Accelerated epigenetic ageing worsens survival and mediates environmental stressors in fibrotic interstitial lung disease

Gillian C Goobie; Daniel-Costin Marinescu; Ayodeji Adegunsoye; Jean Bourbeau; Christopher Carlsten; Rachel L Clifford; Dany Doiron; Qingling Duan; Kevin F Gibson; Amanda Grant-Orser; Ana I Hernandez Cordero; Kerri A Johannson; Daniel J Kass; Sharon E Kim; Janice M Leung; Xiaoyun Li; Wan Tan; Chen Xi Yang; S Mehdi Nouraie; Christopher J Ryerson; Tillie L Hackett; Yingze Zhang

doi:10.1183/13993003.01618-2024

Accelerated epigenetic ageing worsens survival and mediates environmental stressors in fibrotic interstitial lung disease

Eur Respir J. 2025 Jun 5;65(6):2401618. doi: 10.1183/13993003.01618-2024. Print 2025 Jun.

Authors

Gillian C Goobie^{1

2

3}, Daniel-Costin Marinescu^{4

5}, Ayodeji Adegunsoye⁶, Jean Bourbeau⁷, Christopher Carlsten^{4

5

8}, Rachel L Clifford⁹, Dany Doiron¹⁰, Qingling Duan^{11

12}, Kevin F Gibson³, Amanda Grant-Orser¹³, Ana I Hernandez Cordero^{2

14}, Kerri A Johannson¹³, Daniel J Kass³, Sharon E Kim³, Janice M Leung^{4

2

14}, Xiaoyun Li³, Wan Tan^{4

2}, Chen Xi Yang², S Mehdi Nouraie³, Christopher J Ryerson^{4

2}, Tillie L Hackett^{2

15}, Yingze Zhang³

Affiliations

¹ Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada gillian.goobie@hli.ubc.ca.
² Centre for Heart Lung Innovation, St Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
³ Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁴ Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
⁵ Centre for Lung Health, Vancouver General Hospital, Vancouver, BC, Canada.
⁶ Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA.
⁷ Division of Experimental Medicine, Department of Medicine, Faculty of Medicine and Health Sciences, McGill University, Montréal, QC, Canada.
⁸ Air Pollution Exposure Laboratory, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.
⁹ Centre for Respiratory Research, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK.
¹⁰ Respiratory Epidemiology and Clinical Research Unit, Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montréal, QC, Canada.
¹¹ Department of Biomedical and Molecular Sciences, Queens University, Kingston, ON, Canada.
¹² School of Computing, Queens University, Kingston, ON, Canada.
¹³ Division of Respiratory Medicine, Department of Medicine, University of Calgary, Calgary, AB, Canada.
¹⁴ Edwin S.H. Leong Centre for Healthy Aging, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
¹⁵ Department of Anaesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada.

PMID: 39884761
DOI: 10.1183/13993003.01618-2024

Abstract

Background: The role of epigenetic ageing in the environmental pathogenesis and prognosis of fibrotic interstitial lung disease (fILD) is unclear. We evaluated whether ambient particulate matter with diameter ≤2.5 μm (PM_2.5) and neighbourhood disadvantage exposures are associated with accelerated epigenetic ageing, and whether epigenetic age is associated with adverse clinical outcomes in patients with fILD.

Methods: This multicentre, international, cohort study included patients with fILD from the University of Pittsburgh (UPitt, n=306) and University of British Columbia (UBC, n=170). 5-year PM_2.5 exposures were estimated using satellite-derived hybrid models. Neighbourhood disadvantage was calculated using US and Canadian census-based metrics. Epigenetic age difference (EAD=epigenetic age-chronological age) was calculated using GrimAge analysis of blood DNA methylation data. Linear models assessed associations of exposures with EAD. Cox models assessed associations of EAD with transplant-free survival. Causal mediation analysis evaluated EAD mediation of exposure-survival relationships.

Results: Median epigenetic age was 11.7 years older than chronological age in patients with fILD. In combined cohort analysis, each interquartile range (IQR) increase in PM_2.5 was associated with 2.88 years (95% CI 1.39-4.38; p<0.001) increased EAD. In UPitt, each IQR neighbourhood disadvantage increase was associated with 1.16 years (95% CI 0.22-2.09; p=0.02) increased EAD. Increased EAD was associated with worse transplant-free survival (hazard ratio 1.17 per 1-year increase in EAD, 95% CI 1.10-1.24; p<0.001), with EAD mediating 40% of the PM_2.5-survival relationship and 59% of the neighbourhood disadvantage-survival relationship. Epigenetic age was also more strongly associated with transplant-free survival than chronological age.

Conclusions: Epigenetic age acceleration is associated with worse survival and mediates adverse exposure impacts in fILD.

Publication types

Multicenter Study

MeSH terms

Adult
Aged
Aging* / genetics
British Columbia
Cohort Studies
DNA Methylation
Environmental Exposure* / adverse effects
Epigenesis, Genetic*
Female
Humans
Lung Diseases, Interstitial* / genetics
Lung Diseases, Interstitial* / mortality
Male
Middle Aged
Particulate Matter* / adverse effects
Prognosis
Proportional Hazards Models

Substances

Particulate Matter