Abstract
Nicotinamide adenine dinucleotide (NAD+) has been described as central coenzyme of redox reactions and is a key regulator of stress resistance and longevity. Aging is a multifactorial and irreversible process that is characterized by a gradual diminution in physiological functions in an organism over time, leading to development of age-associated pathologies and eventually increasing the probability of death. Ischemia is the lack of nutritive blood flow that causes damage and mortality that mostly occurs in various organs during aging. During the process of aging and related ischemic conditions, NAD+ levels decline and lead to nuclear and mitochondrial dysfunctions, resulting in age-related pathologies. The majority of studies have shown that restoring of NAD+ using supplementation with intermediates such as nicotinamide mononucleotide and nicotinamide riboside can be a valuable strategy for recovery of ischemic injury and age-associated defects. This review summarizes the molecular mechanisms responsible for the reduction in NAD+ levels during ischemic disorders and aging, as well as a particular focus is given to the recent progress in the understanding of NAD+ precursor’s effects on aging and ischemia.
This is a preview of subscription content,
to check access.


Similar content being viewed by others
References
Aksoy P, White TA, Thompson M, Chini EN (2006) Regulation of intracellular levels of NAD: a novel role for CD38. Biochem Biophys Res Commun 345:1386–1392
Alano CC, Ying W, Swanson RA (2004) Poly (ADP-ribose) polymerase-1-mediated cell death in astrocytes requires NAD + depletion and mitochondrial permeability transition. J Biol Chem 279:18895–18902
Alano CC, Garnier P, Ying W, Higashi Y, Kauppinen TM, Swanson RA (2010) NAD + Depletion Is Necessary and Sufficient forPoly (ADP-Ribose) Polymerase-1-Mediated Neuronal Death. J Neurosci 30:2967–2978
Badalzadeh R, Azimi A, Alihemmati A, Yousefi B (2017) Chronic type-I diabetes could not impede the anti-inflammatory and anti-apoptotic effects of combined postconditioning with ischemia and cyclosporine A in myocardial reperfusion injury. J Physiol Biochem 73:111–120
Baldelli S, Aquilano K, Ciriolo M (2014) PGC-1α buffers ROS-mediated removal of mitochondria during myogenesis. Cell Death Dis 5:e1515
Baxter P, Chen Y, Xu Y, Swanson RA (2014) Mitochondrial dysfunction induced by nuclear poly (ADP-ribose) polymerase-1: a treatable cause of cell death in stroke. Trans Stroke Res 5:136–144
Bayrami G et al (2018) Combination of vildagliptin and ischemic postconditioning in diabetic hearts as a working strategy to reduce myocardial reperfusion injury by restoring mitochondrial function and autophagic activity. Adv Pharm Bull 8:319
Beattie MS (2004) Inflammation and apoptosis: linked therapeutic targets in spinal cord injury. Trends Mol Med 10:580–583
Becatti M, Taddei N, Cecchi C, Nassi N, Nassi PA, Fiorillo C (2012) SIRT1 modulates MAPK pathways in ischemic–reperfused cardiomyocytes. Cell Mol Life Sci 69:2245–2260
Bi J, Li H, Ye SQ, Ding S (2012) Pre-B-cell colony-enhancing factor exerts a neuronal protection through its enzymatic activity and the reduction of mitochondrial dysfunction in in vitro ischemic models. J Neurochem 120:334–346
Braidy N, Guillemin GJ, Mansour H, Chan-Ling T, Grant R (2011) Changes in kynurenine pathway metabolism in the brain, liver and kidney of aged female Wistar rats. FEBS J 278:4425–4434
Breckenridge DG, Stojanovic M, Marcellus RC, Shore GC (2003) Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol. J Cell Biol 160:1115–1127
Brooks C, Wei Q, Cho S-G, Dong Z (2009) Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models. J Clin Investig 119:1275–1285
Brown KD et al (2014) Activation of SIRT3 by the NAD + precursor nicotinamide riboside protects from noise-induced hearing loss. Cell Metabol 20:1059–1068
