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Review ELSEVIR TRENDS in Biochemical Sciences Vol32 No1 Full text provided by wwwsciencedirectcom 39 ScexnceDirect NAD metabolism in health and disease Peter Belenky Katrina L Bogan and Charles Brenner Departments of Genetics and of Biochemistry and Norris Cotton Cancer Center Dartmouth Medical School Lebanon NH 03756 USA Nicotinamide adenine dinucleotide NAD is both a coenzyme for hydridetransfer enzymes and a substrate for NADconsuming enzymes which include ADP ribose transferases polyADPribose polymerases cADPribose synthases and sirtuins Recent results establish protective roles for NAD that might be applic able therapeutically to prevent neurodegenerative con ditions and to fight Candida glabrata infection In addition the contribution that NAD metabolism makes to lifespan extension in model systems indicates that therapies to boost NAD might promote some of the beneficial effects of calorie restriction Nicotinamide riboside the recently discovered nucleoside precursor of NAD in eukaryotic systems might have advantages as a therapy to elevate NAD without inhibiting sirtuins which is associated with highdose nicotinamide or incurring the unpleasant sideeffects of highdose nicotinic acid The biology and biosynthesis of NAD Nicotinamide adenine dinucleotide NAD and its phosphorylated and reduced forms NADP NADH and NADPH have central roles in cellular metabolism and energy production as hydrideaccepting and hydride donating coenzymes Discovery of the coenzymatic activity of N AD is reviewed in Box 1 and the redox chemistry that is mediated by NAD is schematized in Figure 1 Such reactions are not destructive in the sense that NAD and N ADH are interconverted by hydride transfer As with all phosphorylated natural products NAD is biosynthesized from smaller units and is broken down Whereas NAD breakdown was thought once to be a nonspeci c process we now realize that NAD consumption is linked intrinsi cally to signaling reactions inside and outside cells that control gene expression Ca2 mobilization cell death and aging In this review we provide a detailed overview of NAD metabolism with emphasis on the potential for NADboosting therapies to maintain health and treat diseases Tryptophan is the de novo precursor of NAD in all vertebrates and almost all eukaryotes investigated People who subsist on tryptophanpoor diets run the risk of Corresponding author Brenner C CharlesBrennerDartmouthedu Disclosure statement GB is inventor of intellectual property related to nicotinamide riboside kinases and uses of nicotinamide riboside The intellectual property is owned by CB s employer Trustees of Dartmouth College and therapeutic uses are licensed by Sirtris Pharmaceuticals a rm for which CB serves on the Scienti c Advisory Board Available online 11 December 2006 developing the nutritional de ciency pellagra unless their diet is supplemented with one of the classical vitamin precursors of NAD nicotinic acid Na or nicotinamide Nam which are collectively termed niacin As shown in Figure 2 the salvage pathways for the two niacins are encoded by different genes and thus might not be expressed equally in all vertebrate tissues The blood borne bacterium Haemophilus in uenza can not synthe size NAD de novo or salvage niacins see Glossary Instead it depends on uptake of nicotinamide riboside NR and a bacterial pathway that converts NR to NAD by phosphorylation and subsequent adenylylation 1 Recently it has become apparent that fungi and verte brates encode eukaryotic NR kinases Nrk isozymes to salvage NR a third vitamin precursor of NAD which occurs in milk 2 Precisely how and where intracellularly and extracellularly NR is produced is unknown and a matter of active research The abundance of N AD in human cells is controlled by many factors For example genes such as IDO which encodes the de novo biosynthetic enzyme indoleamine 23 dioxygenase are under transcriptional control 3 whereas nicotinamide mononucleotide NMN adenylyl transferases Nmnats Nmnatl Nmnat2 and Nmnat3 are localized differentially 4 NAD is partitioned into reduced NADH phosphorylated NADP and reduced phosphorylated NADPH pools in addition to the NAD pool Each pool resides differentially in membranebound compartments and is partially sequestered from free N AD by binding to proteins Three