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  • The Ravages Of Old Age Could Have Been Averted Sixty Years Ago? HISTORY OF NICOTINAMIDE AND AGING

    January 3, 2014: by Bill Sardi

    Recently researchers said they were able to reverse biological aging for the first time using a derivative of vitamin B3 niacin.

    A report in the journal CELL noted that the use of a derivative of vitamin B3/niacin called nicotinamide stimulates the production of nicotinamide adenine dinucleotide (NAD), a key protein in cellular metabolism (use of sugar for cellular energy) and cellular respiration (use of oxygen for cellular energy) in the mitochondria of cells.

    There are a few hundred mitochondria in living cells. Mitochondria are atomic power plants that produce cell energy in the form of adenotriphosphate (ATP).  By molecularly promoting more NAD/ATP in the mitochondria researchers were able to demonstrate that aging largely occurs in the mitochondria rather than the nucleus of cells and that production of NAD was able to reverse aging in muscle tissue of a laboratory mouse equivalent to making a 60-year old human 20-years old again!

    The sad part of this topic is that modern medicine has had evidence for this anti-aging vitamin effect as far back as 60 years ago.  The following abstracts, obtained from the National Library of Medicine, provide evidence that modern medicine has had knowledge that derivatives of niacin are an anti-aging agent decades ago.

    The following 57 published reports, spanning a period from 1953 to 2014 (60+ years), suggests modern medicine has so many financial incentives to develop patentable and profitable prescription drugs that address the many age-related human diseases that it overlooks less problematic and more economical vitamins, in this instance, a vitamin so powerful it can reverse aging itself.

    Imagine, a molecule that addresses aging, the very cause of most chronic disease, has been shunned for six decades.  Humanity could have averted the ravages of old age long ago.  People born in the 1950s who died prematurely might still be alive and healthy.

    No one will say it, but this is another black mark in the history of modern medicine.

    Look for the words nicotinamide, niacinamide, NAD, mitochondria in the titles of the following abstracts.   The title of the earliest citation, an abstract from the Connecticut State Medical Journal published in 1953, is “Niacinamide therapy for joint mobility; therapeutic reversal of a common clinical manifestation of the normal aging process.”  This sounds like the most recent discovery where aging was reversed in laboratory mice.

    ©2014 Bill Sardi, ResveratrolNews.com.


    Cell 2013 Dec 19; 155(7):1624-38. doi: 10.1016/j.cell.2013.11.037.

    Declining NAD(+) Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging.

    Gomes AP1, Price NL2, Ling AJ2, Moslehi JJ3, Montgomery MK4, Rajman L2, White JP5, Teodoro JS6, Wrann CD5, Hubbard BP2, Mercken EM7, Palmeira CM6, de Cabo R7, Rolo AP8, Turner N4, Bell EL9, Sinclair DA10.

    Author information

    Abstract

    Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD(+) and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD(+) levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.

    PMID: 24360282


     J Nutr Biochem. 2014 Jan; 25(1):66-72. doi: 10.1016/j.jnutbio.2013.09.004.

    Nicotinamide improves glucose metabolism and affects the hepatic NAD-sirtuin pathway in a rodent model of obesity and type 2 diabetes.

    Yang SJ, Choi JM, Kim L, Park SE, Rhee EJ, Lee WY, Oh KW, Park SW, Park CY.

    • Department of Food and Nutrition and Human Ecology Research Institute, Chonnam National University, Gwangju, South Korea.

    Abstract

    Nicotinic acid (NA) and nicotinamide (NAM) are major forms of niacin and exert their physiological functions as precursors of nicotinamide adenine dinucleotide (NAD). Sirtuins, which are NAD-dependent deacetylases, regulate glucose and lipid metabolism and are implicated in the pathophysiology of aging, diabetes, and hepatic steatosis. The aim of this study was to investigate the effects of two NAD donors, NA and NAM, on glucose metabolism and the hepatic NAD-sirtuin pathway. The effects were investigated in OLETF rats, a rodent model of obesity and type 2 diabetes. OLETF rats were divided into five groups: (1) high fat (HF) diet, (2) HF diet and 10 mg NA/kg body weight (BW)/day (NA 10), (3) HF diet and 100 mg NA/kg BW/day (NA 100), (4) HF diet and 10 mg NAM/kg BW/day (NAM 10), and (5) HF diet and 100 mg NAM/kg BW/day (NAM 100). NA and NAM were delivered via drinking water for four weeks. NAM 100 treatment affected glucose control significantly, as shown by lower levels of accumulative area under the curve during oral glucose tolerance test, serum fasting glucose, serum fasting insulin, and homeostasis model assessment of insulin resistance, and higher levels of serum adiponectin. With regard to NAD-sirtuin pathway, intracellular nicotinamide phosphoribosyltransferase, NAD, the NAD/NADH ratio, Sirt1, 2, 3, and 6 mRNA expressions, and Sirt1 activity all increased in livers of NAM 100-treated rats. These alterations were accompanied by the increased levels of proliferator-activated receptor gamma, coactivator 1 alpha and mitochondrial DNA. The effect of NA treatment was less evident than that of NAM 100. These results demonstrate that NAM is more effective than NA on the regulation of glucose metabolism and the NAD-sirtuin pathway, which may relate to the altered mitochondrial biogenesis.

    PMID: 24314867


     

    Crit Rev Biochem Mol Biol. 2013 Jul-Aug; 48(4):397-408. doi: 10.3109/10409238.2013.789479.

    NAD⁺ metabolism: a therapeutic target for age-related metabolic disease.

    Mouchiroud L, Houtkooper RH, Auwerx J.

    • Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

    Abstract

    Nicotinamide adenine dinucleotide (NAD) is a central metabolic cofactor by virtue of its redox capacity, and as such regulates a wealth of metabolic transformations. However, the identification of the longevity protein silent regulator 2 (Sir2), the founding member of the sirtuin protein family, as being NAD⁺-dependent reignited interest in this metabolite. The sirtuins (SIRT1-7 in mammals) utilize NAD⁺ to deacetylate proteins in different subcellular compartments with a variety of functions, but with a strong convergence on optimizing mitochondrial function. Since cellular NAD⁺ levels are limiting for sirtuin activity, boosting its levels is a powerful means to activate sirtuins as a potential therapy for mitochondrial, often age-related, diseases. Indeed, supplying excess precursors, or blocking its utilization by poly(ADP-ribose) polymerase (PARP) enzymes or CD38/CD157, boosts NAD⁺ levels, activates sirtuins and promotes healthy aging. Here, we discuss the current state of knowledge of NAD⁺ metabolism, primarily in relation to sirtuin function. We highlight how NAD⁺ levels change in diverse physiological conditions, and how this can be employed as a pharmacological strategy.

    PMID:  23742622


    Mol Cells. 2013 Jun; 35(6):474-80. doi: 10.1007/s10059-013-0130-x.

    Do sirtuins promote mammalian longevity? A critical review on its relevance to the longevity effect induced by calorie restriction.

    Park S, Mori R, Shimokawa I.

    • Department of Investigative Pathology, Unit of Basic Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.

    Abstract

    Sirtuins (SIRTs), a family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, are emerging as key molecules that regulate aging and age-related diseases including cancers, metabolic disorders, and neurodegenerative diseases. Seven isoforms of SIRT (SIRT1-7) have been identified in mammals. SIRT1 and 6, mainly localized in the nucleus, regulate transcription of genes and DNA repair. SIRT3 in the mitochondria regulates mitochondrial bioenergetics. Initial studies in yeasts, nematodes, and flies indicated a strong connection of SIRT with the life-prolonging effects of calorie restriction (CR), a robust experimental intervention for longevity in a range of organisms. However, subsequent studies reported controversial findings regarding SIRT roles in the effect of CR. This review describes the functional roles of mammalian SIRTs and discusses their relevance to mechanisms underlying the longevity effect of CR.

    PMID: 23661364


    J Reprod Dev. 2013; 59(3):238-44.

    Nicotinamide: a class III HDACi delays in vitro aging of mouse oocytes.

    Lee AR, Kishigami S, Amano T, Matsumoto K, Wakayama T, Hosoi Y.

    • Division of Biological Science, Graduate School of Biology-Oriented Science and Technology, Kinki University, Wakayama 649-6493, Japan.

    Abstract

    Postovulatory mammalian oocyte developmental potential decreases with aging in vivo and in vitro. Aging oocytes typically show cellular fragmentation and chromosome scattering with an abnormally shaped spindle over time. Previously, it was shown that histone acetylation in the mouse oocyte increased during aging and that treatment with trichostatin A (TSA), an inhibitor for class I and II histone deacetylases (HDACs), enhanced the acetylation, that is, aging. In this study, we examined the effect of nicotinamide (NAM), an inhibitor for class III HDACs, on in vitro aging of mouse oocytes as well as TSA. We found that treatment with NAM significantly inhibited cellular fragmentation, spindle elongation and astral microtubules up to 48 h of culture. Although presence of TSA partially inhibited cellular fragmentation and spindle elongation up to 36 h of culture, treatment with TSA induced chromosome scattering at 24 h of culture and more severe cellular fragmentation at 48 h of culture. Further, we found that α-tubulin, a non-histone protein, increased acetylation during aging, suggesting that not only histone but non-histone protein acetylation may also increase with oocyte aging. Thus, these data indicate that protein acetylation is abnormally regulated in aging oocytes, which are associated with a variety of aging phenotypes, and that class I/II and class III HDACs may play distinct roles in aging oocytes.

    PMID: 23474603


    Biochem Pharmacol. 2013 May 1; 85(9):1288-96. doi: 10.1016/j.bcp.2013.02.015.

    SIRT1 inhibits NADPH oxidase activation and protects endothelial function in the rat aorta: implications for vascular aging.

    Zarzuelo MJ, López-Sepúlveda R, Sánchez M, Romero M, Gómez-Guzmán M, Ungvary Z, Pérez-Vizcaíno F, Jiménez R, Duarte J.

    • Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain.

