Association of serum cotinine with phenotypic age acceleration and oxidative stress markers in US adults: A cross-sectional study

INTRODUCTION: Tobacco exposure is a plausible accelerator of biological aging, yet population-level evidence and mechanisms remain insufficiently defined. We examined the association between serum cotinine and phenotypic age acceleration (PhenoAgeAccel), and assessed whether oxidative-stress biomarkers were related to the serum cotinine-PhenoAgeAccel association. METHODS: We conducted a cross-sectional, survey-weighted analysis of n=19744 adults from NHANES 2011-2018. PhenoAgeAccel was computed as the residual from regressing PhenoAge on chronological age. Multivariable linear regressions related serum cotinine to PhenoAgeAccel across hierarchical adjustment models. Restricted cubic splines assessed non-linearity. Mediation analysis was conducted to quantify the extent to which oxidative-stress biomarkers contribute to this association. RESULTS: Higher serum cotinine was associated with accelerated biological aging: each doubling of serum cotinine corresponded to a 0.22-year increase in PhenoAgeAccel (β=0.22; 95% CI: 0.16-0.29). Mediation analyses indicated that γ-glutamyl transferase (GGT) and uric acid (UA) statistically accounted for 9.5% of the association between serum cotinine and PhenoAgeAccel (p<0.001). Interactions were observed for sex and PIR, with stronger associations among women and participants with lower socioeconomic status. There was no evidence of non-linearity in the relationships of the serum cotinine with GGT, PhenoAgeAccel, or UA. CONCLUSIONS: In this nationally representative cross-sectional study of US adults, higher serum cotinine levels were associated with greater phenotypic age acceleration. Oxidative-stress biomarkers were related to the observed association, although causal inferences cannot be drawn.