classes of NAD consumers The abundance of NAD is also regulated by breakdown largely because the molecule is not only coenzyme for oxidoreductases but also a substrate for three classes of Glossary Ectoenzymes membranebound enzymes with an extracellular activesite Flushing a painful condition that consists of 39hot flashes reddening and heat in the extremities Reverse cholesterol transport the multistep process by which HDL particles deliver cholesterol to the liver for excretion through bile acids Salvage and de novo biosynthesis biosynthetic pathways are termed salvage if the distinctive piece of the final product is recovered from breakdown products and de novo if the distinctive piece is produced from units that require large rearrangements NAD consists of an ADPribose group linked to Nam Whereas the AMP moiety of ADPribose always derives from ATP the distinctive piece of NAD is nicotinamide which is either salvaged or synthesized de novo The three vertebrate salvage and one de novo NAD biosynthetic pathways are depicted in Figure 2 wwwsciencedirectcom 09680004 see front matter 2006 Elsevier Ltd All rights reserved doi101016jtibs200611006 w Box 1 History of the NAD coenzyme In the early 20th century Arthur Harden and co workers reconstituted cellfree glucose fermentation with two fractions one rmed zymase39 that was heat labile and retained by dialysis and one termed cozymase39 that was heat stable and passed through dialysis Zymase was not a purified enzyme but a protein fraction that contained glycolytic enzymes The cozymase fraction contained TP and the NAD coenzyme the structure of which was determined by Otto Warburg ln glucose fermentation NAD func onsasm it A39A in L r i i y 3 phosphate dehydrogenase producing NADH and diphosphoglyce rate Similarly NADH functions as the hydride donor for alco ol dehydrogenase which is required for the reduction of acetaldehyde to ethanol regenerating NAD Numerous hydride transfer enzymes oroxidoreductases interconvert either NAD and NADH or NADP and NADPH to reduce oroxidize small molecule metabolites see Figure 1 in the main text enzymes that cleave NAD to produce Nam and an ADPribosyl product Although historically these enzymes have been called NAD glycohydrolases NAD dependent ADPribosyl transferase is a more precise term 5 However to avoid confusion with dedicated protein monoADPribosyl transferases we refer to the enzymes historically termed NAD glycohydrolases as NAD con sumers As depicted in Figure 3 the three classes of NAD consumers are i ADPribose transferases or polyADP ribose polymerases ii cADPribose synthases and iii sirtuins type 111 protein lysine deacetylases The substantial ux through NADconsuming pathways explains why people require niacin supple mentation when tryptophan is limiting If NAD were only a coenzyme ie not consumed but merely inter converted between oxidized and reduced forms by hydride transfer the nutritional requirement to support ongoing synthesis in excess of that provided by the ole novo pathway would be dif cult to explain Thus we now believe that either dietary niacins or NR in conjunction with niacin andor NRsalvage are required to maintain TRENDS in Biochemical Sciences Vol32 No1 13 NAD in cells that are undergoing rapid NAD break down Figure 2 AFi39Ts and PAFi39Ps ADPribose transferases ARTs and the more numerous polyADPribose polymerases PARPs consume NAD to create an ADPribosyl protein modi cation andor to form the ADPribose polymer PAR gure 3 In a comprehen sive review of the function of ARTs and PARPs de Murcia describes numerous conditions that induce this type of NAD catabolism and the consequent ADPribose reaction products in DNAdamage responses epigenetic modi ca tion transcription chromosome segregation and pro grammed cell death 6 Because of the roles of PARPs in cell death there are substantial preclinical and inves tigative efforts to inhibit PARP to protect against cardiac in ammatory and neurodegenerative conditions 7 How ever because PARP has complex roles in cell survival and repair signaling in addition to mediating cell death it might be dif cult to develop neuroprotective strategies that involve chronic inhibition of this essential enzyme 7 Moreover much of the bene t associated with inhibi tion of PARP might be related to protecting cellular NAD such that NADboosting therapies targeted