NAD+ in Brain Aging and Neurodegenerative Disorders
Authors: Sofie Lautrup, David A. Sinclair, Mark P. Mattson, Evandro F. Fang
Journal: Cell Metabolism (2019)

NAD+ is a pivotal metabolite involved in cellular bioenergetics, genomic stability, mitochondrial homeostasis, adaptive stress responses, and cell survival. Multiple NAD+-dependent enzymes are involved in synaptic plasticity and neuronal stress resistance. Here, we review emerging findings that reveal key roles for NAD+ and related metabolites in the adaptation of neurons to a wide range of physiological stressors and in counteracting processes in neurodegenerative diseases, such as those occurring in Alzheimer's, Parkinson's, and Huntington diseases, and amyotrophic lateral sclerosis. Advances in understanding the molecular and cellular mechanisms of NAD+-based neuronal resilience will lead to novel approaches for facilitating healthy brain aging and for the treatment of a range of neurological disorders. NAD+ is a pivotal metabolite involved in cellular bioenergetics, genomic stability, mitochondrial homeostasis, adaptive stress responses, and cell survival. Multiple NAD+-dependent enzymes are involved in synaptic plasticity and neuronal stress resistance. Here, we review emerging findings that reveal key roles for NAD+ and related metabolites in the adaptation of neurons to a wide range of physiological stressors and in counteracting processes in neurodegenerative diseases, such as those occurring in Alzheimer's, Parkinson's, and Huntington diseases, and amyotrophic lateral sclerosis. Advances in understanding the molecular and cellular mechanisms of NAD+-based neuronal resilience will lead to novel approaches for facilitating healthy brain aging and for the treatment of a range of neurological disorders. Nicotinamide adenine dinucleotide (NAD+) is a fundamental molecule in health and disease, as it is central to several cellular bioenergetic functions. NAD+ is synthesized via three major pathways, including de novo biosynthesis, the Preiss-Handler pathway, and the salvage pathway (Figure 1). While the aspartate pathway is the de novo NAD+ pathway in most photosynthetic eukaryotes, the kynurenine pathway is the only de novo NAD+ synthetic pathway in mammals. The kynurenine pathway starts with the catabolism of the amino acid tryptophan that is converted via two steps to the intermediate kynurenine, which can generate NAD+, kynurenic acid, or xanthurenic acid (Vécsei et al., 2013Vécsei L. Szalárdy L. Fülöp F. Toldi J. Kynurenines in the CNS: recent advances and new questions.Nat. Rev. Drug Discov. 2013; 12: 64-82Crossref PubMed Scopus (263) Google Scholar). The kynurenine pathway modulates neuronal functions as it is involved in the synthesis of two fundamental neurotransmitters (glutamate and acetylcholine) as well as regulates N-methyl-D-aspartate (NMDA) receptor activity and free radical production (Vécsei et al., 2013Vécsei L. Szalárdy L. Fülöp F. Toldi J. Kynurenines in the CNS: recent advances and new questions.Nat. Rev. Drug Discov. 2013; 12: 64-82Crossref PubMed Scopus (263) Google Scholar). The kynurenine pathway exhibits "double-edged sword" effects on neurons with both neuroprotective metabolites (tryptophan, kynurenic acid, and picolinic acid) and neurotoxic intermediates, including 3-hydroxykynurenine (3-HK) that generates free radicals, 3-hydroxyanthranilic acid (3-HAA), and quinolinic acid (that induces glutamate receptor excitotoxicity) (Figure 1). While kynurenic acid is an NMDA receptor antagonist, quinolinic acid is an NMDA receptor agonist (Vécsei et al., 2013Vécsei L. Szalárdy L. Fülöp F. Toldi J. Kynurenines in the CNS: recent advances and new questions.Nat. Rev. Drug Discov. 