Environmental stress can negatively impact the rate of aging across organisms, however the impact of endogenously derived reactive oxygen species (ROS) that can stem from normal cellular metabolism remains less clear. Previous work identified mutations in
alh-6, a highly conserved enzyme in the mitochondrial proline catabolism pathway, that drive oxidative stress and accelerated aging in C. elegans. Mutations in
alh-6 activate the cytoprotective transcription factor SKN-1 in muscle tissues. Here we demonstrate that of 95 mutations selected for activation of SKN-1 in the muscle, all harbor mutations in
alh-6. These mutations cluster to specific regions in the ALH-6 polypeptide and impact muscle health across the lifespan. Lastly, we identify variants in ALDH4A1, the human ortholog of
alh-6, that differentially impact large muscle group function in adult adults. Taken together, our work uncovers mitochondrial proline catabolism as a critical component of normal muscle aging across species.