to tissues in which PARP is activated might be safer and as effective cADPribose synthases cADPribose synthases are a pair of ectoenzymes also known as the lymphocyte antigens CD38 and CD 157 which produce and hydrolyze the Ca2mobilizing secondmessen ger cADPribose from NAD 8 10 gure 3 CD38 cata lyzes a base exchange between NADP and Na to form Na adenine dinucleotide phosphate NaADP 11 which is also a hydrolytic substrate 12 All the products of CD38 cADP ribose ADPribose and NaADP have distinctive roles in Ca2 mobilization TIES Figure 1 NAD as a coenzyme for reversible nydrlde transfer ln a typical NAD rdependent oxidation an alconol is converted to tne corresponding aldenyde wltn tne production of NADH plus a proton ln tne NADHrdependent direction an aldenyde is reduced to an alconol wnlcn regenerates NAD www5ciencedirectcom M M TRENDS in Biochemical Sciences Vol32 No1 Tm NHE I COOH H ldo or Tdo 34 a Nformylkynurenine o Kynurenine NH2 0 NH2 COOH COOH COOH Kynu Kmo Afmld O N NH NH NH NH2 2 2 H Haao O O o Qulniate COOH NMN o NH2 Qprt Nadsyn1 I gt N COOH N ADP rlbo N ADn Pnbo N M N k2 N consuming PBEF I r SD en mes o 0 2y 0 Na Nam NR o NH2 l NHZ Na N N H H J Ribo Import Import Import m Figure 2 lnlracellular NAD metabolism in vertebrates De novo synthesis begins with the conversion of tryplophan to Nrformylkynuren39ine by either indoieamine dioxygenaseido ortryptophan d39ioxygenase Tdo 39 wnicn39 4 b b kynm v to form 3shydroxykynuren39ine Kynuren39inase Kynu then forms 3rhydroxyamhran39ilate wnicn is convened to Zam39ino rarboxymuconate semiaidenyde not snown by 3shydroxyamhran39ilate d39ioxygenase Tne semiaidenyde undergoes a spontaneous condensation and rearrangement to form quinolate wnicn is convened to NaNIN by quinolate phosphorbosyltransferase Qpn NaNIN is then adenylylated by Nmnat1Nmnat2 and Nmnat3 to form nicotinic acid adenine dinucleotide NaAD wnicn is convenedto AD b oi v 39 A v b M 4 NAD 39 iW rbreakthe bond between the Nam andADPrr39ibosy moieties Nam wnicn is aiso provided in the diet is saivaged by a Nam phosphorbosyltransferase termed PBEF to NMN wnicn is adenylylated to form NAD by Nmnat1Nmnat2 and Nmnat3 Na wnicn is provided in the diet and potentialw by bacteria degradat39ive pathways in vertebrates is saivaged by Na phosphorbosyltransferase Nabn to form NaNIN NR wnicn occurs exiraceiiuiariyin biood and miik and can be provided in the diet is saivaged by nicotinamide riboside kinases Nrk1 and Nrk2 Na and Nam are aiso convened to nicot39iriur39ic acid and Nemethyln39icot39inam39ide elimination products not snown Sirtuins Sir2 was rst identi ed as a positive regulator of gene Sirtuins so named because of their similarity to yeast silent silencing at cryptic matingtype loci It functions in com information regulator 2 Sir2 are enzymes that function plexes that remodel chromatin to repress transcription and primarily in reversing acetyl modi cations of lysine on recombination in a manner that depends on reversing histones and other proteins 5 Also termed typeIII histone acetyl modi cations on histone H3 and histone H4 Sir deacetylases HDACs or more precisely typeIII protein tuins from archaea bacteria yeast invertebrates and lysine deacetylases sirtuins bind two substrates the rst is vertebrates deacetylate histone and nonhistone targets a protein or peptide that contains an acetylated lysine and to alter enzyme activity and proteincomplex formation the second is NAD 13 Figure 3 Sirtuins position the andto activate and repress transcription Reviewed in 5 leaving acetyl group to attack the ribose Cl carbon of the The relationships between sirtuins and ART activities ADPribose moiety of NAD which produces acetylated are intimate and complex For example a trypanosomal ADPribose plus Nam and the deacetylated protein lysine sirtuin possesses both ART and deacetylase activity 16 14 The acetylated ADPribose rearranges to form a mix whereas murine Sirt6 seems to be an ART but not a ture of 2 and 3 acetylADPribose 15 deacetylase 17 In addition activation of the Sir2 ortholog www5ciencedirectcom w TRENDS in Biochemical Sciences Vol32 No1 0 NAD39 I NH2 9 N H HOH mg N f 1 N 2 0 ADPnbose x 7 Nk acceptor O o H H H0H OH a ARTs c PAHPS b cADPribose Nam O synthases N l 0 am 0 NH2 2 7O acetyliADPiribose x N AD ADPribose ADP I IbOSB of 05 0 acceptor O f O H H HO HO cADPribose OH HO H HOH g N