Aging is the leading risk factor for many chronic diseases, accounting for almost 60% of all deaths worldwide. How to achieve healthy aging, alleviate aging-related diseases, and extend healthspan has become a main topic of biomedical research (He et al., 2019). Geroprotective compounds, such as metformin and rapamycin, have been shown to improve both healthspan and lifespan in mice (Martin-Montalvo et al., 2013; Bitto et al., 2016), whereas nicotinamide partially improves healthspan in mice (Mitchell et al., 2018). In addition, senolytics, compounds that eliminate senescent cells, have been proven to improve physical function and increase lifespan in mice (Xu et al., 2018). Although none have proven to be clinically reliable in delaying aging or treating frailty in humans, these compounds have already provoked enthusiasm for identifying a potential “elixir”. Therefore, the exploration of more geroprotective compounds, especially natural active compounds, holds great potential for the development of geriatric medicines. Quercetin (Que) is a natural bioflavonoid found in fruits and vegetables such as apples and onions. Que (50 mg/kg) in combination with dasatinib (5 mg/kg)(abbreviated as D+ Q) has been shown to effectively eliminate senescent cells via induction of apoptosis, thus alleviating senescence-related phenotypes and improving physical function and lifespan in mice (Zhu et al., 2015; Xu et al., 2018). In addition, Que (10 mg/kg) in combination with dasatinib (5 mg/kg) has been reported to reduce hepatic steatosis (Ogrodnik et al., 2017). In each of these in vivo studies, however, Que was used at high doses ranging from 10 to 50 mg/kg body weight, which raises concerns about dose-dependent side effects such as headaches and limb tingling (Shoskes et al., 1999). As a selective tyrosine kinase receptor inhibitor, dasatinib is associated with warnings and precautions including pulmonary arterial hypertension and low blood cell counts. Therefore, high-dose Que and extra side effects of dasatinib would hamper potential clinical applications of Que in geriatric medicines. Through natural products screening using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), we recently identified Que as a geroprotective agent that counteracts accelerated and natural aging of hMSCs at a concentration of as low as 100 nmol/L, which is

100 times lower than the concentration of Que (10 μmol/L) previously used in combination with dasatinib as senolytic drugs to eliminate senescent cells in human umbilical vein cells (HUVECs)(Zhu et al., 2015; Geng et al., 2018). To explore the geroprotective effect of low-dose Que monotherapy in rodents, we evaluated the in vivo effect of long-term low-dose Que administration under physiologicalaging condition. Que was given to 14-month-old C57BL/6J male mice by weekly oral gavage at a concentration of 0.125 mg/kg body weight, which is 80–400 times lower than that of the previously tested D+ Q (10–50 mg/kg body weight) regimens (Fig. 1 A), with vehicle (10% PEG400 in PBS)-treated mice as controls (Zhu et al., 2015; Xu et al., 2018). After eight months of treatment, Que-treated mice showed decreased hair loss with normal food intake, body weight, blood glucose and bone mineral density (Figs. 1 B and S1A–D). Compared to vehicle-treated mice, mice subjected to Que treatment showed markedly improved exercise endurance in the RotaRod and treadmill tests, but normal grip strength by grip strength meter assay (Figs. 1C, 1D, and S1E–G). Accordingly, the cardiac function of these mice was examined by Doppler tissue imaging. Although ejection fraction (EF) and fractional shortening (FS) were …