Age-dependent health risks of smoking: greater harm associated with initiation before alveolar maturation (age 24).

Background: Smoking during the alveolar developmental stage (ADS) (≤24 years) may increase cardiopulmonary disease risk beyond the effects of cumulative exposure, but these interactions remain unclear. We aimed to determine whether smoking initiation during ADS modifies the associations between cumulative smoking exposure and cardiopulmonary disease, multimorbidity, and all-cause mortality. Methods: We analysed 15,077 participants from the US National Health and Nutrition Examination Survey and two UK Biobank cohorts: 121,852 individuals in the disease cohort and 136,528 in the mortality cohort. Multivariable logistic regression and Cox proportional hazards models examined associations of smoking initiation timing (≤24 vs. >24 years), cumulative exposure (>20 vs. ≤20 pack-years), and their interaction with chronic obstructive pulmonary disease (COPD), cardiovascular disease, all-cause mortality, and multimorbidity. We assessed both multiplicative and additive interactions. We also evaluated an ordinal exposure score combining initiation timing and pack-years. Zero-inflated negative binomial regression quantified comorbidity burden, and stratified analyses assessed the effects of smoking cessation duration. Results: Smoking initiation in the ADS amplified smoking-related disease risk. For COPD, ADS initiators with high cumulative exposure had a greater risk (hazard ratio (HR) = 3.45; 95% confidence interval (CI) = 3.29, 3.62) than post-ADS initiators with high exposure (HR = 2.33; 95% CI = 1.91, 2.83; P for multiplicative interaction <0.001). Additive interaction was also observed, with a relative excess risk due to interaction of 0.43 (95% CI = 0.08, 0.79) and an attributable proportion of 0.16 (95% CI = 0.02, 0.29). Each one-point increase in the exposure score was associated with higher COPD risk (HR = 2.29; 95% CI = 2.20, 2.38) and mortality (HR = 1.39; 95% CI = 1.36, 1.43), with 82.1% of COPD burden attributable to score ≥1 exposure. High exposure was associated with a larger reduction in comorbidity-free probability among ADS initiators (OR = 0.55) than post-ADS initiators (OR = 0.65) (P for interaction <0.001). Smoking cessation reduced COPD and mortality risks in both groups, with greater relative reductions among ADS initiators. Conclusions: Smoking initiation during ADS, combined with greater cumulative exposure, is associated with increased risks of COPD, cardiovascular morbidity, multimorbidity, and all-cause mortality. Incorporating developmental timing may improve smoking-related risk stratification.