    Abstract

    Vascular aging is characterized by up-regulation of NADPH oxidase, oxidative stress and endothelial dysfunction. Previous studies demonstrate that the activity of the evolutionarily conserved NAD(+)-dependent deacetylase SIRT1 declines with age and that pharmacological activators of SIRT1 confer significant anti-aging cardiovascular effects. To determine whether dysregulation of SIRT1 promotes NADPH oxidase-dependent production of reactive oxygen species (ROS) and impairs endothelial function we assessed the effects of three structurally different inhibitors of SIRT1 (nicotinamide, sirtinol, EX527) in aorta segments isolated from young Wistar rats. Inhibition of SIRT1 induced endothelial dysfunction, as shown by the significantly reduced relaxation to the endothelium-dependent vasodilators acetylcholine and the calcium ionophore A23187. Endothelial dysfunction induced by SIRT1 inhibition was prevented by treatment of the vessels with the NADPH oxidase inhibitor apocynin or superoxide dismutase. Inhibition of SIRT1 significantly increased vascular superoxide production, enhanced NADPH oxidase activity, and mRNA expression of its subunits p22(phox) and NOX4, which were prevented by resveratrol. Peroxisome proliferator-activated receptor-α (PPARα) activation mimicked the effects of resveratrol while PPARα inhibition prevented the effects of this SIRT1 activator. SIRT1 co-precipitated with PPARα and nicotinamide increased the acetylation of the PPARα coactivator PGC-1α, which was suppressed by resveratrol. In conclusion, impaired activity of SIRT1 induces endothelial dysfunction and up-regulates NADPH oxidase-derived ROS production in the vascular wall, mimicking the vascular aging phenotype. Moreover, a new mechanism for controlling endothelial function after SIRT1 activation involves a decreased PGC-1α acetylation and the subsequent PPARα activation, resulting in both decreased NADPH oxidase-driven ROS production and NO inactivation.

    PMID: 23422569


    Curr Opin Clin Nutr Metab Care. 2013 Nov;16(6):657-61. doi: 10.1097/MCO.0b013e32836510c0.

    Nicotinamide riboside, a trace nutrient in foods, is a vitamin B3 with effects on energy metabolism and neuroprotection.

    Chi Y, Sauve AA.

    • aDepartment of Medicine, Albert Einstein College of Medicine, Bronx bDepartment of Pharmacology, Weill Cornell Medical College, New York, New York, USA.

    Abstract

    PURPOSE OF REVIEW:

    This review focuses upon the biology and metabolism of a trace component in foods called nicotinamide riboside. Nicotinamide riboside is a precursor of nicotinamide adenine dinucleotide (NAD), and is a source of Vitamin B3. Evidence indicates that nicotinamide riboside has unique properties as a Vitamin B3. We review knowledge of the metabolism of this substance, as well as recent work suggesting novel health benefits that might be associated with nicotinamide riboside taken in larger quantities than is found naturally in foods.

    RECENT FINDINGS:

    Recent work investigating the effects of nicotinamide riboside in yeast and mammals established that it is metabolized by at least two types of metabolic pathways. The first of these is degradative and produces nicotinamide. The second pathway involves kinases called nicotinamide riboside kinases (Nrk1 and Nrk2, in humans). The likely involvement of the kinase pathway is implicated in the unique effects of nicotinamide riboside in raising tissue NAD concentrations in rodents and for potent effects in eliciting insulin sensitivity, mitochondrial biogenesis, and enhancement of sirtuin functions. Additional studies with nicotinamide riboside in models of Alzheimer’s disease indicate bioavailability to brain and protective effects, likely by stimulation of brain NAD synthesis.

    SUMMARY:

    Initial studies have clarified the potential for a lesser-known Vitamin B3 called nicotinamide riboside that is available in selected foods, and possibly available to humans by supplements. It has properties that are insulin sensitizing, enhancing to exercise, resisting to negative effects of high-fat diet, and neuroprotecting.

    PMID: 24071780


    Neurobiol Aging. 2013 Jun; 34(6):1581-8. doi: 10.1016/j.neurobiolaging.2012.12.005.

    Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer’s mouse models.

    Gong B, Pan Y, Vempati P, Zhao W, Knable L, Ho L, Wang J, Sastre M, Ono K, Sauve AA, Pasinetti GM.

    • Department of Neurology, Center of Excellence for Novel Approaches to Neurotherapeutics, Mount Sinai School of Medicine, New York, NY, USA.

    Abstract

    Nicotinamide adenine dinucleotide (NAD)(+), a coenzyme involved in redox activities in the mitochondrial electron transport chain, has been identified as a key regulator of the lifespan-extending effects, and the activation of NAD(+) expression has been linked with a decrease in beta-amyloid (Aβ) toxicity in Alzheimer’s disease (AD). Nicotinamide riboside (NR) is a NAD (+) precursor, it promotes peroxisome proliferator-activated receptor-γ coactivator 1 (PGC)-1α expression in the brain. Evidence has shown that PGC-1α is a crucial regulator of Aβ generation because it affects β-secretase (BACE1) degradation. In this study we tested the hypothesis that NR treatment in an AD mouse model could attenuate Aβ toxicity through the activation of PGC-1α-mediated BACE1 degradation. Using the Tg2576 AD mouse model, using in vivo behavioral analyses, biochemistry assays, small hairpin RNA (shRNA) gene silencing and electrophysiological recording, we found (1) dietary treatment of Tg2576 mice with 250 mg/kg/day of NR for 3 months significantly attenuates cognitive deterioration in Tg2576 mice and coincides with an increase in the steady-state levels of NAD(+) in the cerebral cortex; (2) application of NR to hippocampal slices (10 μM) for 4 hours abolishes the deficits in long-term potentiation recorded in the CA1 region of Tg2576 mice; (3) NR treatment promotes PGC-1α expression in the brain coinciding with enhanced degradation of BACE1 and the reduction of Aβ production in Tg2576 mice. Further in vitro studies confirmed that BACE1 protein content is decreased by NR treatment in primary neuronal cultures derived from Tg2576 embryos, in which BACE1 degradation was prevented by PGC-1α-shRNA gene silencing; and (4) NR treatment and PGC-1α overexpression enhance BACE1 ubiquitination and proteasomal degradation. Our studies suggest that dietary treatment with NR might benefit AD cognitive function and synaptic plasticity, in part by promoting PGC-1α-mediated BACE1 ubiquitination and degradation, thus preventing Aβ production in the brain.

    PMID: 23312803


    Neurobiol Aging. 2013 Jun; 34(6):1564-80. doi: 10.1016/j.neurobiolaging.2012.11.020.

    Nicotinamide forestalls pathology and cognitive decline in Alzheimer mice: evidence for improved neuronal bioenergetics and autophagy procession.

    Liu D, Pitta M, Jiang H, Lee JH, Zhang G, Chen X, Kawamoto EM, Mattson MP.

    • Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA.

    Abstract

    Impaired brain energy metabolism and oxidative stress are implicated in cognitive decline and the pathologic accumulations of amyloid β-peptide (Aβ) and hyperphosphorylated tau in Alzheimer’s disease (AD). To determine whether improving brain energy metabolism will forestall disease progress in AD, the impact of the β-nicotinamide adenine dinucleotide precursor nicotinamide on brain cell mitochondrial function and macroautophagy, bioenergetics-related signaling, and cognitive performance were studied in cultured neurons and in a mouse model of AD. Oxidative stress resulted in decreased mitochondrial mass, mitochondrial degeneration, and autophagosome accumulation in neurons. Nicotinamide preserved mitochondrial integrity and autophagy function, and reduced neuronal vulnerability to oxidative/metabolic insults and Aβ toxicity. β-Nicotinamide adenine dinucleotide biosynthesis, autophagy, and phosphatidylinositol-3-kinase signaling were required for the neuroprotective action of nicotinamide. Treatment of 3xTgAD mice with nicotinamide for 8 months resulted in improved cognitive performance, and reduced Aβ and hyperphosphorylated tau pathologies in hippocampus and cerebral cortex. Nicotinamide treatment preserved mitochondrial integrity, and improved autophagy-lysosome procession by enhancing lysosome/autolysosome acidification to reduce autophagosome accumulation. Treatment of 3xTgAD mice with nicotinamide resulted in elevated levels of activated neuroplasticity-related kinases (protein kinase B [Akt] and extracellular signal-regulated kinases) and the transcription factor cyclic adenosine monophosphate (AMP) response element-binding protein in the hippocampus and cerebral cortex. Thus, nicotinamide suppresses AD pathology and cognitive decline in a mouse model of AD by a mechanism involving improved brain bioenergetics with preserved functionality of mitochondria and the autophagy system.

    PMID: 23273573


    Mol Aspects Med. 2011 Aug; 32(4-6):279-304. doi: 10.1016/j.mam.2011.10.007.

    Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity.

    Calabrese VCornelius CCuzzocrea SIavicoli IRizzarelli ECalabrese EJ.

    Abstract

    Understanding mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Extension of maximal life span is currently possible in animal models with measures such as genetic manipulations and caloric restriction (CR). CR appears to prolong life by reducing reactive oxygen species (ROS)-mediated oxidative damage. But ROS formation, which is positively implicated in cellular stress response mechanisms, is a highly regulated process controlled by a complex network of intracellular signaling pathways. By sensing the intracellular nutrient and energy status, the functional state of mitochondria, and the concentration of ROS produced in mitochondria, the longevity network regulates life span across species by co-ordinating information flow along its convergent, divergent and multiply branched signaling pathways, including vitagenes which are genes involved in preserving cellular homeostasis during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. Dietary antioxidants, such as carnosine, carnitines or polyphenols, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. The hormetic dose-response, challenges long-standing beliefs about the nature of the dose-response in a low dose zone, having the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses. In this review we discuss the most current and up to date understanding of the possible signaling mechanisms by which caloric restriction, as well hormetic caloric restriction-mimetics compounds by activating vitagenes can enhance defensive systems involved in bioenergetic and stress resistance homeostasis with consequent impact on longevity processes.

    PMID:  22020114


    Curr Top Med Chem. 2013;13(23):2907-17.

    NAD Biosynthesis in Humans – Enzymes, Metabolites and Therapeutic Aspects.

    Dölle C, Skoge RH, Vanlinden MR, Ziegler M.

    Abstract

    NAD plays a major role in all cells as substrate for signal transduction and as cofactor in metabolic redox reactions. Since NAD-dependent signaling involves degradation of the nucleotide, continuous restoration of cellular NAD pools is essential. Moreover, NAD-dependent signaling reactions, which include ADP-ribosylation, protein deacetylation by sirtuins and calcium messenger synthesis, are regulated by NAD availability. Consequently, perturbations of NAD supply can have severe consequences and, in fact, have been associated with major human diseases such as age- and dietinduced disorders, neurodegenerative diseases and cancer. Given the increasing awareness of the biological roles of NAD, the routes, molecular mechanisms and regulation of NAD biosynthesis have been the subject of intense research over the last decade. Impressive progress has been made regarding the molecular identification, functional and structural characterization as well as regulation of the human NAD biosynthetic enzymes. Exciting therapeutic concepts have emerged, which aim at modulation of NAD availability by interfering with the biosynthetic network to prevent, reduce or reverse pathological conditions. Since there are several entry points into NAD synthesis, including the known vitamin B3 precursors nicotinamide and nicotinic acid, targeted nutritional supplementation is likely to have beneficial effects in various diseases. On the other hand, inhibition of NAD synthesis promotes cell death and has emerged as a therapeutic concept for cancer treatment.

