactly. Those damaged cells stayed put, raising the risk that they could eventually transform into cancer.

Carcinogens like UV radiation stop hair from graying, allowing damaged cells to linger. (Credit: Pixel-Shot on Shutterstock)

When Carcinogens Hijack the System

When the researchers exposed mice to cancer-causing chemicals like DMBA (a lab carcinogen used in skin-cancer models) or strong UV radiation, those substances didn’t trigger gray hair at all. Even when the cells had the same DNA breaks that radiation causes, the carcinogens somehow convinced them to keep dividing.

The trick involves a protein called KIT ligand, or KITL. Normally, cells surrounding the stem cells produce small amounts of KITL to support the stem cell population. But carcinogens cranked up KITL production dramatically, essentially shouting “keep growing!” to cells that should be getting eliminated.

At the same time, the carcinogens turned on arachidonic acid pathways inside the damaged stem cells. When researchers gave mice a prostaglandin E2-like signal (a product of this pathway), it reproduced the effect, blocking the graying response. It’s a two-pronged attack: external survival signals from the environment combined with internal changes that favor growth over elimination.

Mice treated with just a carcinogen didn’t go gray—their damaged stem cells survived and spread into the surrounding skin, forming the pigmented spots that can progress to melanoma. When researchers gave mice both radiation and a carcinogen together, the carcinogen won, blocking the protective gray hair response.

The Skin Stem Cell Niche

To test whether KITL really controls this life-or-death decision, the team created mice with reduced KITL in the cells surrounding stem cells. These mice went gray faster, even without any radiation exposure. Their stem cells couldn’t maintain themselves without enough KITL support.

More tellingly, when these low-KITL mice received both radiation and carcinogens, the carcinogens couldn’t override the protective response anymore. The mice still went gray because their environment lacked enough KITL to keep damaged stem cells alive. The experiment proved that the surrounding niche makes the critical decision about whether damaged stem cells get eliminated or allowed to persist.

The researchers also examined human melanoma samples, specifically the type caused by cumulative sun exposure over many years. In several samples, KITL was elevated not just aroundhair follicles but throughout the skin surrounding tumors. The cancer had essentially expanded its own support system, creating an environment where damaged cells could thrive and spread.

The Mystery of Recovering Gray Hair

Rare case reports describe a puzzling phenomenon. Patients whose gray hair appears to “come back to life” and regain color in certain scalp areas, only to receive a melanoma diagnosis in those exact spots months later. This research offers a possible explanation.

The gray hair wasn’t actually recovering. Instead, early melanoma cells spreading through the epidermis were producing their own KITL and other growth factors, supporting any remaining stem cells and their pigment-producing offspring. The darkening hair was actually a warning sign that cancer precursor cells were colonizing that area of scalp.

This reframes what looks like rejuvenation as an early danger signal—a cancerous field spreading beneath the skin surface, creating conditions that support cell growth rather than elimination.

Is it time to rethink the relationship between aging and cancer? (Photo by Pixel-Shot on Shutterstock)

Aging Skin and Gray Hair: Signals That Shift Skin Cancer Defenses

When the team compared young and old mice, they found that aging naturally reduces KITL and other growth factors produced by the stem cell niche. In older mice, these support signals fall and graying speeds up. Aged skin simply doesn’t support stem cell maintenance as well as young skin does.

But this decline might not be entirely bad. By reducing the signals that promote stem cell survival and growth in mice, aging skin may be tilting the balance toward elimination rather than preservation of cells that have accumulated DNA damage over time. It’s a biological guardrail that becomes more conservative with age.

Single-cell analysis of over 60,000 skin cells from young and old mice revealed that the proportion of both stem cells and melanocyte clusters dropped significantly in aged animals. The stem cell niche itself shrinks with age in mice, not just the stem cells it supports.

When Skin Cancer Mutations Take Control

To test whether cancer-driving mutations could bypass the protective response like carcinogens do, researchers created mice carrying activated versions of NRAS or BRAF — two of the most common genetic changes in human melanoma — specifically in their hair color stem cells.

These mutant mice kept their dark fur even after doses of radiation that would normally eliminate all stem cells and cause complete graying. The mutations made cells independent of external KITL signals, allowing them to survive and multiply despite DNA damage.

The team then flipped the question. Could eliminating stem cells through the protective response prevent melanoma? They irradiated cancer-prone mice before triggering the melanoma mutations. Melanoma development dropped dramatically compared to non-irradiated controls. By depleting the stem cell population first, there were simply fewer cells available to transform into cancer when the mutations hit.

What This Means for Real People

These findings don’t suggest that radiation prevents cancer. Kt clearly doesn’t, and the doses used in research mice don’t match human exposures. But the research does reveal something important about visible aging: those gray hairs represent successful quality control, not just breakdown.

People who gray early or extensively, especially in sun-exposed areas like the temples and crown, may have particularly active protective mechanisms. Each gray hair is a follicle where the body identified damage and chose elimination over risk.

Whether anti-aging treatments aimed at preventing or reversing gray hair could affect melanoma risk remains an open question for future studies. If such treatments work by keeping damaged stem cells alive and functional longer, it’s unclear what that might mean for cancer development in people with significant sun exposure or other DNA damage sources.

The research team calls the protective process “seno-differentiation,” combining cellular aging’s permanent growth arrest with the maturation and migration that clears damaged cells from stem cell homes. It’s natural quality control that doesn’t require drugs or interventions, just the body’s built-in wisdom about when to eliminate rather than repair.

