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 language | English (US) |
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Pages (from-to) | 38-48 |
Number of pages | 11 |
Journal | Cell Metabolism |
Volume | 8 |
Issue number | 1 |
DOIs | |
State | Published - Jul 2 2008 |
Keywords
- HUMDISEASE
- SIGNALING
ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology