Investigation of quercetin and hyperoside as senolytics in adult human endothelial cells

Quercetin has been reported to act as a senolytic by selectively removing senescent endothelial cells, and thus it would seem quercetin could revolutionize the field of gerontology. However, given quercetin's narrow therapeutic index reported in work done with human umbilical vein endothelial cells (HUVECs), we hypothesized that quercetin is not innocuous for non-senescent adult human vascular endothelial cells at concentrations that have been reported to be safe for proliferating HUVECs. Furthermore, we investigated quercetin 3-D-galactoside (Q3G; hyperoside), an inactive quercetin derivative that needs to be cleaved by beta-galactosidase overexpressed in senescent cells to release quercetin, as a potential safer senolytic. We compared the effectiveness of quercetin and Q3G in primary human coronary artery endothelial cells (HCAEC), which are adult microvascular cells. We found that quercetin caused cell death in non-senescent endothelial cells at a concentration that has been reported to selectively remove senescent cells, and that Q3G was not cytotoxic to either young or senescent cells. Thus, in primary adult human endothelial cells, quercetin and Q3G are not senolytics. Earlier work reporting positive results was done with HUVECs, and given their origin and the disparate findings from the current study, these may not be the best cells for evaluating potential senolytics in clinically relevant endothelial cells. NEW AND NOTEWORTHY: Previously, quercetin has been reported to be a senolytic, a drug that selectively removes senescent cells, in HUVECs. However, we found neither quercetin nor Q3G was effective as a senolytic for adult human endothelial cells.