    PMID: 24171775


    Mutat Res. 2013 Sep; 749(1-2):28-38. doi: 10.1016/j.mrfmmm.2013.07.001.

    Mitigation of gamma-radiation induced abasic sites in genomic DNA by dietary nicotinamide supplementation: metabolic up-regulation of NAD(+) biosynthesis.

    Batra V, Kislay B.

    Abstract

    The search for non-toxic radio-protective drugs has yielded many potential agents but most of these compounds have certain amount of toxicity. The objective of the present study was to investigate dietary nicotinamide enrichment dependent adaptive response to potential cytotoxic effect of (60)Co γ-radiation. To elucidate the possible underlying mechanism(s), male Swiss mice were maintained on control diet (CD) and nicotinamide supplemented diet (NSD). After 6 weeks of CD and NSD dietary regimen, we exposed the animals to γ-radiation (2, 4 and 6Gy) and investigated the profile of downstream metabolites and activities of enzymes involved in NAD (+) biosynthesis. Increased activities of nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide mononucleotide adenylyltransferase (NMNAT) were observed up to 48h post-irradiation in NSD fed irradiated mice. Concomitant with increase in liver NAMPT and NMNAT activities, NAD (+) levels were replenished in NSD fed and irradiated animals. However, NAMPT and NMNAT-mediated NAD (+) biosynthesis and ATP levels were severely compromised in liver of CD fed irradiated mice. Another major finding of these studies revealed that under γ-radiation stress, dietary nicotinamide supplementation might induce higher and long-lasting poly(ADP)-ribose polymerase 1 (PARP1) and poly(ADP-ribose) glycohydrolase (PARG) activities in NSD fed animals compared to CD fed animals. To investigate liver DNA damage, number of apurinic/apyrimidinic sites (AP sites) and level of 8-hydroxy-2′-deoxyguanosine (8-oxo-dG) residues were quantified. A significant increase in liver DNA AP sites and 8-oxo-dG levels with concomitant increase in caspase-3 was observed in CD fed and irradiated animals compared to NSD fed and irradiated mice. In conclusion present studies show that under γ-radiation stress conditions, dietary nicotinamide supplementation restores DNA excision repair activity via prolonged activation of PARP1 and PARG activities. Present results clearly indicated that hepatic NAD (+) replenishment might be a novel and potent approach to reduce radiation injury.

    PMID: 23891603


    Immun Ageing. 2013 Apr 25;10(1):15. doi: 10.1186/1742-4933-10-15.

    Stress responses, vitagenes and hormesis as critical determinants in aging and longevity: Mitochondria as a “chi”.

    Cornelius CPerrotta RGraziano ACalabrese EJCalabrese V.

    Abstract

    Understanding mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Extension of maximal life span is currently possible in animal models with measures such as genetic manipulations and caloric restriction (CR). CR appears to prolong life by reducing reactive oxygen species (ROS)-mediated oxidative damage. But ROS formation, which is positively implicated in cellular stress response mechanisms, is a highly regulated process controlled by a complex network of intracellular signaling pathways. By sensing the intracellular nutrient and energy status, the functional state of mitochondria, and the concentration of ROS produced in mitochondria, the longevity network regulates life span across species by coordinating information flow along its convergent, divergent and multiply branched signaling pathways, including vitagenes which are genes involved in preserving cellular homeostasis during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. Dietary antioxidants, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. The hormetic dose-response, challenges long-standing beliefs about the nature of the dose-response in a lowdose zone, having the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses. Here we focus on possible signaling mechanisms involved in the activation of vitagenes resulting in enhanced defense against energy and stress resistance homeostasis dysiruption with consequent impact on longevity processes.

    PMID:  23618527


    Cell Metab. 2012 Jun 6; 15(6):838-47. doi: 10.1016/j.cmet.2012.04.022.

    The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity.

    Cantó C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, Fernandez-Marcos PJ, Yamamoto H, Andreux PA, Cettour-Rose P, Gademann K, Rinsch C, Schoonjans K, Sauve AA, Auwerx J.

    Abstract

    As NAD(+) is a rate-limiting cosubstrate for the sirtuin enzymes, its modulation is emerging as a valuable tool to regulate sirtuin function and, consequently, oxidative metabolism. In line with this premise, decreased activity of PARP-1 or CD38-both NAD(+) consumers-increases NAD(+) bioavailability, resulting in SIRT1 activation and protection against metabolic disease. Here we evaluated whether similar effects could be achieved by increasing the supply of nicotinamide riboside (NR), a recently described natural NAD(+) precursor with the ability to increase NAD(+) levels, Sir2-dependent gene silencing, and replicative life span in yeast. We show that NR supplementation in mammalian cells and mouse tissues increases NAD(+) levels and activates SIRT1 and SIRT3, culminating in enhanced oxidative metabolism and protection against high-fat diet-induced metabolic abnormalities. Consequently, our results indicate that the natural vitamin NR could be used as a nutritional supplement to ameliorate metabolic and age-related disorders characterized by defective mitochondrial function.

    PMID: 22682224


    Mutat Res. 2012 May 1; 733(1-2):14-20.

    Niacin requirements for genomic stability.

    Kirkland JB.

    Abstract

    Through its involvement in over 400 NAD(P)-dependent reactions, niacin status has the potential to influence every area of metabolism. Niacin deficiency has been linked to genomic instability largely through impaired function of the poly ADP-ribose polymerase (PARP) family of enzymes. In various models, niacin deficiency has been found to cause impaired cell cycle arrest and apoptosis, delayed DNA excision repair, accumulation of single and double strand breaks, chromosomal breakage, telomere erosion and cancer development. Rat models suggest that most aspects of genomic instability are minimized by the recommended levels of niacin found in AIN-93 formulations; however, some beneficial responses do occur in the range from adequate up to pharmacological niacin intakes. Mouse models show a wide range of protection against UV-induced skin cancer well into pharmacological levels of niacin intake. It is currently a challenge to compare animal and human data to estimate the role of niacin status in the risk of genomic instability in human populations. It seems fairly certain that some portion of even affluent populations will benefit from niacin supplementation, and some subpopulations are likely well below an optimal intake of this vitamin. With exposure to stressors, like chemotherapy or excess sunlight, suraphysiological doses of niacin may be beneficial.

    PMID: 22138132


    PLoS One. 2012;7(10):e44933. doi: 10.1371/journal.pone.0044933.

    Nicotinamide phosphoribosyltransferase may be involved in age-related brain diseases.

    Liu LY, Wang F, Zhang XY, Huang P, Lu YB, Wei EQ, Zhang WP.

    • Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.

    Abstract

    Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme for nicotinamide adenine dinucleotide (NAD) biosynthesis, and can be found either intracellularly (iNAMPT) or extracellularly (eNAMPT). Studies have shown that both iNAMPT and eNAMPT are implicated in aging and age-related diseases/disorders in the peripheral system. However, their functional roles in aged brain remain to be established. Here we showed that upon aging, NAMPT level increased in serum but decreased in brain, decreased in cortex and hippocampus but remained unchanged in cerebellum and striatum in brain, and increased in microglia but likely decreased in neuron. Accordingly, total NAD (tNAD) level significantly decreased in hippocampus, cerebellum and striatum in aged brain. Application of recombinant NAMPT, mimicking the elevated serum NAMPT level, enhanced the susceptibility of cerebral endothelial cells to ischemic injury, while inhibition of iNAMPT by FK866, a specific inhibitor, reduced intracellular NAD level and induced neuronal death. Taken together, we have revealed a region- and cell-specific change of NAMPT level in brain and serum upon aging, deduced its potential consequences, which suggests that NAMPT is a regulatory factor in aging and age-related brain diseases.

    PMID: 23071504


    Cell Metab. 2011 Oct 5; 14(4):528-36. doi: 10.1016/j.cmet.2011.08.014.

    Nicotinamide mononucleotide, a key NAD (+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice.

    Yoshino J, Mills KF, Yoon MJ, Imai S.

    • Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.

    Abstract

    Type 2 diabetes (T2D) has become epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD(+) biosynthesis, and the NAD(+)-dependent protein deacetylase SIRT1. Here, we show that NAMPT-mediated NAD(+) biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD (+) intermediate, ameliorates glucose intolerance by restoring NAD(+) levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD (+) and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a potential nutriceutical intervention against diet- and age-induced T2D.

    PMID: 21982712


    Rev Clin Esp. 2010 Jun; 210(6):284-8. doi: 10.1016/j.rce.2009.09.015.

    [Nicotinamide adenine dinucleotide (NADH) in patients with chronic fatigue syndrome].

    [Article in Spanish]

    Alegre J, Rosés JM, Javierre C, Ruiz-Baqués A, Segundo MJ, de Sevilla TF.

    Abstract

    BACKGROUND:

    Nicotinamide adenine dinucleotide (NADH) may be depleted in chronic fatigue syndrome (SFC). The purpose of the study was to evaluate the efficacy of supplementation with NADH in these patients.

    MATERIAL AND METHODS:

    A double blind, placebo controlled, 3 month long clinical trial was conducted. The patients were randomized to oral NADH oral 20mg or placebo during the first two months. The intensity of the fatigue, functional performance, mood state, functional impact of the fatigue, quality of life, sleep quality, exercise capacity and functional reserve as well as the investigator’s and patient’s opinion on the efficacy of the intervention prior to and at 30, 60 and 90 days of the onset of the treatment were evaluated. A stress test was performed in the baseline visit and at 60 days (last day of the double blind treatment).

    RESULTS:

    A total of 86 patients, 77 of whom completed the study (mean age, 47 years, 72 women) were enrolled. No significant differences were found in most of the variable studied at the end of the study. Administration of NADH was associated to a decrease in anxiety condition of -1.0 points (p<0.05) and of -0.2 points (p=NS) in the placebo assigned group. Maximum heart rate after the stress test decreased a mean of -8.1l/min (p<0.05) in the NADH group and increased by +1.7l/min in the placebo group (p=0.73). No differences were found in the perception of efficacy with NADH and placebo, by the investigator and patients.

    CONCLUSIONS:

    Administration of oral NADH was associated to a decrease in anxiety and maximum heart rate, after a stress test in patients with CFS. On the contrary, this treatment did not modify other clinical variables and the global functional performance.

