Resveratrol exerts stage- and sex-specific anti-aging and multigenerational effects via epigenetic and metabolic pathways in Drosophila

Quanyong Wu; Boya Ouyang; Wanning Ma; Yuxuan Zhao; Jingyimei Liang; Yi Yuan; Hui Cao; Jesus Simal-Gandara; Shaoping Nie; Jianbo Xiao

Resumen:

Background Resveratrol is a polyphenolic compound with reported anti-aging properties that exhibit complex and context-dependent biological effects, while its potential multigenerational influence remains unclear. Objectives To investigate the stage-specific effects of resveratrol on development and lifespan in Drosophila melanogaster and to determine whether resveratrol-associated longevity benefits can extend across generations through metabolic and epigenetic regulation. Methods Drosophila melanogaster were exposed to 50 μg/ml resveratrol (ER50) either during embryonic development or during adulthood. Developmental timing, lifespan, hormonal and nutrient-sensing signaling pathways, stress-response and autophagy pathways, mTOR signaling, metabolomic profiles, histone modifications, histone-modifying enzyme expression, and multigenerational lifespan effects were evaluated. Results Embryonic exposure to ER50 accelerated pupation and adult emergence but shortened adult lifespan. These effects were accompanied by activation of the juvenile hormone–insulin/IGF signaling axis and impaired antioxidant capacity. In contrast, adult ER50 supplementation extended lifespan in female flies and was associated with enhanced stress-response and autophagy pathways together with suppression of mTOR signaling. Mechanistically, longevity-promoting effects in adults coincided with increased glycolysis and pentose phosphate pathway activity, citrate accumulation, and remodeling of one-carbon metabolism, indicating broad reprogramming of energy and redox metabolism. These metabolic changes were accompanied by increased H3K9 acetylation (H3K9ac), upregulation of the histone acetyltransferase-related factor nej, and downregulation of Ash1, suggesting that resveratrol promotes lifespan extension through coordinated regulation of metabolic state and chromatin remodeling. Notably, maternal adult exposure to ER50 was associated with lifespan extension in female offspring across two subsequent generations, together with persistent metabolic alterations and chromatin changes. Conclusions Resveratrol exhibits stage- and sex-dependent effects in Drosophila and functions as a metabolic–epigenetic modulator. Adult supplementation is associated with extended female lifespan and multigenerational longevity effects, potentially mediated through coordinated regulation of energy metabolism and chromatin homeostasis.