The paradox is clear. Fewer stem cells (and more gray hair) can protect against cancer by limiting the pool of cells available for transformation. Visible aging in this case reflects invisible protection.

The Bigger Picture

So, should we rethink the relationship between aging and cancer? They’re often portrayed as related processes driven by accumulated DNA damage, but this work shows the body’s response to damage matters more than the damage itself.

The stem cells studied here face a fundamental choice when they acquire DNA breaks. Either undergo the protective elimination program that causes gray hair, or bypass it through carcinogen exposure or cancer mutations and risk melanoma. Individual cells make this decision based on signals from their surrounding environment, but the cumulative effects of millions of these decisions determine whether a person develops gray hair or cancer.

The surrounding niche acts as the critical decision-maker, integrating information about growth factor levels, damage signals, and metabolic status to instruct each stem cell about its fate. When carcinogens reprogram the niche to produce high KITL levels, they’re essentially rigging the decision in favor of survival over elimination.

Understanding this antagonism between gray hair and melanoma at the single-cell level opens new ways of thinking about cancer prevention that don’t focus on eliminating all damaged cells but rather on ensuring the right cells get eliminated at the right time through natural pathways.

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Paper Summary

Methodology

The research team used genetically modified mice that express fluorescent markers in melanocyte stem cells, allowing them to track individual cells through microscopy over weeks and months. They synchronized hair growth cycles through depilation and exposed mice to three types of stress at specific times: X-ray radiation (4-5 Gy), topical carcinogen application (DMBA, 100 μg weekly), or UVB radiation (20-200 mJ/cm² three times weekly). Additional mice had specific genes deleted only in stem cells or in the surrounding support cells to test which molecular pathways were required for gray hair versus melanoma development.

The team isolated pure populations of stem cells and surrounding niche cells using flow cytometry and analyzed their gene activity through RNA sequencing. They also examined over 60,000 individual skin cells from young and old mice to understand aging effects. Human melanoma samples from 15 patients were analyzed for KITL expression patterns and compared to normal skin from 3 control subjects.

Results

Stem cells exposed to radiation entered a state where they stopped dividing permanently while simultaneously maturing into pigment cells—a process the researchers termed “seno-differentiation.” These cells migrated out of their protective niche and were naturally cleared away, depleting the stem cell reserve and causing gray hair. This protective elimination depended on the p53 protein, and mice lacking p53 in stem cells kept their dark fur after radiation but retained damaged cells.

Carcinogens like DMBA and UVB radiation prevented gray hair by dramatically increasing KITL production in surrounding niche cells while activating protective fat metabolism inside damaged stem cells. This combination allowed damaged stem cells to survive and spread into the skin rather than being eliminated. When mice were given both radiation and carcinogens together, the carcinogen blocked the protective response and prevented graying. Prostaglandin E2 treatment mimicked this effect, confirming that fat metabolism products help damaged cells evade elimination. Mice engineered to produce less KITL in their niche went gray faster and couldn’t be rescued by carcinogens, proving the niche makes the critical survival-versus-elimination decision.

Gene activity analysis revealed that radiation turned on p53 damage response pathways and immune signaling related to detecting broken DNA, while carcinogens activated drug metabolism and fat processing pathways instead. Aged mice showed reduced KITL and other growth factor production in their niches, contributing to faster stem cell loss and graying. Mice carrying common melanoma mutations (activated NRAS or BRAF) maintained their stem cells despite radiation, and depleting stem cells through radiation before inducing these mutations significantly reduced melanoma development. Human melanoma samples showed elevated KITL in 8 of 15 cases, particularly in skin surrounding tumors.

Limitations

The study used mice rather than humans, and while melanocyte stem cell biology is similar between species, important differences exist in how melanocytes are distributed (mostly in hair follicles in mice versus throughout skin in humans) and how UV radiation affects them. The radiation doses and carcinogen exposures were higher than typical environmental or medical exposures to create clear effects within experimental timeframes, so the findings may not perfectly predict responses to chronic low-level exposures humans experience.

The research examined relatively short timeframes of weeks to months, while human melanoma typically develops over decades. The human melanoma analysis included only 15 cases of one subtype (sun-damage-associated lentigo maligna), so whether other melanoma types show similar KITL patterns remains unclear. The study also didn’t address how genetic variations in DNA repair, KITL production, or other pathways might affect the relationship between hair graying and melanoma risk in human populations.

Funding and Disclosures

This research was supported by multiple grants from the Japan Society for the Promotion of Science and the Japan Agency for Medical Research and Development. E.K. Nishimura is a co-founder and shareholder of EADERM Co., Ltd., which is not related to this research. All other authors report no competing interests. The study was approved by institutional ethics committees at Tokyo Medical and Dental University, the University of Tokyo, and Yamagata University, and human samples were collected with written informed consent.

Publication Details

Mohri, Y., Nie, J., Morinaga, H., Kato, T., Aoto, T., Yamanashi, T., Nanba, D., Matsumura, H., Kirino, S., Kobiyama, K., Ishii, K.J., Hayashi, M., Suzuki, T., Namiki, T., Seita, J., & Nishimura, E.K. (2025). “Antagonistic stem cell fates under stress govern decisions between hair greying and melanoma,” published October 6, 2025 in Nature Cell Biology, 27, 1647-1659. doi:10.1038/s41556-025-01769-9

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