Quercetin is Probably Not a Useful Senolytic

Senolytic compounds are those that preferentially destroy senescent cells. Since these cells are one of the root causes of aging, there is considerable interest in finding and then quantifying the effectiveness of senolytic compounds. The known and alleged senolytics vary widely in effectiveness and quality of evidence, and quercetin is one of the more dubious examples. I don't think that anyone expects quercetin, on its own, to have a useful level of impact on senescent cells and their contribution to degenerative aging. The study here comes to the plausible conclusion that quercetin really can't achieve that goal. Yes, it is true that the 2015 mouse study of the chemotherapeutic dasatinib and quercetin demonstrated that the two together cleared more senescent cells than dasatinib alone, but synergy with other compounds is a very different story from unilateral effects. Quercetin is a widely used and extensively tested supplement compound. Any significant effect on health resulting from quercetin alone would likely have been discovered many years ago.

Previously, quercetin was reported to be a senolytic in irradiation-induced senescent human umbilical vein endothelial cells (HUVECs). HUVECs are derived from the umbilical cord of newborn babies, and for a long time were the only model of primary human endothelial cells (EC); however, these cells are not the best model of diseases associated with human arterial aging. HUVECs have been shown to differ substantially from primary endothelial cells derived from adult human vasculature. In the current study, we investigated whether quercetin is a senolytic in adult EC, and evaluated whether quercetin 3-D-galactoside (Q3G; hyperoside) would be a more selective senolytic.

Quercetin's low therapeutic/toxic ratio in the HUVEC study raised the possibility that quercetin could significantly injure non-senescent cells. It was unclear whether the proliferation of non-senescent cells could be compensating for some of the quercetin-mediated cell death, thus masking its toxicity to the young cells at the lower concentrations found to be selectively cytotoxic to senescent cells. We used adult human coronary artery endothelial cells (HCAEC), which are microvascular cells, as a relevant model, and generated two groups of cells from them to better understand the effect of quercetin: EP (early passage; young) and SEN (senescent), as a model of an aging tissue.

Our key findings are that quercetin at a concentration that reduced SEN EC also caused significant EP EC cell death, and that there was no evidence of senescent cell-specific cell death mediated by quercetin. Thus, quercetin is not a selective senolytic in adult human arterial endothelial cells, where both EP and SEN cells responded similarly to quercetin's toxicity.

To circumvent quercetin's toxicity on healthy, non-senescent cells, we investigated Q3G, a derivative of quercetin with limited toxicity to endothelial cells, which is processed by senescence-associated beta-galactosidase (SABG) enriched in senescent cells to release quercetin in situ. Q3G could act as a selective prodrug in senescent cells. However, Q3G had no significant toxicity to either EP or SEN EC. The lack of Q3G's toxicity in the current study may be due to Q3G being unable to enter the beta-galactosidase-rich lysosomes, or alternatively, Q3G being able to translocate to the lysosomes to release quercetin, which is further processed into an inert compound.

Link: https://doi.org/10.1371/journal.pone.0190374