title: SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons.
abstract: Sirtuins are known to protect cells and extend life span, but our previous studies indicated that S. cerevisiae Sir2 can also increase stress sensitivity and limit life-span extension. Here we provide evidence for a role of the mammalian Sir2 ortholog SirT1 in the sensitization of neurons to oxidative damage. SirT1 inhibition increased acetylation and decreased phosphorylation of IRS-2; it also reduced activation of the Ras/ERK1/2 pathway, suggesting that SirT1 may enhance IGF-I signaling in part by deacetylating IRS-2. Either the inhibition of SirT1 or of Ras/ERK1/2 was associated with resistance to oxidative damage. Markers of oxidized proteins and lipids were reduced in the brain of old SirT1-deficient mice, but the life span of the homozygote knockout mice was reduced under both normal and calorie-restricted conditions. These results are consistent with findings in S. cerevisiae and other model systems, suggesting that mammalian sirtuins can play both protective and proaging roles.
authors.affiliation: Neuroscience Program, University of Southern California, Los Angeles, CA 90089-2520, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Michael W
authors.initials: MW
authors.lastname: McBurney
authors.forename: Valter D
authors.initials: VD
authors.lastname: Longo
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000378:metabolism*; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; C526299:Irs2 protein, rat; D010750:Phosphoproteins; D017526:Receptor, IGF Type 1; D048052:Mitogen-Activated Protein Kinase 3; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D037761:Sirtuins; D018631:ras Proteins