Bueno M et al. (2018) Cyb5R3 an External Mitochondrial NADH-Dependent Reductase Confers Protection Against Lung Fibrosis. In: B107. MECHANISTIC ADVANCES IN PULMONARY FIBROSIS. American Thoracic Society, pp A4351-A4351
Camacho-Pereira J et al (2016) CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab 23:1127–1139
Cantó C et al (2012) The NAD + precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab 15:838–847
Carelli V, Maresca A, Caporali L, Trifunov S, Zanna C, Rugolo M (2015) Mitochondria: biogenesis and mitophagy balance in segregation and clonal expansion of mitochondrial DNA mutations. Int J Biochem Cell Biol 63:21–24
Chen S-D, Yang D-I, Lin T-K, Shaw F-Z, Liou C-W, Chuang Y-C (2011) Roles of oxidative stress, apoptosis, PGC-1α and mitochondrial biogenesis in cerebral ischemia. Int J Mol Sci 12:7199–7215
Chini EN (2009) CD38 as a regulator of cellular NAD: a novel potential pharmacological target for metabolic conditions. Curr Pharm Des 15:57–63
Chini CC, Guerrico AMG, Nin V, Camacho-Pereira J, Escande C, Barbosa MT, Chini EN (2014) Targeting of NAD metabolism in pancreatic cancer cells: potential novel therapy for pancreatic tumors. Clin Cancer Res 20:120–130
Choe CU et al (2011) CD38 exacerbates focal cytokine production, postischemic inflammation and brain injury after focal cerebral ischemia. PLoS ONE 6:e19046
Claire C et al (2003) CD38-dependent ADP-ribosyl cyclase activity in developing and adult mouse brain. Biochem J 370:175–183
D’Annunzio V, Perez V, Boveris A, Gelpi RJ, Poderoso JJ (2016) Role of thioredoxin-1 in ischemic preconditioning, postconditioning and aged ischemic hearts. Pharmacol Res 109:24–31
Dare AJ, Bolton EA, Pettigrew GJ, Bradley JA, Saeb-Parsy K, Murphy MP (2015) Protection against renal ischemia–reperfusion injury in vivo by the mitochondria targeted antioxidant. MitoQ Redox Biol 5:163–168
de Picciotto NE et al (2016) Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell 15:522–530
Di Lisa F, Menabò R, Canton M, Barile M, Bernardi P (2000) Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD + and is a causative event in the death of myocytes in post-ischemic reperfusion of the heart. J Biol Chem 276(4):2571–2575
Egan DF et al (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331:456–461
Elliott G, Rechsteiner M (1975) Pyridine nucleotide metabolism in mitotic cells. J Cell Physiol 86:641–651
Eltzschig HK, Eckle T (2011) Ischemia and reperfusion—from mechanism to translation. Nat Med 17:1391
Esposito E et al (2012) The NAMPT inhibitor FK866 reverts the damage in spinal cord injury. J Neuroinflamm 9:66
Fang EF et al (2014) Defective mitophagy in XPA via PARP-1 hyperactivation and NAD +/SIRT1 reduction. Cell 157:882–896
Frederick DW et al (2016) Loss of NAD homeostasis leads to progressive and reversible degeneration of skeletal muscle. Cell Metab 24:269–282
Gems D, Partridge L (2013) Genetics of longevity in model organisms: debates and paradigm shifts. Annu Rev Physiol 75:621–644
Gomes AP et al (2013) Declining NAD + induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155:1624–1638
Guan X-H et al (2016) CD38 deficiency protects the heart from ischemia/reperfusion injury through activating SIRT1/FOXOs-mediated antioxidative stress pathway. Oxid Med cell Longev. https://doi.org/10.1155/2016/7410257
Guan Y, Wang S-R, Huang X-Z, Xie Q-h XuY-Y, Shang D, Hao C-M (2017) Nicotinamide Mononucleotide, an NAD + Precursor, Rescues Age-Associated Susceptibility to AKI in a Sirtuin 1–Dependent Manner. J Am Soc Nephrol 28(8):2337–2352
Hafner AV, Dai J, Gomes AP, Xiao C-Y, Palmeira CM, Rosenzweig A, Sinclair DA (2010) Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging (Albany NY) 2:914
Han J, Shi S, Min L, Wu T, Xia W, Ying W (2011) NAD + treatment induces delayed autophagy in Neuro2a cells partially by increasing oxidative stress. Neurochem Res 36:2270
Harden A, Young WJ (1906) The alcoholic ferment of yeast-juice Part II.—The coferment of yeast-juice. Proc R Soc Lond B 78:369–375
