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

Lookup NU author(s): Emeritus Professor Thomas Von Zglinicki, Dr Joao Passos, Dr Diana JurkORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2026 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. 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 p16Ink4a-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 p21Cip1-associated stress response and later accumulation of p16Ink4a-positive cells in the brain and liver, which was associated with inflammation and tissue dysfunction. Clearance of p16Ink4a-positive cells at the later stage attenuated these changes. Together, these findings identify p16Ink4a-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.

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Author(s): Valdivieso K, Weigand M, Costa DG, Lee G, Pirius N, Martini H, Oberai S, Inman C, Zhu Y, von Zglinicki T, Khosla S, LeBrasseur N, Passos JF, Tchkonia T, Kirkland JL, Jurk D

Publication type: Article

Publication status: Published

Journal: Aging Cell

Year: 2026

Volume: 25

Issue: 9

Print publication date: 01/09/2026

Online publication date: 26/08/2026

Acceptance date: 20/08/2026

Date deposited: 07/09/2026

ISSN (print): 1474-9718

ISSN (electronic): 1474-9726

Publisher: John Wiley & Sons Ltd

URL: https://doi.org/10.1111/acel.70693

DOI: 10.1111/acel.70693

Data Access Statement: The data supporting the findings of this study are available from the corresponding author upon reasonable request. No large-scale datasets were generated or analyzed in this study.

PubMed id: 42649478

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