Grape Seed Polyphenols Enhance Antioxidant Activity and Prolong the Lifespan of <i>Caenorhabditis elegans</i> Through SKN‐1/Nrf2 Pathway

ABSTRACT This study evaluated the effects of grape seed polyphenols (GSP) on growth, metabolism, lifespan, and antioxidant responses in C. elegans . Under 500 μg/mL GSP treatment, the healthy lifespan of C. elegans was evidently extended compared with the control group, and the body length was significantly shortened, but the head swing speed was improved, the total number of eggs laying and offspring was noticeably increased, and the survival rates under H 2 O 2 stimulation and heat stress conditions were also greatly improved. In addition, the levels of antioxidant enzymes (SOD/CAT/GSH‐Px) were remarkably increased, and ROS levels were down‐regulated. Metabolomics indicated dose‐dependent remodeling of glycolytic/tricarboxylic acid (TCA) and one‐carbon nodes within the targeted panel. Relative to control, GSP increased alanine, glutamine (near‐threshold q ), succinate, and aspartate, while lactate and glutamate decreased; serine, glycine, and G3P rose dose‐dependently—consistent with enhanced 1C/SAM and GSH‐linked redox support and a shift of pyruvate from lactate toward mitochondrial oxidation. s kn‐1 , sod‐3 , gst‐4 , and hsp‐16.2 levels were up‐regulated, suggesting that GSP may affect epigenetic regulation through SKN‐1/Nrf2‐mediated antioxidant signaling pathway and histone H3K4 methylation. These results indicate that GSP may improve the physiological health status of worms by modulating anti‐oxidative stress, metabolic homeostasis, and epigenetic regulation, supporting its use as a natural antioxidant.