Article

Sirt1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons

Neuroscience Program, University of Southern California, Los Angeles, CA 90089-2520, USA.
Cell metabolism (Impact Factor: 17.57). 08/2008; 8(1):38-48. DOI: 10.1016/j.cmet.2008.05.004
Source: PubMed

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.

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    • "However, sirtuin-independent mechanisms have been also proposed to explain the increase in longevity in yeast induced by CR (Kaeberlein et al. 2004). Also, the complexity of sirtuins in mammals has promoted the idea that they can show both pro-and anti-ageing capacities in mice (Kaeberlein, 2008;Li et al. 2008). "
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    • "Previous studies have shown that Nrf2 plays an important role in the protection of hepatocytes from NAFLD [12]. SIRT1 is also known to markedly protect cells from oxidative stress injury [13]. Due to the critical role of SIRT1 and Nrf2 in oxidative stress [14], it might be interesting to explore the synergistic effect of SIRT1/LKB1/AMPK signaling and Nrf2 in NAFLD. "
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