Graying hair may reflect a natural defense against cancer risk, new study finds

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.

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Reference                     
DOI: 10.1038/s41556-025-01769-9

Authors: Yasuaki Mohri1, Jialiang Nie1, Hironobu Morinaga2, Tomoki Kato2, Takahiro Aoto2, Takashi Yamanashi3,4, Daisuke Nanba1, Hiroyuki Matsumura1, Sakura Kirino2, Kouji Kobiyama5,6, Ken J. Ishii5,6, Masahiro Hayashi7, Tamio Suzuki7, Takeshi Namiki8, Jun Seita3,4, and Emi K. Nishimura1,2

Affiliations:                            
1Division of Aging and Regeneration, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

2Department of Stem Cell Biology, Medical Research Institute, Institute of Science Tokyo, Tokyo, Japan

3Advanced Data Science Project, RIKEN Information R&D and Strategy Headquarters, Tokyo, Japan

4Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan

5Division of Vaccine Science, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

6International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

7Department of Dermatology, Faculty of Medicine, Yamagata University, Yamagata, Japan

8Department of Dermatology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
 

About The Institute of Medical Science, The University of Tokyo
The Institute of Medical Science, The University of Tokyo (IMSUT), established in 1892 as the Institute of Infectious Diseases and renamed IMSUT in 1967, is a leading research institution with a rich history spanning over 130 years. It focuses on exploring biological phenomena and disease principles to develop innovative strategies for disease prevention and treatment. IMSUT fosters a collaborative, interdisciplinary research environment and is known for its work in genomic medicine, regenerative medicine, and advanced medical approaches like gene therapy and AI in healthcare. It operates core research departments and numerous specialized centers, including the Human Genome Center and the Advanced Clinical Research Center, and is recognized as Japan’s only International Joint Usage/Research Center in life sciences.

About Professor Emi K. Nishimura from The Institute of Medical Science, The University of Tokyo
Dr. Emi K. Nishimura is Professor in the Division of Aging and Regeneration at the Institute of Medical Science, The University of Tokyo. She is internationally recognized for discovering melanocyte stem cells in the bulge–sub-bulge region of hair follicles—first in mice (Nature, 2002) and later in humans (Science, 2004)—and for demonstrating their critical role in hair graying. Her pioneering studies laid the foundation for pigment cell biology and stem cell aging research. She has since shown that stem cell depletion and cell competition are central mechanisms of skin and hair follicle aging. In 2023, she was elected an International Member of the U.S. National Academy of Sciences.

Funding information
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).