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

Edward Fielder, Tengfei Wan, Ghazaleh Alimohammadiha, Abbas Ishaq, Evon Low, B. Melanie Weigand, George Kelly, Craig Parker, Brigid Griffin, Diana Jurk, Viktor I. Korolchuk, Thomas von Zglinicki, Satomi Miwa

Research output: Contribution to journalArticlepeer-review

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 + quer-cetin) for 10 days or with the senostatic metformin for 10 weeks. Follow-up was for 1 year. Treat-ments 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.

Original languageEnglish (US)
Article numbere75492
JournaleLife
Volume11
DOIs
StatePublished - May 2022

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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