Codonopsis tangshen Attenuates Age-Related Pulmonary Fibrosis through Senescence and Gut–Lung Axis Modulation

Background: Cellular senescence is a critical driver of chronic inflammation, tissue remodeling, and progressive fibrosis during the aging process. Codonopsis tangshen Oliv. is a widely used medicinal and edible homologous plant in traditional Chinese medicine; however, its pharmacological effects on natural aging and age-related pulmonary fibrosis, as well as the underlying mechanisms, are still not fully elucidated. Methods: C57BL/6J mice were randomly divided into five groups: young control (YCtrl), natural-age control (OCtrl), high-dose CT (H-O-CT, 20.8 g/kg), low-dose CT (L-O-CT, 10.4 g/kg), and positive drug YPF (O-YPF, 20.8 g/kg), with n = 10 per group. A bleomycin-induced cellular senescence model in A549 cells was established in vitro to provide complementary evidence. Additionally, the composition of gut microbiota and the expression of intestinal barrier markers were analyzed to explore potential gut–lung axis involvement. Results: The results demonstrated that C. tangshen extract significantly decreased the histological and molecular markers of pulmonary senescence, ameliorated multiple lung function parameters, and attenuated age-related pulmonary fibrosis in aged mice. Transcriptomic analysis and protein validation further revealed that these protective effects were associated with modulation of the FBXW7/TPP1 and HSF1/HSP70 signaling pathways. Moreover, the extract reshaped the gut microbiota composition and enhanced the expression of intestinal MUC2 and tight-junction proteins, which supports possible involvement of the gut–lung axis. Conclusions: These results highlight the potential of Codonopsis tangshen Oliv. as a promising preclinical treatment for the intervention and management of aging and age-related fibrotic lung injury.