Age-stratified susceptibility to atmospheric oxidant exposure and insulin resistance

Atmospheric oxidants (Ox), the biologically integrated ozone (O₃) and nitrogen dioxide (NO₂), are among the most reactive ambient air constituents encountered by urban populations. Despite mechanistic evidence linking Ox to systemic metabolic disruption, no epidemiological study has evaluated Ox against insulin resistance (IR), nor examined whether IR onset age modifies oxidant susceptibility. We aimed to quantify the associations between long-term Ox exposure and both early-onset and late-onset IR, characterised age-stratified mediation by lipid metabolism, and estimate preventable IR burden under targeted Ox reduction scenarios. We conducted a retrospective cohort study including 18,968 adults (31,329 person-visits) who attended routine health examinations between January 2020 and December 2024. Individual Ox, O₃, and NO₂ concentrations were assigned from the CHAP dataset. IR was characterised using seven validated biomarkers. Associations were estimated using linear mixed-effects models. Counterfactual IR burden reduction was estimated via the parametric g-formula. Mediation by six lipid dysregulation indices was decomposed into natural direct and indirect effects. Each 1-unit Ox increment was associated with a 14.8% elevation in Metabolic Score for Insulin Resistance (METS-IR) in the early-onset, compared to 4.5% in the late-onset; β-ratios exceeded 1.0 for all seven IR biomarkers. O₃ and NO₂ showed directionally consistent age-differential patterns. Females conferred higher susceptibility across both subtypes. G-formula estimates indicated that reducing Ox concentrations to the 42.6 ppb would lower early-onset IR prevalence by 10.7 % and late-onset IR prevalence by 4.3 %. Cholesterol Index (CHOLINDEX) mediated 43.0-63.0% of the Ox-early-onset IR association; remnant cholesterol mediated up to 23.1% of the Ox-late-onset IR. Ox exposure confers disproportionately greater IR risk in adults under 40 years, with divergent lipid-mediated pathways across the lifespan. These findings support age-stratified metabolic surveillance in high-Ox settings and provide quantitative evidence for the metabolic co-benefits of ambient Ox abatement.