NH2 ADP bose NH Sirtuins TiBS Figure 3 NAD as a substrate for ADPrribose transfer CADPrribose synthesis and protein lysine deacetyla on a ARTs and PARPs transfer ADPrribose from NAD as a protein modification with production of Na synthases cyclize me ADFrribose moiety of NAD with production of Nam m n the case of FARPs the ADPrribose acceptor X c n a These enzymes also hydrolyze CADPrribose c Sinuins use the ADP so be ADPrribose forming poyADPrrbose b CADPrribose rribose moiety of NAD to accept me acety modification of a protein lysine forming deacetylated protein plus Nam and a er acetylrg roup rearrangement a mixture of 2 and 3 Oracetylated ADPV ribose Each NAD rconsuming enzyme is inhibited by the Nam product Sirtl is associated with reduction of PARPl activity whereas deletion of Sirtl increases the production of PAR 18 Reciprocally the cell death caused by activation of PARPl in cardiac myocytes can be reduced by either administration of NAD or increased NAD biosynthesis and the protective effect of NAD biosynthesis depends largely on the presence ofSirtl 19 This direct evidence that therapy targeted to protect cellular NAD is indicated by activation of PARP in heart failure Nam 39 quot NAD A common theme among NAD consumers is inhibition by Nam ART PARP 20 CD38 21 and sirtuin 22 enzymes each contain a Namproduct site that can be occupied in the presence of substrates and enzyme intermediates Thus each enzyme can be inhibited by Nam which effectively drives the formation of baseexchanged substrates Because of this type of product inhibition the salvage andor elim ination of Nam are crucial steps in NAD metabolism Whereas Nam is salvaged to Na in fungi and many bacteria the gene that encodes nicotinamidase is absent from vertebrate genomes and thus this route is not and 39 and www5ciencedirectcom available to humans except potentially in the gut where commensal bacteria might contribute to Nam salvage in the host There is a human but not fungal gene encoding a Nam N methyltransferase that converts Nam to N methyl nicotinamide in vitro 23 In addition humans express a homolog of the H in uenza nadV gene which has Nam activity 24 gure 2 Remarkably this activity has been identi ed in a polypep tide named preB cell colonyenhancing factor PBEF for which there are convincing reports of intracellular and quot quot Y increases NAD concentrations and as a consequence has cellpro tective bene ts 1924 2 7 Extracellularly PBEF has two known activities First the polypeptide synergizes with stem cell factor and interleukin 7 to promote the formation of preBcell colonies 28 Second as an activity terme visfatin PBEF is secreted by visceral fat in order to bind the insulin receptor and mimic the effects of insulin 29 The relationship between the enzymatic activity of PBEF and its extracellular activities has not been inves tigated However it is reasonable to suggest that PBEF functions in part by relieving Nammediated inhibition of an extracellular NADconsuming enzyme nhu u nm Cell lysis Ti BS Figure 4 A potential emaceHuiar NAD rcycle 39m venebraies EmaceHuiar NAD could be derived from emer ceH lysls or potentially speci c iranspon through Connex39m 43 hemlchannels EmaceHuiar CADPrrlbose synmases such as c033 produce Nam from NAD Nam might be convened to NMN by PBEF Nam phosphorbosyllransferase with subsequent dephosphoryla on 0 NR by CD73 Nam and NR aremougm to be imported byunldeml ed transporters andor by participating in a NAD biosynthetic cycle that is partially extracellular The source of NAD for quot NAD such as ARTs and cADPribose synthase is a matter of interest Although an obvious source of NAD around sites of in ammation is cell lysis there are strong indications that NAD is transported via connexin 43 hemichannels speci cally to provide NAD for the CD38 active site 30 As shown in gure 4 a potential extracellular NAD biosynthetic cycle in vertebrates might be initiated by transport of NAD by connexin 43 for consumption by CD38 to produce Nam and cADPribose PBEF with suf cient phosphoribosyl pyrophosphate PRPP might then convert Nam extracellularly to NMN 24 In addition CD73 an ectoenzyme that is homologous to nadN the NMN nucleotidase of H in uenza 31 might convert NMN to NR Because H in uenza multiplies in vertebrate blood despite mutation of nadN 32 it is reasonable to surmise that NR