Lung mTOR activation leads to lung fibrosis or emphysema via senescence of specific lung cells.

Exaggerated cellular senescence contributes to pulmonary emphysema and fibrosis, yet the mechanisms driving these distinct disease phenotypes remain poorly understood. This study aimed to investigate whether activation of the mammalian target of rapamycin (mTOR) induces senescence in specific lung cell types, promoting emphysema or fibrosis, and whether similar mechanisms are active in aging. To explore this, we generated mice with conditional deletion of TSC1, a negative regulator of the mTOR complex 1, in fibroblasts (SM22-TSC1–/– mice), endothelial cells (PDGF-TSC1–/– mice), or alveolar epithelial cells (SPC-TSC1–/– mice). Compared to their respective littermate controls, SM22-TSC1–/– mice developed pulmonary fibrosis, PDGF-TSC1–/– mice exhibited emphysematous changes, and SPC-TSC1–/– mice manifested a mixed phenotype of emphysema and fibrosis. All models showed elevated expression of senescence markers (p16, p21, γH2AX) and phosphorylated mTORC1 substrates (pAktSer473, pGSK3, and pS6K), which were all abrogated by treatment with the senolytic agent ABT-263. In contrast, ABT-263 treatment of aged mice exhibiting spontaneous emphysema, fibrosis, and mTOR activation, marginally improved the lung pathology. These findings demonstrate that cell type–specific mTOR activation drives distinct senescence-associated lung pathologies, implicating mTOR-mediated senescence as a central, yet only partially reversible, mechanism in age-related pulmonary disease.