Impact of smoking and alcohol consumption on telomere length: A univariable and multivariable Mendelian randomization study

Telomere length is a potential biomarker for biological aging and is associated with many age-related pathologies. Although observational evidence has linked modifiable lifestyle factors to telomere attrition, the causal relationship between smoking, alcohol consumption, and telomere length remains controversial. This study aimed to investigate the causal effects of smoking and alcohol consumption on telomere length using Mendelian randomization (MR) analysis. Genetic data on smoking initiation (N = 805,431), alcohol consumption (N = 666,978), and telomere length (N = 472,174) were extracted from published summary statistics. Univariable and multivariable MR analyses were performed to comprehensively estimate the independent causal effects of smoking and alcohol consumption on telomere length. Cochran Q test and the MR Egger intercept test were used to detect heterogeneity and pleiotropy. A Steiger filtering test was conducted to confirm directional causal effects. Further sensitivity analyses were performed using the leave-one-out method and funnel plots. Inverse variance weighted (IVW) analysis showed that genetically predicted smoking initiation was significantly associated with shorter telomere length (univariable IVW: β = -0.08, 95% confidence interval [CI] = -0.11 to -0.04, P < .001; multivariable IVW: β = -0.06, 95% CI = -0.11 to -0.02, P = .007). Similarly, genetic predisposition to alcohol consumption was causally associated with shorter telomere length (univariable IVW: β = -0.06, 95% CI = -0.10 to -0.02, P = .006; multivariable IVW: β = -0.06, 95% CI = -0.11 to -0.01, P = .030). No pleiotropy was identified in either univariable or multivariable MR analyses. The Steiger filtering test validated the accuracy of directional causality (P < .001). Finally, leave-one-out analysis and funnel plots further confirmed the robustness and reliability of the findings. This study provides genetic evidence for the causal effects of smoking and alcohol consumption on telomere shortening. Interventions targeting tobacco smoking and alcohol consumption may slow down cellular senescence and mitigate the risk of age-related diseases.