Background: Chronic airway diseases are leading causes of mortality and morbidity worldwide. More evidence supports that lung aging can be reflected by changes in DNA methylation, which are relevant for lung diseases, given their ability to capture exposures over a lifetime. Objective: We aimed to investigate the association and sex-specific associations of epigenetic age acceleration in whole blood with chronic respiratory diseases. Methods: We analyzed public data from 2,402 adults from the National Health and Nutrition Examination Surveys (NHANES) 1999-2002 cycles. We examined the association between epigenetic age and respiratory traits using linear regression models corrected for age, age2, gender, race-ethnicity, survey cycles, and survey weights. Multiple comparisons were corrected using a false discovery rate <5%. We conducted stratified analyses by sex and sensitivity analyses adjusted by blood cell counts and clinical and socioeconomic status (SES) confounders. Results: Individuals with wheezing showed accelerated epigenetic aging of up to 3.1 years (95% Confidence Interval [CI], 2.1, 4.1, p=8.4x10-6). Participants with COPD exhibited an epigenetic age acceleration potentially mediated by smoking, while those with emphysema showed epigenetic aging of up to 4.4 years (95% CI: 3.1, 5.8, p=3.4x10-6) independent of SES factors. Participants with early-onset COPD and those who ever have asthma showed suggestive accelerated biological aging (p<0.05). The accelerated pace of biological aging in COPD participants and the telomere length reduction in wheezing subjects were stronger in males than females. Conclusion: Individuals with chronic respiratory diseases, such as wheezing, COPD, and asthma, have accelerated epigenetic aging in whole blood. Among COPD patients, those with emphysema might exhibit higher epigenetic age acceleration. These results suggest that different epigenetic clocks may capture aging mechanisms with sex-specific effects on chronic respiratory diseases.
