SirT1 Inhibition Reduces IGF-I/IRS-2/Ras/ERK1/2 Signaling and Protects Neurons

Ying Li, Wei Xu, Michael W. McBurney, Valter D. Longo

Research output: Contribution to journalArticle

234 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)38-48
Number of pages11
JournalCell Metabolism
Volume8
Issue number1
DOIs
StatePublished - Jul 2 2008

Fingerprint

Sirtuins
Insulin-Like Growth Factor I
Saccharomyces cerevisiae
Neurons
MAP Kinase Signaling System
Homozygote
Acetylation
Life Expectancy
Knockout Mice
Phosphorylation
Lipids
Brain
Proteins

Keywords

  • HUMDISEASE
  • SIGNALING

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

SirT1 Inhibition Reduces IGF-I/IRS-2/Ras/ERK1/2 Signaling and Protects Neurons. / Li, Ying; Xu, Wei; McBurney, Michael W.; Longo, Valter D.

In: Cell Metabolism, Vol. 8, No. 1, 02.07.2008, p. 38-48.

Research output: Contribution to journalArticle

Li, Ying ; Xu, Wei ; McBurney, Michael W. ; Longo, Valter D. / SirT1 Inhibition Reduces IGF-I/IRS-2/Ras/ERK1/2 Signaling and Protects Neurons. In: Cell Metabolism. 2008 ; Vol. 8, No. 1. pp. 38-48.
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