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bioRxiv · 10.1101/2021.09.08.459547

Genetic variation in ALDH4A1 predicts muscle health over the lifespan and across species

Villa, O.·Stuhr, N.·Yen, C.-A.·Crimmins, E.·Arpawong, T. E.·Curran, S. P.
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Abstract

Environmental stress can negatively impact organismal aging, however, the long-term impact of endogenously derived reactive oxygen species from normal cellular metabolism remains less clear. Here we define the evolutionarily conserved mitochondrial enzyme ALH-6/ALDH4A1 as a biomarker for age-related changes in muscle health by combining C. elegans genetics and a gene-wide association study (GeneWAS) from aged human participants of the US Health and Retirement Study (HRS)1-4. In a screen for mutations that activate SKN-1-dependent oxidative stress responses in the muscle of C. elegans5-7, we identified 96 independent genetic mutants harboring loss-of-function alleles of alh-6, exclusively. These genetic mutations map across the ALH-6 polypeptide, which lead to age-dependent loss of muscle health. Intriguingly, genetic variants in ALDH4A1 differentially impact age-related muscle function in humans. Taken together, our work uncovers mitochondrial alh-6/ALDH4A1 as a critical component of normal muscle aging across species and a predictive biomarker for muscle health over the lifespan.

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Villa, O., Stuhr, N., Yen, C.-A., Crimmins, E., Arpawong, T. E., Curran, S. P.. 2021-09-10. Genetic variation in ALDH4A1 predicts muscle health over the lifespan and across species. https://doi.org/10.1101/2021.09.08.459547

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