Cell Metabolism: SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons.
Li Y, Xu W, McBurney MW, Longo VD.
Neuroscience Program, University of Southern California, Los Angeles, CA 90089-2520, USA.
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.
Here's a quote from the discussion section which is quite long:
Numerous studies point to SirT1 as a key regulator of cell survival in response to stress. It exhibits both pro- and antisurvival functions depending on the conditions. For instance, SirT1 countered p53-dependent apoptosis caused by etoposide in MEFs (Luo et al., 2001). In an ALS mouse model, SirT1 rescued neurons (Kim et al., 2007). However, SirT1 can also exacerbate cell death. As described earlier, SirT1 KO MEFs showed higher replicative life spans under chronic, sublethal oxidative stress (Chua et al., 2005). SirT1 also sensitized HEK293 cells to TNFa-induced apoptosis (Yeung et al., 2004). Many factors may contribute to the seemingly contradictory effects of SirT1. First, different nutrient, growth, or stress signals may be sensed by SirT1 and integrated into divergent outputs. Second, SirT1’s subcellular localization may play a role in its regulation of cell death. Some studies suggest that cytoplasm-localized SirT1 may promote apoptosis (Jin et al., 2007; Zhang, 2007), while the antiapoptotic effect may come only from nuclear-localized SirT1 (Tanno et al., 2007). Third, SirT1 has a wide array of targets which may become preferentially (de)activated in different contexts. Deacetylation of p53 and FOXO contributes to the prosurvival effect of SirT1 (Brunet et al., 2004; Langley et al., 2002; Motta et al., 2004), while that of NF-kB and p19ARF mediate the prodeath effect (Chua et al., 2005; Yeung et al., 2004). It is possible that these transcription factors are also implicated in the increased protection in neurons with reduced SirT1 and ERK activity.
The detection of lower oxidative stress in the brain of SirT1 KO mice is consistent with our cell-culture data. The reduced production of hydrogen peroxide by mitochondria and major changes in electron transport and leakage in SirT1 KO mice recently shown by McBurney and colleagues (Boily et al., 2008) may explain part of the protective effect observed after SirT1 inhibition. Yet we cannot conclude that SirT1 promotes oxidative damage in all organs in vivo, as SirT1 may play vastly different roles in various organs. For example, Alcendor et al. (2007) reported the beneficial effect of SirT1 overexpression in the heart against oxidative stress, although they showed that this antioxidant effect becomes a pro-oxidant effect at a higher overexpression level. In agreement with the very different roles of SirT1, here we show that the pro-oxidative stress role of SirT1 in neurons and in the mouse brain is not translated into a longer life span. In fact, SirT1 KO mice live shorter than wild-type controls under both normal and CR diets (Figure 6). Thus, differently from our studies in yeast, we did not find that CR further extends the life span of SirT1 KO mice, which is consistent with a recent report (Boily et al., 2008). Considering that SirT1 +/- mice display a normal mean life span and that SirT1 -/- mice have severe developmental defects including a dwarf phenotype (McBurney et al., 2003), it is likely that these defects contribute to shortening the life span independently of the rate of aging. A brain-specific SirT1 KO mouse model may provide further clues.
In summary, this study suggests that SirT1 can contribute to oxidative damage in mammals by activating IRS-2/Ras/ERK signaling downstream of insulin/IGF-I receptors but also plays a number of roles important for normal growth and life span (McBurney et al., 2003; Moynihan et al., 2005; Picard et al., 2004). There has been a keen interest in developing SirT1 activators for human consumption. Our studies implicating SirT1 in both pro-aging and protective functions in yeast and mammalian cells suggest that additional studies should be carried out before SirT1 activators are considered for chronic use.