    PMID: 20447621


    Rejuvenation Res. 2010 Apr-Jun;13(2-3):159-61. doi: 10.1089/rej.2009.0918.

    Aging-related nicotinamide adenine dinucleotide oxidase response to dietary supplementation: the French paradox revisited.

    Morré DJ, Morré DM, Shelton TB.

    Abstract

    Aging-related cell-surface NADH oxidase (arNOX)-specific activities increase with age between age 30 and ages 50-65. The protein is shed and circulates. Activity correlates with a number of aging-related disorders including low-density lipoprotein (LDL) oxidation as a precondition to atherosclerosis as well as oxidation of collagen and elastin as a major contributor to skin aging. arNOX inhibitors formulated for sustained release are capable of maintaining circulating arNOX at low levels with regular use as food supplements formulated with natural compounds. Among the best sources are certain culinary seasonings, all of which are ingredients used extensively in the French kitchen. Their regular use may contribute to an understanding of the nutritional basis for the French Paradox.

    PMID: 19954304


    Mech Ageing Dev. 2010 Apr;131(4):287-98. doi: 10.1016/j.mad.2010.03.006.

    Vitamin B3, the nicotinamide adenine dinucleotides and aging.

    Xu P, Sauve AA.

    • Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue LC216, New York, NY 10065, USA.

    Abstract

    Organism aging is a process of time and maturation culminating in senescence and death. The molecular details that define and determine aging have been intensely investigated. It has become appreciated that the process is partly an accumulation of random yet inevitable changes, but it can be strongly affected by genes that alter lifespan. In this review, we consider how NAD (+) metabolism plays important roles in the random patterns of aging, and also in the more programmatic aspects. The derivatives of NAD(+), such as reduced and oxidized forms of NAD(P)(+), play important roles in maintaining and regulating cellular redox state, Ca(2+) stores, DNA damage and repair, stress responses, cell cycle timing and lipid and energy metabolism. NAD(+) is also a substrate for signaling enzymes like the sirtuins and poly-ADP-ribosylpolymerases, members of a broad family of protein deacetylases and ADP-ribosyltransferases that regulate fundamental cellular processes such as transcription, recombination, cell division, proliferation, genome maintenance, apoptosis, stress resistance and senescence. NAD (+)-dependent enzymes are increasingly appreciated to regulate the timing of changes that lead to aging phenotypes. We consider how metabolism, specifically connected with Vitamin B3 and the nicotinamide adenine dinucleotides and their derivatives, occupies a central place in the aging processes of mammals.

    (c) 2010. Published by Elsevier Ireland Ltd.

    PMID: 20307564


    Pharmacol Res. 2010 Jul;62(1):42-7. doi: 10.1016/j.phrs.2010.01.006.

    A possibility of nutriceuticals as an anti-aging intervention: activation of sirtuins by promoting mammalian NAD biosynthesis.

    Imai S.

    • Department of Developmental Biology, Washington University School of Medicine, Campus Box 8103, 660 South Euclid Avenue, St. Louis, MO 63110, USA. imaishin@wustl.edu

    Abstract

    Aging science has recently drawn much attention, and discussions on the possibility of anti-aging medicine have multiplied. One potential target for the development of anti-aging drugs is the SIR2 (silent information regulator 2) family of NAD-dependent deacetylases/ADP-ribosyltransferases, called “sirtuins.” Sirtuins regulate many fundamental biological processes in response to a variety of environmental and nutritional stimuli. In mammals, the mammalian SIR2 ortholog SIRT1 has been most studied, and small molecule SIRT1 activators (STACs), including a plant-derived polyphenolic compound resveratrol, have been developed. On the other hand, sirtuin activity is regulated by NAD biosynthetic pathways, and nicotinamide phosphoribosyltransferase (NAMPT) plays a critical role in the regulation of mammalian sirtuin activity. Recent studies have provided a proof of concept for the idea that nicotinamide mononucleotide (NMN), the NAMPT reaction product, can be used as a nutriceutical to activate SIRT1 activity. Based on these recent findings, the possibility of sirtuin-targeted nutriceutical development will be discussed.

    PMID: 20085812


    Rejuvenation Res. 2010 Apr-Jun;13(2-3):159-61. doi: 10.1089/rej.2009.0918.

    Aging-related nicotinamide adenine dinucleotide oxidase response to dietary supplementation: the French paradox revisited.

    Morré DJ, Morré DM, Shelton TB.

    • NOX Technologies, Inc, West Lafayette, Indiana, USA. DJ_morre@yahoo.com

    Abstract

    Aging-related cell-surface NADH oxidase (arNOX)-specific activities increase with age between age 30 and ages 50-65. The protein is shed and circulates. Activity correlates with a number of aging-related disorders including low-density lipoprotein (LDL) oxidation as a precondition to atherosclerosis as well as oxidation of collagen and elastin as a major contributor to skin aging. arNOX inhibitors formulated for sustained release are capable of maintaining circulating arNOX at low levels with regular use as food supplements formulated with natural compounds. Among the best sources are certain culinary seasonings, all of which are ingredients used extensively in the French kitchen. Their regular use may contribute to an understanding of the nutritional basis for the French Paradox.

    PMID: 19954304 


    Mech Ageing Dev. 2010 Jan;131(1):21-8. doi: 10.1016/j.mad.2009.11.002.

    Exercise alters SIRT1, SIRT6, NAD and NAMPT levels in skeletal muscle of aged rats.

    Koltai E, Szabo Z, Atalay M, Boldogh I, Naito H, Goto S, Nyakas C, Radak Z.

    • Research Institute of Sport Science, Faculty of Physical Education and Sport Science, Semmelweis University, Budapest, Hungary.

    Abstract

    Silent information regulators are potent NAD(+)-dependent protein deacetylases, which have been shown to regulate gene silencing, muscle differentiation and DNA damage repair. Here, changes in the level and activity of sirtuin 1 (SIRT1) in response to exercise in groups of young and old rats were studied. There was an age-related increase in SIRT1 level, while exercise training significantly increased the relative activity of SIRT1. A strong inverse correlation was found between the nuclear activity of SIRT1 and the level of acetylated proteins. Exercise training induced SIRT1 activity due to the positive effect of exercise on the activity of nicotinamide phosphoribosyltransferase (NAMPT) and thereby the production of sirtuin-fueling NAD(+). Exercise training normalized the age-associated shift in redox balance, since exercised animals had significantly lower levels of carbonylated proteins, expression of hypoxia-inducible factor-1 alpha and vascular endothelial growth factor. The age-associated increase in the level of SIRT6 was attenuated by exercise training. On the other hand, aging did not significantly increase the level of DNA damage, which was in line with the activity of 8-oxoguanine DNA glycosylase, while exercise training increased the level of this enzyme. Regular exercise decelerates the deleterious effects of the aging process via SIRT1-dependent pathways through the stimulation of NAD(+) biosynthesis by NAMPT.

    PMID: 19913571


    Molecules. 2009 Sep 9;14(9):3446-85. doi: 10.3390/molecules14093446.

    The vitamin nicotinamide: translating nutrition into clinical care.

    Maiese K, Chong ZZ, Hou J, Shang YC.

    • Division of Cellular and Molecular Cerebral Ischemia, Wayne State University School of Medicine, Detroit, Michigan 48201, USA. kmaiese@med.wayne.edu

    Abstract

    Nicotinamide, the amide form of vitamin B(3) (niacin), is changed to its mononucleotide compound with the enzyme nicotinic acide/nicotinamide adenylyltransferase, and participates in the cellular energy metabolism that directly impacts normal physiology. However, nicotinamide also influences oxidative stress and modulates multiple pathways tied to both cellular survival and death. During disorders that include immune system dysfunction, diabetes, and aging-related diseases, nicotinamide is a robust cytoprotectant that blocks cellular inflammatory cell activation, early apoptotic phosphatidylserine exposure, and late nuclear DNA degradation. Nicotinamide relies upon unique cellular pathways that involve forkhead transcription factors, sirtuins, protein kinase B (Akt), Bad, caspases, and poly (ADP-ribose) polymerase that may offer a fine line with determining cellular longevity, cell survival, and unwanted cancer progression. If one is cognizant of the these considerations, it becomes evident that nicotinamide holds great potential for multiple disease entities, but the development of new therapeutic strategies rests heavily upon the elucidation of the novel cellular pathways that nicotinamide closely governs.

    PMID: 19783937


    Aging Cell. 2009 Aug;8(4):426-38. doi: 10.1111/j.1474-9726.2009.00487.x.

    Nicotinamide enhances mitochondria quality through autophagy activation in human cells.

    Kang HT, Hwang ES.

    • Department of Life Science, University of Seoul, Dongdaemungu, Jeonnongdong, Republic of Korea.

    Abstract

    Nicotinamide (NAM) treatment causes a decrease in mitochondrial respiration and reactive oxygen species production in primary human fibroblasts and extends their replicative lifespan. In the current study, it is reported that NAM treatment induces a decrease in mitochondrial mass and an increase in membrane potential (DeltaPsim) by accelerating autophagic degradation of mitochondria. In the NAM-treated cells, the level of LC3-II as well as the number of LC3 puncta and lysosomes co-localizing with mitochondria substantially increased. Furthermore, in the NAM-treated cells, the levels of Fis1, Drp1, and Mfn1, proteins that regulate mitochondrial fission and fusion, increased and mitochondria experienced dramatic changes in structure from filaments to dots or rings. This structural change is required for the decrease of mitochondrial mass indicating that NAM accelerates mitochondrial autophagy, at least in part, by inducing mitochondrial fragmentation. The decrease in mitochondria mass was attenuated by treatment with cyclosporine A, which prevents the loss of mitochondrial membrane potential by blocking the mitochondrial permeability transition, suggesting autophagic degradation selective for mitochondria with low DeltaPsim. All these changes were accompanied by and dependent on an increase in the levels of GAPDH, and are blocked by inhibition of the cellular conversion of NAM to NAD(+). Taken together with our previous findings, these results suggest that up-regulation of GAPDH activity may prolong healthy lifespan of human cells through autophagy-mediated mitochondria quality maintenance.

    PMID: 19473119


    J Biol Chem. 2009 Jun 19; 284(25):17110-9. doi: 10.1074/jbc.M109.004010.

    Assimilation of endogenous nicotinamide riboside is essential for calorie restriction-mediated life span extension in Saccharomyces cerevisiae.

    Lu SP, Kato M, Lin SJ.

    • Department of Microbiology, University of California, Davis, California 95616, USA.

