Resveratroloside alleviates senescence-associated phenotypes in vitro through the coordinated regulation of mitochondrial function and chromatin structure.

Cellular senescence is characterized by coordinated disruptions in mitochondrial function and epigenetic regulation, with perturbation of the mitochondria-chromatin axis emerging as a central hallmark of this process. Resveratrol (RSV) has been extensively investigated as a modulator of this axis; however, its clinical utility is constrained by dose-dependent cytotoxicity. Here, we evaluated the safety profile and anti-aging potential of resveratrol glucoside (R-glc), a glucosylated derivative of RSV. R-glc exhibited markedly reduced cytotoxicity compared to RSV and effectively attenuated multiple senescence-associated phenotypes at low concentrations. Mechanistically, R-glc enhanced mitochondrial function, as evidenced by increased oxidative phosphorylation and reduced glycolytic dependence. At the epigenetic level, R-glc upregulated the NAD+-dependent deacetylase SIRT6 and decreased histone H3 lysine 9 (H3K9) acetylation, indicating improved chromatin stability. Taken together, these findings identify R-glc as a safer and functionally effective modulator of the mitochondria-chromatin axis, supporting its potential as a clinically applicable intervention for age-related functional decline.