circulates in vertebrate vascular systems and is taken up by cells that express a NR transporter NAD synthesis in neuroprotection Damage to nerve bers leads to a series of molecular and cellular responses that are termed Wallerian degeneration or axonopathy Axonopathy is a critical early event in distinct degenerative conditions including Alzheimer s dis ease AD Parkinson s disease and multiple sclerosis MS and it occurs in response to infections alcoholism acute chemotherapyassociated toxicity diabetes and normal aging 33 The Wallerian degeneration slow wlds mouse is a spontaneous mutant that contains an autosomal domi nant genetic alteration that confers resistance to nerve cell damage ex vivo and in vivo The fusion protein encoded by wlalS contains the rst 70 amino acids of ubiquitination factor de2a and fulllength Nmnat1 which is tandemly triplicated 3435 Overexpression of Nmnatl blocks the axon degeneration induced by vincristine and transection in dorsal root ganglion DRG neurons 3637 It has also been shown that axonopathy is accompanied by depletion of NAD and ATP and that expression of wlalS protects neuronal NAD levels 37 Differences between the rst two reports 3637 of protection against axonopathy require reconciliation espe www5ciencedirectcom TRENDS in Biochemical Sciences Vol32 No1 cially in light of a putatively negative report 38 and subsequent clari cations of the protective value of NAD synthesis in ex vivo 27 and in vivo 39 models of neuro degeneration Milbrandt and coworkers have used lenti viral expression in DRG neurons to show that Nmnatl protects against vincristineinduced axonopathy in an activesite dependent manner and that bathing DRG neurons in 1 mM NAD is also protective 36 Based on RNAimediated knockdowns they suggested that NAD mediated protection depends on Sirtl 36 Independently He and coworkers have corroborated protection by Nmnatl and NAD and provided evidence that exposure to vincris tine and nerve transection lead to depletion of NAD i How ever their study casts doubt on the role of Sirtl as the key mediator of protection against axonopathy with the observation that embryonic sirtlii DRG neurons can be protected 37 The report which concludes that Nmnatl does not substitute for the W39ldS fusion protein actually con rms that lentiviral expression of Nmnatl is protective although possibly less so than fulllength W39ldS 38 This latter might be the result of a proteinstabiliz ing mechanism of the de2a fragment Although these investigators failed to produce a mouse transgenic for nmnatl that conferred a robust wlalS phenotype their trans genes expressed Nmnatl from the Bactin promoter 38 rather than the de2a promoter which is highly expressed in neurons 40 Two more recent studies clarify the power if not the precise mechanism of NADmediated protection against neurodegeneration The Milbrandt group devel oped lentiviralexpression systems for eight NAD bio synthetic enzymes and examined the cellular localization and ability of these enzymes to protect mouse DRG axons from dying back after transection from neuronal cell bodies Expression of Nam phosphoribosyltransferase and Na phosphoribosyltransferase genes protects but only when neurons are cultured with Nam and Na respectively and neither Nam nor Na protects without A of the Lui A quot quot gene As in the earlier study Nmnat1 protects without any remnant of de2a but in addition a mutation that abolishes nuclear localization of Nmnat1 has no effect on protection whereas expression of Nmnat3 either in the mitochondria native or nucleus engineered pro tects These results indicate that neurons contain suf cient nicotinic acid mononucleotide NaMN or NMN for the increased expression of Nmnat to elevate NAD and that increasing NAD in the nucleus cytoplasm or mito chondria protects against degeneration which is ulti mately a cytosolic process Four compounds NAD NMN NaMN and NR protect without concomitant gene therapy Although it is unclear how the nondruglike phosphorylated compounds NAD NMN and NaMN enter cells and whether they are transported as nucleo sides NR and Na riboside the data indicate that the Nrk pathway is primed to protect DRG neurons if the NR vitamin is supplemented Indeed the study shows that Nrk2 mRNA increases 20fold in the 2 weeks following sciaticnerve transection in rats 27 A study in experimental