Chemical screen identifies a geroprotective role of quercetin in premature aging

Geng, Lingling; Liu, Zunpeng; Zhang, Weiqi; Li, Wei; Wu, Zeming; Wang, Wei; Ren, Ruotong; Su, Yao; Wang, Peichang; Sun, Liang; Ju, Zhenyu; Chan, Piu; Song, Moshi; Qu, Jing; Liu, Guang-Hui

Discovery of compounds that attenuate senescent phenotypes can lead to therapeutic advances that ameliorate aging-related pathologies (Chang et al., 2016; Kreienkamp et al., 2016; Li et al., 2016b) . Here, by employing a platform with premature aging Werner syndrome (WS) hMSCs for the screening of effective compounds against cellular senescent phenotypes, we have identified ten candidate natural products, including quercetin dihydrate, chrysophanic acid, licochalcone A, luteolin, formononetin, honokiol, berberine HCl, kaempferol, bergenin and synephrine. Except Que and berberine HCl , the other eight compounds have never been implicated in premature aging-related studies, thus greatly broadening our view of geroprotective drug candidates. Further investigation revealed the mechanisms by which the top hit, Que exhibited beneficial effects in attenuating hMSC senescence: (1) Que alleviated senescence by promoting stem cell self-renewal and restoring the heterochromatin architecture in WS hMSCs; (2) transcriptome analysis supported that Que improved the "healthspan" of WS hMSCs; (3) Que and VC exerted geroprotective effects through overlapping mechanisms; (4) Que also alleviated cellular senescent phenotypes in HGPS and physiological-aging hMSCs (Fig. 11) . For the first time, Que was identified as a geroprotective agent against both premature and physiological human aging, supporting the role of Que as a novel therapeutic option for treating premature aging and promoting healthy aging. Additionally, the generalized effectiveness of Que verifies the efficacy of WS hMSCs as a powerful model for geroprotective drug screening.