    Abstract

    NAD(+) (nicotinamide adenine dinucleotide) is an essential cofactor involved in various biological processes including calorie restriction-mediated life span extension. Administration of nicotinamide riboside (NmR) has been shown to ameliorate deficiencies related to aberrant NAD(+) metabolism in both yeast and mammalian cells. However, the biological role of endogenous NmR remains unclear. Here we demonstrate that salvaging endogenous NmR is an integral part of NAD(+) metabolism. A balanced NmR salvage cycle is essential for calorie restriction-induced life span extension and stress resistance in yeast. Our results also suggest that partitioning of the pyridine nucleotide flux between the classical salvage cycle and the NmR salvage branch might be modulated by the NAD(+)-dependent Sir2 deacetylase. Furthermore, two novel deamidation steps leading to nicotinic acid mononucleotide and nicotinic acid riboside production are also uncovered that further underscore the complexity and flexibility of NAD(+) metabolism. In addition, utilization of extracellular nicotinamide mononucleotide requires prior conversion to NmR mediated by a periplasmic phosphatase Pho5. Conversion to NmR may thus represent a strategy for the transport and assimilation of large nonpermeable NAD(+) precursors. Together, our studies provide a molecular basis for how NAD(+) homeostasis factors confer metabolic flexibility.

    PMID: 19416965


    Biogerontology. 2010 Feb;11(1):31-43. doi: 10.1007/s10522-009-9225-3.

    Nicotinamide adenine dinucleotide extends the lifespan of Caenorhabditis elegans mediated by sir-2.1 and daf-16.

    Hashimoto T, Horikawa M, Nomura T, Sakamoto K.

    • Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, Japan.

    Abstract

    It is well understood that sir2 (sirtuin), an NAD-dependent deacetylase, is essential for the extension of lifespan under caloric restriction. However, the mechanism underlying activation of sir2 is unclear. Life extension through caloric restriction requires the sir2 ortholog sir-2.1 in nematodes but occurs independently of the forkhead-type transcription factor DAF-16. We aimed here to elucidate the correlation between life extension in nematodes and NAD-dependent activation of sirtuin by analyzing the relationship between NAD and DAF-16. Lifespan was extended when Caenorhabditis elegans were bred using medium containing NAD. An RNA interference experiment revealed that life extension by NAD was sir-2.1 dependent. However, life extension by NAD did not occur in daf-16-RNAi nematodes, suggesting that NAD-dependent longevity requires daf-16. This result suggested that different signaling pathways are involved in life extension resulting from caloric restriction and from NAD addition. Expression of sod-3, a target gene of daf-16, and increased oxidative-stress resistance and adiposity were observed in response to NAD addition, indicating that NAD activated daf-16 in each phenotype. These results suggest that NAD affected lifespan through the activation of SIR-2.1 and DAF-16 along a signaling pathway, namely insulin-like signalling pathway (at least parts of it), different from that associated with caloric restriction.

    PMID: 19370397


    Neuromolecular Med. 2009; 11(1):28-42. doi: 10.1007/s12017-009-8058-1.

    Nicotinamide prevents NAD+ depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD+ consumption by SIRT1 may endanger energetically compromised neurons.

    Liu D, Gharavi R, Pitta M, Gleichmann M, Mattson MP.

    • Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, USA. liudo@mail.nih.gov

    Abstract

    Neurons require large amounts of energy to support their survival and function, and are therefore susceptible to excitotoxicity, a form of cell death involving bioenergetic stress that may occur in several neurological disorders including stroke and Alzheimer’s disease. Here we studied the roles of NAD(+) bioenergetic state, and the NAD(+)-dependent enzymes SIRT1 and PARP-1, in excitotoxic neuronal death in cultured neurons and in a mouse model of focal ischemic stroke. Excitotoxic activation of NMDA receptors induced a rapid decrease of cellular NAD(P)H levels and mitochondrial membrane potential. Decreased NAD(+) levels and poly (ADP-ribose) polymer (PAR) accumulation in nuclei were relatively early events (<4 h) that preceded the appearance of propidium iodide- and TUNEL-positive cells (markers of necrotic cell death and DNA strand breakage, respectively) which became evident by 6 h. Nicotinamide, an NAD(+) precursor and an inhibitor of SIRT1 and PARP1, inhibited SIRT1 deacetylase activity without affecting SIRT1 protein levels. NAD(+) levels were preserved and PAR accumulation and neuronal death induced by excitotoxic insults were attenuated in nicotinamide-treated cells. Treatment of neurons with the SIRT1 activator resveratrol did not protect them from glutamate/NMDA-induced NAD(+) depletion and death. In a mouse model of focal cerebral ischemic stroke, NAD(+) levels were decreased in both the contralateral and ipsilateral cortex 6 h after the onset of ischemia. Stroke resulted in dynamic changes of SIRT1 protein and activity levels which varied among brain regions. Administration of nicotinamide (200 mg/kg, i.p.) up to 1 h after the onset of ischemia elevated brain NAD(+) levels and reduced ischemic infarct size. Our findings demonstrate that the NAD(+) bioenergetic state is critical in determining whether neurons live or die in excitotoxic and ischemic conditions, and suggest a potential therapeutic benefit in stroke of agents that preserve cellular NAD(+) levels. Our data further suggest that, SIRT1 is linked to bioenergetic state and stress responses in neurons, and that under conditions of reduced cellular energy levels SIRT1 enzyme activity may consume sufficient NAD(+) to nullify any cell survival-promoting effects of its deacetylase action on protein substrates.

    PMID: 19288225


    Biogerontology. 2009 Aug;10(4):531-4. doi: 10.1007/s10522-008-9190-2.

    Converting NADH to NAD+ by nicotinamide nucleotide transhydrogenase as a novel strategy against mitochondrial pathologies during aging.

    Olgun A.

    • Biochemistry Laboratory, Erzincan Mil. Hospital, Erzincan, Turkey. aolgun@yahoo.com

    Abstract

    Mitochondrial DNA defects are involved supposedly via free radicals in many pathologies including aging and cancer. But, interestingly, free radical production was not found increased in prematurely aging mice having higher mutation rate in mtDNA. Therefore, some other mechanisms like the increase of mitochondrial NADH/NAD(+) and ubiquinol/ubiquinone ratios, can be in action in respiratory chain defects. NADH/NAD(+) ratio can be normalized by the activation or overexpression of nicotinamide nucleotide transhydrogenase (NNT), a mitochondrial enzyme catalyzing the following very important reaction: NADH + NADP(+ )<–> NADPH + NAD(+). The products NAD(+) and NADPH are required in many critical biological processes, e.g., NAD(+) is used by histone deacetylase Sir2 which regulates longevity in different species. NADPH is used in a number of biosynthesis reactions (e.g., reduced glutathione synthesis), and processes like apoptosis. Increased ubiquinol/ubiquinone ratio interferes the function of dihydroorotate dehydrogenase, the only mitochondrial enzyme involved in ubiquinone mediated de novo pyrimidine synthesis. Uridine and its prodrug triacetyluridine are used to compensate pyrimidine deficiency but their bioavailability is limited. Therefore, the normalization of the ubiquinol/ubiquinone ratio can be accomplished by allotopic expression of alternative oxidase, a mitochondrial ubiquinol oxidase which converts ubiquinol to ubiquinone.

    PMID: 18932012


    Annu Rev Nutr. 2008;28:115-30. doi: 10.1146/annurev.nutr.28.061807.155443.

    Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition.

    Bogan KL, Brenner C.

    • Department of Genetics and the Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA. charles.brenner@dartmouth.edu

    Abstract

    Although baseline requirements for nicotinamide adenine dinucleotide (NAD+) synthesis can be met either with dietary tryptophan or with less than 20 mg of daily niacin, which consists of nicotinic acid and/or nicotinamide, there is growing evidence that substantially greater rates of NAD+ synthesis may be beneficial to protect against neurological degeneration, Candida glabrata infection, and possibly to enhance reverse cholesterol transport. The distinct and tissue-specific biosynthetic and/or ligand activities of tryptophan, nicotinic acid, nicotinamide, and the newly identified NAD+ precursor, nicotinamide riboside, reviewed herein, are responsible for vitamin-specific effects and side effects. Because current data suggest that nicotinamide riboside may be the only vitamin precursor that supports neuronal NAD+ synthesis, we present prospects for human nicotinamide riboside supplementation and propose areas for future research.

    PMID: 18429699


    Curr Med Chem. 2008;15(7):650-70.

    Nicotinamide adenine dinucleotide based therapeutics.

    Chen L, Petrelli R, Felczak K, Gao G, Bonnac L, Yu JS, Bennett EM, Pankiewicz KW.

    • Center for Drug Design, University of Minnesota, Minneapolis, Minnesota 55455, USA.

    Abstract

    Nicotinamide adenine dinucleotide (NAD), generally considered a key component involved in redox reactions, has been found to participate in an increasingly diverse range of cellular processes, including signal transduction, DNA repair, and post-translational protein modifications. In recent years, medicinal chemists have become interested in the therapeutic potential of molecules affecting interactions of NAD with NAD-dependent enzymes. Also, enzymes involved in de novo biosynthesis, salvage pathways, and down-stream utilization of NAD have been extensively investigated and implicated in a wide variety of diseases. These studies have bolstered NAD-based therapeutics as a new avenue for the discovery and development of novel treatments for medical conditions ranging from cancer to aging. Industrial and academic groups have produced structurally diverse molecules which target NAD metabolic pathways, with some candidates advancing into clinical trials. However, further intensive structural, biological, and medical studies are needed to facilitate the design and evaluation of new generations of NAD-based therapeutics. At this time, the field of NAD-therapeutics is most likely at a stage similar to that of the early successful development of protein kinase inhibitors, where analogs of ATP (a more widely utilized metabolite than NAD) began to show selectivity against target enzymes. This review focuses on key representative opportunities for research in this area, which extends beyond the scope of this article.

    PMID: 18336280


    Cell. 2007 May 4; 129(3):473-84.

    Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+.

    Belenky P, Racette FG, Bogan KL, McClure JM, Smith JS, Brenner C.

    • Departments of Genetics and Biochemistry and the Norris Cotton Cancer Center, Dartmouth Medical School, Rubin 733-HB7937, Lebanon, NH 03756, USA.

    Abstract

    Although NAD(+) biosynthesis is required for Sir2 functions and replicative lifespan in yeast, alterations in NAD(+) precursors have been reported to accelerate aging but not to extend lifespan. In eukaryotes, nicotinamide riboside is a newly discovered NAD(+) precursor that is converted to nicotinamide mononucleotide by specific nicotinamide riboside kinases, Nrk1 and Nrk2. In this study, we discovered that exogenous nicotinamide riboside promotes Sir2-dependent repression of recombination, improves gene silencing, and extends lifespan without calorie restriction. The mechanism of action of nicotinamide riboside is totally dependent on increased net NAD(+) synthesis through two pathways, the Nrk1 pathway and the Urh1/Pnp1/Meu1 pathway, which is Nrk1 independent. Additionally, the two nicotinamide riboside salvage pathways contribute to NAD(+) metabolism in the absence of nicotinamide-riboside supplementation. Thus, like calorie restriction in the mouse, nicotinamide riboside elevates NAD(+) and increases Sir2 function.

