{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T21:37:41Z","timestamp":1793655461531,"version":"4.5.1"},"reference-count":117,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"SDSU Big Idea Grant"},{"name":"SDSU Innovation grant"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Age-related chronic, low-grade inflammation, known as inflammaging, contributes to tissue damage and disease. In the lungs, inflammaging leads to abnormal tissue remodeling, reduced function, and decreased immunity. A key factor in inflammaging is declining acetylcholine signaling, which normally suppresses inflammation and promotes tissue repair. We tested whether increasing acetylcholine responsiveness could reverse age-related lung damage. Aged mice were treated with donepezil to increase acetylcholine availability. After six months, blood oxygen saturation and voluntary activity were significantly improved. Histologically, treated mice showed a reversal of alveolar enlargement (a hallmark of emphysema) and complete restoration of elastic fibers. Donepezil treatment also dramatically increased bronchus-associated lymphoid tissue (iBALT) formation. iBALT is the repository of tissue-resident memory lymphocytes, including memory cholinergic lymphocytes that produce acetylcholine to suppress inflammation during secondary infections. The age-related loss of iBALT contributes to the increased risks associated with respiratory infection in the elderly. This indicates that age-related lung function and respiratory immune deficits can be modulated by improving acetylcholine signaling. Repurposing an approved medication provides a direct pathway to clinical application for improving respiratory health and infection resistance during aging.<\/jats:p>","DOI":"10.3390\/biology15030270","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T09:00:58Z","timestamp":1770109258000},"page":"270","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Acetylcholinesterase Inhibition Reverses Age-Related Pulmonary Decline and Increases Bronchus-Associated Lymphoid Tissue Formation in Aged Mice"],"prefix":"10.3390","volume":"15","author":[{"given":"Kyle","family":"Kenny","sequence":"first","affiliation":[{"name":"Department of Biology, San Diego State University, San Diego, CA 92182, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid R.","family":"Niesman","sequence":"additional","affiliation":[{"name":"Department of Biology, San Diego State University, San Diego, CA 92182, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0172-9369","authenticated-orcid":false,"given":"Kee S.","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering, San Diego State University, San Diego, CA 92182, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0104-4799","authenticated-orcid":false,"given":"Mark","family":"Sussman","sequence":"additional","affiliation":[{"name":"Department of Biology, San Diego State University, San Diego, CA 92182, USA"},{"name":"SDSU Integrated Regenerative Research Institute, San Diego, CA 92182, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6490-9932","authenticated-orcid":false,"given":"Morgan K.","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Biology, San Diego State University, San Diego, CA 92182, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4912-3760","authenticated-orcid":false,"given":"Dylan","family":"Dawood","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3074-7696","authenticated-orcid":false,"given":"Joy A.","family":"Phillips","sequence":"additional","affiliation":[{"name":"Department of Biology, San Diego State University, San Diego, CA 92182, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"533","DOI":"10.4103\/0019-5049.165849","article-title":"Anatomy and physiology of respiratory system relevant to anaesthesia","volume":"59","author":"Patwa","year":"2015","journal-title":"Indian J. Anaesth."},{"key":"ref_2","first-page":"379","article-title":"Internal surface area of normal and emphysematous lungs","volume":"10","author":"Thurlbeck","year":"1967","journal-title":"Aspen Emphysema Conf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1152\/japplphysiol.01087.2004","article-title":"Biomechanics of the lung parenchyma: Critical roles of collagen and mechanical forces","volume":"98","author":"Suki","year":"2005","journal-title":"J. Appl. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1111\/bph.15759","article-title":"Inflammation, ageing and diseases of the lung: Potential therapeutic strategies from shared biological pathways","volume":"179","author":"Faniyi","year":"2022","journal-title":"Br. J. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Bou Jawde, S., Takahashi, A., Bates, J.H.T., and Suki, B. (2020). An Analytical Model for Estimating Alveolar Wall Elastic Moduli From Lung Tissue Uniaxial Stress-Strain Curves. