title: SIRT1 protects against emphysema via FOXO3-mediated reduction of premature             senescence in mice.
abstract: Chronic obstructive pulmonary disease/emphysema (COPD/emphysema) is characterized             by chronic inflammation and premature lung aging. Anti-aging sirtuin 1 (SIRT1), a             NAD+-dependent protein/histone deacetylase, is reduced in lungs of patients with COPD.             However, the molecular signals underlying the premature aging in lungs, and whether             SIRT1 protects against cellular senescence and various pathophysiological alterations in             emphysema, remain unknown. Here, we showed increased cellular senescence in lungs of             COPD patients. SIRT1 activation by both genetic overexpression and a selective             pharmacological activator, SRT1720, attenuated stress-induced premature cellular             senescence and protected against emphysema induced by cigarette smoke and elastase in             mice. Ablation of Sirt1 in airway epithelium, but not in myeloid cells, aggravated             airspace enlargement, impaired lung function, and reduced exercise tolerance. These             effects were due to the ability of SIRT1 to deacetylate the FOXO3 transcription factor,             since Foxo3 deficiency diminished the protective effect of SRT1720 on cellular             senescence and emphysematous changes. Inhibition of lung inflammation by an             NF-κB/IKK2 inhibitor did not have any beneficial effect on emphysema. Thus,             SIRT1 protects against emphysema through FOXO3-mediated reduction of cellular             senescence, independently of inflammation. Activation of SIRT1 may be an attractive             therapeutic strategy in COPD/emphysema.
authors.affiliation: Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yao
authors.forename: Sangwoon
authors.initials: S
authors.lastname: Chung
authors.forename: Jae-woong
authors.initials: JW
authors.lastname: Hwang
authors.forename: Saravanan
authors.initials: S
authors.lastname: Rajendrasozhan
authors.forename: Isaac K
authors.initials: IK
authors.lastname: Sundar
authors.forename: David A
authors.initials: DA
authors.lastname: Dean
authors.forename: Michael W
authors.initials: MW
authors.lastname: McBurney
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Mikko
authors.initials: M
authors.lastname: Rönty
authors.forename: Vuokko L
authors.initials: VL
authors.lastname: Kinnula
authors.forename: Irfan
authors.initials: I
authors.lastname: Rahman
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D016922:Cellular Senescence; D020536:Enzyme Activators / Q000494:pharmacology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D011656:Pulmonary Emphysema / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020536:Enzyme Activators; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D006576:Heterocyclic Compounds, 4 or More Rings; C525422:SRT1720; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1