2013; 12: 64-82Crossref PubMed Scopus (263) Google Scholar). The ambient levels of these metabolites are determined by different enzymes, which in the brain are preferentially localized in microglia and astrocytes, suggesting necessary glial cell-neuron communication (Schwarcz and Pellicciari, 2002Schwarcz R. Pellicciari R. Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities.J. Pharmacol. Exp. Ther. 2002; 303: 1-10Crossref PubMed Scopus (399) Google Scholar). The Preiss-Handler pathway and the salvage pathway synthesize NAD+ from pyridine bases. The Preiss-Handler pathway synthesizes NAD+ from nicotinic acid (NA) in three steps via the intermediate nicotinic acid adenine dinucleotide (NAAD). One important step in the Preiss-Handler pathway constitutes the nicotinamide mononucleotide adenylyltransferases (NMNATs), which are also involved in the kynurenine and salvage pathways. Three mammalian NMNATs exist, NMNAT1–3, showing neuroprotective effects in both mice and D. melanogaster models (Ali et al., 2013Ali Y.O. Li-Kroeger D. Bellen H.J. Zhai R.G. Lu H.C. NMNATs, evolutionarily conserved neuronal maintenance factors.Trends Neurosci. 2013; 36: 632-640Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). While NMNAT1 and NMNAT3 are ubiquitously expressed, NMNAT2 is enriched in the brain, and adequate levels of NMNAT2 seem to be essential for axon development and survival (Gilley et al., 2019Gilley J. Mayer P.R. Yu G. Coleman M.P. Low levels of NMNAT2 compromise axon development and survival.Hum. Mol. Genet. 2019; 28: 448-458Crossref PubMed Scopus (4) Google Scholar). The NAD+ salvage pathway starts from the recycling of nicotinamide (NAM) to nicotinamide mononucleotide (NMN) by intracellular nicotinamide phosphoribosyltransferase (iNAMPT), followed by the conversion of NMN into NAD+ via the NMNATs (Bogan and Brenner, 2008Bogan K.L. Brenner C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition.Annu. Rev. Nutr. 2008; 28: 115-130Crossref PubMed Scopus (269) Google Scholar, Verdin, 2015Verdin E. NAD(+) in aging, metabolism, and neurodegeneration.Science. 2015; 350: 1208-1213Crossref PubMed Scopus (234) Google Scholar). Additionally, nicotinamide riboside (NR) integrates in this pathway via the conversion of NR into NMN by nicotinamide riboside kinase 1 (NRK1) or NRK2 (Bieganowski and Brenner, 2004Bieganowski P. Brenner C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans.Cell. 2004; 117: 495-502Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar, Ratajczak et al., 2016Ratajczak J. Joffraud M. Trammell S.A. Ras R. Canela N. Boutant M. Kulkarni S.S. Rodrigues M. Redpath P. Migaud M.E. et al.NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells.Nat. Commun. 2016; 7: 13103Crossref PubMed Scopus (82) Google Scholar). Despite NAMPT being relatively highly expressed in brown adipocyte, liver, and kidney tissues compared to brain tissue in mice, several studies have supported an essential role of iNAMPT in neuronal NAD+ metabolism (Stein and Imai, 2014Stein L.R. Imai S. Specific ablation of Nampt in adult neural stem cells recapitulates their functional defects during aging.EMBO J. 2014; 33: 1321-1340PubMed Google Scholar, Stein et al., 2014Stein L.R. Wozniak D.F. Dearborn J.T. Kubota S. Apte R.S. Izumi Y. Zorumski C.F. Imai S. Expression of Nampt in hippocampal and cortical excitatory neurons is critical for cognitive function.J. Neurosci. 2014; 34: 5800-5815Crossref PubMed Google Scholar, Zhang et al., 2010Zhang W. Xie Y. Wang T. Bi J. Li H. Zhang L.Q. Ye S.Q. Ding S. Neuronal protective role of PBEF in a mouse model of cerebral ischemia.J. Cereb. Blood Flow Metab. 2010; 30: 1962-1971Crossref PubMed Scopus (62) Google Scholar). Experimental evidence suggests that blood NA and NAM are able to cross the plasma membrane, while blood NAD+ cannot be taken up by cells directly but needs to be converted to smaller uncharged molecules to enter the cells (Hara et al., 2007Hara N. Yamada K. Shibata T. Osago H. Hashimoto T. Tsuchiya M. Elevation of cellular NAD levels by nicotinic acid and involvement of nicotinic acid phosphoribosyltransferase in human cells.J. Biol. Chem. 2007; 282: 24574-24582Crossref PubMed Scopus (104) Google Scholar, Ratajczak et al., 2016Ratajczak J. Joffraud M. Trammell S.A. Ras R. Canela N. Boutant M. Kulkarni S.S. Rodrigues M. Redpath P. Migaud M.E. et al.NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells.Nat. Commun. 2016; 7: 13103Crossref PubMed Scopus (82) Google Scholar). Extracellularly, NAD+ can be digested to NAM by the membrane-bound CD38 and CD157, with NAM further metabolized into NMN by extracellular NAMPT (eNAMPT); however, NAD+ can also be converted directly into NMN by CD73 (Bogan and Brenner, 2008Bogan K.L. Brenner C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition.Annu. Rev. Nutr. 2008; 28: 115-130Crossref PubMed Scopus (269) Google Scholar, Verdin, 2015Verdin E. NAD(+) in aging, metabolism, and neurodegeneration.Science. 2015; 350: 1208-1213Crossref PubMed Scopus (234) Google Scholar). Three ways for extracellular NMN to enter the cells have been proposed. First, extracellular NMN converts into NR by CD73, followed by NR being taken up by the cells via a presumptive nucleoside transporter (Fletcher et al., 2017Fletcher R.S. Ratajczak J. Doig C.L. Oakey L.A. Callingham R. Da Silva Xavier G. Garten A. Elhassan Y.S. Redpath P. Migaud M.E. et al.Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells.Mol. Metab. 2017; 6: 819-832Crossref PubMed Scopus (11) Google Scholar, Grozio et al., 2013Grozio A. Sociali G. Sturla L. Caffa I. Soncini D. Salis A. Raffaelli N. De Flora A. Nencioni A. Bruzzone S. CD73 protein as a source of extracellular precursors for sustained NAD+ biosynthesis in FK866-treated tumor cells.J. Biol. Chem. 2013; 288: 25938-25949Crossref PubMed Scopus (55) Google Scholar, Nikiforov et al., 2011Nikiforov A. Dölle C. Niere M. Ziegler M. Pathways and subcellular compartmentation of NAD biosynthesis in human cells: from entry of extracellular precursors to mitochondrial NAD generation.J. Biol. Chem. 2011; 286: 21767-21778Crossref PubMed Scopus (154) Google Scholar, Ratajczak et al., 2016Ratajczak J. Joffraud M. Trammell S.A. Ras R. Canela N. Boutant M. Kulkarni S.S. Rodrigues M. Redpath P. Migaud M.E. et al.NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells.Nat. Commun. 2016; 7: 13103Crossref PubMed Scopus (82) Google Scholar, Sociali et al., 2016Sociali G. Raffaghello L. Magnone M. Zamporlini F. Emionite L. Sturla L. Bianchi G. Vigliarolo T. Nahimana A. Nencioni A. et al.Antitumor effect of combined NAMPT and CD73 inhibition in an ovarian cancer model.Oncotarget. 2016; 7: 2968-2984Crossref PubMed Scopus (16) Google Scholar). Second, CD38 may metabolize NMN, but not NR, into NAM, which is able to cross the plasma membrane (Camacho-Pereira et al., 2016Camacho-Pereira J. Tarragó M.G. Chini C.C.S. Nin V. Escande C. Warner G.M. Puranik A.S. Schoon R.A. Reid J.M. Galina A. et al.CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism.Cell Metab. 