Pathogenesis of idiopathic pulmonary fibrosis (IPF) involves alveolar injury, fibroblast accumulation and extracellular matrix (ECM) deposition, but the exact etiology is not known. Recently, metabolic perturbations were identified as potential drivers of fibrosis giving rise to new therapeutic approaches. The most common preclinical model for IPF is bleomycin-induced lung fibrosis in young mice. However, its translatability to the human disease is limited. One reason might be the common use of juvenile mice, resembling humans of around 20 years. In contrast, most often IPF patients are older than 60 years. To comprehensively identify changes in lung fibrosis depending on age we analyzed young (3 months) and old mice (21 months) 21 days after intratracheal bleomycin instillation by a multi-omics profiling approach. Transcriptomics and proteomics showed a similar response in young and old mice after Bleomycin treatment revealing hallmark pathways of IPF. Metabolomics data identified a turnover and repair response, seen by breakdown of proteins, nucleic acids, lipids, and ECM turnover. Cellular energy pathways were increased, like glycolysis, TCA cycle, and fatty acid oxidation. Strikingly, old mice showed a deranged protein homeostasis compared to young mice and an increased inflammatory state in the fibrotic phase. Together, our data revealed that young and old animals similarly develop molecular hallmarks of IPF. Metabolomic and lipidomic changes in fibrosis were reflecting higher energy demand and structural tissue remodeling, collagen deposition and inflammation. Our data builds a large knowledgebase to leverage for improving the link from potential therapeutic options to fibrotic lung diseases.
