title: SIRT1 markedly extends replicative lifespan if the NAD+ salvage pathway is enhanced.
abstract: Sir2 mediates lifespan extension in lower eukaryotes but whether its mammalian homolog, sirtuin 1, silent mating type information regulation 2 homolog (SIRT1), is a longevity protein is controversial. We stably introduced the SIRT1 gene into human vascular smooth muscle cells (SMCs) and observed minimal extension of replicative lifespan. However, SIRT1 activity was found to be exquisitely dependent on nicotinamide phosphoribosyltransferase (Nampt) activity. Moreover, overexpression of Nampt converted SIRT1-overexpressing SMCs to senescence-resistant cells together with heightened SIRT1 activity, suppressed p21, and strikingly lengthened replicative lifespan. Thus, SIRT1 can markedly postpone SMC senescence, but this requires overcoming an otherwise vulnerable nicotinamide adenine dinucleotide salvage reaction in aging SMCs.
authors.affiliation: Robarts Research Institute, London Health Sciences Centre, Department of Medicine (Cardiology), University of Western Ontario, London, Canada N6A 5K8.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Ho
authors.forename: Eric
authors.initials: E
authors.lastname: van der Veer
authors.forename: Oula
authors.initials: O
authors.lastname: Akawi
authors.forename: J Geoffrey
authors.initials: JG
authors.lastname: Pickering
mesh_terms: D002478:Cells, Cultured; D016922:Cellular Senescence; D016207:Cytokines / Q000235:genetics / Q000502:physiology; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D009243:NAD / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics / Q000502:physiology; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D020741:rho GTP-Binding Proteins / Q000032:analysis
chemical_list: D016207:Cytokines; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D020741:rho GTP-Binding Proteins