Title | Genetic variation in ALDH4A1 predicts muscle health over the lifespan and across species |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Villa, O, Stuhr, NL, Yen, C-A, Crimmins, EM, Arpawong, TE, Curran, SP |
Journal | Elife |
Volume | 11 |
Issue | e74308 |
Keywords | Genetic Variation, muscle health |
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.Competing Interest StatementThe authors have declared no competing interest. |
DOI | 10.7554/eLife.74308 |
Citation Key | Villa2021.09.08.459547 |
PubMed ID | 35470798 |
PubMed Central ID | PMC9106327 |