Harman D (1956) A theory based on free radical and radiation chemistry. J. ior Handbook of Essential Fatty Acid Biology: Biochemistry, Physiology
Helley MP, Pinnell J, Sportelli C, Tieu K (2017) Mitochondria: a common target for genetic mutations and environmental toxicants in parkinson’s disease. Front Genet 8:177
Hernández-Jiménez M et al (2013) Silent information regulator 1 protects the brain against cerebral ischemic damage. Stroke 44:2333–2337
Houtkooper RH, Auwerx J (2012) Exploring the therapeutic space around NAD+. Rockefeller University Press, New York
Hsu C-P, Oka S, Shao D, Hariharan N, Sadoshima J (2009) Nicotinamide phosphoribosyltransferase regulates cell survival through NAD + synthesis in cardiac myocytes. Circ Res 105:481–491
Hwang ES, Yoon G, Kang HT (2009) A comparative analysis of the cell biology of senescence and aging. Cell Mol Life Sci 66:2503–2524
Imai SI, Guarente L (2014) NAD + and sirtuins in aging and disease. Trends Cell Biol 24:464–471
Imai SI, Yoshino J (2013) The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metabolism and ageing Diabetes. Obesity Metab 15:26–33
Jang SY, Kang HT, Hwang ES (2012) Nicotinamide-induced mitophagy: an event mediated by high NAD +/NADH ratio and SIRT1 activation. J Biol Chem 287(23):19304
Khalili H, Talasaz AH, Jenab Y, Salarifar M (2012) Clinical characteristics and risk assessment of ST-segment elevation myocardial infarction patients of an Iranian referral center. J Cardiovasc Med 13:708–715
Kitani T, Okuno S, Fujisawa H (2003) Growth phase-dependent changes in the subcellular localization of pre-B-cell colony-enhancing factor 1. FEBS Lett 544:74–78
Kuo C-Y, Chiu Y-C, Lee AY-L, Hwang T-L (2015) Mitochondrial Lon protease controls ROS-dependent apoptosis in cardiomyocyte under hypoxia. Mitochondrion 23:7–16
Lee JS et al (2012) Beta-lapachone, a modulator of NAD metabolism, prevents health declines in aged mice. PLoS ONE 7:e47122
Lee CF et al (2016) Normalization of NAD + redox balance as a therapy for heart failure. Circulation 134(12):883
Levine ME et al (2014) Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab 19:407–417
Li J et al (2012) Reperfusion promotes mitochondrial dysfunction following focal cerebral ischemia in rats. PLoS ONE 7:e46498
Liesa M, Palacín M, Zorzano A (2009) Mitochondrial dynamics in mammalian health and disease. Physiol Rev 89:799–845
Lim SY, Davidson SM, Paramanathan AJ, Smith CC, Yellon DM, Hausenloy DJ (2008) The novel adipocytokine visfatin exerts direct cardioprotective effects. J Cell Mol Med 12:1395–1403
Liu JP (2014) Molecular mechanisms of ageing and related diseases. Clin Exp Pharmacol Physiol 41:445–458
Liu D, Pitta M, Mattson MP (2008) Preventing NAD + depletion protects neurons against excitotoxicity: bioenergetic effects of mild mitochondrial uncoupling and caloric restriction. Ann N Y Acad Sci 1147:275–282
Liu L, Wang P, Liu X, He D, Liang C, Yu Y (2014) Exogenous NAD + supplementation protects H9c2 cardiac myoblasts against hypoxia/reoxygenation injury via Sirt1-p53 pathway. Fundam Clin Pharmacol 28:180–189
Long AN, Owens K, Schlappal AE, Kristian T, Fishman PS, Schuh RA (2015) Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model. BMC Neurol 15:19
Long A, Park JH, Klimova N, Fowler C, Loane DJ, Kristian T (2017) CD38 knockout mice show significant protection against ischemic brain damage despite high level poly-ADP-ribosylation. Neurochem Res 42:283–293
López-Lluch G, Irusta PM, Navas P, de Cabo R (2008) Mitochondrial biogenesis and healthy aging. Exp Gerontol 43:813–819
López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217
Lu L-F et al (2009) Elevated visfatin/pre-B-cell colony-enhancing factor plasma concentration in ischemic stroke. J Stroke Cerebrovasc Dis 18:354–359
Martin LJ (2010) Mitochondrial and cell death mechanisms in neurodegenerative diseases. Pharmaceuticals 3:839–915
