Journal
ELIFE
Volume 11, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.74308
Keywords
aging; sarcopenia; HRS; muscle; genetic variation; genetics; C; elegans; Human
Categories
Funding
- National Institute on Aging [R01 AG058610, RF1 AG063947, T32 AG052374, T32 GM118289, P30 AG068345]
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This study identifies the evolutionarily conserved mitochondrial enzyme ALH-6/ALDH4A1 as a predictive biomarker for age-related changes in muscle health. Through Caenorhabditis elegans genetics and gene-wide association scanning, the research uncovers that loss-of-function mutations in alh-6 lead to the age-dependent loss of muscle health in C. elegans, while genetic variants in ALDH4A1 show associations with age-related muscle-related function in humans.
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 Caenorhabditis elegans 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 C. elegans, we identified 96 independent genetic mutants harboring loss-of-function alleles of alh-6, 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 ALDH4A1 show associations with age-related muscle-related function in humans. Taken together, our work uncovers mitochondrial alh-6/ALDH4A1 as a critical component to impact normal muscle aging across species and a predictive biomarker for muscle health over the lifespan.
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