The association of epigenetic age acceleration with internal smoking dose, risk of lung cancer, and all-cause mortality in cigarette smokers: the Multiethnic Cohort study.
Level 3 - non-randomized controlled study
Prospective cohort follow-up study
PubMed 42021368 · doi:10.1186/s13148-026-02137-6
What was done
In a subgroup of 1,969 current smokers from the Multiethnic Cohort Study, researchers measured urinary total nicotine equivalents (TNE) as an internal smoking dose biomarker and computed six blood DNA methylation-based epigenetic clocks and age acceleration (EAA) measures. Linear regression models adjusted for age, sex, BMI, cell composition, population stratification, and self-reported pack-years evaluated associations between TNE and EAA. Cox proportional hazard models over 13 years of follow-up evaluated associations between EAA measures, incident lung cancer (176 cases), and all-cause mortality (780 deaths), adjusting for demographics, cell composition, self-reported pack-years, and urinary TNE.
What was found
A standard deviation (SD) increase in log-TNE was significantly associated with increased AgeAccelPheno (beta = 0.416, 95% CI 0.134 to 0.698), AgeAccelGrim (beta = 0.771, 95% CI 0.603 to 0.939), and DunedinPACE (beta = 0.015, 95% CI 0.010 to 0.020). For incident lung cancer, each SD increase in AgeAccelGrim (HR = 1.40, 95% CI 1.16 to 1.71) and DunedinPACE (HR = 1.31, 95% CI 1.11 to 1.55) was associated with elevated risk, whereas DNAm-based telomere length acceleration was inversely associated (HR = 0.79, 95% CI 0.67 to 0.93). Findings were similar for all-cause mortality.
Why it matters
Epigenetic clocks capture lung cancer and mortality risk beyond both self-reported pack-years and short-term objective internal nicotine dose. These biological aging markers could help identify high-risk smokers who may benefit from enhanced screening or prevention strategies.
Limits
The study was restricted to participants who were actively smoking at biospecimen collection, limiting direct generalizability to former or never smokers. Urinary TNE reflects only short-term internal smoking exposure rather than cumulative lifetime dose. Residual confounding from unmeasured lifestyle or exposure variables remains possible, and findings require replication in external cohorts.
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