Senolytic and anti-inflammatory efficacy of quercetin in men and women undergoing coronary artery by-pass surgery

Recent studies suggest that vascular senescence and its associated inflammation could fuel the so-called inflammaging to favor atherogenesis; whether these pathways can be inactivated in CAD patients (male and female) is unknown. We performed a randomized, double-blind trial involving patients undergoing an elective coronary artery by-pass graft surgery. The patients were randomly assigned to receive either quercetin (500 mg twice daily) or placebo starting two days before surgery. The primary efficacy end point was a reduction in post-operative systemic inflammation. The secondary efficacy end-point was an improved endothelial function ex vivo of discarded segments of internal thoracic artery (ITA). The exploratory end-point was to acquire a vascular transcriptomic signature per treatment and sex by single nucleus RNA sequencing. A total of 97 patients (78 men) were recruited, 50 were assigned to the placebo group and 47 to the quercetin group. In the intent-to-treat population (ITT), quercetin tended to reduce C-reactive protein at hospital discharge (F value 3.39; p=0.073); this tendency was confirmed by a plasma proteomic analysis revealing a significant shift of differentially expressed inflammatory proteins between sexes (-48 in men and +12 in women). Quercetin increased endothelial sensitivity to acetylcholine-dependent relaxation (F value 4.01; p=0.0487). In a sub-group analysis, this effect of quercetin remained significant in men (F value 3.92; p=0.0513) but not in women (F value 0.17; p=0.678). The transcriptomic signature of the ITA revealed overexpression of classic cellular senescence pathways of both replicative- and stress-induced senescence, together with an inflammatory signature typical of inflammaging and oxidative stress; quercetin reversed this signature towards reduced senescence, stress and inflammation. In female ITA, the response to quercetin was heterogeneous and limited in efficacy, with a “cooling” of the endothelium, but a promotion of the inflammaging signature in fibroblasts. No adverse events were reported. Quercetin reduced global post-operative inflammation and improved endothelial dysfunction in the ITT population; men benefited from quercetin but not women. This study suggests that a hit-and-run senolytic strategy to reduce the vascular inflammaging may benefit men more than women with CAD. Nuclei were isolated from internal thoracic arteries from 12 patients with coronary artery disease (CAD) undergoing an in-patient CABG. In this clinical study, patients randomly received quercetin or placebo pills (500mg BID). Our dataset include 3 men quercetin, 3 men placebo, 3 women quercetin and 3 women placebo.