title: Senescent Cells Contribute to the Physiological Remodeling of Aged Lungs.
abstract: Age-associated decline in organ function governs life span. We determined the effect of aging on lung function and cellular/molecular changes of 8- to 32-month old mice. Proteomic analysis of lung matrix indicated significant compositional changes with advanced age consistent with a profibrotic environment that leads to a significant increase in dynamic compliance and airway resistance. The excess of matrix proteins deposition was associated modestly with the activation of myofibroblasts and transforming growth factor-beta signaling pathway. More importantly, detection of senescent cells in the lungs increased with age and these cells contributed toward the excess extracellular matrix deposition observed in our aged mouse model and in elderly human samples. Mechanistic target of rapamycin (mTOR)/AKT activity was enhanced in aged mouse lungs compared with those from younger mice associated with the increased expression of the histone variant protein, MH2A, a marker for aging and potentially for senescence. Introduction in the mouse diet of rapamycin, significantly blocked the mTOR activity and limited the activation of myofibroblasts but did not result in a reduction in lung collagen deposition unless it was associated with prevention of cellular senescence. Together these data indicate that cellular senescence significantly contributes to the extracellular matrix changes associated with aging in a mTOR 1-dependent mechanism.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Texas Health Science Center at San Antonio.
authors.forename: Cheresa
authors.initials: C
authors.lastname: Calhoun
authors.affiliation: Division of Cardiology, Department of Medicine, University of Texas Health Science Center at San Antonio.
authors.forename: Pooja
authors.initials: P
authors.lastname: Shivshankar
authors.affiliation: Team 8, INSERM U955-Biomedical Research of Mondor Institute, University of Paris East, Créteil, France.
authors.forename: Mirna
authors.initials: M
authors.lastname: Saker
authors.affiliation: Sam and Ann Barshop Institute of Aging and Longevity Studies.
authors.forename: Lauren B
authors.initials: LB
authors.lastname: Sloane
authors.affiliation: Sam and Ann Barshop Institute of Aging and Longevity Studies, Department of Molecular Medicine.
authors.forename: Carolina B
authors.initials: CB
authors.lastname: Livi
authors.forename: Zelton D
authors.initials: ZD
authors.lastname: Sharp
authors.affiliation: Department of Microbiology and Immunology, University of Texas Health Science Center at San Antonio.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Orihuela
authors.affiliation: Team 8, INSERM U955-Biomedical Research of Mondor Institute, University of Paris East, Créteil, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Adnot
authors.affiliation: Department of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor.
authors.forename: Eric S
authors.initials: ES
authors.lastname: White
authors.affiliation: Sam and Ann Barshop Institute of Aging and Longevity Studies.
authors.forename: Arlan
authors.initials: A
authors.lastname: Richardson
authors.affiliation: Division of Cardiology, Department of Medicine, University of Texas Health Science Center at San Antonio. lesaux@uthscsa.edu.
authors.forename: Claude Jourdan
authors.initials: CJ
authors.lastname: Le Saux
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology; D056151:Airway Remodeling / Q000502:physiology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016922:Cellular Senescence / Q000502:physiology*; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D040901:Proteomics; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D019063:Tenascin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000199:Actins; D015415:Biomarkers; D019063:Tenascin; D016212:Transforming Growth Factor beta; D003094:Collagen; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: Aging; Rapamycin; Remodeling; Senescence; mTOR pathway