2016; 23: 1127-1139Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, Grozio et al., 2013Grozio A. Sociali G. Sturla L. Caffa I. Soncini D. Salis A. Raffaelli N. De Flora A. Nencioni A. Bruzzone S. CD73 protein as a source of extracellular precursors for sustained NAD+ biosynthesis in FK866-treated tumor cells.J. Biol. Chem. 2013; 288: 25938-25949Crossref PubMed Scopus (55) Google Scholar, Sauve et al., 1998Sauve A.A. Munshi C. Lee H.C. Schramm V.L. The reaction mechanism for CD38. A single intermediate is responsible for cyclization, hydrolysis, and base-exchange chemistries.Biochemistry. 1998; 37: 13239-13249Crossref PubMed Scopus (83) Google Scholar). Third, NMN has been reported to enter cells directly (Grozio et al., 2019Grozio A. Mills K.F. Yoshino J. Bruzzone S. Sociali G. Tokizane K. Lei H.C. Cunningham R. Sasaki Y. Migaud M.E. et al.Slc12a8 is a nicotinamide mononucleotide transporter.Nat. Metab. 2019; 1: 47-57Crossref PubMed Scopus (88) Google Scholar, Yoshino et al., 2011Yoshino J. Mills K.F. Yoon M.J. Imai S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice.Cell Metab. 2011; 14: 528-536Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar). A newly reported NMN transporter, the Slc12a8, is highly expressed and regulated by NAD+, in the murine small intestine, and Slc12a8 deficiency abrogates the uptake of NMN in vitro and in vivo (Grozio et al., 2019Grozio A. Mills K.F. Yoshino J. Bruzzone S. Sociali G. Tokizane K. Lei H.C. Cunningham R. Sasaki Y. Migaud M.E. et al.Slc12a8 is a nicotinamide mononucleotide transporter.Nat. Metab. 2019; 1: 47-57Crossref PubMed Scopus (88) Google Scholar). These pathways are detailed in Figure 1. Studies in mice and humans indicate that NR supplementation dramatically upregulates intracellular NAAD, suggesting unknown NAD+ metabolic pathways, including possibilities of NAD+ conversion to NAAD and/or NMN to nicotinic acid mononucleotide (NAMN) (Trammell et al., 2016aTrammell S.A. Schmidt M.S. Weidemann B.J. Redpath P. Jaksch F. Dellinger R.W. Li Z. Abel E.D. Migaud M.E. Brenner C. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans.Nat. Commun. 2016; 7: 12948Crossref PubMed Scopus (131) Google Scholar). Thus, although the NAD+ metabolic pathways have been intensively characterized for a long time, there are steps remaining to be determined. NAD+ is a vital redox cofactor for metabolism and ATP production, and a key substrate for at least four families of enzymes involved in healthspan and longevity (Fang et al., 2017Fang E.F. Lautrup S. Hou Y.J. Demarest T.G. Croteau D.L. Mattson M.P. Bohr V.A. NAD(+) in aging: molecular mechanisms and translational implications.Trends Mol. Med. 2017; 23: 899-916Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Gomes et al., 2013Gomes A.P. Price N.L. Ling A.J. Moslehi J.J. Montgomery M.K. Rajman L. White J.P. Teodoro J.S. Wrann C.D. Hubbard B.P. et al.Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging.Cell. 2013; 155: 1624-1638Abstract Full Text Full Text PDF PubMed Scopus (529) Google Scholar, Verdin, 2015Verdin E. NAD(+) in aging, metabolism, and neurodegeneration.Science. 2015; 350: 1208-1213Crossref PubMed Scopus (234) Google Scholar). NAD+ plays an essential role in glycolysis and the citric acid (TCA) cycle, by its ability to accept hydride equivalents, forming NADH during ATP production (Krebs, 1970Krebs H.A. Rate control of the tricarboxylic acid cycle.Adv. Enzyme Regul. 1970; 8: 335-353Crossref PubMed Scopus (0) Google Scholar, Wallace, 2012Wallace D.C. Mitochondria and cancer.Nat. Rev. Cancer. 