Genetic variation in ALDH4A1 is associated with muscle health over the lifespan and across species.

TitleGenetic variation in ALDH4A1 is associated with muscle health over the lifespan and across species.
Publication TypeJournal Article
Year of Publication2022
AuthorsVilla, O, Stuhr, NL, Yen, C-A, Crimmins, EM, Arpawong, TEm, Curran, SP
JournalElife
Volume11
Paginatione74308
ISSN Number2050-084X
KeywordsC. elegans, evolutionary biology, Genetics, Genomics
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 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 , we identified 96 independent genetic mutants harboring loss-of-function alleles of , 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 show associations with age-related muscle-related function in humans. Taken together, our work uncovers mitochondrial as a critical component to impact normal muscle aging across species and a predictive biomarker for muscle health over the lifespan.

DOI10.7554/eLife.74308
Citation Key12357
PubMed ID35470798
PubMed Central IDPMC9106327
Grant ListR01 AG058610 / AG / NIA NIH HHS / United States
RF1 AG063947 / AG / NIA NIH HHS / United States
T32 AG052374 / AG / NIA NIH HHS / United States
T32 GM118289 / GM / NIGMS NIH HHS / United States
P30 AG068345 / AG / NIA NIH HHS / United States