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

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

  1. Edward Fielder

    Newcastle University, Newcastle, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2834-8706
  2. Tengfei Wan

    Newcastle University, Newcastle, United Kingdom
    Competing interests
    No competing interests declared.
  3. Ghazaleh Alimohammadiha

    Newcastle University, Newcastle, United Kingdom
    Competing interests
    No competing interests declared.
  4. Abbas Ishaq

    Newcastle University, Newcastle, United Kingdom
    Competing interests
    Abbas Ishaq, Abbas Ishaq is affiliated with Alcyomics Ltd. The author has no financial interests to declare..
  5. Evon Low

    Newcastle University, Newcastle, United Kingdom
    Competing interests
    No competing interests declared.
  6. B Melanie Weigand

    Newcastle University, Newcastle, United Kingdom
    Competing interests
    No competing interests declared.
  7. George Kelly

    Newcastle University, Newcastle, United Kingdom
    Competing interests
    No competing interests declared.
  8. Craig Parker

    Newcastle University, Newcastle, United Kingdom
    Competing interests
    No competing interests declared.
  9. Brigid Griffin

    Newcastle University, Newcastle, United Kingdom
    Competing interests
    No competing interests declared.
  10. Diana Jurk

    Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, United States
    Competing interests
    No competing interests declared.
  11. Viktor I Korolchuk

    Newcastle University, Newcastle, United Kingdom
    Competing interests
    No competing interests declared.
  12. Thomas von Zglinicki

    Newcastle University, Newcastle, United Kingdom
    For correspondence
    t.vonzglinicki@ncl.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5939-0248
  13. Satomi Miwa

    Newcastle University, Newcastle, United Kingdom
    Competing interests
    No competing interests declared.

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.

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)

Reviewing Editor

  1. Carlos Isales, Medical College of Georgia at Augusta University, United States

Publication history

  1. Received: November 11, 2021
  2. Accepted: May 3, 2022
  3. Accepted Manuscript published: May 4, 2022 (version 1)

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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  1. Edward Fielder
  2. Tengfei Wan
  3. Ghazaleh Alimohammadiha
  4. Abbas Ishaq
  5. Evon Low
  6. B Melanie Weigand
  7. George Kelly
  8. Craig Parker
  9. Brigid Griffin
  10. Diana Jurk
  11. Viktor I Korolchuk
  12. Thomas von Zglinicki
  13. Satomi Miwa
(2022)
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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