Genetic variation in ALDH4A1 is associated with muscle health over the lifespan and across species
- University of Southern California, United States
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
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Health and Retirement Study (HRS)dbGaP Study Accession: phs000428.v2.p2.
Article and author information
Author details
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.
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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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