2012; 12: 685-698Crossref PubMed Scopus (853) Google Scholar). NADH is one of the central electron donors in oxidative phosphorylation (OXPHOS) in the mitochondria, providing electrons to the electron transport chain (ETC) to generate ATP (Krebs, 1970Krebs H.A. Rate control of the tricarboxylic acid cycle.Adv. Enzyme Regul. 1970; 8: 335-353Crossref PubMed Scopus (0) Google Scholar, Wallace, 2012Wallace D.C. Mitochondria and cancer.Nat. Rev. Cancer. 2012; 12: 685-698Crossref PubMed Scopus (853) Google Scholar). The ratio of NAD+/NADH is important in various bioenergetic reactions in different subcellular compartments, and increased activity of one of these reactions can influence the metabolic homeostasis via changes in the NAD+/NADH ratio (Ying, 2008Ying W. NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences.Antioxid. Redox Signal. 2008; 10: 179-206Crossref PubMed Scopus (649) Google Scholar). Additionally, the conversion of NAD+ to NADP+/NADPH is important in the involvement of different cellular functions, including antioxidation and generation of oxidative stress, calcium homeostasis, and cell survival or death (Ying, 2008Ying W. NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences.Antioxid. Redox Signal. 2008; 10: 179-206Crossref PubMed Scopus (649) Google Scholar). In addition to cellular bioenergetics, NAD+ is also a substrate for different NAD+-consuming proteins, which catabolize NAD+ to NAM. They are class III histone deacetylases sirtuins (SIRTs), poly (ADP-ribose) polymerases (PARPs), ADP ribosyl-cyclases (CD38/CD157), and NADase sterile alpha and TIR motif-containing 1 (SARM1) (Figure 1). In mammals, there are seven SIRTs, which regulate a large number of cellular pathways, including neuronal survival, stem cell rejuvenation, cancer, and healthy longevity (Chalkiadaki and Guarente, 2015Chalkiadaki A. Guarente L. The multifaceted functions of sirtuins in cancer.Nat. Rev. Cancer. 2015; 15: 608-624Crossref PubMed Scopus (150) Google Scholar). The SIRTs are NAD+-dependent enzymes that regulate a wide spectrum of cellular pathways involved in health and disease (Chalkiadaki and Guarente, 2015Chalkiadaki A. Guarente L. The multifaceted functions of sirtuins in cancer.Nat. Rev. Cancer. 2015; 15: 608-624Crossref PubMed Scopus (150) Google Scholar, Imai et al., 2000Imai S. Armstrong C.M. Kaeberlein M. Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase.Nature. 2000; 403: 795-800Crossref PubMed Scopus (2280) Google Scholar). For example, SIRT1 consumes NAD+ to regulate glycolysis, gluconeogenesis, and mitochondrial homeostasis via the balance between mitochondrial biogenesis and mitophagy and adaptive responses of neurons to exercise and metabolic/excitatory challenges (Bonkowski and Sinclair, 2016Bonkowski M.S. Sinclair D.A. Slowing ageing by design: the rise of NAD(+) and sirtuin-activating compounds.Nat. Rev. Mol. Cell Biol. 2016; 17: 679-690Crossref PubMed Google Scholar, Cheng et al., 2016Cheng A. Yang Y. Zhou Y. Maharana C. Lu D. Peng W. Liu Y. Wan R. Marosi K. Misiak M. et al.Mitochondrial SIRT3 mediates adaptive responses of neurons to exercise and metabolic and excitatory challenges.Cell Metab. 2016; 23: 128-142Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, Fang, 2019Fang E.F. Mitophagy and NAD(+) inhibit Alzheimer disease.Autophagy. 2019; 15: 1112-1114Crossref PubMed Scopus (2) Google Scholar). Furthermore, SIRT1 has been shown to promote neurite outgrowth and axon development, in addition to regulating dendritic arborization, long-term potentiation and learning, and memory (Gao et al., 2010Gao J. Wang W.Y. Mao Y.W. Gräff J. Guan J.S. Pan L. Mak G. Kim D. Su S.C. Tsai L.H. A novel pathway regulates memory and plasticity via SIRT1 and miR-134.Nature. 