Martorell‐Riera A et al (2014) Mfn2 downregulation in excitotoxicity causes mitochondrial dysfunction and delayed neuronal death. EMBO J 33:2388–2407
Matsuda A et al (2014) FK866, a visfatin inhibitor, protects against acute lung injury after intestinal ischemia–reperfusion in mice via NF-κB pathway. Ann Surg 259:1007–1017
Matsuura S, Egi Y, Yuki S, Horikawa T, Satoh H, Akira T (2011) MP-124, a novel poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor, ameliorates ischemic brain damage in a non-human primate model. Brain Res 1410:122–131
Mendelsohn AR, Larrick JW (2014) Partial reversal of skeletal muscle aging by restoration of normal NAD + levels. Rejuvenation Res 17:62–69
Mills KF et al (2016) Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab 24:795–806
Miquel J, Economos A, Fleming J, Johnson J Jr (1980) Mitochondrial role in cell aging. Exp Gerontol 15:575–591
Mokudai T, Ayoub IA, Sakakibara Y, Lee E-J, Ogilvy CS, Maynard KI (2000) Delayed treatment with nicotinamide (vitamin B3) improves neurological outcome and reduces infarct volume after transient focal cerebral ischemia in Wistar rats. Stroke 31:1679–1685
Moraga A et al (2015) Aging increases microglial proliferation, delays cell migration, and decreases cortical neurogenesis after focal cerebral ischemia. J Neuroinflamm 12:87
Mouchiroud L et al (2013) The NAD +/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154:430–441
Murphy E, Steenbergen C (2008) Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev 88:581–609
Nakagawa T, Guarente L (2014) SnapShot: sirtuins, NAD, and aging. Cell Metab 20:192
Nakamura N, Kimura Y, Tokuda M, Honda S, Hirose S (2006) MARCH-V is a novel mitofusin 2-and Drp1-binding protein able to change mitochondrial morphology. EMBO Rep 7:1019–1022
Palikaras K, Tavernarakis N (2014) Mitochondrial homeostasis: the interplay between mitophagy and mitochondrial biogenesis. Exp Gerontol 56:182–188
Palikaras K, Lionaki E, Tavernarakis N (2015) Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature 521:525
Park JH, Long A, Owens K, Kristian T (2016) Nicotinamide mononucleotide inhibits post-ischemic NAD + degradation and dramatically ameliorates brain damage following global cerebral ischemia. Neurobiol Dis 95:102–110
Peng C et al (2015) Mitofusin 2 ameliorates hypoxia-induced apoptosis via mitochondrial function and signaling pathways. Int J Biochem Cell Biol 69:29–40
Pillai VB, Sundaresan NR, Kim G, Samant S, Moreno-Vinasco L, Garcia JG, Gupta MP (2012) Nampt secreted from cardiomyocytes promotes development of cardiac hypertrophy and adverse ventricular remodeling. Am J Physiol-Heart Circ Physiol 304:H415–H426
Ping L, Yin Z, Li Y (2016) GW27-e0632 NR reduced myocardial ischemia-reperfusion injury by improving mitochondrial biogenesis and reducing excessive autophagy via Sirt3-PGC-1α/P53 pathway. J Am Coll Cardiol 68:C24–C25
Polzonetti V, Carpi FM, Micozzi D, Pucciarelli S, Vincenzetti S, Napolioni V (2012) Population variability in CD38 activity: correlation with age and significant effect of TNF-α-308G > A and CD38 184C > G SNPs. Mol Genet Metab 105:502–507
Radogna F, Albertini M, De Nicola M, Diederich M, Bejarano I, Ghibelli L (2015) Melatonin promotes Bax sequestration to mitochondria reducing cell susceptibility to apoptosis via the lipoxygenase metabolite 5-hydroxyeicosatetraenoic acid. Mitochondrion 21:113–121
Rechsteiner M, Hillyard D, Olivera BM (1976) Turnover of nicotinamide adenine dinucleotide in cultures of human cells. J Cell Physiol 88:207–217
Revollo JR et al (2007) Nampt/PBEF/visfatin regulates insulin secretion in β cells as a systemic NAD biosynthetic enzyme. Cell Metab 6:363–375
Rex A, Spychalla M, Fink H (2004) Treatment with reduced nicotinamide adenine dinucleotide (NADH) improves water maze performance in old Wistar rats. Behav Brain Res 154:149–153
Rodgers JT, Lerin C, Gerhart-Hines Z, Puigserver P (2008) Metabolic adaptations through the PGC-1α and SIRT1 pathways. FEBS Lett 582:46–53
