Chemical Screen Identifies a Geroprotective Role of Quercetin in Premature and Physiological Aging

Aging increases the vulnerability to various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a nature product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate targets were identified and quercetin was further investigated due to its leading effects. Mechanistic studies revealed that in WS hMSCs, quercetin alleviated senescence via the enhancement of cell proliferation and the restoration and differentiation of heterochromatin architecture. RNA-seq analysis uncovered that quercetin and Vitamin C exerted geroprotective effects through different mechanisms. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS), physiological-aging and replicative-senescent hMSCs. More importantly, quercetin significantly improved the exercise endurance of old C57Bl/6 mice. Taken together, our study identifies quercetin as a geroprotective agent against premature and physiological aging, providing a novel therapeutic intervention for treating premature aging and promoting healthy aging.