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.

The authors have declared no competing interest.

This work was supported by grants from the National Institute of Environmental Health Sciences (NIEHS) (R01ES031259 and P42ES004705) and the National Institute on Minority Health and Health Disparities (NIMHD) (R01MD011721) of the United States National Institutes of Health (NIH). The study funders had no role in study design, data collection, data analysis, interpretation, or report writing.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

NHANES 1999-2000 and 2001-2002 survey cycles: https://wwwn.cdc.gov/nchs/nhanes/continuousnhanes/default.aspx?BeginYear=1999 https://wwwn.cdc.gov/nchs/nhanes/continuousnhanes/default.aspx?BeginYear=2001

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Demographic data, health records, and DNA methylation epigenetic clocks estimated in the analyzed participants are publicly available on the NHANES website. The full summary statistic report of all association analyses supporting the main conclusions of this study will be openly available in the Zenodo repository (DOI: 10.5281/zenodo.14549722) after the publication of the manuscript.