SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons

被引:285
作者
Li, Ying [1 ,2 ,3 ]
Xu, Wei [1 ]
McBurney, Michael W. [4 ]
Longo, Valter D. [1 ,2 ,3 ]
机构
[1] Univ So Calif, Neurosci Program, Los Angeles, CA 90089 USA
[2] Univ So Calif, Ethel Percy Andrus Gerontol Ctr, Los Angeles, CA 90089 USA
[3] Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA
[4] Univ Ottawa, Dept Med, Ottawa Hlth Res Inst, Ottawa, ON, Canada
关键词
D O I
10.1016/j.cmet.2008.05.004
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:38 / 48
页数:11
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