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.00121"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S213","DOI":"10.1097\/01.CCM.0000057846.21303.AB","article-title":"Coagulation, fibrinolysis, and fibrin deposition in acute lung injury","volume":"31","author":"Idell","year":"2003","journal-title":"Crit. Care Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.tem.2016.09.005","article-title":"Inflammaging and \u2018Garb-aging\u2019","volume":"28","author":"Franceschi","year":"2017","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"afac328","DOI":"10.1093\/ageing\/afac328","article-title":"Inflammaging as a target for healthy ageing","volume":"52","author":"Dugan","year":"2023","journal-title":"Age Ageing"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s12016-021-08899-6","article-title":"Immunology of Aging: The Birth of Inflammaging","volume":"64","author":"Fulop","year":"2023","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_10","first-page":"100","article-title":"Pulmonary surfactant","volume":"66","author":"Murakami","year":"1971","journal-title":"Nihon Ishikai Zasshi"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1146\/annurev-physiol-021119-034610","article-title":"Aging and Lung Disease","volume":"82","author":"Cho","year":"2020","journal-title":"Annu. Rev. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Zuo, L., Prather, E.R., Stetskiv, M., Garrison, D.E., Meade, J.R., Peace, T.I., and Zhou, T. (2019). Inflammaging and oxidative stress in human diseases: From molecular mechanisms to novel treatments. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184472"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1165\/rcmb.2023-0176PS","article-title":"Extracellular Matrix as a Driver of Chronic Lung Diseases","volume":"70","author":"Burgess","year":"2024","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1136\/thx.48.1.39","article-title":"Airspace size in lungs of lifelong non-smokers: Effect of age and sex","volume":"48","author":"Gillooly","year":"1993","journal-title":"Thorax"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1513\/pats.200603-054MS","article-title":"State of the art. Cellular and molecular mechanisms of alveolar destruction in emphysema: An evolutionary perspective","volume":"3","author":"Tuder","year":"2006","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"253","DOI":"10.2147\/ciia.2006.1.3.253","article-title":"Effect of aging on respiratory system physiology and immunology","volume":"1","author":"Sharma","year":"2006","journal-title":"Clin. Interv. Aging"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1016\/j.rmed.2008.04.013","article-title":"Aging and induced senescence as factors in the pathogenesis of lung emphysema","volume":"102","author":"Karrasch","year":"2008","journal-title":"Respir. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"20897","DOI":"10.1074\/jbc.M117.792416","article-title":"Mechanisms and modulation of microvesicle uptake in a model of alveolar cell communication","volume":"292","author":"Schneider","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1183\/09031936.99.14614549","article-title":"Physiological changes in respiratory function associated with ageing","volume":"13","author":"Janssens","year":"1999","journal-title":"Eur. Respir. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0079-6336(87)80004-9","article-title":"Cytochemistry of the gas-exchange area in vertebrate lungs","volume":"17","author":"Meban","year":"1987","journal-title":"Prog. Histochem. Cytochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.cger.2017.06.001","article-title":"The Effects of Aging on Lung Structure and Function","volume":"33","author":"Skloot","year":"2017","journal-title":"Clin. Geriatr. Med."},{"key":"ref_22","first-page":"L487","article-title":"Mechanisms of fibrin formation and lysis by human lung fibroblasts: Influence of TGF-beta and TNF-alpha","volume":"263","author":"Idell","year":"1992","journal-title":"Am. J. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"101422","DOI":"10.1016\/j.arr.2021.101422","article-title":"Immunosenescence and inflammaging in the aging process: Age-related diseases or longevity?","volume":"71","author":"Santoro","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Soma, T., and Nagata, M. (2022). Immunosenescence, Inflammaging, and Lung Senescence in Asthma in the Elderly. Biomolecules, 12.","DOI":"10.3390\/biom12101456"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.imlet.2014.06.006","article-title":"Immunosenescence and vaccine failure in the elderly: Strategies for improving response","volume":"162","author":"Boraschi","year":"2014","journal-title":"Immunol. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1080\/21645515.2017.1343226","article-title":"Influenza vaccination in the elderly","volume":"14","author":"Smetana","year":"2018","journal-title":"Hum. Vaccin. Immunother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1093\/ilar.47.1.22","article-title":"Use of transgenic mice to study lung morphogenesis and function","volume":"47","author":"Bridges","year":"2006","journal-title":"ILAR J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.pharmthera.2007.05.007","article-title":"The non-neuronal cholinergic system in the airways: An unappreciated regulatory role in pulmonary inflammation?","volume":"115","author":"Gwilt","year":"2007","journal-title":"Pharmacol. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"681258","DOI":"10.1155\/2012\/681258","article-title":"Cholinergic regulation of airway inflammation and remodelling","volume":"2012","author":"Kolahian","year":"2012","journal-title":"J. Allergy"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s10020-020-00184-0","article-title":"The cholinergic anti-inflammatory pathway alleviates acute lung injury","volume":"26","author":"Andersson","year":"2020","journal-title":"Mol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Foulad, D.P., Cirillo, N., and Grando, S.A. (2023). The Role of Non-Neuronal Acetylcholine in the Autoimmune Blistering Disease Pemphigus Vulgaris. Biology, 12.","DOI":"10.3390\/biology12030354"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Kakinuma, Y. (2024). Non-neuronal cholinergic system in the heart influences its homeostasis and an extra-cardiac site, the blood-brain barrier. Front. Cardiovasc. Med., 11.","DOI":"10.3389\/fcvm.2024.1384637"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Sonobe, T., and Kakinuma, Y. (2024). Non-neuronal cell-derived acetylcholine, a key modulator of the vascular endothelial function in health and disease. Front. Cardiovasc. Med., 11.","DOI":"10.3389\/fcvm.2024.1388528"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s00418-008-0455-2","article-title":"The epithelial cholinergic system of the airways","volume":"130","author":"Kummer","year":"2008","journal-title":"Histochem. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.coph.2014.03.001","article-title":"Non-neuronal cholinergic airway epithelium biology","volume":"16","author":"Kummer","year":"2014","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jphs.2017.05.002","article-title":"Physiological functions of the cholinergic system in immune cells","volume":"134","author":"Fujii","year":"2017","journal-title":"J. Pharmacol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e2402143121","DOI":"10.1073\/pnas.2402143121","article-title":"Cholinergic macrophages promote the resolution of peritoneal inflammation","volume":"121","author":"Luo","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Li, H., Wang, Y., Duan, H., Bao, Y., Deng, X., He, Y., Gao, Q., Li, P., and Liu, X. (2025). Immune cell regulatory networks in chronic obstructive pulmonary disease: Mechanistic analysis from innate to adaptive immunity. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1651808"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1093\/qjmed\/hcy154","article-title":"Neuroimmune regulation of lung infection and inflammation","volume":"112","author":"Huang","year":"2019","journal-title":"QJM"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Roa-Vidal, N., Rodriguez-Aponte, A.S., Lasalde-Dominicci, J.A., Capo-Velez, C.M., and Delgado-Velez, M. (2023). Cholinergic Polarization of Human Macrophages. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202309.1647.v1"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Cunha, L.L., Perazzio, S.F., Azzi, J., Cravedi, P., and Riella, L.V. (2020). Remodeling of the Immune Response With Aging: Immunosenescence and Its Potential Impact on COVID-19 Immune Response. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01748"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e162547","DOI":"10.1172\/jci.insight.162547","article-title":"alpha7nAChR activation in AT2 cells promotes alveolar regeneration through WNT7B signaling in acute lung injury","volume":"8","author":"Chen","year":"2023","journal-title":"JCI Insight"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"100696","DOI":"10.1016\/j.xcrm.2022.100696","article-title":"Manipulation of the inflammatory reflex as a therapeutic strategy","volume":"3","author":"Kelly","year":"2022","journal-title":"Cell Rep. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"ofac492.928","DOI":"10.1093\/ofid\/ofac492.928","article-title":"1088. Evaluating the Effect of Donepezil on Mortality Among Alzheimer\u2019s Disease Patients With and Without COVID-19 Infection","volume":"9","author":"Bej","year":"2022","journal-title":"Open Forum Infect. