TY - JOUR T1 - Genetic variation in ALDH4A1 predicts muscle health over the lifespan and across species JF - Elife Y1 - 2022 A1 - Villa, Osvaldo A1 - Stuhr, Nicole L. A1 - Yen, Chia-An A1 - Eileen M. Crimmins A1 - Thalida E. Arpawong A1 - Curran, Sean P. KW - Genetic Variation KW - muscle health AB - 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. VL - 11 IS - e74308 ER -