Elexacaftor/tezacaftor/ivacaftor treatment is associated with epigenetic age deceleration in cystic fibrosis

Background: Cystic fibrosis (CF) is associated with chronic inflammation and progressive multisystem disease, which may contribute to accelerated biological aging. Elexacaftor/tezacaftor/ivacaftor (ETI) substantially improves clinical outcomes in people with CF (pwCF), but its effects on epigenetic aging and their relationship with inflammation remain poorly understood. Methods: We performed a pilot longitudinal study of 8 modulator-naive pwCF. Blood DNA methylation was profiled before ETI initiation and after 1 year of treatment. DNAmGrimAge2 age acceleration was calculated adjusting for chronological age and blood cell composition. Associations with inflammatory biomarkers and clinical measures were assessed using repeated measures correlation. Results: DNAmGrimAge2 was strongly correlated with chronological age at baseline and follow-up. DNAmGrimAge2 age acceleration decreased after ETI treatment, from a median of 1.92 years before treatment to -1.70 years after 1 year (p=0.008). Greater age acceleration was associated with higher IL-6, IL-1{beta}, and calprotectin concentrations. Higher FEV1pp was associated with lower age acceleration, whereas higher sweat chloride was associated with greater age acceleration. Conclusions: DNAmGrimAge2 age acceleration decreased following ETI initiation and was associated with markers of innate and neutrophilic inflammation and CF disease activity. These findings suggest that epigenetic aging in CF may be dynamic and responsive to improvements in CFTR function and inflammatory disease burden. Larger longitudinal studies are needed to validate these findings and determine their relationship with long-term clinical outcomes.