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1111\/ggi.13177","article-title":"Donepezil is associated with decreased in-hospital mortality as a result of pneumonia among older patients with dementia: A retrospective cohort study","volume":"18","author":"Abe","year":"2018","journal-title":"Geriatr. Gerontol. Int."},{"key":"ref_46","first-page":"20499361231174289","article-title":"Donepezil-associated survival benefits among Alzheimer\u2019s disease patients are retained but not enhanced during COVID-19 infections","volume":"10","author":"Edmiston","year":"2023","journal-title":"Ther. Adv. Infect. Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/s11095-007-9362-9","article-title":"Decreased biosynthesis of lung surfactant constituent phosphatidylcholine due to inhibition of choline transporter by gefitinib in lung alveolar cells","volume":"25","author":"Ishiguro","year":"2008","journal-title":"Pharm. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3025","DOI":"10.1172\/JCI68782","article-title":"Type 2 alveolar cells are stem cells in adult lung","volume":"123","author":"Barkauskas","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1016\/j.immuni.2022.08.010","article-title":"Biology of lung macrophages in health and disease","volume":"55","author":"Aegerter","year":"2022","journal-title":"Immunity"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/s41577-019-0240-6","article-title":"Efferocytosis in health and disease","volume":"20","author":"Doran","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1080\/09629359990711","article-title":"Evaluation of inflammatory cytokine secretion by human alveolar macrophages","volume":"8","author":"Rodriguez","year":"1999","journal-title":"Mediators Inflamm."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Rossi, J.F., Lu, Z.Y., Massart, C., and Levon, K. (2021). Dynamic Immune\/Inflammation Precision Medicine: The Good and the Bad Inflammation in Infection and Cancer. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.595722"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"16063","DOI":"10.1038\/cddiscovery.2016.63","article-title":"Targeting the non-neuronal cholinergic system in macrophages for the management of infectious diseases and cancer: Challenge and promise","volume":"2","author":"Reichrath","year":"2016","journal-title":"Cell Death Discov."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"L715","DOI":"10.1152\/ajplung.00361.2009","article-title":"Epithelial repair mechanisms in the lung","volume":"298","author":"Crosby","year":"2010","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1164\/rccm.200509-1434OC","article-title":"Alteration of fibroblast architecture and loss of Basal lamina apertures in human emphysematous lung","volume":"173","author":"Sirianni","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/nature25786","article-title":"Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor","volume":"555","author":"Zacharias","year":"2018","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/978-1-59259-921-9_15","article-title":"Methods of lung fixation","volume":"4","author":"Hausmann","year":"2006","journal-title":"Forensic Pathol. Rev."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"An, Y.H., and Martin, K.L. (2003). Principles of Embedding and Common Protocols. Handbook of Histology Methods for Bone and Cartilage, Humana Press. [1st ed.].","DOI":"10.1007\/978-1-59259-417-7_11"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1101\/pdb.prot073411","article-title":"Manual hematoxylin and eosin staining of mouse tissue sections","volume":"2014","author":"Cardiff","year":"2014","journal-title":"Cold Spring Harb. Protoc."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1056\/NEJMoa032158","article-title":"The nature of small-airway obstruction in chronic obstructive pulmonary disease","volume":"350","author":"Hogg","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.yexmp.2005.04.006","article-title":"Deficient innervation characterizes intestinal strictures in a rat model of colitis","volume":"80","author":"Marlow","year":"2006","journal-title":"Exp. Mol. Pathol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.pharmthera.2018.02.010","article-title":"Safer approaches to therapeutic modulation of TGF-beta signaling for respiratory disease","volume":"187","author":"Lachapelle","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"34","DOI":"10.2119\/molmed.2016.00083","article-title":"Deficiency of alpha7 nicotinic acetylcholine receptor attenuates bleomycin-induced lung fibrosis in mice","volume":"23","author":"Sun","year":"2017","journal-title":"Mol. