Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice
- Newcastle University, United Kingdom
- Mayo Clinic, United States
Abstract
Cancer survivors suffer from progressive frailty, multimorbidity and premature morbidity. We hypothesize that therapy-induced senescence and senescence progression via bystander effects is a significant cause 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 sub-lethally 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 one 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 ROS production via NOX4 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.
Data availability
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.
Article and author information
Author details
Thomas von Zglinicki
Funding
Cancer Research UK (C12161/A24009)
- Thomas von Zglinicki
Biotechnology and Biological Sciences Research Council (BB/S006710/1)
- Thomas von Zglinicki
UK SPINE Bridge (B06)
- Thomas von Zglinicki
- Satomi Miwa
Biotechnology and Biological Sciences Research Council (BH174490)
- Viktor I Korolchuk
Biotechnology and Biological Sciences Research Council
- Diana Jurk
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Carlos Isales, Medical College of Georgia at Augusta University, United States
Ethics
Animal experimentation: All animal experimentation was performed in compliance with the guiding principles for the care and use of laboratory animals (ARRIVE guidelines). The study was licenced by the UK Home Office (PB048F3A0)
Version history
- Received: November 11, 2021
- Preprint posted: December 16, 2021 (view preprint)
- Accepted: May 3, 2022
- Accepted Manuscript published: May 4, 2022 (version 1)
- Version of Record published: May 31, 2022 (version 2)
Copyright
© 2022, Fielder et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice
eLife 11:e75492.
https://doi.org/10.7554/eLife.75492
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