Romero JR (2007) Prevention of ischemic stroke: overview of traditional risk factors. Curr Drug Targets 8:794–801
Saeid F, Aniseh J, Reza B, Manouchehr VS (2018) Signaling mediators modulated by cardioprotective interventions in healthy and diabetic myocardium with ischaemia–reperfusion injury. Eur J Prev Cardiol 25(14):1463
Salehpour F et al (2019) Photobiomodulation and Coenzyme Q10 Treatments Attenuate Cognitive Impairment Associated with Model of Transient Global Brain Ischemia in Artificially Aged Mice. Front Cell Neurosci 13:74
Samal B, Sun Y, Stearns G, Xie C, Suggs S, McNiece I (1994) Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor. Mol Cell Biol 14:1431–1437
Scheibye-Knudsen M et al (2014) A high-fat diet and NAD + activate Sirt1 to rescue premature aging in cockayne syndrome. Cell Metab 20:840–855
Seo AY, Joseph A-M, Dutta D, Hwang JC, Aris JP, Leeuwenburgh C (2010) New insights into the role of mitochondria in aging: mitochondrial dynamics and more. J Cell Sci 123:2533–2542
Shanmughapriya S et al (2015) SPG7 is an essential and conserved component of the mitochondrial permeability transition pore. Mol Cell 60:47–62
Smith CM, Chen Y, Sullivan ML, Kochanek PM, Clark RS (2011) Autophagy in acute brain injury: feast, famine, or folly? Neurobiol Dis 43:52–59
Song HK et al (2008) Visfatin: a new player in mesangial cell physiology and diabetic nephropathy. Am J Physiol-Renal Physiol 295:F1485–F1494
Song L et al (2014) Inhibition of 12/15 lipoxygenase by baicalein reduces myocardial ischemia/reperfusion injury via modulation of multiple signaling pathways. Apoptosis 19:567–580
Stein LR, Imai SI (2014) Specific ablation of Nampt in adult neural stem cells recapitulates their functional defects during aging. EMBO J 33:1321–1340
Strosznajder RP, Gadamski R, Czapski GA, Jesko H, Strosznajder JB (2003) Poly (ADP-ribose) polymerase during reperfusion after transient forebrain ischemia. J Mol Neurosci 20:61–71
Su C-F, Liu DD, Kao SJ, Chen HI (2007) Nicotinamide abrogates acute lung injury caused by ischemia-reperfusion. Eur Respir J 30(2):199
Sukhodub A, Du Q, Jovanović S, Jovanović A (2010) Nicotinamide-rich diet protects the heart against ischaemia–reperfusion in mice: a crucial role for cardiac SUR2A. Pharmacol Res 61:564–570
Sun Z, Lei H, Zhang Z (2013) Pre-B cell colony enhancing factor (PBEF), a cytokine with multiple physiological functions. Cytokine Growth Factor Rev 24:433–442
Tong D-L et al (2012) Nicotinamide pretreatment protects cardiomyocytes against hypoxia-induced cell death by improving mitochondrial stress. Pharmacology 90:11–18
Ungvari Z, Labinskyy N, Gupte S, Chander PN, Edwards JG, Csiszar A (2008) Dysregulation of mitochondrial biogenesis in vascular endothelial and smooth muscle cells of aged rats. Am J Physiol-Heart Circ Physiol 294:H2121–H2128
Van Gool F et al (2009) Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner. Nat Med 15:206
Veith S, Mangerich A (2015) RecQ helicases and PARP1 team up in maintaining genome integrity. Ageing Res Rev 23:12–28
von Euler H (1999) Fermentation of sugars and fermentative enzymes, In: Nobelstiftelsen (eds) Nobel Lectures in Chemistry, New Jersey: World Scientific, pp. 144-155
Wallace DC (2012) Mitochondria and cancer. Nat Rev Cancer 12:685
Wang P et al (2011) Nicotinamide phosphoribosyltransferase protects against ischemic stroke through SIRT1-dependent adenosine monophosphate–activated kinase pathway. Ann Neurol 69:360–374
Wang P, Guan Y-F, Du H, Zhai Q-W, Su D-F, Miao C-Y (2012) Induction of autophagy contributes to the neuroprotection of nicotinamide phosphoribosyltransferase in cerebral ischemia. Autophagy 8:77–87
Wang C, Zhang Y, Ding J, Zhao Z, Qian C, Luan Y, Teng G-J (2017) Nicotinamide administration improves remyelination after stroke. Neural plast 2017:12
Wei CC et al (2017) NAD replenishment with nicotinamide mononucleotide protects blood–brain barrier integrity and attenuates delayed tissue plasminogen activator-induced haemorrhagic transformation after cerebral ischaemia. Br J Pharmacol 174:3823–3836
