Cell Science at a Glance 833 Sirtuins at a glance Rogina and Helfand, 2004). In mammals, enzymatic activity (Imai et al., 2000). NAD is an there are seven sirtuins (SIRT1-7). All important co-factor for the electron transport Takashi Nakagawa1,2 and Leonard mammalian sirtuins contain a conserved chain and is also involved in many enzymatic Guarente1,2,* NAD-binding and catalytic domain, termed reactions (Houtkooper et al., 2010). Owing to 1Paul F. Glenn Laboratory for the Science of Aging, the sirtuin core domain, but differ in their N- the characteristic NAD requirement for their Department of Biology, Massachusetts Institute of and C-terminal domains (Frye, 2000). They enzymatic reaction, the activity of sirtuins is Technology, 77 Massachusetts Avenue, Building 68- have different specific substrates and directly linked to the metabolic state in the cell. 280, Cambridge, Cambridge, MA 02139, USA 2Department of Biology, Massachusetts Institute of biological functions, and are found in various Initially, yeast SIR2 was discovered as a histone Technology, Cambridge, MA 02139, USA cell compartments. The fact that sirtuins deacetylase, but mammalian sirtuins have also *Author for correspondence ([email protected]) require NAD for their enzymatic activity various non-histone protein substrates. The Journal of Cell Science 124, 833-838 connects metabolism to aging and aging- deacetylation reaction of sirtuins consists of two © 2011. Published by The Company of Biologists Ltd related diseases. In this Cell Science at a steps. In the first, sirtuins cleave NAD and doi:10.1242/jcs.081067 Glance article, we summarize the recent data produce nicotinamide (NAM), and in the second related to the role of sirtuins in aging and step the acetyl group is transferred from the Sirtuins are NAD-dependent deacetylases that aging-related diseases, and describe the substrate to the ADP-ribose moiety of NAD to are highly conserved from bacteria to human underlying molecular mechanisms. generate O-acetyl-ADP ribose and the and SIR2 was originally shown to extend deacetylated substrate (Tanner et al., 2000). lifespan in budding yeast (Imai et al., 2000; Enzymatic activity of sirtuins and NAD Although most of sirtuins have deacetylase Kaeberlein et al., 1999). Since then, sirtuins biosynthesis activity, SIRT4 has been shown to have only have been shown to also regulate longevity in Sirtuins belong to the class III protein ADP-ribosyltransferase activity, whereas SIRT1 other lower organisms, such as flies and deacetylase family, which are the only histone and SIRT6 have both deacetylation and a worms (Tissenbaum and Guarente, 2001; deactyalses (HDACs) that require NAD for their relatively weak ADP-ribosyltransferase activity Sirtuins at a Glance jcs.biologists.org Takashi Nakagawa and Leonard Guarente Enzymatic reaction of sirtuins Substrates and biological functions of SIRT1 Deacetylation Small molecules CyclinB1/CDK1 AROS NAD/NADH HIC1 DBC1 Necdin Deacetylated protein NH Acetylated O 2 protein N CH3 Deacetylated lysine H Sirtuin Activators Acetylated lysine Resveratrol O NH NH2 2 SRT1720 SIRT1 N N N + NH2 N SRT501 O O O O O N N N N N OOPP O OH Oxazolopyridine O U PPU U O O O + + NH2 HHO O HH HHO O HH N OH OH OH O O Inhibitors OH OH OH OH Chromatin/ Inflammation or + 2’-O-actetyl-ADP ribose Nicotinamide Cardiovascular functionunction NAD CH3 NAM Cancer Metabolismetabolism Neuronal function O Suramin Epigenetics Stress response + NH2 EX-572 O N Journal of Cell Science Sirtinol HO P O O Tenovine O Adipose Nmnat HH Nampt Liver pose MMuscleuscle Pancreas OH OH Liver tissuesue Panc NMN Key Histone H3K9 p53 eNOS PGC1α PPARγ PGC1α UCP2 RARβ NF-κB WRN Histone H3K56 β-catenin NF-κB FOXO PGC1α MyoD FOXO miR134 HIF2α Ku70 ADP-ribosylation NH2 Effects to or by SIRT1 Mono ADP- Histone H4K16 Survivin LKB1 CRTC2 PCAF Ox2R HIF1α NBS1 N N ribosylated Red: Activation O O Histone H1K26 Ku70 PGC1α PPARα FOXO Tle1 HSF1 PARP1 Substrate N N protein Blue: Suppression NH OOPP O Suv39h1 E2F1 PARP1 LXR PTP1B BMAL1 Smad7 protein 2 O O HHO O HH Black: Both or p300 Rb SREBP-1/2 FXR Per2 OH OH OH OH not known + TSC2 HNF4a AceCS1 PIP5Kγ Sirtuin Transcriptional suppression Cell survival Cardioprotection Gluconeogenesis, Fatty acid oxidation Alzheimer’s disease Inflammation O NH2 Heterochromatin formation Cell death Vascular relaxation Insulin secretion, Insulin sensitivity Memory formation Hypoxic response O N N + NH2 Methylation Oncogenes Atherosclerosis Fat mobilization, Muscle differentiation Feeding behavior Heat shock response O O Biological N N N + NH2 Acetylation Tumor suppression Cholesterol metabolism Adult neurogenesis DNA damage O O PPO O N functions O Mitochondrial biogenesis, Respiration Circadian rhythm HHO O HH O OH OH + OH OH NAM Hormone release NAD + NH2 O