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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, Professor Viktor KorolchukORCiD, Professor Thomas von Zglinicki, Dr Satomi Miwa
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
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: 2022
Volume: 11
Pages: e75492
Print publication date: 31/05/2022
Online publication date: 04/05/2022
Acceptance date: 03/05/2022
Date deposited: 23/02/2024
ISSN (electronic): 2050-084X
Publisher: eLife Science publications
URL: https://doi.org/10.7554/eLife.75492
DOI: 10.7554/eLife.75492
Data Access Statement: All data generated or analysed during this study are included in the manuscript and supporting files; Source Data files have been provided for all Figures.
PubMed id: 35507395
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