2010; 466: 1105-1109Crossref PubMed Scopus (585) Google Scholar). Among the 17 PARPs, only four of them are capable of adding multiple ADP-ribose units (poly[ADP-ribosyl]ation) or PARylation; they are PARP1, PARP2, PARP5a (tankyrase 1), and PARP5b (tankyrase 2) (Leung, 2017Leung A.K.L. PARPs.Curr. Biol. 2017; 27: R1256-R1258Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Rouleau et al., 2010Rouleau M. Patel A. Hendzel M.J. Kaufmann S.H. Poirier G.G. PARP inhibition: PARP1 and beyond.Nat. Rev. Cancer. 2010; 10: 293-301Crossref PubMed Scopus (813) Google Scholar). Experimental evidence supports that PARP1 transfers the first ADP-ribose moiety from NAD+ to lysine, arginine, glutamate, aspartate, and serine residues on an acceptor protein, followed by addition of multiple ADP-ribose units to the preceding ones, thereby forming poly(ADP-ribose) (PAR) chains (Bonfiglio et al., 2017Bonfiglio J.J. Fontana P. Zhang Q. Colby T. Gibbs-Seymour I. Atanassov I. Bartlett E. Zaja R. Ahel I. Matic I. Serine ADP-ribosylation depends on HPF1.Mol. Cell. 2017; 940: 932-940Abstract Full Text Full Text PDF Scopus (62) Google Scholar, Daniels et al., 2014Daniels C.M. Ong S.E. Leung A.K. Phosphoproteomic approach to characterize protein mono- and poly(ADP-ribosyl)ation sites from cells.J. Proteome Res. 2014; 13: 3510-3522Crossref PubMed Scopus (74) Google Scholar). The majority of PARylation is executed by PARP1, which participates in a number of necessary cellular processes, such as DNA repair, DNA/RNA metabolism, and cellular stress response. Additionally, PAR is serving as a signaling molecule and scaffolding element (Fang et al., 2016bFang E.F. Scheibye-Knudsen M. Chua K.F. Mattson M.P. Croteau D.L. Bohr V.A. Nuclear DNA damage signalling to mitochondria in ageing.Nat. Rev. Mol. Cell Biol. 2016; 17: 308-321Crossref PubMed Google Scholar, Leung, 2017Leung A.K.L. PARPs.Curr. Biol. 2017; 27: R1256-R1258Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), e.g., PARP1 is critical in the stabilization of DNA repair forks, with its catalytic activity necessary for multiple DNA repair pathways, such as the repair of single-strand breaks, bulky lesions, and double-strand breaks (DSBs) (Ray Chaudhuri and Nussenzweig, 2017Ray Chaudhuri A. Nussenzweig A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling.Nat. Rev. Mol. Cell Biol. 2017; 18: 610-621Crossref PubMed Scopus (33) Google Scholar). However, excessive PARP1 activation can trigger cell death, termed parthanatos, through a mechanism in which PAR formation triggers the release of mitochondrial apoptosis-inducing factor (AIF) from the cytosolic side of the mitochondrial outer membrane. AIF is then translocated to the nucleus to activate macrophage migration inhibitory factor (MIF, a nuclease), which finally results in MIF-dependent chromatinolysis and cell death (Wang et al., 2011Wang Y. Kim N.S. Haince J.F. Kang H.C. David K.K. Andrabi S.A. Poirier G.G. Dawson V.L. Dawson T.M. Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos).Sci. Signal. 2011; 4: ra20Crossref PubMed Scopus (198) Google Scholar, Wang et al., 2016Wang Y. An R. Umanah G.K. Park H. Nambiar K. Eacker S.M. Kim B. Bao L. Harraz M.M. Chang C. et al.A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1.Science. 2016; 354Crossref Scopus (65) Google Scholar, Yu et al., 2002Yu S.W. Wang H. Poitras M.F. Coombs C. Bowers W.J. Federoff H.J. Poirier G.G. Dawson T.M. Dawson V.L. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor.Science. 