The lifespan and healthspan extending effects of ellagic acid in Caenorhabditis elegans require an intact insulin/IGF-1 signaling pathway

Introduction: Ellagic acid (EA) is a naturally occurring polyphenolic antioxidant speculated to influence aging, but its precise biological mechanisms remain poorly understood. Methods: Using Caenorhabditis elegans as a model system, we investigated the anti-aging properties of EA. Lifespan assays were performed at multiple concentrations, and healthspan(definition) parameters including locomotor activity, lipofuscin accumulation, and reactive oxygen species (ROS) levels were assessed under thermal and oxidative stress. Genetic requirement was examined using loss-of-function mutants of daf-16, hsf-1, hlh-30, and skn-1. Gene expression was analyzed by qRT-PCR and reporter strains, and global transcriptional changes were mapped by RNA-sequencing. Results: EA extended lifespan and preserved key healthspan features, including improved locomotor activity, reduced intestinal lipofuscin accumulation, and decreased ROS levels under stress conditions. The lifespan-extending effects of EA required daf-16, hsf-1, hlh-30, and skn-1, as EA failed to extend lifespan in these mutants. EA also enhanced the expression of downstream cytoprotective genes. Complementary RNA-sequencing revealed broader transcriptional remodeling, including metabolic pathways. Discussion: These findings position EA as a modulator of a coordinated transcriptional network-rather than a single pathway-involving the insulin/IGF-1 signaling pathway and interconnected stress-response networks to promote longevity and stress resistance.