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

TitleGenetic variation in ALDH4A1 predicts muscle health over the lifespan and across species
Publication TypeJournal Article
Year of Publication2022
AuthorsVilla, O, Stuhr, NL, Yen, C-A, Crimmins, EM, Arpawong, TE, Curran, SP
KeywordsGenetic Variation, muscle health

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.Competing Interest StatementThe authors have declared no competing interest.

Citation KeyVilla2021.09.08.459547
PubMed ID35470798
PubMed Central IDPMC9106327