Abstract
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.
Data availability
All data generated or analysed during this study are included in this published article and its supplementary information file.
References
Freund, A., Orjalo, A. V., Desprez, P. Y. & Campisi, J. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol. Med. 16, 238–246 (2010).
Munoz-Espin, D. & Serrano, M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 (2014).
Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013).
Childs, B. G. et al. Senescent cells: an emerging target for diseases of ageing. Nat. Rev. Drug Discov. https://doi.org/10.1038/nrd.2017.116 (2017).
Armanios, M. & Blackburn, E. H. The telomere syndromes. Nat. Rev. Genet. 13, 693–704 (2012).
Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).
Amsellem, V. et al. Telomere dysfunction causes sustained inflammation in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 184, 1358–1366 (2011).
Adnot, S. et al. Telomere dysfunction and cell senescence in chronic lung diseases: therapeutic potential. Pharmacol. Ther. 153, 125–134 (2015).
Schafer, M. J. et al. Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 8, 14532 (2017).
Armanios, M. Y. et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N. Engl. J. Med. 356, 1317–1326 (2007).
Stanley, S. E. et al. Telomerase mutations in smokers with severe emphysema. J. Clin. Invest 125, 563–570 (2014).
Selman, M., Martinez, F. J. & Pardo, A. Why does an aging smoker’s lung develop idiopathic pulmonary fibrosis and not chronic obstructive pulmonary disease?. Am. J. Respir. Crit. Care Med. 199, 279–285 (2019).
Houssaini, A. et al. mTOR pathway activation drives lung cell senescence and emphysema. JCI. Insight https://doi.org/10.1172/jci.insight.93203 (2018).
Plate, M., Guillotin, D. & Chambers, R. C. The promise of mTOR as a therapeutic target pathway in idiopathic pulmonary fibrosis. Eur. Respir. Rev. https://doi.org/10.1183/16000617.0269-2020 (2020).
Barnes, P. J. Senotherapy for lung diseases. Adv. Pharmacol. 98, 249–271 (2023).
Lipskaia, L. et al. mTert induction in p21-positive cells counteracts capillary rarefaction and pulmonary emphysema. EMBO Rep. 25, 1650–1684 (2024).
Calhoun, C. et al. Senescent cells contribute to the physiological remodeling of aged lungs. J. Gerontol. A Biol. Sci. Med. Sci. 71, 153–160 (2016).
Mannick, J. B. & Lamming, D. W. Targeting the biology of aging with mTOR inhibitors. Nat. Aging 3, 642–660 (2023).
Tse, C. et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 68, 3421–3428 (2008).
Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966–972 (2013).
Gil, J. The challenge of identifying senescent cells. Nat. Cell Biol. 25, 1554–1556 (2023).
Saul D, Jurk D, Doolittle ML, Kosinsky RL, Monroe DG, LeBrasseur NK, Robbins PD, Niedernhofer LJ, Khosla S, Passos JF. Distinct secretomes in p16- and p21- positive senescent cells across tissues. bioRxiv (2023).
Tao, W., Yu, Z. & Han, J. J. Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators. Cell Metab. 36(5), 1126–1143 (2024).
Romero, Y. et al. mTORC1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts. Aging Cell 15, 1103–1112 (2016).
Melo-Narvaez, M. C. et al. Stimuli-specific senescence of primary human lung fibroblasts modulates alveolar stem cell function. Cells https://doi.org/10.3390/cells13131129 (2024).
Lee JY, Reyes NS, Ravishankar S, Zhou M, Krasilnikov M, Ringler C, Pohan G, Wilson C, Ang KK, Wolters PJ, Tsukui T, Sheppard D, Arkin MR, Peng T. An in vivo screening platform identifies senolytic compounds that target p16INK4a+ fibroblasts in lung fibrosis. J Clin Invest 134 (2024)
Kortlever, R. M., Higgins, P. J. & Bernards, R. Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nat. Cell Biol. 8, 877–884 (2006).
Rana, T. et al. PAI-1 regulation of TGF-beta1-induced alveolar type II cell senescence, SASP secretion, and SASP-mediated activation of alveolar macrophages. Am. J. Respir. Cell Mol. Biol. 62, 319–330 (2020).
Wiley, C. D. et al. Secretion of leukotrienes by senescent lung fibroblasts promotes pulmonary fibrosis. JCI. Insight https://doi.org/10.1172/jci.insight.130056 (2019).
Hernandez-Gonzalez, F. et al. Human senescent fibroblasts trigger progressive lung fibrosis in mice. Aging (Albany NY) 15, 6641–6657 (2023).