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1183\/09031936.00186914","article-title":"Hallmarks of the ageing lung","volume":"45","author":"Meiners","year":"2015","journal-title":"Eur. Respir. J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"105581","DOI":"10.1016\/j.jmbbm.2022.105581","article-title":"Characterization of mechanical properties of soft tissues using sub-microscale tensile testing and 3D-Printed sample holder","volume":"138","author":"Kang","year":"2023","journal-title":"J. Mech. Behav. Biomed. Mater."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1007\/s40520-019-01359-4","article-title":"Acetylcholinesterase inhibitors targeting the cholinergic anti-inflammatory pathway: A new therapeutic perspective in aging-related disorders","volume":"33","author":"Benfante","year":"2021","journal-title":"Aging Clin. Exp. Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"L53","DOI":"10.1152\/ajplung.00179.2022","article-title":"The diversity of neuroimmune circuits controlling lung inflammation","volume":"324","author":"Cremin","year":"2023","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.coph.2017.12.003","article-title":"The cholinergic anti-inflammatory pathway: An innovative treatment strategy for respiratory diseases and their comorbidities","volume":"40","author":"Yamada","year":"2018","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1006\/pupt.2001.0313","article-title":"The Non-neuronal cholinergic system: An emerging drug target in the airways","volume":"14","author":"Wessler","year":"2001","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1007\/s11136-012-0206-7","article-title":"Health-related quality of life among adults with work-related asthma in the United States","volume":"22","author":"Knoeller","year":"2013","journal-title":"Qual. Life Res."},{"key":"ref_71","first-page":"1","article-title":"Repurposing donepezil to treat COVID-19: A call for retrospective analysis of existing patient datasets","volume":"2","author":"Phillips","year":"2021","journal-title":"J. Clin. Immunol. Microbiol."},{"key":"ref_72","first-page":"20140210","article-title":"Wheel running in the wild","volume":"281","author":"Meijer","year":"2014","journal-title":"Proc. Biol. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1152\/ajplegacy.1898.1.1.40","article-title":"Variations in Daily Activity Produced by Alcohol and by Changes in Barometric Pressure and Diet, with a Description of Recording Methods","volume":"1","author":"Stewart","year":"1898","journal-title":"Am. J. Physiol.-Leg. Content"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1002\/9780470942390.mo140295","article-title":"Voluntary Wheel Running in Mice","volume":"5","author":"Goh","year":"2015","journal-title":"Curr. Protoc. Mouse Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0889-8561(02)00056-5","article-title":"Age-related inflammatory cytokines and disease","volume":"23","author":"Bruunsgaard","year":"2003","journal-title":"Immunol. Allergy Clin. North Am."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1111\/ene.13872","article-title":"Donepezil for gait and falls in mild cognitive impairment: A randomized controlled trial","volume":"26","author":"Speechley","year":"2019","journal-title":"Eur. J. Neurol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1080\/23279095.2023.2172681","article-title":"Investigation of the gait parameters after donepezil treatment in patients with alzheimer\u2019 s disease","volume":"32","author":"Bizpinar","year":"2025","journal-title":"Appl. Neuropsychol. Adult"},{"key":"ref_78","first-page":"193","article-title":"Donepezil improves gait performance in older adults with mild Alzheimer\u2019s disease: A phase II clinical trial","volume":"43","author":"Gopaul","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s40266-014-0175-3","article-title":"Gait changes with anti-dementia drugs: A prospective, open-label study combining single and dual task assessments in patients with Alzheimer\u2019s disease","volume":"31","author":"Beauchet","year":"2014","journal-title":"Drugs Aging"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1111\/j.1532-5415.2008.01657.x","article-title":"Galantamine improves gait performance in patients with Alzheimer\u2019s disease","volume":"56","author":"Assal","year":"2008","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1093\/gerona\/60.10.1304","article-title":"Gait velocity as a single predictor of adverse events in healthy seniors aged 75 years and older","volume":"60","author":"Schapira","year":"2005","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1157\/13081247","article-title":"Efficacy of the 6-minute walk test in evaluating ambulatory oxygen therapy","volume":"41","author":"Morante","year":"2005","journal-title":"Arch. Bronconeumol."