Genetic variation in ALDH4A1 is associated with muscle health over the lifespan and across species

Abstract

The influence of genetic variation on the aging process, including the incidence and severity of age-related diseases, is complex. Here we define the evolutionarily conserved mitochondrial enzyme ALH-6/ALDH4A1 as a predictive biomarker for age-related changes in muscle health by combining C. elegans genetics and a gene-wide association scanning (GeneWAS) from older human participants of the US Health and Retirement Study (HRS). In a screen for mutations that activate oxidative stress responses, specifically in the muscle of C. elegans, we identified 96 independent genetic mutants harboring loss-of-function alleles of alh-6, exclusively. Each of these genetic mutations mapped to the ALH-6 polypeptide and led to the age-dependent loss of muscle health. Intriguingly, genetic variants in ALDH4A1 show associations with age-related muscle-related function in humans. Taken together, our work uncovers mitochondrial alh-6/ALDH4A1 as a critical component to impact normal muscle aging across species and a predictive biomarker for muscle health over the lifespan.

Data availability

All data is available within the manuscript. Health and retirement study (HRS) data is maintained at the University of Michigan - https://hrs.isr.umich.edu/about

The following data sets were generated

Article and author information

Author details

  1. Osvaldo Villa

    Leonard Davis School of Gerontology, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Nicole L Stuhr

    Leonard Davis School of Gerontology, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2537-7114
  3. Chia-an Yen

    Leonard Davis School of Gerontology, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Eileen M Crimmins

    Leonard Davis School of Gerontology, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Thalida Em Arpawong

    Leonard Davis School of Gerontology, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sean P Curran

    Leonard Davis School of Gerontology, University of Southern California, Los Angeles, United States
    For correspondence
    spcurran@usc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7791-6453

Funding

National Institute on Aging (R01 AG058610)

  • Sean P Curran

National Institute on Aging (RF1 AG063947)

  • Sean P Curran

National Institute on Aging (T32 AG052374)

  • Osvaldo Villa
  • Nicole L Stuhr

National Institute of General Medical Sciences (T32 GM118289)

  • Nicole L Stuhr

National Institute on Aging (P30 AG068345)

  • Sean P Curran

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

Reviewing Editor

  1. Monica Driscoll, Rutgers University, United States

Version history

  1. Preprint posted: September 10, 2021 (view preprint)
  2. Received: September 29, 2021
  3. Accepted: April 13, 2022
  4. Accepted Manuscript published: April 26, 2022 (version 1)
  5. Version of Record published: May 13, 2022 (version 2)

Copyright

© 2022, Villa 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. Osvaldo Villa
  2. Nicole L Stuhr
  3. Chia-an Yen
  4. Eileen M Crimmins
  5. Thalida Em Arpawong
  6. Sean P Curran
(2022)
Genetic variation in ALDH4A1 is associated with muscle health over the lifespan and across species
eLife 11:e74308.
https://doi.org/10.7554/eLife.74308

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https://doi.org/10.7554/eLife.74308

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