Ketone bodies as signaling metabolites

Trends in Endocrinology & Metabolism - Tập 25 - Trang 42-52 - 2014
John C. Newman1, Eric Verdin1
1Gladstone Institutes and University of California San Francisco, 1650 Owens Street, San Francisco, CA 94158, USA

Tài liệu tham khảo

Fontana, 2006, Excessive adiposity, calorie restriction, and aging, JAMA, 295, 1577, 10.1001/jama.295.13.1577 Kenyon, 2010, The genetics of ageing, Nature, 464, 504, 10.1038/nature08980 Bjedov, 2011, A longer and healthier life with TOR down-regulation: genetics and drugs, Biochem. Soc. Trans., 39, 460, 10.1042/BST0390460 Someya, 2010, Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction, Cell, 143, 802, 10.1016/j.cell.2010.10.002 Shimazu, 2013, Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor, Science, 339, 211, 10.1126/science.1227166 Katada, 2012, Connecting threads: epigenetics and metabolism, Cell, 148, 24, 10.1016/j.cell.2012.01.001 Stein, 2012, The dynamic regulation of NAD metabolism in mitochondria, Trends Endocrinol. Metab., 23, 420, 10.1016/j.tem.2012.06.005 Shyh-Chang, 2013, Influence of threonine metabolism on S-adenosylmethionine and histone methylation, Science, 339, 222, 10.1126/science.1226603 Berg, 2012 Cahill, 1966, Hormone–fuel interrelationships during fasting, J. Clin. Invest., 45, 1751, 10.1172/JCI105481 Robinson, 1980, Physiological roles of ketone bodies as substrates and signals in mammalian tissues, Physiol. Rev., 60, 143, 10.1152/physrev.1980.60.1.143 Cahill, 2006, Fuel metabolism in starvation, Annu. Rev. Nutr., 26, 1, 10.1146/annurev.nutr.26.061505.111258 Koeslag, 1980, Post-exercise ketosis, J. Physiol., 301, 79, 10.1113/jphysiol.1980.sp013190 Kim do, 2008, The ketogenic diet and epilepsy, Curr. Opin. Clin. Nutr. Metab. Care, 11, 113, 10.1097/MCO.0b013e3282f44c06 London, 1986, Effects of fasting on ketone body concentrations in healthy men of different ages, J. Gerontol., 41, 599, 10.1093/geronj/41.5.599 Freemantle, 2009, Metabolic response to a ketogenic breakfast in the healthy elderly, J. Nutr. Health Aging, 13, 293, 10.1007/s12603-009-0026-9 Thumelin, 1993, Developmental changes in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene expression in rat liver, intestine and kidney, Biochem. J., 292, 493, 10.1042/bj2920493 Zhang, 2011, Proteomics analysis reveals diabetic kidney as a ketogenic organ in type 2 diabetes, Am. J. Physiol. Endocrinol. Metab., 300, E287, 10.1152/ajpendo.00308.2010 Fink, 1988, Pseudoketogenesis in the perfused rat heart, J. Biol. Chem., 263, 18036, 10.1016/S0021-9258(19)81320-0 Weidemann, 1969, The fuel of respiration of rat kidney cortex, Biochem. J., 112, 149, 10.1042/bj1120149 Fukao, 1997, Enzymes of ketone body utilization in human tissues: protein and messenger RNA levels of succinyl-coenzyme A (CoA):3-ketoacid CoA transferase and mitochondrial and cytosolic acetoacetyl-CoA thiolases, Pediatr. Res., 42, 498, 10.1203/00006450-199710000-00013 Fukao, 2004, Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry, Prostaglandins Leukot. Essent. Fatty Acids, 70, 243, 10.1016/j.plefa.2003.11.001 Hegardt, 1999, Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in ketogenesis, Biochem. J., 338, 569, 10.1042/0264-6021:3380569 Wolfrum, 2004, Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes, Nature, 432, 1027, 10.1038/nature03047 Wolfrum, 2003, Insulin regulates the activity of forkhead transcription factor