1. Cancer Biology
  2. Cell Biology

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

  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  Is a corresponding author
  13. Satomi Miwa
  1. Newcastle University, United Kingdom
  2. Mayo Clinic, United States
https://doi.org/10.7554/eLife.75492
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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.

Reviewing Editor

  1. 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

  1. Received: November 11, 2021
  2. Preprint posted: December 16, 2021 (view preprint)
  3. Accepted: May 3, 2022
  4. Accepted Manuscript published: May 4, 2022 (version 1)
  5. 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.

Metrics

  • 4,509
    views
  • 841
    downloads
  • 29
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

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

Categories and tags

Research organism

Further reading

    1. Cancer Biology

    Recording and classifying MET receptor mutations in cancers

    Célia Guérin, David Tulasne
    Review Article

    Tyrosine kinase inhibitors (TKI) directed against MET have been recently approved to treat advanced non-small cell lung cancer (NSCLC) harbouring activating MET mutations. This success is the consequence of a long characterization of MET mutations in cancers, which we propose to outline in this review. MET, a receptor tyrosine kinase (RTK), displays in a broad panel of cancers many deregulations liable to promote tumour progression. The first MET mutation was discovered in 1997, in hereditary papillary renal cancer (HPRC), providing the first direct link between MET mutations and cancer development. As in other RTKs, these mutations are located in the kinase domain, leading in most cases to ligand-independent MET activation. In 2014, novel MET mutations were identified in several advanced cancers, including lung cancers. These mutations alter splice sites of exon 14, causing in-frame exon 14 skipping and deletion of a regulatory domain. Because these mutations are not located in the kinase domain, they are original and their mode of action has yet to be fully elucidated. Less than five years after the discovery of such mutations, the efficacy of a MET TKI was evidenced in NSCLC patients displaying MET exon 14 skipping. Yet its use led to a resistance mechanism involving acquisition of novel and already characterized MET mutations. Furthermore, novel somatic MET mutations are constantly being discovered. The challenge is no longer to identify them but to characterize them in order to predict their transforming activity and their sensitivity or resistance to MET TKIs, in order to adapt treatment.

    1. Cancer Biology
    2. Genetics and Genomics

    Convergent epigenetic evolution drives relapse in acute myeloid leukemia

    Kevin Nuno, Armon Azizi ... Ravindra Majeti
    Research Article

    Relapse of acute myeloid leukemia (AML) is highly aggressive and often treatment refractory. We analyzed previously published AML relapse cohorts and found that 40% of relapses occur without changes in driver mutations, suggesting that non-genetic mechanisms drive relapse in a large proportion of cases. We therefore characterized epigenetic patterns of AML relapse using 26 matched diagnosis-relapse samples with ATAC-seq. This analysis identified a relapse-specific chromatin accessibility signature for mutationally stable AML, suggesting that AML undergoes epigenetic evolution at relapse independent of mutational changes. Analysis of leukemia stem cell (LSC) chromatin changes at relapse indicated that this leukemic compartment underwent significantly less epigenetic evolution than non-LSCs, while epigenetic changes in non-LSCs reflected overall evolution of the bulk leukemia. Finally, we used single-cell ATAC-seq paired with mitochondrial sequencing (mtscATAC) to map clones from diagnosis into relapse along with their epigenetic features. We found that distinct mitochondrially-defined clones exhibit more similar chromatin accessibility at relapse relative to diagnosis, demonstrating convergent epigenetic evolution in relapsed AML. These results demonstrate that epigenetic evolution is a feature of relapsed AML and that convergent epigenetic evolution can occur following treatment with induction chemotherapy.

    1. Cancer Biology
    2. Cell Biology

    Early recovery of proteasome activity in cells pulse-treated with proteasome inhibitors is independent of DDI2

    Ibtisam Ibtisam, Alexei F Kisselev
    Short Report

    Rapid recovery of proteasome activity may contribute to intrinsic and acquired resistance to FDA-approved proteasome inhibitors. Previous studies have demonstrated that the expression of proteasome genes in cells treated with sub-lethal concentrations of proteasome inhibitors is upregulated by the transcription factor Nrf1 (NFE2L1), which is activated by a DDI2 protease. Here, we demonstrate that the recovery of proteasome activity is DDI2-independent and occurs before transcription of proteasomal genes is upregulated but requires protein translation. Thus, mammalian cells possess an additional DDI2 and transcription-independent pathway for the rapid recovery of proteasome activity after proteasome inhibition.