Quercetin Cuts Vascular Aging in Men With Heart Disease but Not Women

**Why this matters:** Residual cardiovascular risk persists even with optimal medical therapy, and cellular senescence—the accumulation of metabolically active but non-dividing cells that secrete pro-inflammatory factors (the SASP)—is increasingly recognized as a driver of atherosclerosis and inflammaging. Senolytics like quercetin, which selectively eliminate senescent endothelial cells, offer a novel therapeutic angle, but no prior trial had tested them specifically in coronary artery disease (CAD) patients.

**What was studied:** The Q-CABG trial (NCT04907253) was a prospective, multi-centre, randomized, double-blind, placebo-controlled study enrolling 97 patients (78 men, 19 women) who experienced a recent acute coronary syndrome and were scheduled for coronary artery bypass graft (CABG) surgery at the Montreal Heart Institute. Patients received quercetin 500 mg twice daily or placebo starting two days before surgery through hospital discharge (up to 7 post-operative days). Primary endpoints were post-operative systemic inflammation (hs-CRP) and ex vivo endothelial relaxation of discarded internal thoracic artery (ITA) segments. Exploratory endpoints included plasma proteomics (384 markers via Olink) and single-nucleus RNA sequencing (snRNA-seq) of ITA tissue in 12 per-protocol patients.

**Key results:** Quercetin showed a trend toward reduced C-reactive protein at discharge (p=0.073). Ex vivo acetylcholine-induced endothelial relaxation improved significantly overall (p=0.049), driven entirely by men (p=0.043); women showed no benefit (p=0.852). Plasma proteomics revealed quercetin differentially modulated circulating inflammatory proteins by sex—suppressing inflammation in men but producing a pro-inflammatory shift in women. snRNA-seq of ITA tissue demonstrated that male vascular cells (endothelial cells, smooth muscle cells, fibroblasts) overexpressed senescence and inflammaging pathways at baseline, which quercetin reversed. In female cells, senescence burden was minimal, quercetin provided negligible endothelial benefit, and actually increased inflammaging in fibroblasts. A candidate molecular mechanism in men involves the PLAUR receptor and its ligands PLAU and SERPINE1—components of the plasminogen activator system implicated in senescence signaling. A striking secondary finding: post-operative atrial fibrillation occurred in only 4% of quercetin-treated patients versus 18% in the placebo group (p=0.033).

**Implications:** These results suggest that vascular senescence is a sex-dimorphic phenomenon in CAD—more pronounced in men—and that quercetin's senolytic/senomorphic activity is correspondingly sex-specific. Short-term perioperative quercetin may represent a safe, low-cost adjunct for male CAD patients to reduce vascular aging burden, improve endothelial function, and potentially lower post-operative complications like atrial fibrillation.

**Caveats:** The trial was underpowered for sex-stratified analyses given only 19 women were enrolled, limiting conclusions about female biology. The snRNA-seq substudy included only 12 patients. The short treatment window (roughly one week) may not reflect longer-term senolytic effects, and the atrial fibrillation finding, while intriguing, was a secondary outcome requiring confirmation in a dedicated trial.