Genetic variation in <i>ALDH4A1</i> 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 <i>Caenorhabditis elegans</i> 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 <i>C. elegans</i>, we identified 96 independent genetic mutants harboring loss-of-function alleles of <i>alh-6</i>, 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 <i>ALDH4A1</i> show associations with age-related muscle-related function in humans. Taken together, our work uncovers mitochondrial <i>alh-6/ALDH4A1</i> as a critical component to impact normal muscle aging across species and a predictive biomarker for muscle health over the lifespan.