Quercetin activates the SIRT6–Nrf2 axis during oxidative stress, modulating DNA repair and ageing-associated markers

Quercetin is a dietary flavonoid with antioxidant, anti-inflammatory, and senolytic properties, yet its effects on the DNA damage response and inflammatory markers in healthy humans remain unclear. We conducted a double-blind, placebo-controlled crossover trial in n =13 apparently healthy male participants, using acute high-intensity interval exercise (HIIE) as the primary stimulus to induce DNA damage/repair combined with acute and 21-day quercetin supplementation (1000 mg/day). Plasma quercetin concentrations and intracellular nuclear localisation was quantified alongside the transcription of several DNA repair genes and sirtuin molecules ( SIRT1, SIRT6 ), markers of DNA damage (single-strand breaks, oxidised purine bases, double-strand breaks), and IgG/plasma glycomic profiles, including a preliminary marker of biological age (GlycanAge), to characterise molecular and systemic adaptations. Quercetin accumulated in plasma and exhibited enhanced nuclear localisation post-exercise ( p < 0.001 and p < 0.05, respectively). Compared to placebo, quercetin supplementation increased the post-exercise SIRT6–quercetin nuclear colocalisation ( p < 0.001 in all timepoints) and Nrf2 nuclear translocation ( p < 0.001). Gene expression of SIRT1, PARP1 , and RAD51 increased post-exercise in placebo ( p < 0.05 in all timepoints), but not in quercetin. Meanwhile, SIRT6 and OGG1 expression decreased post-exercise in placebo ( p < 0.05 in all timepoints), but increased post-exercise in quercetin ( p < 0.05 in all timepoints). Oxidative DNA damage markers were reduced in the quercetin arm compared to placebo ( p < 0.001 in all timepoints). Glycomic analysis revealed significant decreases in plasma core fucosylation and agalactosylation post-exercise in placebo ( p < 0.05 for both) but not in the quercetin arm, suggesting that quercetin attenuated exercise-induced inflammatory glycan shifts. There was a non-significant trend towards increased GlycanAge post-exercise in placebo, and a non-significant decrease after short-term quercetin supplementation. In summary, short-term quercetin supplementation activated the SIRT6–Nrf2 axis during exercise-induced oxidative stress, sustaining DNA repair capacity, and modulating systemic inflammatory glycomic markers. These findings provide mechanistic insights into how dietary polyphenols modulate redox-sensitive nuclear and post-translational markers of inflammageing in vivo .