Weng XF, Li ST, Song Q, Zhu Q, D-d Song, Qin ZH, Xie Y (2018) Protective effect of nicotinamide adenine dinucleotide phosphate on renal ischemia-reperfusion injury. Kidney Blood Press Res 43:651–663
Williams PA et al (2017) Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science 355:756–760
Wu G-C et al (2017) Targeting of nicotinamide phosphoribosyltransferase enzymatic activity ameliorates lung damage induced by ischemia/reperfusion in rats. Respir Res 18:71
Xiao J, Sun B, Li M, Wu Y, Sun XB (2013) A novel adipocytokine visfatin protects against H2O2-induced myocardial apoptosis: a missing link between obesity and cardiovascular disease. J Cell Physiol 228:495–501
Xie L, Wang Z, Li C, Yang K, Liang Y (2017a) Protective effect of nicotinamide adenine dinucleotide (NAD +) against spinal cord ischemia–reperfusion injury via reducing oxidative stress-induced neuronal apoptosis. J Clin Neurosci 36:114–119
Xie L, Yu S, Wang Z, Yang K, Liu Z, Li C, Liang Y (2017b) Nicotinamide adenine dinucleotide protects against spinal cord ischemia reperfusion injury-induced apoptosis by blocking autophagy. Oxid Med Cell Longev. https://doi.org/10.1155/2017/7063874
Yamamoto T, Byun J, Zhai P, Ikeda Y, Oka S, Sadoshima J (2014) Nicotinamide mononucleotide, an intermediate of NAD + synthesis, protects the heart from ischemia and reperfusion. PLoS ONE 9:e98972
Yang H et al (2007) Nutrient-sensitive mitochondrial NAD + levels dictate cell survival. Cell 130:1095–1107
Ying W (2008) NAD +/NADH and NADP +/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid Redox Signal 10:179–206
Ying W et al (2007) Intranasal administration with NAD + profoundly decreases brain injury in a rat model of transient focal ischemia. Front Biosci 12:2728–2734
Yoshino J, Mills KF, Yoon MJ, S-i Imai (2011) Nicotinamide mononucleotide, a key NAD + intermediate, treats the pathophysiology of diet-and age-induced diabetes in mice. Cell Metab 14:528–536
Yuan Y, Cruzat VF, Newsholme P, Cheng J, Chen Y, Lu Y (2016) Regulation of SIRT1 in aging: roles in mitochondrial function and biogenesis. Mech Ageing Dev 155:10–21
Zhang T et al (2009) Enzymes in the NAD + salvage pathway regulate SIRT1 activity at target gene promoters. J Biol Chem 284(30):20408
Zhang Y et al (2016) Exogenous NAD + administration significantly protects against myocardial ischemia/reperfusion injury in rat model. Am J Trans Res 8:3342
Zhao Y, Liu XZ, Tian WW, Guan YF, Wang P, Miao CY (2014) Extracellular visfatin has nicotinamide phosphoribosyltransferase enzymatic activity and is neuroprotective against ischemic injury. CNS Neurosci Ther 20:539–547
Zhao Y et al (2015) Regenerative neurogenesis after ischemic stroke promoted by nicotinamide phosphoribosyltransferase–nicotinamide adenine dinucleotide cascade. Stroke 46:1966–1974
Zheng C, Han J, Xia W, Shi S, Liu J, Ying W (2012) NAD + administration decreases ischemic brain damage partially by blocking autophagy in a mouse model of brain ischemia. Neurosci Lett 512:67–71
Zhou H et al (2017) Ripk3 induces mitochondrial apoptosis via inhibition of FUNDC1 mitophagy in cardiac IR injury. Redox Biol 13:498–507
Zorov DB, Juhaszova M, Sollott SJ (2014) Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev 94:909–950
Acknowledgements
This work has been supported by Aging Research Institute, Drug Applied Research Centre, Tabriz University of Medical Sciences, Tabriz-Iran.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that there are no conflicts of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Hosseini, L., Vafaee, M.S., Mahmoudi, J. et al. Nicotinamide adenine dinucleotide emerges as a therapeutic target in aging and ischemic conditions. Biogerontology 20, 381–395 (2019). https://doi.org/10.1007/s10522-019-09805-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10522-019-09805-6