Quercetin activates the SIRT6-Nrf2 axis during oxidative stress, modulating ageing-associated markers in healthy men

Quercetin is a dietary flavonoid with antioxidant, anti-inflammatory, and senolytic properties, yet its effects on exercise-induced DNA damage responses in healthy humans are unclear. We conducted a double-blind, placebo-controlled crossover trial (n = 13, middle-aged men) combining acute high-intensity interval exercise (HIIE) with 21-day quercetin supplementation (1000 mg/day). We quantified plasma quercetin and nuclear localisation, DNA repair and sirtuin gene expression, oxidative DNA damage (single and double-strand breaks, oxidised purines), and plasma/IgG glycomics including a preliminary GlycanAge index. Quercetin increased in plasma and nucleus post-exercise (p < 0.001; p < 0.05). Compared with placebo, quercetin increased post-exercise SIRT6-quercetin nuclear colocalisation (p < 0.001 at all timepoints) and Nrf2 nuclear translocation (p < 0.001). In placebo, SIRT1, PARP1 and RAD51 expression increased post-exercise, whereas SIRT6 and OGG1 decreased; this pattern was reversed with quercetin (all p < 0.05). Oxidative DNA damage markers were reduced with quercetin versus placebo (p < 0.001). Exercise-induced increases in plasma galactosylation and decreases in agalactosylation were observed in placebo but not with quercetin (all p < 0.05); GlycanAge showed non-significant increases post-exercise in placebo and a non-significant decrease following 21-day quercetin supplementation. In summary, short-term quercetin activates a SIRT6-Nrf2-linked response during HIIE, sustains DNA repair capacity, and stabilises inflammatory glycomic dynamics, consistent with a shift toward energetically economical, chromatin-associated repair. By providing evidence that quercetin biases DNA repair pathway usage under physiological oxidative stress, this work advances a framework of repair efficiency and energetic economy in human genome maintenance.