Born E, Lipskaia L, Breau M, Houssaini A, Beaulieu D, Marcos E, Pierre R, Do Cruzeiro M, Derumeaux G, Delcroix M, Quarck R, Adnot S, Abid S. Eliminating senescent cells can promote pulmonary hypertension development and progression. Circulation in press. (2022)
Cottin, V. et al. Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity. Eur. Respir. J. 26, 586–593 (2005).
Gredic, M. et al. Combined pulmonary fibrosis and emphysema: When Scylla and Charybdis ally. Cells https://doi.org/10.3390/cells12091278 (2023).
Gauldie, J. et al. Smad3 signaling involved in pulmonary fibrosis and emphysema. Proc. Am. Thorac. Soc. 3, 696–702 (2006).
Xu, L., Bian, W., Gu, X. H. & Shen, C. Genetic polymorphism in matrix metalloproteinase-9 and transforming growth factor-beta1 and susceptibility to combined pulmonary fibrosis and emphysema in a Chinese population. Kaohsiung J. Med. Sci. 33, 124–129 (2017).
Liang, J. et al. Reciprocal interactions between alveolar progenitor dysfunction and aging promote lung fibrosis. Elife https://doi.org/10.7554/eLife.85415 (2023).
Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. Hallmarks of aging: an expanding universe. Cell 186, 243–278 (2023).
Grosse, L. et al. Defined p16(High) senescent cell types are indispensable for mouse healthspan. Cell Metab 32(87–99), e86 (2020).
Houssaini, A. et al. Selective tuberous sclerosis complex 1 gene deletion in smooth muscle activates mammalian target of rapamycin signaling and induces pulmonary hypertension. Am. J. Respir. Cell Mol. Biol. 55(3), 352–367 (2016).
Claxton, S. et al. Efficient, inducible Cre-recombinase activation in vascular endothelium. Genesis 46(2), 74–80 (2008).
Perl, A. K., Wert, S. E., Nagy, A., Lobe, C. G. & Whitsett, J. A. Early restriction of peripheral and proximal cell lineages during formation of the lung. Proc. Natl. Acad. Sci. U.S.A. 99(16), 10482–10487 (2002).
Knudsen, L., Weibel, E. R., Gundersen, H. J., Weinstein, F. V. & Ochs, M. Assessment of air space size characteristics by intercept (chord) measurement: an accurate and efficient stereological approach. J. Appl. Physiol. (1985) 108, 412–421 (2010).
Bancroft, J. D. & Gamble, M. Theory and practice of histological techniques 6th edn, 146–147 (Churchill Livingstone Elsevier, 2008).
Hubner, R. H. et al. Standardized quantification of pulmonary fibrosis in histological samples. Biotechniques 44(507–511), 514–507 (2008).
Acknowledgments
The authors are grateful to A. Lalot and D. Gelperowic from the Animal Facility and X. Decrouy, L. Wingertsmann, and W. Verbecq-Morlot from the Imaging Facility from the Institut Mondor de Recherche Biomédicale (IMRB) and Laura Kahnke from Institute for Lung Health, Justus Liebig University in Giessen. CJLS was supported by NIH grants R35HL150767 and U01HL134766 and California Institute for Regenerative Medicine grant DISC0-13788. We thank the researchers’ families and friends for their indispensable support, patience, and encouragement, which are essential to scientific discoveries. We also honor the memory of those who have passed away, whose memories inspire our efforts. Your love and support strengthen our determination in research. Thank you for being present and for playing a key role in the scientific community, your impact is immense and unforgettable.
Funding
CJLS was supported by NIH grants R35HL150767 and U01HL134766 and California Institute for Regenerative Medicine grant DISC0-13788. For other authors, no funding to declare.
Author information
Authors and Affiliations
Contributions
S.A. and C.JLS. conceived and supervised the study. S.A., C.JLS. and A.H. designed the experiments. A.H., S.A., E.B., D.R., R.S., G.D. and E.M. performed the animal experiments. A.H., V.G., M.G. and L.L. performed immunohistochemistry and immunofluorescence. A.H., E.M, J.J., H.N. and N.V. managed the lung preparations, interpretation of lung structure and assessment of pulmonary biological parameters. A.H. and D.R. performed the western blotting. S.A., A.H., G.D., L.B., and C.JLS. analyzed the resulting data. A.H. and E.M designed the figures, S.A. and C.JLS. drafted the manuscript. All the authors revised the manuscript and provided critical comments. S.A. and C.JLS. obtained fundings.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Houssaini, A., Marcos, E., Gros, V. et al. Lung mTOR activation leads to lung fibrosis or emphysema via senescence of specific lung cells. Sci Rep (2026). https://doi.org/10.1038/s41598-026-43628-z
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41598-026-43628-z
