Smoking initiation during the alveolar developmental stage (≤24 years), combined with greater cumulative exposure, is associated with increased risks of COPD, cardiovascular morbidity, multimorbidity, and all-cause mortality beyond the effects of cumulative exposure alone.
Key Findings
Results
Smoking initiation during the alveolar developmental stage (ADS, ≤24 years) amplified COPD risk beyond what cumulative exposure alone explained.
ADS initiators with high cumulative exposure (>20 pack-years) had a hazard ratio of 3.45 (95% CI = 3.29, 3.62) for COPD.
Post-ADS initiators (>24 years) with high cumulative exposure had a hazard ratio of 2.33 (95% CI = 1.91, 2.83) for COPD.
Multiplicative interaction was statistically significant (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).
Results
An ordinal exposure score combining initiation timing and pack-years was associated with progressively higher COPD risk and all-cause mortality.
Each one-point increase in the exposure score was associated with higher COPD risk (HR = 2.29; 95% CI = 2.20, 2.38).
Each one-point increase in the exposure score was associated with higher all-cause mortality (HR = 1.39; 95% CI = 1.36, 1.43).
82.1% of COPD burden was attributable to a score ≥1 exposure.
The score combined both initiation timing (≤24 vs. >24 years) and cumulative pack-years (>20 vs. ≤20).
Results
High cumulative smoking exposure was associated with a greater reduction in comorbidity-free probability among ADS initiators compared to post-ADS initiators.
Among ADS initiators with high exposure, the odds ratio for remaining comorbidity-free was 0.55.
Among post-ADS initiators with high exposure, the odds ratio for remaining comorbidity-free was 0.65.
The interaction between initiation timing and cumulative exposure for multimorbidity was statistically significant (P for interaction <0.001).
Zero-inflated negative binomial regression was used to quantify comorbidity burden.
Results
Smoking cessation reduced COPD and mortality risks in both ADS and post-ADS initiator groups, with greater relative reductions observed among ADS initiators.
Stratified analyses assessed the effects of smoking cessation duration on disease risk.
Both ADS initiators and post-ADS initiators benefited from cessation in terms of reduced COPD and all-cause mortality risk.
The relative risk reductions from cessation were greater among those who initiated smoking during the alveolar developmental stage.
Methods
The study used large, multi-cohort data from both the US and UK to examine age-dependent smoking risks.
15,077 participants from the US National Health and Nutrition Examination Survey (NHANES) were analyzed.
Two UK Biobank cohorts were included: 121,852 individuals in the disease cohort and 136,528 in the mortality cohort.
Multivariable logistic regression and Cox proportional hazards models were used to examine associations.
Both multiplicative and additive interactions between initiation timing and cumulative exposure were assessed.
Outcomes included COPD, cardiovascular disease, all-cause mortality, and multimorbidity.
Background
Smoking initiation during alveolar development (≤24 years) was hypothesized to increase cardiopulmonary disease risk beyond effects of cumulative exposure due to disruption of lung maturation.
The alveolar developmental stage (ADS) was defined as age ≤24 years, corresponding to the period of ongoing alveolar maturation.
The study aimed to determine whether smoking initiation timing during ADS modifies associations between cumulative smoking exposure and disease outcomes.
Initiation timing was categorized as ≤24 years (ADS) versus >24 years (post-ADS).
Cumulative exposure was categorized as >20 versus ≤20 pack-years.
Conclusions
The authors conclude that incorporating developmental timing of smoking initiation may improve smoking-related risk stratification.
Current risk stratification typically relies primarily on cumulative pack-year exposure.
The findings suggest that age at initiation, specifically whether smoking began before or after alveolar maturation, modifies disease risk independently.
The authors propose that developmental timing should be incorporated into smoking-related risk models.
What This Means
This research suggests that when people start smoking matters as much as how much they smoke, particularly whether they begin before the lungs have fully matured. The lungs, specifically the tiny air sacs called alveoli, continue developing until around age 24. People who start smoking during this developmental window face significantly greater risks of chronic obstructive pulmonary disease (COPD), cardiovascular disease, having multiple simultaneous health conditions (multimorbidity), and dying earlier — compared to people who start smoking after age 24, even when total lifetime tobacco exposure is similar. For example, early starters who also smoked heavily (more than 20 pack-years) had a COPD hazard ratio of 3.45, compared to 2.33 for later starters with the same heavy exposure.
The study drew on data from over 270,000 people across US and UK populations and used a combined exposure score that accounts for both when someone started smoking and how much they smoked. This score was strongly predictive of COPD and mortality risk, with 82% of COPD burden attributed to those with at least one risk factor on the score. Importantly, quitting smoking reduced risks for everyone, but those who started young showed greater relative benefit from cessation, suggesting it is never too late to quit.
This research suggests that standard ways of measuring smoking risk — which typically focus only on pack-years smoked — may underestimate harm for people who began smoking as teenagers or young adults. Accounting for the timing of smoking initiation relative to lung development could help doctors better identify who is at highest risk for serious lung and heart disease, potentially leading to earlier and more targeted interventions for those who started smoking young.
Liu Z, Zhao Z, Xiao Y, Xiong R, Zheng H, Liu Y, et al.. (2026). Age-dependent health risks of smoking: greater harm associated with initiation before alveolar maturation (age 24).. Journal of global health. https://doi.org/10.7189/jogh.16.04215