Measurements of damage and repair of binary health attributes in aging mice and humans reveal that robustness and resilience decrease with age, operate over broad timescales, and are affected differently by interventions

  1. Spencer Farrell  Is a corresponding author
  2. Alice E Kane
  3. Elise Bisset
  4. Susan E Howlett
  5. Andrew David Rutenberg  Is a corresponding author
  1. University of Toronto, Canada
  2. Harvard Medical School, United States
  3. Dalhousie University, Canada

Abstract

As an organism ages, its health-state is determined by a balance between the processes of damage and repair. Measuring these processes requires longitudinal data. We extract damage and repair transition rates from repeated observations of binary health attributes in mice and humans to explore robustness and resilience, which respectively represent resisting or recovering from damage. We assess differences in robustness and resilience using changes in damage rates and repair rates of binary health attributes. We find a conserved decline with age in robustness and resilience in mice and humans, implying that both contribute to worsening aging health – as assessed by the frailty index (FI). A decline in robustness, however, has a greater effect than a decline in resilience on the accelerated increase of the FI with age, and a greater association with reduced survival. We also find that deficits are damaged and repaired over a wide range of timescales ranging from the shortest measurement scales towards organismal lifetime timescales. We explore the effect of systemic interventions that have been shown to improve health, including the angiotensin-converting enzyme inhibitor enalapril and voluntary exercise for mice. We have also explored the correlations with household wealth for humans. We find that these interventions and factors can affect both damage and repair rates, and hence robustness and resilience, in age and sex-dependent manners.

Data availability

Source data files for all figures and summary statistics for all fitting parameters and diagnostics of the models are provided. Only pre-existing datasets were used in this study. Information about the datasets and data cleaning is in the methods section. Raw data for mouse dataset 3 are freely available from https://github.com/SinclairLab/frailty. Raw human data are available from https://www.elsa-project.ac.uk/accessing-elsa-data after registering. All code is available at https://github.com/Spencerfar/aging-damagerepair. Our code for cleaning these raw datasets is provided.

Article and author information

Author details

  1. Spencer Farrell

    University of Toronto, Toronto, Canada
    For correspondence
    spencer.farrell@utoronto.ca
    Competing interests
    The authors declare that no competing interests exist.
  2. Alice E Kane

    Department of Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Elise Bisset

    Department of Pharmacology, Dalhousie University, Halifax, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Susan E Howlett

    Department of Pharmacology, Dalhousie University, Halifax, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5351-6308
  5. Andrew David Rutenberg

    Department of Physics and Atmospheric Science, Dalhousie University, Halifax, Canada
    For correspondence
    adr@dal.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4264-6809

Funding

Natural Sciences and Engineering Research Council of Canada (RGPIN-2019-05888)

  • Andrew David Rutenberg

Canadian Institutes of Health Research (PJT 155961)

  • Susan E Howlett

Heart and Stroke Foundation of Canada (G-22-0031992)

  • Susan E Howlett

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Jamie Justice, Wake Forest School of Medicine, United States

Publication history

  1. Received: February 5, 2022
  2. Accepted: November 20, 2022
  3. Accepted Manuscript published: November 21, 2022 (version 1)

Copyright

© 2022, Farrell 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. Spencer Farrell
  2. Alice E Kane
  3. Elise Bisset
  4. Susan E Howlett
  5. Andrew David Rutenberg
(2022)
Measurements of damage and repair of binary health attributes in aging mice and humans reveal that robustness and resilience decrease with age, operate over broad timescales, and are affected differently by interventions
eLife 11:e77632.
https://doi.org/10.7554/eLife.77632

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