autoimmune encephalomyelitis a mouse model of MS shows that the wlalS mutation has a w mild protective effect against development of neuromuscu lar de cits whereas Nam provides striking dosedependent delay and protection against the development of hindlimb weakness and paralysis Indeed Nam provides even greater protection to wlalS mice than to wildtype mice probably because large doses of Nam render the Nmnatbiosynthetic step limiting 39 In summary the diseases and conditions that involve Wallerian degeneration eg AD chemother apyinduced and diabeticinduced peripheral MS and alcoholism are collectively common and occur increasingly with advancing age Thus therapies that pro tect neuronal NAD might prove to be quite powerful However the most effective compounds and formulations remain to be determined NAD synthesis in candidiasis Candida glabrata the second leading cause of candidiasis is a fungus with an interesting variation in NAD meta bolism Saccharomyces cerevisiae NAD metabolism differs from that of humans because the yeast lacks ARTs PARPs and cADPribose synthases and contains nicotinamidase Pncl rather than PBEF The C glabrata genome is additionally missing genes for the ole novo biosynthesis of NAD such that it is a Na auxotroph 41 Just as S cerevisiae Sir2 represses transcription of subtelomeric genes in an NADdependent manner 42 so C glabrata Sir2 represses transcription of subtelomeric EPA1 EPA6 and EPA7 genes which encode adhesins that promote urinarytract infection Because C glabrata cannot make NAD ale novo low Na levels limit the function of Sir2 thereby derepressing adhesin genes and inducing a switch to adhere to host cells As a consequence increased dietary Na provides some protection against urinary tract infection in mice 41 Highdose Na is a common overthecounter and prescription drug that increases highdensity lipoprotein HDL otherwise known as good cholesterol and reduces triglyceride levels 43 via an unknown mechanism How ever highdose Na causes ushing via a receptor mechan ism 44 that is unrelated to NAD synthesis Because patients with candidiasis might be particularly sensitive to ushing we suggest that Nam and NR should be tested as antiC glabrata agents The C glabrata homologs of Pncl and Nrk1 are represented in National Center for Biotechnology Information NCBI databases NCBI codes CAG57733 and XP 448957 respectively Nam might fail to support Sir2dependent repression of adhesin genes because it is an inhibitor of Sir2 45 which might result in adhesin gene derepression Indeed because there is no known route to produce Na in vertebrates we suggest that C glabrata is NADlimited after depletion of NR which is known to circulate based on the Haemophilus literature 32 and that the C glabrata geneexpression switch might be either prevented or reversed by supplementation with NR NAD synthesis in the regulation of aging All fungi and animals that have been examined have characteristic rates of aging that depend on environmental conditions and yield mutations that confer either progeric or longlived phenotypes Calorie restriction CR is the www5ciencedirectcom TRENDS in Biochemical Sciences Vol32 No1 17 most powerful intervention known to extend the lifespan of yeasts worms ies and mammals Reviewed in 46 CR increases lifespan and delays the onset of distinct debili tating diseases in different models CR reduces carcinogen esis in mouse models prevents kidney disease in rats and forestalls diabetes and cardiovascular disease in monkeys In addition although there is no experimental proof that CR extends human lifespan the hematological hormonal an of the eight people on a CR diet for almost two years in the Biosphere were similar to those of mice or monkeys on CR 47 Although most humans would balk at CR diets that might leave us colder smaller and lacking in sex drive the longevitypromoting effects of CR are so profound in so many models that if we could understand the molecular basis of these effects we might be able to develop tools to delay consequences of aging and promote some of the cellular and physiological changes that occur in CR In yeast the proximal cause of replicative senescence failure of a mother cell to produce a daughter cell of wild type cells is the accumulation of extrachromosomal rDNA circles ERCs that are formed by recombination between tandemly