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Chronic obstructive pulmonary disease (COPD) is a highly prevalent and devastating condition for which no curative treatment is available. Exaggerated lung-cell senescence may contribute substantially to the pathogenesis of COPD. Here, we explored the potential role for the mTOR signaling pathway in cell senescence and lung alterations in COPD, using lung specimens and derived cultured cells from patients with COPD and from age- and sex-matched control smokers. Cell senescence in COPD was linked to mTOR activation, and mTOR inhibition by low-dose rapamycin prevented cell senescence and inhibited the pro-inflammatory senescence-associated secretory phenotype. To assess whether mTOR activation was causal in lung pathology, we generated mice with constitutive or conditional deletion of the tuberous sclerosis complex heterodimer TSC1 (a negative regulator of mTOR complex 1), in smooth muscle cells (SMCs), endothelial cells (ECs), or alveolar epithelial cells (AECs). In this model, mTOR activation was sufficient to induce early-onset replicative cell senescence in cultured pulmonary artery SMCs from mice with TSC1 deletion. Mice with conditional TSC1 deletion in ECs or AECs developed lung emphysema, pulmonary hypertension, and inflammation in the absence of any other stimuli and concomitantly with the accumulation of senescent lung cells. Rapamycin prevented all these effects. These results support causal links between mTOR activation, cell senescence, and lung alterations in COPD, thereby identifying the mTOR pathway as a new therapeutic target for COPD. Keywords: mTOR, senescence, COPD

Cell senescence, defined as a stable cell-cycle arrest combined with stereotyped phenotypic changes, might play a causal role in COPD. We previously reported that senescent cells are increased in lungs from patients with COPD and express a robust senescence-associated secretory phenotype (SASP), which is proinflammatory. Here, we investigated whether lung cell senescence in COPD was related to overactivation of the mTOR (mechanistic target of rapamycin) signaling pathway and whether targeting this pathway inhibited cell senescence and/or suppressed the SASP in COPD. Strong activation of the mTOR-Akt signaling pathway was found in lungs from patients with COPD compared to controls, with a marked PTEN decrease and activation of mTOR complex 1 (mTORC1) substrates, and of mTORC2 substrates, together with an increase in p21 and p16 protein levels. Similar activation of the mTORC1 and mTORC2 substrates were found in cultured PA-SMCs and P-ECs from patients with COPD compared to controls. Cultured P-ECs or PA-SMCs from patients with COPD exhibited an early onset of cell senescence as assessed by a decrease in the number of population doubling (PDLs).Treatment of the cells from patients with COPD with rapamycin (10 nM) normalized the number of PDLs to that seen in controls and decreased the number of beta-gal-positive cells. Cultured PA-SMCs from SM22-TSC1-/- mice, which exhibited strong mTORC1 activation in PA-SMCs, were characterized by an early onset of cell senescence compared to control mice.These results show that the increased propensity of lung cells to senescence in COPD is related to overactivation of the mTOR signaling pathway and can be suppressed by low doses of rapamycin.