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

Abstract 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. Graphical abstractAgeing and high-intensity interval exercise (HIIE) engage overlapping oxidative stress, DNA damage, and inflammatory signalling pathways, but with distinct temporal profiles. Acute HIIE induces reactive oxygen species (ROS) and increases peripheral blood mononuclear cell (PBMC) expression of stress-responsive DNA damage response genes PARP1, SIRT1, and RAD51, whereas SIRT6, OGG1, and nuclear Nrf2 are selectively increased with quercetin supplementation. Exercise-induced plasma N-glycosylation remodelling—characterised by increased galactosylation and reduced agalactosylation—was observed after HIIE but was abolished by quercetin supplementation, indicating stabilisation of glycosylation dynamics under reduced oxidative signalling. GlycanAge (an inflammaging index) exhibited only non-significant acute changes but may require longer-term supplementation to shift measurably. Dashed arrows indicate inferred or integrative relationships. Competing Interest Statement The authors have declared no competing interest. Clinical Trial REC/23/0020; ISRCTN34136514 Funding Statement https://DoNotAge.org provided quercetin aglycone and supported LC-MS/MS analyses. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This human trial was approved by Ulster University Research Ethics Committee (REC/23/0020) and registered in a publicly accessible database recognised by the World Health Organization (ISRCTN34136514). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Article was shortened to meet Aging Cell's word count limit. Graphical abstract was edited. Data Availability Statement The data that support the findings of this study are available from the corresponding author upon reasonable request.