arranged rRNA genes 48 Thus sir2 mutants have shorter replicative life spans because Sir2 has a crucial role in repressing rDNA recombination 49 In a landmark paper Guarente and colleagues showed that CR extends replicative lifespan in yeast in a manner that depends on Sir2 and Npt1 the Na phosphoribosyl transferase 50 The mechanisms by which CR promotes NADdependent activities of Sir2 might include increas ing the NAD2NADH ratio 51 reducing inhibitory Nam 52 elevating NAD and increasing levels of either Sir2 or speci c Sir27substrate complexes Of the mechanisms that involve relief of inhibition biochemical and cellular data suggest that Nam is a more effective inhibitor than NADH 225354 There are Sir2independent mechan isms by which CR extends lifespan in yeast fob mutants that do not accumulate ERCs 55 The proximal causes of death in yeast fob mutants and their interactions with CR are being pursued to identify additional targets that might be conserved in humans There is also evidence that a Sir2 independent target of Nam limits the effects of CR 56 but much or all of this regulation might involve the paralogous sirtuin Hst2 57 In worms and ies increased gene dosage of the Sir2 ortholog extends lifespan 5859 and in ies the bene cial effect of CR depends on dSir2 59 Hyperactivity a phy siological response to CR in vertebrates depends on Sirtl in mouse 60 Because Sir2 has been conserved to alter gene expression in response to CR in metazoans sirtuin activators are being developed as agents that might pro vide some of the bene ts of CR Resveratrol a plant poly phenol that is enriched in red wine was identi ed as an activator of human Sirtl in a highthroughput screen 61 Although activation by resveratrol depends on the identity of the Sirtl substrate 6263 and resveratrol has other targets in addition to Sirtl multiple reports indicate that Sirtl is one of the key targets of resveratrol 181964 Indeed hard data now support the ability of highdose resveratrol to increase the lifespan of worms and ies 65 and the health and vitality of overfed mice 6667 m Em Although the data do not establish Sirt1 orthologs as the only mediators of the complex bene cial effects of resver atrol in vertebrates increased mitochondrial biogenesis in liver 66 and muscle 67 can be explained by increased Sirt1dependent deacetylation of the transcriptional coac tivator PGCloi 68 In the liver of mice fasted for 1 day the levels of NAD and Sirt1 are increased which leads to Sirt1dependent deacetylation of PGC1q and consequent induction of gluconeogenic genes 68 In a murine model of AD that overexpresses a human mutant amyloid B protein CR increases levels of NAD and Sirt1 and reduces Nam in the brain 69 In this model Sirt1 and NAD reduce the production of amyloidogenic peptides and the resulting neuropathology 69 Thus although Sir2dependent repression of the formation of ERCs is yeastspeci c there is broad conservation of CR NAD and sirtuin function Moreover the AD model indicates that speci c NAD boosting molecules might replace CR in treating speci c diseases which was a far from trivial assumption cardiac and neuronal models there are indications that some aspects of the protective effects of NAD synth esis are mediated by sirtuins 1969 but other effects might be sirtuinindependent 3 7 In light of the localiza tion of three human sirtuins to mitochondria the control of mitochondrial acetylcoA synthetase 2 by Sirt3 707 1 and the connection between mitochondrial function and aging a key area for future investigation to identify cellprotec tive and antiaging targets of NAD within mitochondria Na and plasma lipids Finally it is important to reinvestigate the mechanisms by which Na reduces levels of triglycerides and lowden sity lipoprotein cholesterol and elevates HDL cholesterol It has long been assumed that the bene cial effects of Na on plasma lipids are mediated via a receptor rather than a vitamin mechanism because of the high dose required 100fold higher than that required to prevent pellagra and the failure of Nam to provide similar bene ts 72 Today however low HDL cholesterol and poor reverse cholesterol transport are regarded as a distinct molecular pathology and as risk factors for coronary heart disease 73 and AD 74 Maintaining reverse cholesterol trans port in the face of a distinct pathology might necessitate