    PMID: 17482543


    Cell. 2007 May 4; 129(3):453-4.

    Vitamins and aging: pathways to NAD+ synthesis.

    Denu JM.

    • Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, 1300 University Avenue, Madison, WI 53706, USA. jmdenu@wisc.edu <jmdenu@wisc.edu>

    Abstract

    Recent genetic evidence reveals additional salvage pathways for NAD(+) synthesis. In this issue, Belenky et al. (2007) report that nicotinamide riboside, a new NAD(+) precursor, regulates Sir2 deacetylase activity and life span in yeast. The ability of nicotinamide riboside to enhance life span does not depend on calorie restriction.

    PMID: 17482537 


    Trends Biochem Sci. 2007 Jan;32(1):12-9.

    NAD+ metabolism in health and disease.

    Belenky P, Bogan KL, Brenner C.

    • Departments of Genetics and of Biochemistry and Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03756, USA.

    Abstract

    Nicotinamide adenine dinucleotide (NAD(+)) is both a coenzyme for hydride-transfer enzymes and a substrate for NAD(+)-consuming enzymes, which include ADP-ribose transferases, poly(ADP-ribose) polymerases, cADP-ribose synthases and sirtuins. Recent results establish protective roles for NAD(+) that might be applicable therapeutically to prevent neurodegenerative conditions 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 high-dose nicotinamide, or incurring the unpleasant side-effects of high-dose nicotinic acid.

    PMID: 17161604


    Cell. 2007 May 4; 129(3):473-84.

    Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+.

    Belenky P, Racette FG, Bogan KL, McClure JM, Smith JS, Brenner C.

    • Departments of Genetics and Biochemistry and the Norris Cotton Cancer Center, Dartmouth Medical School, Rubin 733-HB7937, Lebanon, NH 03756, USA.

    Abstract

    Although NAD(+) biosynthesis is required for Sir2 functions and replicative lifespan in yeast, alterations in NAD(+) precursors have been reported to accelerate aging but not to extend lifespan. In eukaryotes, nicotinamide riboside is a newly discovered NAD(+) precursor that is converted to nicotinamide mononucleotide by specific nicotinamide riboside kinases, Nrk1 and Nrk2. In this study, we discovered that exogenous nicotinamide riboside promotes Sir2-dependent repression of recombination, improves gene silencing, and extends lifespan without calorie restriction. The mechanism of action of nicotinamide riboside is totally dependent on increased net NAD(+) synthesis through two pathways, the Nrk1 pathway and the Urh1/Pnp1/Meu1 pathway, which is Nrk1 independent. Additionally, the two nicotinamide riboside salvage pathways contribute to NAD(+) metabolism in the absence of nicotinamide-riboside supplementation. Thus, like calorie restriction in the mouse, nicotinamide riboside elevates NAD(+) and increases Sir2 function.

    PMID: 17482543


    Expert Opin Ther Targets. 2007 May;11(5):695-705.

    Nicotinamide adenine dinucleotide metabolism as an attractive target for drug discovery.

    Khan JA, Forouhar F, Tao X, Tong L.

    • Columbia University, Department of Biological Sciences, New York, NY 10027, USA.

    Abstract

    Nicotinamide adenine dinucleotide (NAD(+)) has crucial roles in many cellular processes, both as a coenzyme for redox reactions and as a substrate to donate ADP-ribose units. Enzymes involved in NAD(+) metabolism are attractive targets for drug discovery against a variety of human diseases, including cancer, multiple sclerosis, neurodegeneration and Huntington’s disease. A small-molecule inhibitor of nicotinamide phosphoribosyltransferase, an enzyme in the salvage pathway of NAD(+) biosynthesis, is presently in clinical trials against cancer. An analog of a kynurenine pathway intermediate is efficacious against multiple sclerosis in an animal model. Indoleamine 2,3-dioxygenase plays an important role in immune evasion by cancer cells and other disease processes. Inhibitors against kynurenine 3-hydroxylase can reduce the production of neurotoxic metabolites while increasing the production of neuroprotective compounds. This review summarizes the existing knowledge on NAD(+) metabolic enzymes, with emphasis on their relevance for drug discovery.

    PMID: 17465726


    Aging Cell. 2006 Dec;5(6):505-14.

    Sirtuin-independent effects of nicotinamide on lifespan extension from calorie restriction in yeast.

    Tsuchiya M, Dang N, Kerr EO, Hu D, Steffen KK, Oakes JA, Kennedy BK, Kaeberlein M.

    • Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.

    Abstract

    Two models have been proposed for how calorie restriction (CR) enhances replicative longevity in yeast: (i) suppression of rDNA recombination through activation of the sirtuin protein deacetylase Sir2 or (ii) decreased activity of the nutrient-responsive kinases Sch9 and TOR. We report here that CR increases lifespan independently of all Sir2-family proteins in yeast. Furthermore, we demonstrate that nicotinamide, an inhibitor of Sir2-mediated deacetylation, interferes with lifespan extension from CR, but does so independent of Sir2, Hst1, Hst2, and Hst4. We also find that 5 mm nicotinamide, a concentration sufficient to inhibit other sirtuins, does not phenocopy deletion of HST3. Thus, we propose that lifespan extension by CR is independent of sirtuins and that nicotinamide has sirtuin-independent effects on lifespan extension by CR.

    PMID: 17129213


    Front Biosci. 2007 Jan 1;12: 1863-88.

    NAD+ and NADH in brain functions, brain diseases and brain aging.

    Ying W.

    • Department of Neurology, University of California at San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121, USA. shine863@gmail.com

    Abstract

    Numerous studies have suggested that NAD+ and NADH mediate multiple major biological processes, including calcium homeostasis, energy metabolism, mitochondrial functions, cell death and aging. In particular, NAD+ and NADH have emerged as novel, fundamental regulators of calcium homeostasis. It appears that most of the components in the metabolic pathways of NAD+ and NADH, including poly(ADP-ribose), ADP-ribose, cyclic ADP-ribose, O-acetyl-ADP-ribose, nicotinamide and kynurenine, can produce significant biological effects. This exquisiteness of NAD+ and NADH metabolism could epitomize the exquisiteness of life, through which we may grasp the intrinsic harmony life has evolved to produce. The exquisiteness also suggests a central regulatory role of NAD+ and NADH in life. It is tempted to propose that NAD+ and NADH, together with ATP and Ca2+, constitute a Central Regulatory Network of life. Increasing evidence has also suggested that NAD+ and NADH play important roles in multiple biological processes in brains, such as neurotransmission and learning and memory. NAD+ and NADH may also mediate brain aging and the tissue damage in various brain illnesses. Our latest studies have suggested that NADH can be transported across the plasma membranes of astrocytes, and that NAD+ administration can markedly decrease ischemic brain injury. Based on this information, it is proposed that NAD+ and NADH are fundamental mediators of brain functions, brain senescence and multiple brain diseases. Because numerous properties of NAD+ and NADH remain unclear, future studies regarding NAD+ and NADH may expose some fundamental mechanisms underlying brain functions, brain pathologies and brain aging.

    PMID: 17127427


    Aging Cell. 2006 Oct;5(5):423-36.

    Nicotinamide extends replicative lifespan of human cells.

    Kang HT, Lee HI, Hwang ES.

    • Department of Life Science, University of Seoul, Dongdaemungu, Jeonnongdong, Seoul, Korea.

    Abstract

    We found that an ongoing application of nicotinamide to normal human fibroblasts not only attenuated expression of the aging phenotype but also increased their replicative lifespan, causing a greater than 1.6-fold increase in the number of population doublings. Although nicotinamide by itself does not act as an antioxidant, the cells cultured in the presence of nicotinamide exhibited reduced levels of reactive oxygen species (ROS) and oxidative damage products associated with cellular senescence, and a decelerated telomere shortening rate without a detectable increase in telomerase activity. Furthermore, in the treated cells growing beyond the original Hayflick limit, the levels of p53, p21WAF1, and phospho-Rb proteins were similar to those in actively proliferating cells. The nicotinamide treatment caused a decrease in ATP levels, which was stably maintained until the delayed senescence point. Nicotinamide-treated cells also maintained high mitochondrial membrane potential but a lower respiration rate and superoxide anion level. Taken together, in contrast to its demonstrated pro-aging effect in yeast, nicotinamide extends the lifespan of human fibroblasts, possibly through reduction in mitochondrial activity and ROS production.

    PMID: 16939485


    Curr Med Chem. 2006; 13(8):883-95.

    Cell Life versus cell longevity: the mysteries surrounding the NAD+ precursor nicotinamide.

    Li F, Chong ZZ, Maiese K.

    • Division of Cellular and Molecular Cerebral Ischemia, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.

    Abstract

    Nicotinamide, the amide form of niacin (vitamin B(3)), is the precursor for the coenzyme beta-nicotinamide adenine dinucleotide (NAD(+)) and plays a significant role during the enhancement of cell survival as well as cell longevity. Yet, these abilities of nicotinamide appear to be diametrically opposed. Here we describe the development of nicotinamide as a novel agent that is critical for modulating cellular metabolism, plasticity, longevity, and inflammatory microglial function as well as for influencing cellular life span. The capacity of nicotinamide to govern not only intrinsic cellular integrity, but also extrinsic cellular inflammation rests with the modulation of a host of cellular targets that involve mitochondrial membrane potential, poly(ADP-ribose) polymerase, protein kinase B (Akt), Forkhead transcription factors, Bad, caspases, and microglial activation. Further knowledge acquired in regards to the ability of nicotinamide to foster cellular survival and regulate cellular lifespan should significantly promote the development of therapies against a host of disorders, such as aging, Alzheimer’s disease, diabetes, cerebral ischemia, Parkinson’s disease, and cancer.

    PMID: 16611073


    Mech Ageing Dev. 2006 Jun; 127(6):511-4.

    Nicotinamide extends the replicative life span of primary human cells.

    Lim CS, Potts M, Helm RF.

    • Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061, USA. lim@vt.edu

    PMID: 16545428


    Behav Brain Res. 2004 Sep 23;154(1):149-53.

    Treatment with reduced nicotinamide adenine dinucleotide (NADH) improves water maze performance in old Wistar rats.

