Li, Qintong

ABSTRACT The insulin‐like growth factor‐1 (IGF‐1) signaling pathway is known as a potent aging modifier, disruption of which consistently associates with lifespan extension across diverse species. Despite this established association, the mechanisms by which IGF‐1 signaling modulates organ aging remain poorly understood. In this study, we assessed age‐related changes in IGF‐1 expression across multiple organs in mice and identified a more prominent increase in skin IGF‐1 levels with aging—a phenomenon also observed in human skin. To explore the consequences of elevated IGF‐1, we developed transgenic mice ectopically expressing human IGF‐1 in the epidermis, driven by the bovine keratin 5 promoter (IGF‐1 Tg). These mice exhibited premature aging of hair follicles, as evidenced by accelerated hair graying and loss. Single‐cell RNA sequencing analyses of dorsal skin highlighted an upsurge in cellular senescence markers and the senescence‐associated secretory phenotype (SASP) in hair follicle stem cells (HFSCs), alongside a decline in hair growth and HFSC exhaustion. Our findings indicate that excessive IGF‐1 triggers HFSC senescence, thereby disrupting hair follicle homeostasis. Remarkably, interventions in IGF‐1 signaling via downstream mechanisms—specifically blocking Ac‐p53 activation via SIRT1 overexpression or senolytic treatment for senescent cell clearance, or reducing IGF‐1 through dietary restriction—significantly reduced senescence markers, mitigated premature hair follicle aging phenotypes, and restored the stem cell pool. Our findings provide fundamental insights into the biological processes of hair aging and highlight the therapeutic promise of targeted interventions to rejuvenate aged HFSCs and promote hair follicle health.

Summary Cellular senescence, which is known to halt proliferation of aged and stressed cells, plays a key role against cancer development and is also closely associated with organismal aging. While increased insulin‐like growth factor ( IGF ) signaling induces cell proliferation, survival and cancer progression, disrupted IGF signaling is known to enhance longevity concomitantly with delay in aging processes. The molecular mechanisms involved in the regulation of aging by IGF signaling and whether IGF regulates cellular senescence are still poorly understood. In this study, we demonstrate that IGF ‐1 exerts a dual function in promoting cell proliferation as well as cellular senescence. While acute IGF ‐1 exposure promotes cell proliferation and is opposed by p53, prolonged IGF ‐1 treatment induces premature cellular senescence in a p53‐dependent manner. We show that prolonged IGF ‐1 treatment inhibits SIRT 1 deacetylase activity, resulting in increased p53 acetylation as well as p53 stabilization and activation, thus leading to premature cellular senescence. In addition, either expression of SIRT 1 or inhibition of p53 prevented IGF ‐1‐induced premature cellular senescence. Together, these findings suggest that p53 acts as a molecular switch in monitoring IGF ‐1‐induced proliferation and premature senescence, and suggest a possible molecular connection involving IGF ‐1‐ SIRT 1‐p53 signaling in cellular senescence and aging.