Graying Hair May Reflect a Natural Defense Against Cancer Risk

The study uncovers how hair pigment stem cells, under DNA damage, make fate decisions—leading to graying or melanoma

Hair graying and melanoma—a form of skin cancer—may seem like unrelated phenomena. But according to a new study from The University of Tokyo, both outcomes may arise from how pigment-producing stem cells respond to DNA damage. These cells, located in hair follicles, face a critical decision under genotoxic stress: either to differentiate and exit the system—leading to graying—or to continue dividing, which may eventually lead to tumor formation.

Throughout life, our cells are constantly exposed to environmental and internal factors that can damage DNA. While such DNA damage is known to contribute to both aging and cancer, the precise connection—particularly how damaged stem cells shape long-term tissue health—has remained elusive.

Melanocyte stem cells (McSCs) are tissue-resident stem cells that serve as the source of mature melanocytes, the pigment-producing cells responsible for hair and skin coloration. In mammals, these stem cells reside in the bulge–sub-bulge region of hair follicles as immature melanoblasts, maintaining pigmentation through cyclical regeneration.

Published online on October 6, 2025, in the journal Nature Cell Biology, the study led by Professor Emi Nishimura and Assistant Professor Yasuaki Mohri from The University of Tokyo used long-term in vivo lineage tracing and gene expression profiling in mice to investigate how McSCs respond to different types of DNA damage. The team identified a specific response to DNA double-strand breaks: senescence-coupled differentiation (seno-differentiation), a process in which McSCs irreversibly differentiate and are then lost, leading to hair graying. This process is driven by activation of the p53–p21 pathway.

In contrast, when exposed to certain carcinogens, such as 7,12-dimethylbenz(a)anthracene or ultraviolet B, McSCs bypass this protective differentiation program—even in the presence of DNA damage. Instead, they retain self-renewal capacity and expand clonally, a process supported by KIT ligand secreted both from the local niche and within the epidermis. This niche-derived signal suppresses seno-differentiation, tipping McSCs toward a tumor-prone fate.

Nishimura says, “These findings reveal that the same stem cell population can follow antagonistic fates—exhaustion or expansion—depending on the type of stress and microenvironmental signals.” She adds, “It reframes hair graying and melanoma not as unrelated events, but as divergent outcomes of stem cell stress responses.”

Importantly, this study does not suggest that graying hair prevents cancer, but rather that seno-differentiation represents a stress-induced protective pathway that removes potentially harmful cells. Conversely, when this mechanism is bypassed, the persistence of damaged McSCs may predispose to melanomagenesis. 

By identifying the molecular circuits that govern this fate bifurcation, the study provides a conceptual framework that links tissue aging and cancer, and highlights the beneficial role of eliminating potentially harmful stem cells through natural "senolysis," resulting in a phenotype that safeguards against cancer.

Genotoxic insults drive divergent outcomes in melanocyte stem cells (McSCs). Under cytotoxic genotoxin exposure, such as X-ray irradiation, McSC self-renewal is impaired, leading to depletion and hair graying. In homeostasis, McSCs maintain self-renewal and pigment balance. Carcinogenic genotoxins, however, promote KIT signaling and alter arachidonic acid metabolism, giving rise to melanoma founder clones and progression to melanoma.

Reference: Mohri Y, Nie J, Morinaga H, et al. Antagonistic stem cell fates under stress govern decisions between hair greying and melanoma. Nat Cell Biol. 2025;27(10):1647-1659. doi: 10.1038/s41556-025-01769-9

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source. Our press release publishing policy can be accessed here.