    Rex A, Spychalla M, Fink H.

    • Institute of Pharmacology and Toxicology, School of Veterinary Medicine, Freie Universität, Koserstr. 20, 14195 Berlin, Germany. andrerex@zedat.fu-berlin.de

    Abstract

    Age-associated cognitive impairment and related neurodegenerative disorders are an increasing major public health problem. Nicotinamide adenine dinucleotide (NADH), a co-substrate for energy transfer in the mitochondrial respiratory chain, is speculated to induce positive effects in some of these diseases. Studies showed diminished mitochondrial function in patients with M. Alzheimer. In a preliminary clinical trial NADH given peripherally improved cognitive function in Alzheimer disease. Previous own experiments revealed an increased NADH level in the rat brain following peripheral application of NADH (10-100 mg/kg, i.p.+ i.v.). Therefore, we wanted to know, whether or not NADH has an effect on cognitive function in animals. We analysed the effect of repeated i.p. injection of NADH on the performance of 3-month-old and 22-month-old Wistar rats in the Morris water maze and in the rota-rod test of motor coordination. The rats were injected for 10 days once daily with the doses of NADH used in the bioavailability study (10-100 mg/kg) or vehicle 20 min before the behavioural tests. The repeated administration of NADH improved the performance of old rats in the acquisition phase (place version) and the spatial probe of the Morris water maze compared to vehicle-treated controls. The effect of NADH on learning-related processes is supported by the lack of effects on motor performance on the rota-rod. In summary, our results suggest cognitive enhancing properties of NADH in learning impaired old rats.

    PMID: 15302120


    Cell. 2004 May 14; 117(4):495-502.

    Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans.

    Bieganowski P, Brenner C.

    • Departments of Genetics and Biochemistry and the Norris Cotton Cancer Center, Dartmouth Medical School, Rubin 733-HB7937, Lebanon, NH 03756, USA.

    Abstract

    NAD+ is essential for life in all organisms, both as a coenzyme for oxidoreductases and as a source of ADPribosyl groups used in various reactions, including those that retard aging in experimental systems. Nicotinic acid and nicotinamide were defined as the vitamin precursors of NAD+ in Elvehjem’s classic discoveries of the 1930s. The accepted view of eukaryotic NAD+ biosynthesis, that all anabolism flows through nicotinic acid mononucleotide, was challenged experimentally and revealed that nicotinamide riboside is an unanticipated NAD+ precursor in yeast. Nicotinamide riboside kinases from yeast and humans essential for this pathway were identified and found to be highly specific for phosphorylation of nicotinamide riboside and the cancer drug tiazofurin. Nicotinamide riboside was discovered as a nutrient in milk, suggesting that nicotinamide riboside is a useful compound for elevation of NAD+ levels in humans.

    PMID: 15137942


    Eur J Endocrinol. 2004 May;150(5):719-24.

    A randomized trial of nicotinamide and vitamin E in children with recent onset type 1 diabetes (IMDIAB IX).

    Crinò A, Schiaffini R, Manfrini S, Mesturino C, Visalli N, Beretta Anguissola G, Suraci C, Pitocco D, Spera S, Corbi S, Matteoli MC, Patera IP, Manca Bitti ML, Bizzarri C, Pozzilli P; IMDIAB group.

    • Ospedale Bambino Gesu, Piazza S. Onofrio 4, 00163 Rome, Italy.

    Abstract

    OBJECTIVE:

    Various adjuvant therapies have been introduced along with intensive insulin therapy in patients with recent onset type 1 diabetes. Nicotinamide (NA), administered at diagnosis of the disease, can have beneficial effects on the clinical remission rate, improve metabolic control and preserve or slightly increase beta-cell function, probably by reducing toxicity due to free oxygen radicals. Vitamin E, a known antioxidant, inhibits lipid peroxidation; this can lead to protection of islet beta cells from the combined effects of interleukin 1, tumor necrosis factor and gamma interferon. The aim of the present study was to investigate whether the addition of vitamin E to NA could improve metabolic control and the residual beta-cell function, as measured by C-peptide secretion, in children and adolescents with recent onset type 1 diabetes; patients were followed-up for 2 years after diagnosis.

    PATIENTS AND STUDY DESIGN:

    Recent onset type 1 diabetes patients (n=64, mean age 8.8 years) were recruited by participating centres of the IMDIAB group. Thirty-two patients were randomized to NA (25 mg/kg body weight) plus vitamin E (15 mg/kg body weight); 32 patients acted as controls and received NA only at the same dose as above. Intensive insulin therapy was applied to both treatment groups.

    RESULTS:

    There were three drop outs during the 2-year follow-up period. Overall, patients assigned to the NA+vitamin E group or the NA group did not significantly differ in terms of glycated hemoglobin (HbA1c) levels, insulin requirement or baseline C-peptide secretion. Patients diagnosed at an age of less than 9 years showed significantly reduced C-peptide levels compared with those aged over 9 years at diagnosis and at the 2-year follow-up but there were no differences between the NA and NA+vitamin E treated groups. However at 6 months, patients over 9 years of age treated with NA+vitamin E showed significantly higher C-peptide compared with the NA group (P<0.003). In both age groups and in the different treatment groups, C-peptide levels found at diagnosis were preserved 2 years later.

    CONCLUSIONS:

    The use of NA alone, or in combination with vitamin E, along with intensive insulin therapy is able to preserve baseline C-peptide secretion for up to 2 years after diagnosis. This finding is of particular interest for pre-pubertal children with type 1 diabetes and has never been reported before.

    PMID: 15132730


    Curr Opin Cell Biol. 2003 Apr; 15 (2):241-6.

    Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease.

    Lin SJ, Guarente L.

    • Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, MA 02139, USA

    Abstract

    Nicotinamide adenine dinucleotide (NAD) is a ubiquitous biological molecule that participates in many metabolic reactions. Recent studies show that NAD also plays important roles in transcriptional regulation, longevity, calorie-restriction-mediated life-span extension and age-associated diseases. It has been shown that NAD affects longevity and transcriptional silencing through the regulation of the Sir2p family, which are NAD-dependent deacetylases. Many human diseases are associated with changes in NAD level and/or the NAD : NADH ratio, raising the possibility that the Sir2p family might play a role in these diseases.

    PMID: 12648681


    J Biol Chem. 2002 Nov 22; 277(47):45099-107. Epub 2002 Sep 23.

    Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1.

    Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, Sinclair DA.

    • Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.

    Abstract

    The Saccharomyces cerevisiae Sir2 protein is an NAD(+)-dependent histone deacetylase that plays a critical role in transcriptional silencing, genome stability, and longevity. A human homologue of Sir2, SIRT1, regulates the activity of the p53 tumor suppressor and inhibits apoptosis. The Sir2 deacetylation reaction generates two products: O-acetyl-ADP-ribose and nicotinamide, a precursor of nicotinic acid and a form of niacin/vitamin B(3). We show here that nicotinamide strongly inhibits yeast silencing, increases rDNA recombination, and shortens replicative life span to that of a sir2 mutant. Nicotinamide abolishes silencing and leads to an eventual delocalization of Sir2 even in G(1)-arrested cells, demonstrating that silent heterochromatin requires continual Sir2 activity. We show that physiological concentrations of nicotinamide noncompetitively inhibit both Sir2 and SIRT1 in vitro. The degree of inhibition by nicotinamide (IC(50) < 50 microm) is equal to or better than the most effective known synthetic inhibitors of this class of proteins. We propose a model whereby nicotinamide inhibits deacetylation by binding to a conserved pocket adjacent to NAD(+), thereby blocking NAD(+) hydrolysis. We discuss the possibility that nicotinamide is a physiologically relevant regulator of Sir2 enzymes.

    PMID: 12297502


    J Comp Neurol. 2002 May 13; 446(4):342-8.

    Postnatal development of nicotinamide adenine dinucleotide phosphate-diaphorase-positive neurons in the retina of the golden hamster.

    Tay D, Diao YC, Xiao YM, So KF.

    • Department of Anatomy, Faculty of Medicine, University of Hong Kong, Hong Kong, China.

    Abstract

    The histochemical method was used to investigate the postnatal development of nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) -positive neurons in retinas of the golden hamster. NADPH-d-positive neurons were discernible in the retina at postnatal day (P)1. From P4 onward to adulthood, when the retina acquired its laminated characteristics, NADPH-d- positive neurons were observed in the inner nuclear layer (INL) and the ganglion cell layer (GCL). Results showed that NADPH-d-positive neurons in INL and GCL followed different time courses and patterns in their development. NADPH-d-positive neurons in INL underwent a sharp increase from P4 to P8 (3.6-fold), followed by a decrease to 46% of the maximum at P12. This value was maintained relatively constant to the adult level. The mean diameters of NADPH-d-positive neurons in INL, which were smaller than those in the GCL for all ages, increased from P8 to P12 and from P20 to adulthood. As for neurons in the GCL, the increase in cell number was not so apparent for the earlier postnatal days until P20; thereafter, an obvious increase to the adult level was observed. The mean diameters of the NADPH-d-positive cell bodies in the GCL increased with age, except for P16-P20, during which time there was a slight and insignificant decrease. The tendency of changes in cell density was basically similar to that of the total number for both the INL and the GCL. Between P12 and P20, the density distribution map of the NADPH-d-positive neurons underwent dramatic changes: The highest density shifted from the upper central retina at the earlier postnatal days to the lower central retina in the adult. The two waves of increase in NADPH-d-positive neurons coincide with the process of axonal elongation and synaptogenesis and the acquisition of visual function and experience. It is suggested that these NADPH-d-positive neurons are related to these two developmental events.

    PMID: 11954033


    Nature. 2003 May 8; 423(6936):181-5.

    Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae.

    Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Sinclair DA.

    • Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.

    Abstract

    Calorie restriction extends lifespan in a broad range of organisms, from yeasts to mammals. Numerous hypotheses have been proposed to explain this phenomenon, including decreased oxidative damage and altered energy metabolism. In Saccharomyces cerevisiae, lifespan extension by calorie restriction requires the NAD+-dependent histone deacetylase, Sir2 (ref. 1). We have recently shown that Sir2 and its closest human homologue SIRT1, a p53 deacetylase, are strongly inhibited by the vitamin B3 precursor nicotinamide. Here we show that increased expression of PNC1 (pyrazinamidase/nicotinamidase 1), which encodes an enzyme that deaminates nicotinamide, is both necessary and sufficient for lifespan extension by calorie restriction and low-intensity stress. We also identify PNC1 as a longevity gene that is responsive to all stimuli that extend lifespan. We provide evidence that nicotinamide depletion is sufficient to activate Sir2 and that this is the mechanism by which PNC1 regulates longevity. We conclude that yeast lifespan extension by calorie restriction is the consequence of an active cellular response to a low-intensity stress and speculate that nicotinamide might regulate critical cellular processes in higher organisms.

