{"doi":"10.1101/2021.09.08.459547","title":"Genetic variation in <i>ALDH4A1</i> predicts muscle health over the lifespan and across species","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. elegans 5–7 , 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":226783,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":277108,"name":"Nicole L. Stuhr","orcid":"0000-0003-2537-7114","position":1,"is_corresponding":false},{"id":458169,"name":"Chia‐An Yen","orcid":null,"position":2,"is_corresponding":false},{"id":256213,"name":"Eileen M. Crimmins","orcid":"0000-0001-5459-5239","position":3,"is_corresponding":false},{"id":681744,"name":"Thalida Em Arpawong","orcid":"0000-0001-9671-9535","position":4,"is_corresponding":false},{"id":277109,"name":"Sean P. Curran","orcid":"0000-0001-7791-6453","position":5,"is_corresponding":false},{"id":830127,"name":"Osvaldo Villa","orcid":"0000-0002-0803-0752","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:54:38.004707Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}