Is SIRT6 Activity Neuroprotective and How Does It Differ from SIRT1 in This Regard?

Abstract

The NAD+-dependent type III histone deacetylases, or Sirtuins, have differing cellular localizations, and can have nuclear (SIRT1 and SIRT6), cytoplasmic (SIRT2), mitochondrial (SIRT3, SIRT4, and SIRT5) or nucleolar (SIRT7) localization. The founding member of the Sirtuin family, S. cerevisiae Sir2p, and its orthologs have important roles in senescence and aging, with manipulation of their activities resulting in modest lifespan extension, as verified in several model organisms. Sirtuins have a wide range of nuclear and cytoplasmic substrates, and are implicated in the transcriptional and epigenetic regulations of cellular and systemic processes of energy metabolism, stress response, death and survival, as well as pathological conditions such as malignancy (Chalkiadaki and Guarente, 2015) and neurodegeneration (Herskovits and Guarente, 2013). Perhaps the most extensively studied member of the mammalian Sirtuin paralogs is SIRT1, but the cellular and systemic roles of other paralogs have also been intensively investigated in recent years. SIRT6, like SIRT1, is nuclear localized. Acting primarily as a histone deacetylase, earlier studies have delineated its roles in telomere maintenance (Michishita et al., 2008), DNA repair (Mao et al., 2011) and transcription regulation of glucose homeostasis (Zhong et al., 2010). The importance of SIRT6 in mammals is illustrated by the fact that SIRT6 deficient mice have retarded postnatal development associated with cellular genomic instability, systemic metabolic defects, and exhibited premature senescence and aging, with early death occurring at around 4 weeks after birth (Mostoslavsky et al., 2006). In the past several years, many other emerging physiological as well as pathological functions for SIRT6 in multiple tissue contexts have also been reported (Tasselli et al., 2017). These include the regulation of the circadian clock (Masri et al., 2014), tumor suppression (Kugel et al., 2016) as well as lifespan extension in mammals (Kanfi et al., 2012), among others. In many of these cases, SIRT6 functions at first glance appear to have significant overlaps with that of SIRT1. Unlike SIRT1, which has been extensively studied with regards to its roles in neurons and the central nervous system (CNS) (Herskovits and Guarente, 2014; Ng et al., 2015), the function of SIRT6 in neural tissues has been less well explored. Like SIRT1, SIRT6 appears to have anti-aging activities through the regulation of inflammation (Kawahara et al., 2009), the expression of antioxidant genes (Pan et al., 2016) as well as proteasomal degradation of senescence factors (Zhao et al., 2016), all of which are related to neuroprotection. Like SIRT1, SIRT6 activity may therefore be largely neuroprotective, and this expectation appears to have been borne out by several recent reports, which suggest that loss of SIRT6 during aging and neuropathological settings contributes to neurodegenerative processes. However, elevated SIRT6 level has also been noted to be undesirable under certain conditions. SIRT6 may also differ from SIRT1 in terms of enzymatic activity and mechanism of action. In the paragraphs below, I shall explore current evidence (as well as counterevidence) for the neuroprotective potential of SIRT6, and draw comparisons with that of SIRT1.