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.

Metrics

  • 1,479
    Page views
  • 230
    Downloads
  • 3
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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. 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

Further reading

    1. Evolutionary Biology
    John S Favate, Kyle S Skalenko ... Premal Shah
    Research Article

    Changes in an organism’s environment, genome, or gene expression patterns can lead to changes in its metabolism. The metabolic phenotype can be under selection and contributes to adaptation. However, the networked and convoluted nature of an organism’s metabolism makes relating mutations, metabolic changes, and effects on fitness challenging. To overcome this challenge, we use the long-term evolution experiment (LTEE) with E. coli as a model to understand how mutations can eventually affect metabolism and perhaps fitness. We used mass spectrometry to broadly survey the metabolomes of the ancestral strains and all 12 evolved lines. We combined this metabolic data with mutation and expression data to suggest how mutations that alter specific reaction pathways, such as the biosynthesis of nicotinamide adenine dinucleotide, might increase fitness in the system. Our work provides a better understanding of how mutations might affect fitness through the metabolic changes in the LTEE and thus provides a major step in developing a complete genotype–phenotype map for this experimental system.

    1. Ecology
    2. Evolutionary Biology
    Songdou Zhang, Jianying Li ... Xiaoxia Liu
    Research Article

    Temperature determines the geographical distribution of organisms and affects the outbreak and damage of pests. Insects seasonal polyphenism is a successful strategy adopted by some species to adapt the changeable external environment. Cacopsylla chinensis (Yang & Li) showed two seasonal morphotypes, summer-form and winter-form, with significant differences in morphological characteristics. Low temperature is the key environmental factor to induce its transition from summer-form to winter-form. However, the detailed molecular mechanism remains unknown. Here, we firstly confirmed that low temperature of 10 °C induced the transition from summer-form to winter-form by affecting the cuticle thickness and chitin content. Subsequently, we demonstrated that CcTRPM functions as a temperature receptor to regulate this transition. In addition, miR-252 was identified to mediate the expression of CcTRPM to involve in this morphological transition. Finally, we found CcTre1 and CcCHS1, two rate-limiting enzymes of insect chitin biosyntheis, act as the critical down-stream signal of CcTRPM in mediating this behavioral transition. Taken together, our results revealed that a signal transduction cascade mediates the seasonal polyphenism in C. chinensis. These findings not only lay a solid foundation for fully clarifying the ecological adaptation mechanism of C. chinensis outbreak, but also broaden our understanding about insect polymorphism.