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

Background: The role of epigenetic aging in the environmental pathogenesis and prognosis of fibrotic interstitial lung disease (fILD) is unclear. We evaluated whether ambient particulate matter ≤2.5 μm (PM) and neighbourhood disadvantage exposures are associated with accelerated epigenetic aging, 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). Five-year PM exposures were estimated using satellite-derived models. Neighbourhood disadvantage was calculated using U.S. 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) PM increase 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 (HR=1.17 per 1-year increase EAD, 95%CI 1.10-1.24, p<0.001), with EAD mediating 40% of PM-survival relationship and 59% of neighbourhood disadvantage-survival relationships. 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.