Hnf-3beta/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localization, Proc. Natl. Acad. Sci. U.S.A., 100, 11624, 10.1073/pnas.1931483100 von Meyenn, 2013, Glucagon-induced acetylation of Foxa2 regulates hepatic lipid metabolism, Cell Metab., 17, 436, 10.1016/j.cmet.2013.01.014 Badman, 2007, Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states, Cell Metab., 5, 426, 10.1016/j.cmet.2007.05.002 Badman, 2009, Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis, Endocrinology, 150, 4931, 10.1210/en.2009-0532 Sengupta, 2010, mTORC1 controls fasting-induced ketogenesis and its modulation by ageing, Nature, 468, 1100, 10.1038/nature09584 Shimazu, 2010, SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production, Cell Metab., 12, 654, 10.1016/j.cmet.2010.11.003 Hebert, 2013, Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome, Mol. Cell, 49, 186, 10.1016/j.molcel.2012.10.024 Rardin, 2013, Label-free quantitative proteomics of the lysine acetylome in mitochondria identifies substrates of SIRT3 in metabolic pathways, Proc. Natl. Acad. Sci. U.S.A., 110, 6601, 10.1073/pnas.1302961110 Quant, 1990, Glucagon activates mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in vivo by decreasing the extent of succinylation of the enzyme, Eur. J. Biochem., 187, 169, 10.1111/j.1432-1033.1990.tb15291.x Quant, 1989, Treatment of rats with glucagon or mannoheptulose increases mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase activity and decreases succinyl-CoA content in liver, Biochem. J., 262, 159, 10.1042/bj2620159 He, 2012, Mitochondrial sirtuins: regulators of protein acylation and metabolism, Trends Endocrinol. Metab., 23, 467, 10.1016/j.tem.2012.07.004 Turko, 2001, Diabetes-associated nitration of tyrosine and inactivation of succinyl-CoA:3-oxoacid CoA-transferase, Am. J. Physiol. Heart Circ. Physiol., 281, H2289, 10.1152/ajpheart.2001.281.6.H2289 Pellerin, 2005, Cellular and subcellular distribution of monocarboxylate transporters in cultured brain cells and in the adult brain, J. Neurosci. Res., 79, 55, 10.1002/jnr.20307 Balietti, 2010, Ketogenic diets: an historical antiepileptic therapy with promising potentialities for the aging brain, Ageing Res. Rev., 9, 273, 10.1016/j.arr.2010.02.003 Hugo, 2012, A monocarboxylate transporter required for hepatocyte secretion of ketone bodies during fasting, Genes Dev., 26, 282, 10.1101/gad.180968.111 Hankermeyer, 1999, Polyhydroxybutyrate: plastic made and degraded by microorganisms, Rev. Environ. Contam. Toxicol., 159, 1 NCBI Resource Coordinators, 2013, Database resources of the National Center for Biotechnology Information, Nucleic Acids Res., 41, D8, 10.1093/nar/gks1189 Tunaru, 2003, PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect, Nat. Med., 9, 352, 10.1038/nm824 Taggart, 2005, (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G, J. Biol. Chem., 280, 26649, 10.1074/jbc.C500213200 Offermanns, 2011, International Union of Basic and Clinical Pharmacology. LXXXII: nomenclature and classification of hydroxy-carboxylic acid receptors (GPR81, GPR109A, and GPR109B), Pharmacol. Rev., 63, 269, 10.1124/pr.110.003301 Kimura, 2011, Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41), Proc. Natl. Acad. Sci. U.S.A., 108, 8030, 10.1073/pnas.1016088108 Blad, 2012, G protein-coupled receptors for energy metabolites as new therapeutic targets, Nat. Rev. Drug Discov., 11, 603, 10.1038/nrd3777 Layden, 2013, Short chain fatty acids and their receptors: new metabolic targets, Transl. Res., 