Highlights of the Keystone Symposium sirtuins in

Authors: Michele M Maxwell Julien Francisco Zaldivar‐Jolissaint Antonello Mai Tiago F Outeiro Aleksey G Kazanstev

Publish Date: 2012/07/03

Volume: 4, Issue: 7, Pages: 557-560

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Abstract

From February 12–16 2012 leading members of the sirtuin scientific community assembled in Tahoe CA to attend the Keystone Symposium “Sirtuins in Aging Metabolism and Disease” It was a vibrant and lively meeting and in the spirit of Keystone Symposia both established sirtuin researchers and those new to the field enjoyed a unique opportunity to interact and exchange ideasAleksey Kazantsev opened the Symposium by highlighting the explosion of research on sirtuins the evolutionarily conserved NAD+nicotinamide adenine dinucleotide‐dependent protein deacetylases that are homologues of the yeast longevity gene Sir2 In the Keynote Address Leonard Guarente provided an overview of the sirtuin deacetylases which act on a wide variety of protein targets including histones transcription factors and apoptotic modulators Moreover some sirtuins possess other enzymatic activities such as the mono‐ADP‐ribosyl transferase activity attributed to mammalian SIRT4 Dr Guarente described the sirtuins as key sensors for available energy stores that function as a link between protein acetylation and metabolism Referencing the ongoing debate over the role of sirtuins in the positive responses to calorie restriction CR he emphasized that most available data in yeast and invertebrates strongly suggest that the beneficial effects of CR require sirtuin activity and stressed the importance of extending these findings to mammals Dr Guarente also discussed evidence from current studies demonstrating that i sirtuins appear to suppress diseases of aging ii sirtuin activity declines with aging and iii sirtuins are novel therapeutic targets for many age‐related diseases More specifically he showed compelling evidence that mammalian SIRT1 activity protects against age‐associated pathologies such as diabetes and obesityThe emerging roles of sirtuins particularly mammalian SIRT1 in regulating both cellular and organismal metabolism were emphasized throughout the meeting John Denu discussed the role of SIRT1 as a major regulator of central cellular metabolic pathways focusing on new protein targets of this enzyme He showed that SIRT1 deacetylates and thereby downregulates activity of phosphoglycerate mutase 1 PGAM1 an enzyme not thought to be regulated in the glycolytic pathway but now known to catalyse a rate‐limiting step of glycolysis in cancer cells This raises the possibility that reduced activity of SIRT1 in high‐glucose conditions results in hyperacetylated PGAM1 which increases energy production via the glycolytic pathwayIntriguing insights have been gleaned from new mouse models – developed to circumvent the embryonic lethality of SIRT1 knockout KO mice – that either lack or overexpress SIRT1 in a tissue‐specific and/or inducible manner Vittorio Sartorelli described a tamoxifen‐inducible muscle‐specific SIRT1 KO mouse On a high‐fat diet HFD these KO mice gain more weight than their wild‐type WT counterparts and exhibit decreased peripheral insulin sensitivity and increased fatty acid FA accumulation KO mice also show marked reduction in the expression of enzymes involved in oxidative phosphorylation This study suggests that muscle SIRT1 is important for adaptation to HFD and that its loss is sufficient to induce a pathologic responseDavid Sinclair described studies in tamoxifen‐inducible whole body SIRT1 KO mice WT and KO mice were fed either a standard diet SD or a HFD with or without supplementation with the natural polyphenol compound resveratrol SIRT1 KO mice showed decreased mitochondrial function on SD similar to WT mice on HFD Mitochondrial function improved in WT but not KO mice in response to low‐dose resveratrol treatment suggesting that these effects are SIRT1‐dependent however treatment with high‐dose resveratrol showed SIRT1‐independent effects presumably due to the compound acting on other targetsRafael de Cabo further illuminated the role of SIRT1 in regulating metabolism and promoting healthy aging describing longitudinal studies in mice and primates treated with resveratrol and other SIRT1‐activating compounds STACs In mice resveratrol treatment of HFD‐fed animals normalized both survival and overall metabolic indicators to those observed in animals fed SD without resveratrol Dr de Cabo emphasized that although resveratrol likely acts via multiple targets to exert broad effects significant benefits of this compound have been observed in many models Further the novel STAC SRT1720 also exerts positive effects in HFD‐challenged mice treated animals exhibited a slight decrease in body weight improved insulin sensitivity and decreased incidence of cataractsOther speakers highlighted the role of SIRT1 and microRNAs in age‐dependent cardiovascular disease CVD Stefanie Dimmeler pointed out that age is the biggest risk factor for CVD in humans and is associated with increased cardiac fibrosis apoptosis heart failure and decreased neovascularization after ischemia Several microRNAs have been shown to be regulated by aging notably a subset of these microRNAs also control SIRT1 expression and cardiovascular functions In line with these observations Lindsey Gano showed that age‐related vascular endothelial dysfunction an indicated by impaired endothelium‐dependent dilation EDD was ameliorated in aged mice treated with the STAC SRT1720 Improvement in EDD was accompanied by restoration of aortic SIRT1 activity in treated animalsSeveral presentations directly addressed the ongoing debate over the mechanisms of action of resveratrol and other STACs David Sinclair and George Vlasuk both showed data demonstrating that a specific amino acid residue E230 which lies in a structured amino‐terminal region of SIRT1 is required for activation via resveratrol and other STACs developed by Sirtris/GSK These results suggest that STACs that fail to activate E230 mutants are direct activators of SIRT1

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