Neurodegeneration that follows a stroke, leads to a serious and devastating damages that affect people’s quality of life. No therapeutic agents aimed at preventing neuronal death in stroke and at protecting patients at high risk are available or truly effective. Sirtuins are NAD⁺-dependent deacetylase proteins found to influence the extent of neuronal death in stroke. However, different sirtuins appear to have opposite roles in neuronal protection. We used well characterized models of neuronal death such as mec-4(d)-induced death of touch sensory neurons and anoxic ischemia to test the role of sirtuins in neuronal death in C. elegans. We found that knock-out of this mitochondrial sirtuin 2.3 confers neuroprotection in both models of neurodegeneration. Importantly rescue experiments demonstrated that the effect is mediated by sir-2.3. In addition we observed a maximum expression of sir-2.3 mRNA in wild type animals 4-5 hours after exposure to hypoxic injury. These data confirm the involvement of the mitochondrial sir-2.3 in neurodegeneration. Since caloric restriction protects against several neurodegenerative and cardiovascular diseases through the activation of sirtuins, we tested the involvement of caloric restriction in the neuroprotection provided by sir-2.3 knock-out in mec-4(d)-induced excitotoxicity neuronal death. We used the well-known genetic model of caloric restriction eat-2(ad1116) mutation and we compared the extent of neuronal death in wild-type and sir-2.3 knock-out backgrounds. Similar analysis was performed in vitro where cultured neurons were treated with 2-deoxyglucose (2-DG), which mimics caloric restriction. We found that in both in vivo and in vitro, caloric restriction enhanced the neuroprotective effect of knock out of sir-2.3, but had no effect on basal level of neurodegeneration. These data suggest a synergistic effect of caloric restriction and knock-out of mitochondrial sir-2.3. Experiments are under way to establish whether neuroprotection induced by the combination of caloric restriction and sir-2.3 knock out is mediated by reduced Ca2+ overload in these neurons. Our study will lay the groundwork for developing future pharmacologic approaches to prevent and treat neuronal damage in neurological disorders including stroke.