Pharmacology of Senolytics for Lung Aging and COPD: An Emerging Therapeutic Frontier
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Abstract
Chronic obstructive pulmonary disease is strongly influenced by accelerated lung aging and an accumulation of senescent cells within airway epithelial and immune compartments. Senescent cells release a spectrum of inflammatory mediators that worsen tissue destruction and impair repair mechanisms. Conventional COPD therapeutics do not adequately address cellular senescence, which has led to growing interest in senolytic drugs that selectively eliminate senescent cells or reduce harmful secretory signaling. Several senolytic candidates, including Dasatinib–Quercetin, Fisetin, Navitoclax, HSP90 inhibitors, and peptide-based approaches, have demonstrated promising effects in preclinical respiratory models. These agents modulate pathways such as BCL-2 inhibition, suppression of PI3K/AKT signaling, activation of mitochondrial apoptosis, or disruption of FOXO4–p53 interactions. Early studies suggest potential for reducing chronic inflammation, restoring epithelial function, and slowing structural deterioration in the lung. Although human evidence remains limited and concerns surrounding toxicity, delivery, and biomarker development persist, senolytics represent an emerging pharmacological avenue for targeting lung aging and may hold therapeutic value in COPD.
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Barnes PJ. Cellular and molecular mechanisms of chronic obstructive pulmonary disease. Clin Chest Med. 2014;35(1):71–86. Available from: https://doi.org/10.1016/j.ccm.2013.10.004 DOI: https://doi.org/10.1016/j.ccm.2013.10.004
Tsuji T, Aoshiba K, Nagai A. Alveolar cell senescence in aging and chronic lung diseases. Respir Investig. 2012;50(1):30–37.
Birch J, Passos JF. Targeting the SASP to combat ageing: Mitochondria as possible intracellular allies? Bioessays. 2017;39(5):1600235. Available from: https://doi.org/10.1002/bies.201600235 DOI: https://doi.org/10.1002/bies.201600235
Kirkland JL, Tchkonia T. Cellular senescence: A translational perspective. EBioMedicine. 2017;21:21–28. Available from: https://doi.org/10.1016/j.ebiom.2017.04.013 DOI: https://doi.org/10.1016/j.ebiom.2017.04.013
Nyunoya T, Monick MM, Klingelhutz A, Yarovinsky TO, Cagley JR, Hunninghake GW. Cigarette smoke–induced cellular senescence in the lung. Am J Respir Cell Mol Biol. 2014;51(3):361–369. Available from: https://doi.org/10.1165/rcmb.2006-0169oc DOI: https://doi.org/10.1165/rcmb.2006-0169OC
Sharpless NE, Sherr CJ. Forging a signature of in vivo senescence. Nat Rev Cancer. 2015;15(7):397–408. Available from: https://doi.org/10.1038/nrc3960 DOI: https://doi.org/10.1038/nrc3960
Coppe JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: The dark side of tumor suppression. Annu Rev Pathol. 2010;5:99–118. Available from: https://doi.org/10.1146/annurev-pathol-121808-102144 DOI: https://doi.org/10.1146/annurev-pathol-121808-102144
Walters MS. Airway epithelial senescence in COPD. Am J Physiol Lung Cell Mol Physiol. 2014;306(5):L364–L370.
Sohal SS. Epithelial and endothelial cell senescence in COPD. Chest. 2020;158(2):476–488. Available from: https://doi.org/10.1016/j.resinv.2016.11.006 DOI: https://doi.org/10.1016/j.resinv.2016.11.006
Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, et al. The Achilles’ heel of senescent cells: Targeting anti-apoptotic pathways. Aging Cell. 2015;14(4):644–658. Available from: https://doi.org/10.1111/acel.12344 DOI: https://doi.org/10.1111/acel.12344
Chilosi M, Carloni A. Cellular senescence and chronic lung disease. Curr Opin Pharmacol. 2021;56:1–9.
Houssaini A. Senescence in pulmonary diseases. Eur Respir Rev. 2021;30(159):200261.
Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, et al. Dasatinib and quercetin as senolytics. Nature Med. 2018;24(8):1246–1256. DOI: https://doi.org/10.1038/s41591-018-0092-9
Schafer MJ. Senolytics improve lung function in aged mice. Aging Cell. 2017;16(5):973–977.
Kirkland JL. Intermittent senolytic dosing. J Am Geriatr Soc. 2020;68(S2):S7–S13.
Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, et al. Fisetin is a senotherapeutic compound. EBioMedicine. 2018;36:18–28. Available from: https://doi.org/10.1016/j.ebiom.2018.09.015 DOI: https://doi.org/10.1016/j.ebiom.2018.09.015
Yosef R. Navitoclax as a senolytic agent. Nat Commun. 2016;7:11190. DOI: https://doi.org/10.1038/ncomms11190
Lehmann M. Senolytic therapy in lung fibrosis. Nat Commun. 2017;8:14532.
Rudin CM. Navitoclax toxicity profile. J Clin Oncol. 2012;30(9):1002–1008.
Baar MP. FOXO4–DRI peptide targets senescent cells. Cell. 2017;169(1):132–147.
Parikh P. FOXO4 modulation in pulmonary senescence. Respir Res. 2019;20(1):254.