161, 131, 10.1016/j.trsl.2012.10.007 Gregoretti, 2004, Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis, J. Mol. Biol., 338, 17, 10.1016/j.jmb.2004.02.006 Yang, 2008, The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men, Nat. Rev. Mol. Cell Biol., 9, 206, 10.1038/nrm2346 Mihaylova, 2013, Metabolic reprogramming by class I and II histone deacetylases, Trends Endocrinol. Metab., 24, 48, 10.1016/j.tem.2012.09.003 New, 2012, HDAC inhibitor-based therapies: can we interpret the code?, Mol. Oncol., 6, 637, 10.1016/j.molonc.2012.09.003 Glozak, 2005, Acetylation and deacetylation of non-histone proteins, Gene, 363, 15, 10.1016/j.gene.2005.09.010 Cousens, 1979, Different accessibilities in chromatin to histone acetylase, J. Biol. Chem., 254, 1716, 10.1016/S0021-9258(17)37831-6 Bolden, 2006, Anticancer activities of histone deacetylase inhibitors, Nat. Rev. Drug Discov., 5, 769, 10.1038/nrd2133 Vannini, 2004, Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor, Proc. Natl. Acad. Sci. U.S.A., 101, 15064, 10.1073/pnas.0404603101 Somoza, 2004, Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases, Structure, 12, 1325, 10.1016/j.str.2004.04.012 Wang, 2005, Toward selective histone deacetylase inhibitor design: homology modeling, docking studies, and molecular dynamics simulations of human class I histone deacetylases, J. Med. Chem., 48, 6936, 10.1021/jm0505011 Sekhavat, 2007, Competitive inhibition of histone deacetylase activity by trichostatin A and butyrate, Biochem. Cell Biol., 85, 751, 10.1139/O07-145 Madiraju, 2009, Mitochondrial acetylcarnitine provides acetyl groups for nuclear histone acetylation, Epigenetics, 4, 399, 10.4161/epi.4.6.9767 Wellen, 2009, ATP-citrate lyase links cellular metabolism to histone acetylation, Science, 324, 1076, 10.1126/science.1164097 Muoio, 2012, Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility, Cell Metab., 15, 764, 10.1016/j.cmet.2012.04.005 Anson, 2005, The diet restriction paradigm: a brief review of the effects of every-other-day feeding, Age, 27, 17, 10.1007/s11357-005-3286-2 Hatori, 2012, Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet, Cell Metab., 15, 848, 10.1016/j.cmet.2012.04.019 Bainbridge, 1925, The reduced sensitivity to insulin of rats and mice fed on a carbohydrate-free, excess-fat diet, J. Physiol., 60, 293, 10.1113/jphysiol.1925.sp002248 Burcelin, 2002, Heterogeneous metabolic adaptation of C57BL/6J mice to high-fat diet, Am. J. Physiol. Endocrinol. Metab., 282, E834, 10.1152/ajpendo.00332.2001 Kinzig, 2010, Insulin sensitivity and glucose tolerance are altered by maintenance on a ketogenic diet, Endocrinology, 151, 3105, 10.1210/en.2010-0175 Borghjid, 2012, Response of C57Bl/6 mice to a carbohydrate-free diet, Nutr. Metab. (Lond.), 9, 69, 10.1186/1743-7075-9-69 Garbow, 2011, Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet, Am. J. Physiol. Gastrointest. Liver Physiol., 300, G956, 10.1152/ajpgi.00539.2010 Freedland, 2008, Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis, Prostate, 68, 11, 10.1002/pros.20683 Mavropoulos, 2009, The effects of varying dietary carbohydrate and fat content on survival in a murine LNCaP prostate cancer xenograft model, Cancer Prev. Res. (Phila.), 2, 557, 10.1158/1940-6207.CAPR-08-0188 McDaniel, 2011, The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway, Epilepsia, 52, e7, 10.1111/j.1528-1167.2011.02981.x Kennedy, 2007, A high-fat, ketogenic diet induces a unique