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Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice

Lookup NU author(s): Dr Ed FielderORCiD, Dr Tengfei Wan, Ghazaleh Alimohammadiha, Abbas Ishaq, Evon Low, Melanie Weigand, George Kelly, Dr Craig Parker, Brigid Griffin, Dr Diana JurkORCiD, Dr Viktor Korolchuk, Professor Thomas von Zglinicki, Dr Satomi Miwa

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Abstract

Cancer survivors suffer from progressive frailty, multimorbidity, and premature morbidity. We hypothesise that therapy-induced senescence and senescence progression via bystander effects are significant causes of this premature ageing phenotype. Accordingly, the study addresses the question whether a short anti-senescence intervention is able to block progression of radiation-induced frailty and disability in a pre-clinical setting. Male mice were sublethally irradiated at 5 months of age and treated (or not) with either a senolytic drug (Navitoclax or dasatinib + quercetin) for 10 days or with the senostatic metformin for 10 weeks. Follow-up was for 1 year. Treatments commencing within a month after irradiation effectively reduced frailty progression (p<0.05) and improved muscle (p<0.01) and liver (p<0.05) function as well as short-term memory (p<0.05) until advanced age with no need for repeated interventions. Senolytic interventions that started late, after radiation-induced premature frailty was manifest, still had beneficial effects on frailty (p<0.05) and short-term memory (p<0.05). Metformin was similarly effective as senolytics. At therapeutically achievable concentrations, metformin acted as a senostatic neither via inhibition of mitochondrial complex I, nor via improvement of mitophagy or mitochondrial function, but by reducing non-mitochondrial reactive oxygen species production via NADPH oxidase 4 inhibition in senescent cells. Our study suggests that the progression of adverse long-term health and quality-of-life effects of radiation exposure, as experienced by cancer survivors, might be rescued by short-term adjuvant anti-senescence interventions.


Publication metadata

Author(s): Fielder E, Wan T, Alimohammadiha G, Ishaq A, Low E, Weigand BM, Kelly G, Parker C, Griffin B, Jurk D, Korolchuk V, von Zglinicki T, Miwa S

Publication type: Article

Publication status: Published

Journal: eLife

Year: 2023

Volume: 11

Pages: e75492

Print publication date: 04/05/2023

Online publication date: 02/05/2023

Acceptance date: 01/12/2021

ISSN (electronic): 2050-084X

Publisher: eLife Science publications

URL: https://doi.org/10.7554/eLife.75492

DOI: 10.7554/eLife.75492

PubMed id: 35507395


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