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

We have previously shown that VC alleviates aging defects in WS hMSCs by decreasing oxidative stress, preventing telomere attrition, suppressing excessive secretion of inflammatory factors, as well as reorganizing nuclear lamina and heterochromatin (Li et al., 2016b) . Our comparative analysis of the RNA-seq data in WS hMSCs illustrated the mechanistic commonalities and differences of the geroprotective effects by Que and VC, with the commonly upregulated genes mainly enriched in gene terms related to cell cycle, chromatin condensation and anti-oxidation. Likewise, we observed that Que restored heterochromatin architecture and decreased ROS levels in WS hMSCs. It has been shown that increased ROS levels lead to heterochromatin disorganization. Therefore, in our study decreased ROS levels may also contribute to the restoration of heterochromatin architecture. In addition, we have recently demonstrated that, the premature aging phenotypes in HGPS hMSCs partially attributes to the repression of NRF2mediated anti-oxidative response, whereas the reactivation of NRF2 reverses the nuclear defects in HGPS cells and restores their in vivo viability in mice (Fang et al., 2018; Kubben et al., 2016) . Interestingly, Que is reported as an activator of NRF2-mediated anti-oxidative pathway (Bahar et al., 2017; Dai et al., 2018; Gao et al., 2018; Kim et al., 2018) . Consistently, by RNA-seq analysis we identified that Que upregulated a series of anti-oxidative genes including GSTP1, GSR and GSTM1, all of which are NRF2 targets, indicating that Que may exert anti-oxidative effect via the activation of NRF2. Furthermore, despite of the multiple mechanistic commonalities of the geroprotective effects, Que-specific upregulated genes were mostly enriched in response to stimulus and cell homeostasis and the VCspecific ones in DNA replication, DNA repair and telomere maintenance, raising the possibility that Que and VC in combination might exhibit a synergistic geroprotective effect.