Kulkarni AS, Gubbi S, Barzilai N. Metformin in aging biology. Cell Metab. 2020;32(1):15–25. DOI: https://doi.org/10.1016/j.cmet.2020.04.001
Houssaini A. mTOR signaling in lung aging. Sci Transl Med. 2018;10(449):eaao4163.
Fuhrmann-Stroissnigg H, et al. HSP90 inhibitors as senolytics. Cell Rep. 2017;21(1):199–208.
Li J. USP7 inhibition promotes senolysis. Aging Cell. 2021;20(1):e13305.
Chapman J. Mitochondrial-targeting senolytics. Geroscience. 2022;44(2):885–900.
Yan J. AI-driven identification of senolytics. Nat Biotechnol. 2023;41(2):216–225.
Chuang HC. Senolytics in cigarette smoke–induced models. Environ Pollut. 2022;292:118369.
Birukova A. Senolytic modulation of airspace enlargement. Am J Respir Crit Care Med. 2023;207(4):449–460.
Lin W. Macrophage senescence in COPD models. J Transl Med. 2021;19(1):236.
Lin W. Macrophage senescence in COPD models. J Transl Med. 2021;19(1):236.
Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK, et al. Senolytics in pulmonary fibrosis patients. EBioMedicine. 2019;40:554–563. Available from: https://doi.org/10.1016/j.ebiom.2018.12.052
Mehdizadeh M. Clinical challenges of senolytics. Drugs Aging. 2022;39(2):127–141.
Li X. Inhalable senolytics for lung diseases. Adv Drug Deliv Rev. 2023;198:114903.
Ramanathan S. Nanocarrier-based senolytics. Int J Pharm. 2024;635:122897.
Ashkenazi A. Mechanisms of Navitoclax toxicity. Cell Death Dis. 2020;11(9):712.
Narita M. Senescence biomarkers in clinical research. Nat Rev Mol Cell Biol. 2019;20(11):671–684. DOI: https://doi.org/10.1038/s41580-019-0156-9
Childs BG. Risks of senolytic therapy. Nat Med. 2015;21(12):1424–1435.
Vasto S. Ethics of senolytic treatment. Aging Clin Exp Res. 2023;35:1607–1614.
Fini MA. Combination senolytic strategies. J Mol Med. 2024;102:1501–1512.
Wang C. Biomarkers for senescence-targeted therapy. Trends Pharmacol Sci. 2024;45(3):217–229.
Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, et al. Identification of a novel senolytic agent targeting the BCL-2 family of anti-apoptotic factors. Aging Cell. 2016;15(3):428–435. Available from: https://doi.org/10.1111/acel.12445 DOI: https://doi.org/10.1111/acel.12445
Kirkland JL, Tchkonia T. Senolytic drugs: From discovery to translation. J Intern Med. 2020;288(5):518–536. Available from: https://doi.org/10.1111/joim.13141 DOI: https://doi.org/10.1111/joim.13141
Baar MP, Brandt RMC, Putavet DA, Klein JD, Derks KWJ, Bourgeois BRM, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell. 2017;169(1):132–147.e16. Available from: https://doi.org/10.1016/j.cell.2017.02.031 DOI: https://doi.org/10.1016/j.cell.2017.02.031
Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol. 2018;28(6):436–453. Available from: https://doi.org/10.1016/j.tcb.2018.02.001 DOI: https://doi.org/10.1016/j.tcb.2018.02.001
Ito K, Barnes PJ. COPD is a disease of accelerated lung aging. Chest. 2009;135(1):173–180. Available from: https://doi.org/10.1378/chest.08-1419 DOI: https://doi.org/10.1378/chest.08-1419
Tsuji T, Aoshiba K, Nagai A. Alveolar cell senescence in aging and chronic lung diseases. Respir Investig. 2012;50(1):30–37. Available from: https://doi.org/10.1164/rccm.200509-1374oc DOI: https://doi.org/10.1164/rccm.200509-1374OC
Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age-related disease: From mechanisms to therapy. Nat Med. 2015;21(12):1424–1435. Available from: https://doi.org/10.1038/nm.4000 DOI: https://doi.org/10.1038/nm.4000
Niedernhofer LJ, Kirkland JL, Ladiges W. Molecular pathology endpoints useful for aging studies. Nat Rev Drug Discov. 2018;17(5):377–377. DOI: https://doi.org/10.1038/nrd.2018.44
Fini MA, Monzon ME, Campos M, Declerck YA. Combination senolytic strategies in chronic lung diseases. J Mol Med. 2024;102(11):1501–1512.
Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK, et al. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human pilot study. EBioMedicine. 2019;40:554–563. Available from: https://doi.org/10.1016/j.ebiom.2018.12.052 DOI: https://doi.org/10.1016/j.ebiom.2018.12.052
Mehdizadeh M, Aguilar M, Thorin E. Clinical challenges and translational considerations of senolytic therapy. Drugs Aging. 2022;39(2):127–141.
Li X, Wu Y, Chen J, Zhang M, Gong L. Inhalable delivery systems for senolytic therapy in lung diseases. Adv Drug Deliv Rev. 2023;198:114903.
Ramanathan S, Subramanian R, Iyer AKV. Nanocarrier-based pulmonary delivery of senotherapeutics: Emerging strategies. Int J Pharm. 2024;635:122897.