Telomere Integrity, Epigenetic Aging, and Genetic Burden Shape Biological Aging Trajectories in Idiopathic Pulmonary Fibrosis
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Idiopathic pulmonary fibrosis (IPF) is a paradigmatic aging-related lung disorder. We studied 101 treatment-naïve patients at diagnosis (T0) and a subgroup (n = 31) after one year of antifibrotic therapy (T1) including leukocyte telomere length (LTL), DNA methylation age (DNAmAge by Horvath, Levine/PhenoAge, and a 5-CpGs panel), age acceleration (AgeAcc), and 17 IPF-associated SNPs summarized as Effect Allele Count (EAC). Multiple regression models showed that at T1, LTL was independently predicted by baseline LTL (p = 0.0004) and treatment duration (p = 0.0056). ΔLTL increased in nintedanib- versus pirfenidone-treated patients (p = 0.0402) and with treatment duration (p = 0.0233). ΔAgeAcc decreased at follow-up (p = 0.0435), while was higher in males (p = 0.0204). Among epigenetic clocks, Levine’s PhenoAge was the most therapy-responsive (p < 0.0001), whereas the 5-CpGs panel show clinical scalability. Genotyping revealed enrichment of MUC5B , TERT , TOLLIP , DPP9 , and ATP11A variants, and higher EAC associated with lower FVC (p = 0.0136). These findings frame IPF as an aging-aligned disorder and support biomarker-informed precision medicine.
