SIRTUINS 6º Part

SIRT6

SIRT6 is a nuclear sirtuin and has roles that differ from those of SIRT1. SIRT6-knockout mice exhibit aging-like phenotypes, such as lymphopenia, loss of subcutaneous fat and severe hypoglycemia, which lead to their death by 4-5 weeks (Mostoslavsky et al., 2006; Xiao et al., 2010). MEFs and embryonic stem cells that are deficient in SIRT6 show genomic instability and impaired base-excision repair (Mostoslavsky et al., 2006). SIRT6 is also involved in DNA double-strand break repair by regulating C-terminal binding protein (CtBP) and DNA protein kinase (McCord et al., 2009; Kaidi et al., 2010). Biochemically, SIRT6 was shown to have ADP-ribosyltransferase activity, but recent studies suggest that SIRT6 has also a deacetylase activity, preferentially acting on histone H3K9 and H3K56 (Liszt et al., 2005; Michishita et al., 2008; Michishita et al., 2009).

SIRT6 also associates with telomeric chromatin and depletion of SIRT6 results in premature cellular senescence and telomere dysfunction (Michishita et al., 2008). Similarly to SIRT1, SIRT6 also interacts with the RelA subunit of NF-κB and deacetylates histone H3K9 at NF-κB target gene promoters, which leads to their repression (Kawahara et al., 2009). Disruption of the SIRT6 gene leads to hyperactivation of NF-κB signaling and is, thus, the likely cause for the premature aging phenotype observed in SIRT6-knockout mice, as haploinsufficiency of RelA attenuates the lethality and aging-like phenotypes of SIRT6-knockout mice. Another recent paper has revealed that SIRT6 also selectively binds to the promoter regions of HIF1α target genes, at which it deacetylates histone H3K9 (Zhong et al., 2010). Here, SIRT6 functions as a co-repressor of HIF1α and inhibits the transcription of glycolytic genes. Consistent with this notion, MEFs and mice that are deficient in SIRT6 exhibit amplified HIF1α activity and increased glycolysis together with diminished mitochondrial respiration, thus providing a possible explanation for the observed hypoglycemia in SIRT6-knockout mice. In addition, a recent report shows that liver-specific deletion of SIRT6 in mice leads to increased glycolysis, triglyceride synthesis, reduced β oxidation, and fatty liver formation (Kim et al., 2010). Taken together, these data suggest that SIRT6, similar to SIRT1, also has pivotal roles in metabolism.

SIRT7

Among the sirtuins, SIRT7 is the least studied. SIRT7 has been shown to be a positive regulator of RNA polymerase I transcription (Ford et al., 2006), but the enzymatic activity of SIRT7 remains undetermined thus far. Recently, SIRT7-knockout mice were reported to exhibit various signs of aging-related changes, such as kyphosis, loss of subcutaneous fat and premature death (Vakhrusheva et al., 2008), and they also suffer from degenerative heart hypertrophy. However, SIRT7-specific substrates have not been reported yet and additional studies are necessary to reveal the biological roles of SIRT7.

Perspectives

Over the last decade, the study of sirtuins has made remarkable progress and expanded our knowledge regarding aging and aging-related diseases. However, our understanding of sirtuin biology is still far from complete and many important questions remain to be answered. For example, it has been shown that activation of SIRT1 can slow down phenotypes of aging, such as diabetes and bone loss, but an extension of life span has only been demonstrated in mice that are fed a high-fat diet. It is possible that this crucially important sirtuin turns out to have opposing roles in aging, which might make it a good target for specific aging diseases, but not for life span extension. Moreover, one or several of the other sirtuins (SIRT2 to SIRT7) might need to be modulated in concert with SIRT1 to be able to extend life span. What has become clear is that sirtuins are required to exert many of the beneficial aspects of calorie restriction. Most recently, SIRT3 has been shown essential in CR-mediated protection against aging-related hearing loss (Someya et al., 2010).

Finally, it will be extremely important to determine what happens to the activity of sirtuins during aging. There are hints that their activity declines, which provide further rationales to develop drugs that activate sirtuins to combat aging. Thus, to achieve the goal of a therapeutic intervention of aging, it will be important to fully elucidate the functions of all seven sirtuins and in many different tissues.