N HOP O O O HH Nmnat OH OH Nampt Mitochondrial sirtuins Other sirtuins NMN Parkinson’s Cell Heart Metabolism Oxidative stress disease Oxidative proliferation function Glioma stress Phenotypes of sirtuin KO or Tg mice FOXO3a p53 SDH CypD p53 SIRT2 SIRT1 KO (WB) Die right after birth (C57/B6 background), some can survive postnatally (mixed background), shorter and smaller in body size, closed eyelids, infertility, no adaptive feeding response to CR Metabolism MRPL10 Memory deficit, no adaptive feeding response to CR, less serum IGF1 Hearing loss IDH2 KO (Brain) SIRT7 KO (Liver) Defect in circadian gene oscillation, develop hepatic steatosis and inflammation Protein synthesis α Histone Increased inflammation, glucose intolerance and insulin resistancy induced by HFD -tubulin FOXO1 KO (Macrophage) H4K16 Tg (WB) Protected against various metabolic disorders (fatty liver and type 2 diabetes) induced by HFD, IDE protected against age-induced cancer, osteoporosis and glucose intolerance SIRT4 SIRT3 SIRT5 RNA Polymerase I Enhanced memory formation and feeding behavior, protected against Alzheimer’s disease Cell death? Tg (Brain) Oligodendroglia Cell cycle WAT Cardioprotection (mild expression), cardiac hypertrophy (high expression) Tg (Heart) proliferation differentiation rDNA transcription Protected against colon cancer Cyt c Tg (Gut) Tg (Kidney) Protected against acute renal failure ANT2/3 GDH AceCS2 LCAD NDUFA9 CPS1 TNFα production SIRT2 KO (WB) Develop and grown normaly Telomere DNA damage Defect in fatty acid oxidation, cancer prone, their oocytes exhibit developmental arrest after IVF, SIRT3 KO (WB) accumulation of hyperacetylated mitochondrial proteins, reduced respiration and ATP levels maintenance Insulin Acetate β-oxidation Oxidative Urea cycle (DSB repair, BER) Protected against cardiac hypertrophy SIRT6 Tg (Heart) secretion metabolism phosphorylation CtBP, DNA-PK Hyperinsulinemia, sensitive to GSIS and AASIS SIRT4 KO (WB) Mitochondrion Defect in urea cycle, hyperammonemia after fasting SIRT5 KO (WB) Tg (Liver) Increased urea cycle activity, increased urea production Cytoplasm NF-κB Histones α Transcription Histone Cardiac HIF1 SIRT6 KO (WB) Die around 4 weeks showing premature aging phenotype (lymphopenia, loss of subcutaneous fat), LKB1 H3K9, H3K56 Cell death p53 H4K16 hypertrophy p50 RelA hyperglycemia, increased glucose uptake, genomic instability Key KO (Liver) Increased glycolysis, triglyceride synthesis, reduced β oxidation and fatty liver formation Deacetylation Ku70 SIRT3 FOXO3a Tg (WB) Protected against metabolic disorder induced by HFD SIRT7 KO (WB) Die around 1 year showing premature aging phenotypes (kyphosis, loss of subcutaneous fat, ADP ribosylation degenerative cardiac hypertrophy), increased apoptosis Inflammation Glycolysis Abbreviations: AASIS, amino-acid-stimulated insulin secretion; AceCS, acetyl-CoA synthetase; ANT, a denine nucleo- NAM, nicotinamide; Nampt, nicotinamide phosphoribosyltransferase; NDUFA9, NADH dehydrogenase (ubiquinone) 1 alpha tide translocase; AROS, active regulator of SIRT1; BER, base excision repair; BMAL1, brain and muscle Aryl hydrocarbon subcomplex subunit 9; NF-κB, nuclear factor kappa-B; NMN, nicotinamid mononucleotide; Nmnat, nicotinamide receptor nuclear translocator-like 1; CDK1, cyclin-dependent kinase 1; CPS1, carbamoyl phosphate synthetase 1; CR, mononucleotide adenylyltransferase; NBS1, nijmegen breakage syndrome protein 1; Ox2R, orexin receptor type 2; PARP1, calorie restriction; CRTC2, cAMP responsive element binding protein regulated transcription coactivator 2; CtBP, C-terminal poly (ADP-ribose) polymerase 1; PCAF, p300/CBP-associated factor; Per2, period circadian protein homolog 2; PGC1α, binding protein; CypD, cyclophilin D; Cyt c, cyctochrome c; DBC1, deleted in bladder cancer protein 1; DNA-PK PPAR gamma coactivator 1-alpha; PIP5Kγ, phosphatidylinositol 4-phosphate 5-kinase type-1 gamma; PPAR, peroxisome DNA-dependent protein kinase; DSB, double-strand break; E2F1, E2F transcription factor 1; eNOS, endothelial nitric oxide proliferator-activated receptor; PTPB1, protein-tyrosine phosphatase 1B; Rb, retinoblastoma associated protein; rDNA, synthase; FOXO, forkhead box protein O; FXR, farnesoid X receptor; GDH, glutamate dehydrogenase; GSIS, glucose- ribosomal DNA; RelA, reticuloendotheliosis viral oncogene homolog A; RARβ, retinoic acid receptor-beta; SDH, succinate stimulated insulin secretion; HFD, high fat diet; HIC1, hypermethylated in cancer 1; HIF, hypoxia-inducible factor; HNF4α, dehydrogenase; Smad7, mothers against decapentaplegic homolog 7; SREBP, sterol regulatory element-binding protein; hepatocyte nuclear factor 4-alpha; HSF1, heat shock factor protein 1; IDE, insulin-degrading enzyme; IDH2, isocitrate Suv39h1, suppressor of variegation