metabolic state in mice, Am. J. Physiol. Endocrinol. Metab., 292, E1724, 10.1152/ajpendo.00717.2006 Badman, 2009, A very low carbohydrate ketogenic diet improves glucose tolerance in ob/ob mice independently of weight loss, Am. J. Physiol. Endocrinol. Metab., 297, E1197, 10.1152/ajpendo.00357.2009 Jornayvaz, 2010, A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain, Am. J. Physiol. Endocrinol. Metab., 299, E808, 10.1152/ajpendo.00361.2010 Srivastava, 2013, A ketogenic diet increases brown adipose tissue mitochondrial proteins and UCP1 levels in mice, IUBMB Life, 65, 58, 10.1002/iub.1102 Laeger, 2010, Role of beta-hydroxybutyric acid in the central regulation of energy balance, Appetite, 54, 450, 10.1016/j.appet.2010.04.005 Schugar, 2012, Low-carbohydrate ketogenic diets, glucose homeostasis, and nonalcoholic fatty liver disease, Curr. Opin. Clin. Nutr. Metab. Care, 15, 374, 10.1097/MCO.0b013e3283547157 Orentreich, 1993, Low methionine ingestion by rats extends life span, J. Nutr., 123, 269 Pamplona, 2006, Mitochondrial oxidative stress, aging and caloric restriction: the protein and methionine connection, Biochim. Biophys. Acta, 1757, 496, 10.1016/j.bbabio.2006.01.009 Ables, 2012, Methionine-restricted C57BL/6J mice are resistant to diet-induced obesity and insulin resistance but have low bone density, PLoS ONE, 7, e51357, 10.1371/journal.pone.0051357 Hirschey, 2011, SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome, Mol. Cell, 44, 177, 10.1016/j.molcel.2011.07.019 Ahola-Erkkila, 2010, Ketogenic diet slows down mitochondrial myopathy progression in mice, Hum. Mol. Genet., 19, 1974, 10.1093/hmg/ddq076 Houtkooper, 2012, Sirtuins as regulators of metabolism and healthspan, Nat. Rev. Mol. Cell Biol., 13, 225, 10.1038/nrm3293 Poplawski, 2011, Reversal of diabetic nephropathy by a ketogenic diet, PLoS ONE, 6, e18604, 10.1371/journal.pone.0018604 Harvie, 2013, The effect of intermittent energy and carbohydrate restriction v. daily energy restriction on weight loss and metabolic disease risk markers in overweight women, Br. J. Nutr., 1 Westman, 2008, The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus, Nutr. Metab. (Lond.), 5, 36, 10.1186/1743-7075-5-36 Nordmann, 2006, Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials, Arch. Intern. Med., 166, 285, 10.1001/archinte.166.3.285 Hartman, 2007, Clinical aspects of the ketogenic diet, Epilepsia, 48, 31, 10.1111/j.1528-1167.2007.00914.x Kashiwaya, 2013, A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's disease, Neurobiol. Aging, 34, 1530, 10.1016/j.neurobiolaging.2012.11.023 Henderson, 2009, Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial, Nutr. Metab. (Lond.), 6, 31, 10.1186/1743-7075-6-31 Reger, 2004, Effects of beta-hydroxybutyrate on cognition in memory-impaired adults, Neurobiol. Aging, 25, 311, 10.1016/S0197-4580(03)00087-3 Tieu, 2003, D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease, J. Clin. Invest., 112, 892, 10.1172/JCI200318797 Vanitallie, 2005, Treatment of Parkinson disease with diet-induced hyperketonemia: a feasibility study, Neurology, 64, 728, 10.1212/01.WNL.0000152046.11390.45 Zhao, 2006, A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis, BMC Neurosci., 7, 29, 10.1186/1471-2202-7-29 Noh, 2008, Neuroprotective effects of the ketogenic diet, Epilepsia, 49, 120, 10.1111/j.1528-1167.2008.01855.x Lim, 2011, D-beta-hydroxybutyrate is protective in mouse models of Huntington's disease, PLoS ONE, 