},{"key":"ref_83","first-page":"110","article-title":"Six-minute walk test: A valuable tool for assessing pulmonary impairment","volume":"37","author":"Zamboni","year":"2011","journal-title":"J. Bras. Pneumol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/j.rmed.2005.08.003","article-title":"Six minute walk distance in healthy subjects aged 55\u201375 years","volume":"100","author":"Camarri","year":"2006","journal-title":"Respir. Med."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Vold, M.L., Aasebo, U., Wilsgaard, T., and Melbye, H. (2015). Low oxygen saturation and mortality in an adult cohort: The Tromso study. BMC Pulm. Med., 15.","DOI":"10.1186\/s12890-015-0003-5"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"229","DOI":"10.5664\/jcsm.10838","article-title":"Nocturnal oxygen saturation is associated with all-cause mortality: A community-based study","volume":"20","author":"Yan","year":"2024","journal-title":"J. Clin. Sleep. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"S1544","DOI":"10.21037\/jtd.2017.11.41","article-title":"Best of Milan 2017-repair of the emphysematous lung: Mesenchymal stromal cell and matrix","volume":"9","author":"Polverino","year":"2017","journal-title":"J. Thorac. Dis."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"333","DOI":"10.2147\/ITT.S279228","article-title":"Acetylcholine Regulates Pulmonary Pathology During Viral Infection and Recovery","volume":"9","author":"Horkowitz","year":"2020","journal-title":"Immunotargets Ther."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1172\/JCI115204","article-title":"Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon","volume":"87","author":"Shapiro","year":"1991","journal-title":"J. Clin. Investig."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/978-94-007-7893-1_3","article-title":"Basic components of connective tissues and extracellular matrix: Elastin, fibrillin, fibulins, fibrinogen, fibronectin, laminin, tenascins and thrombospondins","volume":"802","author":"Halper","year":"2014","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Fujii, T., Mashimo, M., Moriwaki, Y., Misawa, H., Ono, S., Horiguchi, K., and Kawashima, K. (2017). Expression and Function of the Cholinergic System in Immune Cells. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.01085"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Pinheiro, N.M., Miranda, C.J., Perini, A., Camara, N.O., Costa, S.K., Alonso-Vale, M.I., Caperuto, L.C., Tiberio, I.F., Prado, M.A., and Martins, M.A. (2015). Pulmonary inflammation is regulated by the levels of the vesicular acetylcholine transporter. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0120441"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"485","DOI":"10.4049\/jimmunol.1801513","article-title":"Nicotine Attenuates Osteoarthritis Pain and Matrix Metalloproteinase-9 Expression via the alpha7 Nicotinic Acetylcholine Receptor","volume":"203","author":"Teng","year":"2019","journal-title":"J. Immunol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.tcm.2012.12.004","article-title":"Elastin fragmentation and atherosclerosis progression: The elastokine concept","volume":"23","author":"Maurice","year":"2013","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1165\/ajrcmb.21.2.3641","article-title":"Fibroblast tropoelastin and alpha-smooth-muscle actin expression are repressed by particulate-activated macrophage-derived tumor necrosis factor-alpha in experimental silicosis","volume":"21","author":"Mariani","year":"1999","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1165\/ajrcmb.26.2.4666","article-title":"Transforming growth factor-beta stabilizes elastin mRNA by a pathway requiring active Smads, protein kinase C-delta, and p38","volume":"26","author":"Kucich","year":"2002","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.matbio.2012.11.004","article-title":"A cytokine axis regulates elastin formation and degradation","volume":"32","author":"Sproul","year":"2013","journal-title":"Matrix Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"L944","DOI":"10.1152\/ajplung.00184.2006","article-title":"Activation of elastin transcription by transforming growth factor-beta in human lung fibroblasts","volume":"292","author":"Kuang","year":"2007","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"170073","DOI":"10.1183\/16000617.0073-2017","article-title":"Lung ageing and COPD: Is there a role for ageing in abnormal tissue repair?","volume":"26","author":"Brandsma","year":"2017","journal-title":"Eur. Respir. Rev."