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. Transcriptome analysis of Werner syndrome (WS) human mesenchymal stem cells under basal or quercetin treated condition.

衰老会提升机体对多种疾病的易感性。衰老研究的核心目标，是开发能够延缓衰老进程、缓解衰老相关疾病的治疗手段。本研究依托近期构建的早衰老模型——沃纳综合征（Werner syndrome, WS）人间充质干细胞（human mesenchymal stem cells, hMSCs），对天然产物库开展筛选以寻找具有抗衰老活性的化合物。本研究共鉴定出10个候选靶点，其中槲皮素因活性突出而被选为后续深入研究对象。机制研究显示，在沃纳综合征人间充质干细胞中，槲皮素可通过促进细胞增殖、修复异染色质结构并重塑其组装模式，有效缓解细胞衰老进程。转录组测序（RNA-seq）分析结果表明，槲皮素与维生素C（Vitamin C）通过不同的分子机制发挥抗衰老作用。除沃纳综合征人间充质干细胞外，槲皮素还可在哈钦森-吉尔福德早衰综合征（Hutchinson-Gilford progeria syndrome, HGPS）模型细胞、生理性衰老及复制性衰老的人间充质干细胞中延缓细胞衰老。更为关键的是，槲皮素可显著提升老年C57BL/6小鼠的运动耐力。综上，本研究证实槲皮素是一种可对抗早衰老与生理性衰老的抗衰老制剂，为早衰老相关疾病的治疗以及促进健康衰老提供了全新的干预策略。本数据集涵盖基础培养条件及槲皮素处理条件下沃纳综合征人间充质干细胞的转录组测序数据。