Throughout life, our cells are continually exposed to both internal and external influences that can harm DNA. This DNA damage is a well-known factor in the development of aging and cancer, yet scientists have long struggled to understand the exact link -- especially how DNA-damaged stem cells affect tissue health over time.
Melanocyte stem cells (McSCs) are specialized cells that give rise to melanocytes, the pigment-producing cells responsible for the color of our hair and skin. In mammals, these stem cells are found in a region of the hair follicle known as the bulge-sub-bulge area. Here, they exist as immature melanoblasts, ensuring that hair and skin maintain their color through repeated cycles of regeneration.
Discovering How DNA Damage Drives Hair Graying
Published online on October 6, 2025, in Nature Cell Biology, a study led by Professor Emi Nishimura and Assistant Professor Yasuaki Mohri at The University of Tokyo explored how McSCs react to different types of DNA damage. Using long-term lineage tracing and gene expression profiling in mice, the researchers discovered that when McSCs experience DNA double-strand breaks, they undergo a process known as senescence-coupled differentiation (seno-differentiation). In this state, the stem cells permanently mature and are eventually lost, which leads to hair turning gray. The process is controlled by the activation of the p53-p21 signaling pathway.
When McSCs are exposed to certain carcinogens, including 7,12-dimethylbenz(a)anthracene or ultraviolet B radiation, they do not follow the same protective path. Even with DNA damage present, these cells avoid seno-differentiation and continue to renew themselves. They expand clonally instead, aided by KIT ligand signals released from surrounding tissue and the epidermis. These niche-derived signals block the protective differentiation response, pushing the stem cells toward a cancer-prone state.
Opposing Cellular Fates: Graying or Cancer
According to Nishimura, "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."
The researchers emphasize that their findings do not imply that developing gray hair prevents cancer. Instead, seno-differentiation appears to serve as a stress-triggered defense mechanism that removes damaged stem cells before they can become harmful. When this safeguard fails or is bypassed, those damaged cells can survive and potentially lead to melanoma.
Linking Aging, Cancer, and Cellular Self-Destruction
By uncovering the molecular pathways that determine whether stem cells undergo protective exhaustion or dangerous expansion, this study connects the biology of tissue aging with cancer formation. It also highlights the value of naturally removing compromised stem cells through "senolysis," a biological process that helps prevent cancer by sacrificing cells that could otherwise become malignant.
E.K.N. is supported by a JSPS Grant-in-Aid for Scientific Research (S) (25H00439), an AMED CREST Project (JP22gm1710003-JP25gm1710003), an AMED Project for Elucidating and Controlling Mechanisms of Ageing and Longevity (JP17gm5010002-JP21gm5010002), an AMED SCARDA Japan Initiative for World-leading Vaccine Research and Development Centers (JP223fa627001), a JSPS Grant-in-Aid for Scientific Research (A) (20H00532), and a JSPS Grant-in-Aid for Scientific Research on Innovative Areas 'Stem Cell Aging and Disease' (26115003), International Joint Research Projects Selected for FY 2025 (No: K25-1185).
Yasuaki Mohri is supported by a JSPS Grant-in-Aid for Young Scientists (18K15114) and a JSPS Grant-in-Aid for Scientific Research (C) (25K10315).
Jun Seita is supported by an AMED Project for Elucidating and Controlling Mechanisms of Ageing and Longevity (JP19gm5010003, JP20gm5010003) and a JSPS Grant-in-Aid for Scientific Research (C) (18K08377).
