Association of smoking behaviors with GOLD biological age acceleration and potential mediation: Evidence from NHANES 1999-2023.

INTRODUCTION: The association between smoking and biological age acceleration, such as KDM and PhenoAge, has been reported, but the dose-response relationship between smoking and the acceleration of GOLD biological age remains unclear. This study aims to explore the association between smoking behavior and the acceleration of GOLD biological age, and to assess the potential mediating roles of oxidative stress and inflammation. METHODS: This cross-sectional study used data from 12 cycles of NHANES (1999-2023), a survey with a complex multi-stage probability sampling design, and included eligible participants. Smoking exposure (daily amount and status) was assessed via standardized self-report questionnaires. The outcome, GoldBioAge-BAaccel, was calculated as residuals from regressing GOLD biological age on chronological age. Multivariable linear regression and restricted cubic splines were applied to evaluate associations, with subgroup analyses stratified by sex, age, and other covariates, and Wald tests for interaction. Sensitivity analyses were performed to test robustness, and mediation analyses explored the mediating effects of uric acid and C-reactive protein. RESULTS: The study included 12941 eligible participants. In multivariable linear regression models, each additional cigarette smoked per day was associated with a 0.0763-year increase in BAaccel (β=0.0763; 95% CI: 0.0522-0.1003). Compared with never smokers, current smokers had a 1.5387-year higher BAaccel (β=1.5387; 95% CI: 1.1197-1.9577). Restricted cubic spline analysis showed no evidence of a nonlinear association between CPD and BAaccel (p for nonlinearity=0.285). The association between current smoking and BAaccel differed significantly by age group (p for interaction=0.019). The findings remained consistent across multiple sensitivity analyses. CRP and UA mediated 14.88% and 5.10% of the total effect between daily smoking amount and BAaccel, respectively; for current smoking status (vs never smoking), the corresponding mediated proportions were 9.19 % and 2.40%. CONCLUSIONS: Smoking behavior is positively associated with GOLD biological age acceleration, and this association is partially mediated by systemic inflammation and oxidative stress.