Aging, a complex process influenced by genetic and environmental factors, is a major determinant of health and disease. The polyphenolic compound resveratrol, known for its antioxidant properties, has been widely studied for its potential anti-aging effects. In this study, we investigated the age-dependent effects of resveratrol in Caenorhabditis elegans (C. elegans). Treatment with resveratrol for four consecutive days in young worms (adulthood day 1-4) significantly enhanced lifespan, healthspan, and reduced reactive oxygen species (ROS) generation. In contrast, the same treatment in middle-aged worms (adulthood day 8-11) unexpectedly impaired these phenotypes. Genetic experiments using mutant strains and RNA interference revealed that the gerosuppressor daf-16 and its downstream antioxidant sod-3 mediate these age-specific effects, as deletion of daf-16 or silencing of sod-3 eliminated the age-dependent opposing responses. Transcriptomic analysis identified distinct gene expression patterns between young and middle-aged worms, with the daf-16-regulated gene dod-6 being up-regulated in young worms but down-regulated in middle-aged worms. Silencing dod-6 abolished the age-dependent opposing effects on lifespan, healthspan, and ROS generation. Further studies confirmed that daf-16 regulates sod-3 through dod-6. Then, the divergent effects of resveratrol were validated in human fibroblast BJ cells: resveratrol reduced β-galactosidase staining and pro-inflammatory cytokine expression in normal cells but exacerbated these markers in D-galactose-induced senescent cells. Together, these findings demonstrate that resveratrol exerts anti-aging effects in young organisms but promotes aging in middle-aged organisms, likely through differential regulation of the daf-16/dod-6/sod-3 axis. This study highlights the importance of understanding age-related drug susceptibility to develop safer and more effective anti-aging interventions.