2002; 297: 259-263Crossref PubMed Scopus (1386) Google Scholar). Notably, excessive PARP1 activation induces ATP depletion through PAR-dependent inhibition of hexokinase activity, resulting in dysfunctional glycolysis, a mechanism likely independent of NAD+ depletion (Andrabi et al., 2014Andrabi S.A. Umanah G.K. Chang C. Stevens D.A. Karuppagounder S.S. Gagné J.P. Poirier G.G. Dawson V.L. Dawson T.M. Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis.Proc. Natl. Acad. Sci. USA. 2014; 111: 10209-10214Crossref PubMed Scopus (128) Google Scholar, Fouquerel et al., 2014Fouquerel E. Goellner E.M. Yu Z. Gagné J.P. Barbi de Moura M. Feinstein T. Wheeler D. Redpath P. Li J. Romero G. et al.ARTD1/PARP1 negatively regulates glycolysis by inhibiting hexokinase 1 independent of NAD+ depletion.Cell Rep. 2014; 8: 1819-1831Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). In addition to ATP loss, hyperactivation of PARP1-induced NAD+ depletion can induce neuronal loss and accelerated aging (Fang et al., 2016aFang E.F. Kassahun H. Croteau D.L. Scheibye-Knudsen M. Marosi K. Lu H. Shamanna R.A. Kalyanasundaram S. Bollineni R.C. Wilson M.A. et al.NAD(+) replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair.Cell Metab. 2016; 24: 566-581Abstract Full Text Full Text PDF PubMed Google Scholar). In view of such detrimental roles of PARP1 in endogenous and exogenous stress, e.g., glutamate excitotoxicity, ischemia-reperfusion injury, and inflammation-induced (Yu et al., 2002Yu S.W. Wang H. Poitras M.F. Coombs C. Bowers W.J. Federoff H.J. Poirier G.G. Dawson T.M. Dawson V.L. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor.Science. 2002; 297: 259-263Crossref PubMed Scopus (1386) Google Scholar) neuronal death, targeting the regulation of PARP1 activity may provide therapeutic strategies for neurodegenerative diseases. CD38 catalyzes the synthesis of the Ca2+-responsive messenger cyclic ADP-ribose (cADPR) by use of NAD+ and plays a key role in multiple physiological processes such as immunity, metabolism, inflammation, and even social behaviors (Jin et al., 2007Jin D. Liu H.X. Hirai H. Torashima T. Nagai T. Lopatina O. Shnayder N.A. Yamada K. Noda M. Seike T. et al.CD38 is critical for social behaviour by regulating oxytocin secretion.Nature. 2007; 446: 41-45Crossref PubMed Scopus (395) Google Scholar). While CD38 molecules are expressed in both a type II form (i.e., large extracellular C-terminal) and a type III form (with its catalytic domain facing the cytosol) (Liu et al., 2017Liu J. Zhao Y.J. Li W.H. Hou Y.N. Li T. Zhao Z.Y. Fang C. Li S.L. Lee H.C. Cytosolic interaction of type III human CD38 with CIB1 modulates cellular cyclic ADP-ribose levels.Proc. Natl. Acad. Sci. USA. 2017; Google Scholar, Liu et al., 2008Liu Q. Graeff R. Kriksunov I.A. Lam C.M. Lee H.C. Hao Q. Conformational closure of the catalytic site of human CD38 induced by calcium (dagger) (double dagger).Biochemistry. 2008; 47: 13966-13973Crossref Scopus (0) Google Scholar), there is an age-dependent increase of CD38, which may contribute to cellular NAD+ depletion and impaired mitochondrial function (Camacho-Pereira et al., 2016Camacho-Pereira J. Tarragó M.G. Chini C.C.S. Nin V. Escande C. Warner G.M. Puranik A.S. Schoon R.A. Reid J.M. Galina A. et al.CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism.Cell Metab. 