Telomere integrity, epigenetic aging, and genetic burden shape biological aging trajectories in idiopathic pulmonary fibrosis

: Idiopathic pulmonary fibrosis (IPF) is a paradigmatic aging-related lung disorder. In this retrospective cohort study, we evaluated 101 treatment-naïve patients at diagnosis (T0) and a subgroup (n = 31) after one year of antifibrotic therapy (T1). Analyses included leukocyte telomere length (LTL), DNA methylation age [DNAmAge assessed by Horvath, Levine (PhenoAge), Skin & Blood, Hannum, BLUP, Elastic Net (EN), and a 5-CpG panel], age acceleration (AgeAcc), and genetic susceptibility. At T1, LTL was independently predicted by baseline LTL (p = 0.0004) and treatment duration (p = 0.0056). Longitudinally, ΔLTL increased in nintedanib- versus pirfenidone-treated patients (p = 0.0402) and with treatment duration (p = 0.0233). DNAmAge modestly increased with chronological aging across all clocks, while AgeAcc remained stable, decreasing at follow-up (p = 0.0435) and higher in males (p = 0.0204). Genetic analyses on 17 IPF-associated SNPs confirmed enrichment of established risk variants, including MUC5B and DPP9, and identified an association between higher genetic burden and lower forced vital capacity (p = 0.0136). Extending this approach, genome-wide imputation enabled polygenic risk score (PRS) analysis, revealing significant case-control differences and discrimination (AUC up to 0.79), supporting a measurable polygenic contribution to disease susceptibility. These findings highlight the added value of integrating telomeric, epigenetic, and genome-wide genetic burden-captured through PRS-for improved risk stratification in IPF.