large doses of a vitamin particularly because Na meta bolism involves competition between synthesis and break down of NAD production of nicotinuric acid and metabolite excretion Although lack of a bene cial effect of Nam might be interpreted as evidence of a receptorbased mechanism it is also consistent with a mechanism in which a si target is activated by NAD and inhibited by highdose Nam Moreover the Gpr109a receptor which recognizes Na to the exclusion of Nam mediates the ushing response 44 which is clearly an offtarget effect We suggest that in some individuals reverse cholesterol transport might be limited by a sirtuindependent deacetylation reaction such that highdose Na and resveratrol both result in altered expression of apolipoproteins transporters receptors andor enzymes that are involved in lipid metabolism The ability to elevate NAD with NR will enable the www5ciencedirectcom TRENDS in Biochemical Sciences Vol32 No1 longstanding problem of the mechanism of action of NA in pl 1 1 to be g Concluding remarks The rst century of NAD research has been punctuated by multiple discoveries Elucidation of the essential role of NAD in glycolysis was followed by discoveries in human nutrition and coenzyme biosynthesis In recent years the role of NAD in protein deacetylation has been discovered AD precursors have been used to protect severed axons from degeneration ameliorate neuromuscular de cits in a mouse model of MS and reduce the severity of candidiasis in a mouse model Studies are needed to clarify the targets and mechanisms of NAD function in these models and to determine the safe effective boundaries of nutritional and therapeutic interventions to replenish NAD in humans References Kurnasov OV et al 2002 Ribosylnicotinamide kinase domain of NadR rotein identi cation and implications in NAD biosynthesis J Bacteriol 184 6906 6917 2 Bieganowski P and Brenner C 2004 Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss Handler independent route to NAD in fungi and humans Cell 11 95 502 nain HH et al 1993 Differential regulation of human 0 e gene expression y interferonsgamma Analysis of the regulatory region of the gene and identi cation of an interferongammainducible DNAbinding factor J Biol Chem 268 5077 5084 4 Berger F et al 2005 Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms J Biol Chem 280 36334 36341 5 Sauve AA et al 2006 The biochemistry of sirtuins Annu Rev Biochem 3 4 6 Schreiber V et al 2006 PolyADPribose novel functions for an old molecule Nat Rev Mol Cell Biol 7 517 528 7 Graziani G and Szabo C 2005 Clinical perspectives of PARP inhibitors Pharmacol Res 52 109 118 Kim H et al 1993 Synthesis and degradation ofcyclic ADPribose by NAD glycohydrolases Science 261 1330 1333 9 Howard M et al 1993 Formation and hydrolysis of cyclic ADPribose catalyzed by lymphocyte antigen CD38 Science 262 1056 1059 10 Hirata Y et al 1994 ADP ribosyl cyclase activity of a novel bone marrow stromal cell surface molecule BST1 FEBS Lett 356 244 248 11 Aarhus R et al 1995 ADPribosyl cyclase and CD38 catalyze the synthesis of a calciummobilizing metabolite from NADP J Biol Chem 270 30327 30333 12 Graeff R et al 2006 Acidic residues at the active sites of CD38 and ADPribosyl cyclase determine NAADP synthesis and hydrolysis J Chem 281 28951 28957 13 Imai S et al 2000 Transcriptional silencing and longevity protein Sir2 is an NADdependent histone deacetylase Nature 403 795 800 14 Tanner KG et al 2 000 Silent information regulator 2 family of NAD A n m1 i 39 39 1 4 I 1 an ap OacetylADPribose Proc Natl Acad Sci U S A 97 14178 14182 15 Sauve AA et al 2001 Chemistry ofgene silencing the mechanism of NADdependent deacetylation reactions Biochemistry 40 15456 5463 16 GarciaSalcedo JA et al 2003 A chromosomal SIR2 homologue with both histone NADdependent ADPribosyltransferase and deacetylase activities is involved in DNA repair in Trypanosoma brucei MBO J 22 5851 5862 17 Liszt G et al 2005 Mouse Sir2 homolog SIRT6 is a nuclear ADP ribosyltransferase J Biol Chem 280 21313 21320 18 KolthurSeetharam U et al 2006 Control of AIFmediated cell death t functional interplay of SIRT1 and PARPl in response to DNA damage Cell Cycle 5 873 877 19 Pillai JB et al 2005 PolyADPribose polymeraseldependent cardiac myocyte cell death during heart failure is mediated by
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