2016; 23: 1127-1139Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). Despite CD38 being a lymphocyte differentiation antigen, it is also expressed in the brain (Mizuguchi et al., 1995Mizuguchi M. Otsuka N. Sato M. Ishii Y. Kon S. Yamada M. Nishina H. Katada T. Ikeda K. Neuronal localization of CD38 antigen in the human brain.Brain Res. 1995; 697: 235-240Crossref PubMed Scopus (57) Google Scholar), and CD38 knockout mice show significant protection against ischemic brain damage (Long et al., 2017Long A. Park J.H. Klimova N. Fowler C. Loane D.J. Kristian T. CD38 knockout mice show significant protection against ischemic brain damage despite high level poly-ADP-ribosylation.Neurochem. Res. 2017; 42: 283-293Crossref PubMed Scopus (1) Google Scholar). SARM1 is a newly recognized class of NADase that cleaves NAD+ into NAM, ADPR, and cADPR via its TIR domain. It is expressed in both brain and non-brain tissues, including the liver (Essuman et al., 2017Essuman K. Summers D.W. Sasaki Y. Mao X. DiAntonio A. Milbrandt J. The SARM1 toll/interleukin-1 receptor domain possesses intrinsic NAD(+) cleavage activity that promotes pathological axonal degeneration.Neuron. 2017; 93: 1334-1343Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, Pan and An, 2018Pan Z.G. An X.S. SARM1 deletion restrains NAFLD induced by high fat diet (HFD) through reducing inflammation, oxidative stress and lipid accumulation.Biochem. Biophys. Res. Commun. 2018; 498: 416-423Crossref PubMed Scopus (7) Google Scholar). SARM1 exhibits both cyclase and glycohydrolase activities, and the estimated Michaelis constant (Km) is 24 μM, which is similar to that of the other known NAD+-consumers (PARP1, 50–97 μM; SIRT1, 94–96 μM; CD38, 15–25 μM) (Cantó et al., 2015Cantó C. Menzies K.J. Auwerx J. NAD(+) metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus.Cell Metab. 2015; 22: 31-53Abstract Full Text Full Text PDF PubMed Google Scholar). The NADase activity of SARM1 may contribute to its role in axonal degeneration (Essuman et al., 2017Essuman K. Summers D.W. Sasaki Y. Mao X. DiAntonio A. Milbrandt J. The SARM1 toll/interleukin-1 receptor domain possesses intrinsic NAD(+) cleavage activity that promotes pathological axonal degeneration.Neuron. 2017; 93: 1334-1343Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar) and is therefore a potential target for therapeutic intervention in neurodegenerative diseases. SARM1 also holds a mitochondrial localization signal, but its role in mitochondrial function is not clear. SIRTS, PARPs, CD38/CD157, and SARM1 compete with each other to consume cellular NAD+; thus, the hyperactivation of one enzyme can impair the activities of other NAD+-dependent enzymes. The interrelationships of these enzymes have been reviewed recently (Bonkowski and Sinclair, 2016Bonkowski M.S. Sinclair D.A. Slowing ageing by design: the rise of NAD(+) and sirtuin-activating compounds.Nat. Rev. Mol. Cell Biol. 2016; 17: 679-690Crossref PubMed Google Scholar, Fang et al., 2017Fang E.F. Lautrup S. Hou Y.J. Demarest T.G. Croteau D.L. Mattson M.P. Bohr V.A. NAD(+) in aging: molecular mechanisms and translational implications.Trends Mol. Med. 2017; 23: 899-916Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Verdin, 2015Verdin E. NAD(+) in aging, metabolism, and neurodegeneration.Science. 2015; 350: 1208-1213Crossref PubMed Scopus (234) Google Scholar). NAD+ is in constant equilibrium between synthesis, consumption, and recycling in various subcellular compartments, including the cytoplasm, nucleus, mitochondria, and Golgi apparatus. Two major mechanisms are involved in the regulation of subcellular balance of NAD+, including the expression of subcellular-specific NAD+-synthetic enzymes and subcellular transporters for NAD+ and related metabolites. NMNATs convert NMN to NAD+. The three mammalian NMNATs include