Antioxidant Peptide Leu–Tyr in Skeletal Muscle Actin Improves Longevity and Healthspan in C. elegans via the IIS, MAPK, and HSF Signaling Pathways

Aging is associated with oxidative stress, prompting the exploration of natural antioxidants to enhance longevity. Food‐derived peptides are safe and promising natural antioxidants. This study demonstrated the antioxidant properties of dipeptide Leu–Tyr derived from skeletal muscle actin and its antiaging effects in Caenorhabditis elegans . Our results showed that Leu–Tyr extended the lifespan of wild‐type nematodes while improving healthspan indicators, including enhanced motility, reduced age‐associated lipofuscin accumulation, and increased tolerance to oxidative and thermal stress. Gene expression analysis demonstrated that Leu–Tyr upregulated key stress‐responsive and longevity‐associated genes ( ctl-1 , hsp-12.6 , hsf-1 , gcs-1 , gst-4 , mtl-1 , and sod-3 ) and downregulated hsp-16.1. This result suggests that Leu–Tyr modulates signaling pathways related to proteostasis and oxidative defense. To elucidate pathway dependency, lifespan assays were conducted in loss‐of‐function mutants. Leu–Tyr treatment did not affect the lifespan of daf-16 (mu86) , skn-1 (tm4241) , and hsf-1 (sy441) mutants, indicating that its effects require functional insulin/IGF‐1, MAPK, and HSF‐1 pathways‐mediated stress response pathways. These findings establish Leu–Tyr as a muscle‐derived antioxidant peptide capable of delaying aging through multipathway activation, highlighting Leu–Tyr as a promising candidate for further research into natural interventions against age‐related decline.