Timing‐Dependent Clearance of p16‐Positive Cells Mitigates Radiation‐Induced Accelerated Aging

ABSTRACT Genotoxic stress induced by cancer therapies is increasingly recognized as a driver of accelerated aging in long‐term cancer survivors, yet the mechanisms responsible for the emergence of age‐related dysfunction months to years after treatment remain poorly understood. Here, we use sublethal whole‐body irradiation as a model of systemic genotoxic stress to test whether senescent cells contribute to the progression of post‐therapy age‐related dysfunction and whether the benefits of senescent cell clearance depend on the timing of intervention. Using the INK‐ATTAC mouse model, we selectively eliminated p16 Ink4a ‐positive cells either early (1 month) or later (4 months) after irradiation. Early clearance had no effect on lifespan or functional outcomes. In contrast, delayed clearance markedly reduced frailty, improved neuromuscular and cognitive function, restored blood–brain barrier integrity, improved hepatic metabolic dysfunction, and increased median survival, with the survival benefit being most evident in female mice. Mechanistically, irradiation induced an early p21 Cip1 ‐associated stress response and later accumulation of p16 Ink4a ‐positive cells in the brain and liver, which was associated with inflammation and tissue dysfunction. Clearance of p16 Ink4a ‐positive cells at the later stage attenuated these changes. Together, these findings identify p16 Ink4a ‐positive cells as key drivers of the radiation‐induced accelerated aging‐like state that emerges progressively after genotoxic stress. They also show that the efficacy of senescence‐targeted interventions depends on when treatment is initiated, with implications for improving long‐term outcomes in cancer survivors.