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1165\/rcmb.2006-0240OC","article-title":"Activation of the alpha7 nAChR reduces acid-induced acute lung injury in mice and rats","volume":"37","author":"Su","year":"2007","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"401","DOI":"10.4049\/jimmunol.0901808","article-title":"Requisite role of the cholinergic alpha7 nicotinic acetylcholine receptor pathway in suppressing Gram-negative sepsis-induced acute lung inflammatory injury","volume":"184","author":"Su","year":"2010","journal-title":"J. Immunol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1096\/fj.201600431r","article-title":"Acute lung injury is reduced by the alpha7nAChR agonist PNU-282987 through changes in the macrophage profile","volume":"31","author":"Pinheiro","year":"2017","journal-title":"FASEB J."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1038\/s41401-020-00579-z","article-title":"Vagal-alpha7nAChR signaling is required for lung anti-inflammatory responses and arginase 1 expression during an influenza infection","volume":"42","author":"Gao","year":"2021","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1111\/joim.13006","article-title":"Beyond neurotransmission: Acetylcholine in immunity and inflammation","volume":"287","author":"Cox","year":"2020","journal-title":"J. Intern. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1080\/01902148.2019.1605633","article-title":"The effects of aging and exercise on lung mechanics, surfactant and alveolar macrophages","volume":"45","author":"Veldhuizen","year":"2019","journal-title":"Exp. Lung Res."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Hwang, J.Y., Randall, T.D., and Silva-Sanchez, A. (2016). Inducible Bronchus-Associated Lymphoid Tissue: Taming Inflammation in the Lung. Front. Immunol., 7.","DOI":"10.3389\/fimmu.2016.00258"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.4049\/jimmunol.1801135","article-title":"Friend or Foe: The Protective and Pathological Roles of Inducible Bronchus-Associated Lymphoid Tissue in Pulmonary Diseases","volume":"202","author":"Marin","year":"2019","journal-title":"J. Immunol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1038\/nm1091","article-title":"Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity","volume":"10","author":"Kusser","year":"2004","journal-title":"Nat. Med."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Silva-Sanchez, A., and Randall, T.D. (2020). Anatomical Uniqueness of the Mucosal Immune System (GALT, NALT, iBALT) for the Induction and Regulation of Mucosal Immunity and Tolerance. Mucosal Vaccines, Academic Press.","DOI":"10.1016\/B978-0-12-811924-2.00002-X"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/s00259-016-3555-6","article-title":"Cholinergic PET imaging in infections and inflammation using (11)C-donepezil and (18)F-FEOBV","volume":"44","author":"Jorgensen","year":"2017","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0165-5728(97)00195-1","article-title":"Induction of choline acetyltransferase mRNA in human mononuclear leukocytes stimulated by phytohemagglutinin, a T-cell activator","volume":"82","author":"Fujii","year":"1998","journal-title":"J. Neuroimmunol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/nri.2016.90","article-title":"Sex differences in immune responses","volume":"16","author":"Klein","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1002\/alz.13481","article-title":"Sex-dependent cholinergic effects on amyloid pathology: A translational study","volume":"20","author":"Shanks","year":"2024","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Rio, P., Caldarelli, M., Miccoli, E., Guazzarotti, G., Gasbarrini, A., Gambassi, G., and Cianci, R. (2025). Sex Differences in Immune Responses to Infectious Diseases: The Role of Genetics, Hormones, and Aging. Diseases, 13.","DOI":"10.3390\/diseases13060179"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/s41467-020-14396-9","article-title":"Sexual-dimorphism in human immune system aging","volume":"11","author":"Marquez","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1002\/cne.23456","article-title":"Expression of m1-type muscarinic acetylcholine receptors by parvalbumin-immunoreactive neurons in the primary visual cortex: A comparative study of rat, guinea pig, ferret, macaque, and human","volume":"522","author":"Disney","year":"2014","journal-title":"J. Comp. Neurol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"26181","DOI":"10.1073\/pnas.1902280116","article-title":"Translational implications of the anatomical nonequivalence of functionally equivalent cholinergic circuit motifs","volume":"116","author":"Disney","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/3\/270\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T09:32:08Z","timestamp":1770111128000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/3\/270"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,3]]},"references-count":117,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["biology15030270"],"URL":"https:\/\/doi.org\/10.3390\/biology15030270","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,3]]}}}