6, e24620, 10.1371/journal.pone.0024620 Sadri-Vakili, 2006, Mechanisms of disease: histone modifications in Huntington's disease, Nat. Clin. Pract. Neurol., 2, 330, 10.1038/ncpneuro0199 Kashiwaya, 2000, D-beta-hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease, Proc. Natl. Acad. Sci. U.S.A., 97, 5440, 10.1073/pnas.97.10.5440 Hu, 2009, Ketogenic diet reduces cytochrome c release and cellular apoptosis following traumatic brain injury in juvenile rats, Ann. Clin. Lab. Sci., 39, 76 Appelberg, 2009, The effects of a ketogenic diet on behavioral outcome after controlled cortical impact injury in the juvenile and adult rat, J. Neurotrauma, 26, 497, 10.1089/neu.2008.0664 Puchowicz, 2008, Neuroprotection in diet-induced ketotic rat brain after focal ischemia, J. Cereb. Blood Flow Metab., 28, 1907, 10.1038/jcbfm.2008.79 Tai, 2008, Ketogenic diet prevents cardiac arrest-induced cerebral ischemic neurodegeneration, J. Neural Transm., 115, 1011, 10.1007/s00702-008-0050-7 Masuda, 2005, D-beta-hydroxybutyrate is neuroprotective against hypoxia in serum-free hippocampal primary cultures, J. Neurosci. Res., 80, 501, 10.1002/jnr.20464 Samoilova, 2010, Chronic in vitro ketosis is neuroprotective but not anti-convulsant, J. Neurochem., 113, 826, 10.1111/j.1471-4159.2010.06645.x Juge, 2010, Metabolic control of vesicular glutamate transport and release, Neuron, 68, 99, 10.1016/j.neuron.2010.09.002 Miller, 2009, Cell stress and new emphasis on multiplex resistance mechanisms, J. Gerontol. Ser. A: Biol. Sci. Med. Sci., 64, 179, 10.1093/gerona/gln072 Shore, 2012, Induction of cytoprotective pathways is central to the extension of lifespan conferred by multiple longevity pathways, PLoS Genet., 8, e1002792, 10.1371/journal.pgen.1002792 Alam, 2001, Resuscitation-induced pulmonary apoptosis and intracellular adhesion molecule-1 expression in rats are attenuated by the use of Ketone Ringer's solution, J. Am. Coll. Surg., 193, 255, 10.1016/S1072-7515(01)01004-3 Koustova, 2003, Ketone and pyruvate Ringer's solutions decrease pulmonary apoptosis in a rat model of severe hemorrhagic shock and resuscitation, Surgery, 134, 267, 10.1067/msy.2003.245 Ayuste, 2006, Hepatic and pulmonary apoptosis after hemorrhagic shock in swine can be reduced through modifications of conventional Ringer's solution, J. Trauma, 60, 52, 10.1097/01.ta.0000200156.05397.0b Jaskille, 2006, Hepatic apoptosis after hemorrhagic shock in rats can be reduced through modifications of conventional Ringer's solution, J. Am. Coll. Surg., 202, 25, 10.1016/j.jamcollsurg.2005.08.027 Klein, 2010, Small-volume D-beta-hydroxybutyrate solution infusion increases survivability of lethal hemorrhagic shock in rats, Shock, 34, 565, 10.1097/SHK.0b013e3181e15063 Mulier, 2012, Treatment with beta-hydroxybutyrate and melatonin is associated with improved survival in a porcine model of hemorrhagic shock, Resuscitation, 83, 253, 10.1016/j.resuscitation.2011.08.003 Zou, 2002, DL-3-Hydroxybutyrate administration prevents myocardial damage after coronary occlusion in rat hearts, Am. J. Physiol. Heart Circ. Physiol., 283, H1968, 10.1152/ajpheart.00250.2002 Mihaylova, 2011, Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis, Cell, 145, 607, 10.1016/j.cell.2011.03.043 Knutson, 2008, Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks, EMBO J., 27, 1017, 10.1038/emboj.2008.51 Fajas, 2002, The retinoblastoma-histone deacetylase 3 complex inhibits PPARgamma and adipocyte