...This study aims to investigate if chalcones exhibit anti-senescence activities. Anti-senescence effect of 11 chalcone derivatives on the replicative senescence human aortic endothelial cells (HAEC) and human fetal lung fibroblasts (IMR90) was evaluated. Compound 2 (4-methoxychalcone) and compound 4 (4-bromo-4'-methoxychalcone) demonstrated increased cytotoxicity in senescent HAEC compared to young HAEC, with significant differences on IC50 values. Their anti-senescence effects on HAEC exceeded fisetin. Higher selectivity of compound 4 toward HAEC over IMR90 could be attributed to 4-methoxy (4-OMe) substitution at ring A (R1). Chalcone derivatives have potentials as senolytics in mitigating replicative senescence, warranting further research and development on chalcones as anti-senescent agent.