An epithelial-derived epigenetic clock reveals pathway-level aging mechanisms in chronic lung disease

Biological aging is strongly associated with tissue vulnerability in the respiratory system, yet existing epigenetic clocks remain limited by insufficient tissue specificity and poor mechanistic interpretability. We developed and validated tissue-specific PathwayAge clocks for airway epithelium and pulmonary parenchyma by projecting DNA methylation profiles onto gene ontology pathways. The epithelial clock yielded a mean absolute error (MAE) of 2.86, and a Pearson correlation (Rho) of 0.97, and the parenchymal clock remained consistent (MAE = 4.36–4.60; Rho = 0.889–0.899) across independent cohorts. Pathway-level analyses revealed distinct tissue-specific aging architectures. Epithelial aging was characterized by dysregulation of ABL1-, SOX9-, and MEF2C-centered pathways governing cell adhesion, apoptosis, and morphogenetic stability, suggesting early loss of adhesion-mediated signaling fidelity as a hallmark of epithelial aging. In contrast, pulmonary parenchymal aging was shaped by coordinated rewiring of developmental, cytoskeletal, inflammatory, and metabolic programs involving SOX4, WNT3A, LRRK2, HIPK2, EXT1, and TNF, consistent with a transition toward a pro-inflammatory and metabolically fragile state. Age acceleration further correlated with key clinical indices, including smoking burden, inhaled corticosteroid exposure, serum IgE levels, and disease severity. Convergent pathway association analyses identified shared disease mechanisms centered on impaired epithelial regeneration, sustained inflammatory activation, and maladaptive extracellular matrix remodeling.