differentiation, Dev Cell, 3, 903, 10.1016/S1534-5807(02)00360-X Bhaskara, 2010, Hdac3 is essential for the maintenance of chromatin structure and genome stability, Cancer Cell, 18, 436, 10.1016/j.ccr.2010.10.022 Gao, 2009, Butyrate improves insulin sensitivity and increases energy expenditure in mice, Diabetes, 58, 1509, 10.2337/db08-1637 Zhang, 2007, Sodium butyrate prevents lethality of severe sepsis in rats, Shock, 27, 672, 10.1097/SHK.0b013e31802e3f4c Ni, 2010, Histone deacetylase inhibitor, butyrate, attenuates lipopolysaccharide-induced acute lung injury in mice, Respir. Res., 11, 33, 10.1186/1465-9921-11-33 Fischer, 2007, Recovery of learning and memory is associated with chromatin remodelling, Nature, 447, 178, 10.1038/nature05772 Peleg, 2010, Altered histone acetylation is associated with age-dependent memory impairment in mice, Science, 328, 753, 10.1126/science.1186088 Guan, 2009, HDAC2 negatively regulates memory formation and synaptic plasticity, Nature, 459, 55, 10.1038/nature07925 Graff, 2012, An epigenetic blockade of cognitive functions in the neurodegenerating brain, Nature, 483, 222, 10.1038/nature10849 Kim, 2008, Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity, Neuron, 60, 803, 10.1016/j.neuron.2008.10.015 Dobbin, 2013, SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons, Nat. Neurosci., 16, 1008, 10.1038/nn.3460 Kim, 1999, Modulation of life-span by histone deacetylase genes in Saccharomyces cerevisiae, Mol. Biol. Cell, 10, 3125, 10.1091/mbc.10.10.3125 Kaeberlein, 2010, Lessons on longevity from budding yeast, Nature, 464, 513, 10.1038/nature08981 Yi, 2012, Function and molecular mechanism of acetylation in autophagy regulation, Science, 336, 474, 10.1126/science.1216990 Rogina, 2002, Longevity regulation by Drosophila Rpd3 deacetylase and caloric restriction, Science, 298, 1745, 10.1126/science.1078986 Rogina, 2004, Sir2 mediates longevity in the fly through a pathway related to calorie restriction, Proc. Natl. Acad. Sci. U.S.A., 101, 15998, 10.1073/pnas.0404184101 Mannervik, 1999, The Rpd3 histone deacetylase is required for segmentation of the Drosophila embryo, Proc. Natl. Acad. Sci. U.S.A., 96, 6797, 10.1073/pnas.96.12.6797 Zhao, 2005, Lifespan extension and elevated hsp gene expression in Drosophila caused by histone deacetylase inhibitors, J. Exp. Biol., 208, 697, 10.1242/jeb.01439 Kang, 2002, Life extension in Drosophila by feeding a drug, Proc. Natl. Acad. Sci. U.S.A., 99, 838, 10.1073/pnas.022631999 Evason, 2008, Valproic acid extends Caenorhabditis elegans lifespan, Aging Cell, 7, 305, 10.1111/j.1474-9726.2008.00375.x Lagger, 2002, Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression, EMBO J., 21, 2672, 10.1093/emboj/21.11.2672 Zimmermann, 2007, Reduced body size and decreased intestinal tumor rates in HDAC2-mutant mice, Cancer Res., 67, 9047, 10.1158/0008-5472.CAN-07-0312 Wilting, 2010, Overlapping functions of Hdac1 and Hdac2 in cell cycle regulation and haematopoiesis, EMBO J., 29, 2586, 10.1038/emboj.2010.136 Dovey, 2010, Histone deacetylase 1 (HDAC1), but not HDAC2, controls embryonic stem cell differentiation, Proc. Natl. Acad. Sci. U.S.A., 107, 8242, 10.1073/pnas.1000478107 Kossoff, 2012, Ketogenic diets: new advances for metabolism-based therapies, Curr. Opin. Neurol., 25, 173, 10.1097/WCO.0b013e3283515e4a Schwer, 2009, Calorie restriction alters mitochondrial protein acetylation, Aging Cell, 8, 604, 10.1111/j.1474-9726.2009.00503.x