Resveratroloside alleviates senescence-associated phenotypes in vitro through the coordinated regulation of...

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.