    PMID: 12736687


    Cell Mol Life Sci. 2001 Dec; 58(14):2108-16.

    Rapid reversion of aging phenotypes by nicotinamide through possible modulation of histone acetylation.

    Matuoka K, Chen KY, Takenawa T.

    • Institute of Medical Science, University of Tokyo, Japan. kmatuoka@mailhost.net

    Abstract

    Aging appears to be an irreversible process. Here we report that nicotinamide (NAA) can induce rapid and reversible reversion of aging phenotypes in human diploid fibroblasts in terms of cell morphology and senescence-associated beta-galactosidase activity. Although NAA seems to enhance the replicative potential of the cells, it has little effect on their growth rate and life span, suggesting that NAA action is rather separated from the cellular replicative system. The effects are unique to NAA: none ofthe NAA-related compounds examined (an NAD precursor/niacin, NAD analogs, and poly(ADP-ribose) polymerase inhibitors) exerted similar effects. Thus, NAD-related metabolism and poly(ADP-ribosyl)ation are unlikely related to the NAA action. On the other hand, histone acetyltransferase (HAT) activity was elevated in NAA-exposed cells, while in aged cells, HAT activity and histone H4 acetylation were lowered. Taken together, the results suggest that NAA may cause rejuvenation by restoring, at least in part, altered gene expression in aged cells through its activation of HAT.

    PMID: 11814060


    Geriatr Nephrol Urol. 1998; 8(2):95-100.

    Oral reduced B-nicotinamide adenine dinucleotide (NADH) affects blood pressure, lipid peroxidation, and lipid profile in hypertensive rats (SHR).

    Bushehri N, Jarrell ST, Lieberman S, Mirdamadi-Zonozi N, Birkmayer G, Preuss HG.

    • Department of Medicine, Georgetown University Medical Center, Washington, DC, USA.

    Abstract

    A gradual increase in blood pressure (BP), often attaining hypertensive levels, is common during aging–“age-related hypertension.” Therefore, means to prevent or ameliorate this elevated BP safely are important. Although oral B-nicotinamide adenine dinucleotide (NADH), a natural coenzyme, is used principally to treat various neurologic disorders, we wished to investigate whether this agent had the same potential to lower BP and benefit the cardiovascular system as does coenzyme Q10, a similar-type agent. As a first approximation, spontaneously hypertensive rats (SHR) were used to determine effects of oral NADH. In a blinded, placebo-controlled study, ten rats received placebo; and ten, NADH for ten weeks. Systolic BP was measured by tail plethysmography. Blood was collected terminally, and chemistries were performed by routine methodologies. Thiobarbituric acid reactive species (TBARS) (an estimate of lipid peroxidation/free radical formation) was measured in renal and hepatic tissues. The following was noted: water and food intake were comparable, and the steady weight gain of young SHR were similar in the placebo and NADH groups. Although systolic BP did not differ between the two groups over the first month, it decreased and stayed markedly lower for the remainder of study in SHR receiving oral NADH. At the end of 60 days, SBP in NADH-treated SHR was 184 mm Hg +/- 2.8 (SEM) compared to 201 mm Hg +/- 2.1 (SEM) in control SHR (p < 0.001). No significant differences were seen in blood levels of glucose, insulin, triglyceride, and HDL levels but NADH intake lowered total cholesterol (p < 0.002) and LDL (p < 0.02). Renal TBARS were also significantly lower in SHR receiving NADH (P < 0.001). Accordingly, supplementation with the natural coenzyme NADH theoretically could prove to be useful in preventing age-related increases in BP and, thus, various cardiovascular maladies.

    PMID: 9893217


    Drugs Aging. 1998 Oct; 13(4):263-8.

    Is NADH effective in the treatment of Parkinson’s disease?

    Swerdlow RH.

    • Center for the Study of Neurodegenerative Diseases, University of Virginia, Charlottesville, USA.

    Abstract

    Most Parkinson’s disease (PD) treatments palliate symptoms by increasing nigrostriatal dopaminergic tone. A unique strategy for accomplishing this pharmacological end-point proposes using reduced nicotinamide adenine dinucleotide (NADH) to boost endogenous dopamine production, since NADH indirectly supplies reducing equivalents to the rate-limiting, tyrosine hydroxylase-catalysed step of dopamine synthesis. Support for using NADH in PD treatment includes claims that NADH stimulates tyrosine hydroxylase and dopamine biosynthesis in tissue culture and humans, as well as case series associating intravenous and oral NADH administration with PD rating scale improvements. Theoretical and practical arguments against NADH include underlying NADH disposal impairment in PD and failure of a placebo-controlled trial to show any clear benefit. While NADH may yet prove to ameliorate parkinsonism, recommendations for its use in PD are premature.

    PMID: 9805207


    Mol Chem Neuropathol. 1997 Sep-Dec; 32(1-3):59-74.

    The effects of aging and neurodegeneration on apoptosis-associated DNA fragmentation and the benefits of nicotinamide.

    Mukherjee SK, Adams JD Jr.

    • School of Pharmacy, Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles 90033, USA.

    Abstract

    In this work, the tertiary butylhydroperoxide- (t-BuOOH) treated mouse was used as a model to study the oxidative stress that is associated with various neurodegenerative diseases. DNA was found to be an early target of t-BuOOH attack. Necrosis was associated with extensive DNA fragmentation that occurred in almost all regions of the brain within 20 min following intracerebroventricular (icv) injection of 109.7 mg/kg t-BuOOH. Apoptosis was associated with high levels of DNA fragmentation that was observed at 48 h after icv administration of 21.9 mg/kg t-BuOOH. Susceptibility to DNA damage was found to be age-dependent, since 24-mo-old mice exhibited consistently higher and more pervasive DNA damage than 8 mo-old-mice. Extensive DNA damage was seen in various brain regions in patients with Alzheimer disease (AD) and with both Alzheimer and Parkinson disease (AD-PD). These results directly implicate DNA damage in neurodegeneration. The DNA fragmentation ob-served can lead to both apoptosis and necrosis, as suggested by gel electrophoresis. Nicotinamide, a precursor of NAD in the brain, was able to prevent DNA fragmentation induced by low-dose t-BuOOH, when coadministered with the toxin.

    PMID: 9437658


    Pharmacol Biochem Behav. 1996 Apr; 53(4):783-90.

    Effects of nicotinamide on central cholinergic transmission and on spatial learning in rats.

    Köppen A, Klein J, Schmidt BH, van der Staay FJ, Löffelholz K.

    • Department of Pharmacology, University of Mainz, Germany.

    Abstract

    High-dose nicotinamide (1000 mg/kg) leads to a minor increase of plasma choline but to a major increase of the choline concentrations in the intra- and extracellular spaces of the brain. In the hippocampus, the nicotinamide-induced increase in choline was associated with an increase in the release of acetylcholine under stimulated conditions. In young rats, nicotinamide in doses between 10 and 1000 mg/kg did not influence spatial learning, as tested in the Morris water maze. In old rats, low doses of nicotinamide were ineffective whereas the high dose of 1000 mg/kg even impaired spatial learning. The combined administration of choline and nicotinamide had a synergistic effect on brain choline levels but had similar effects as nicotinamide given alone in the behavioral experiments. Additional tests for spontaneous behaviour and locomotion revealed procholinergic and sedative effects of the compound. We conclude that the ineffectiveness of the putative cognition enhancer nicotinamide in the learning task may be due to the observed sedative effect. Therefore, the development of nonsedative nicotinamide derivatives is recommended.

    PMID: 8801579


    Mech Ageing Dev. 1986 Jul; 35(2):123-31.

    Modulatory effect of nicotinamide on unscheduled DNA synthesis in lymphocytes from young and old mice.

    Licastro F, Walford RL.

    Abstract

    We studied the DNA repair capacity, as measured by unscheduled DNA synthesis, of resting lymphocytes from a long-lived strain of mouse after UV irradiation. Lymphocytes from old mice showed a lower level of repair than lymphocytes from young mice. After in vitro treatment with nicotinamide, a precursor of cellular NAD+, the level of UV-induced DNA repair increased in resting lymphocytes from both young and old mice. This effect was more dramatic in old mice, which showed a twofold relative increase in repair. Nicotinamide at a concentration of 0.5-5 mM did not inhibit the proliferation of concanavalin A (Con A) stimulated mouse lymphocytes; on the contrary, 3-amino benzamide, a potent poly(ADP-ribose)polymerase inhibitor, strongly affected the lymphocyte responsiveness to Con A. Nicotinamide did not significantly increase the UV-induced DNA repair in lymphocytes stimulated to proliferate by Con A. However, Con A activated, but non-proliferating (hydroxyurea-treated) lymphocytes from old mice displayed a level of DNA repair similar to that of lymphocytes from young animals. These results suggest that one of the limiting factors affecting the DNA repair activity of resting lymphocytes from old mice is the level of intracellular NAD+.

    PMID: 2942735


    Biochem J. 1967 Jan; 102(1):331-7.

    Nicotinamide-adenine dinucleotide phosphate enzymes in the mosquito during growth and aging.

    Lang CA, Stephan JK.

    Abstract

    1. Optimum conditions were established for determining the activities of the NADP(+)-linked enzymes, glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase and isocitrate dehydrogenase, in mosquito tissues. 2. The activity of each dehydrogenase was determined in samples of mosquitoes of different ages throughout the life-span. The specific-activity curves attained maximal values in the pupal or early adult period. From these maxima an 81% decrease in glucose 6-phosphate-dehydrogenase and 67% decrease in 6-phosphogluconate-dehydrogenase activities occurred after the tenth day of adult life; a 77% decrease in isocitrate-dehydrogenase activity occurred before the fifth day. 3. The activity differences were found in different body regions as well as in whole organisms. 4. Starvation of the larva or adult did not result in decreases in enzyme activity. 5. These findings support the hypothesis that the activities of enzymes that form NADPH are related to the biosynthetic activity, for the enzyme activities increased during the period of cellular growth and decreased during the aging period.

    PMID: 4382147


    Folia Haematol Int Mag Klin Morphol Blutforsch. 1962; 78:690-3.

    Age difference in nicotinamide mononucleotide synthesis by human erythrocytes.

    HABERMANN V, HABERMANNOVA S.

    PMID:

    13903394


    Conn State Med J. 1953 Jul; 17(7):584-9.

    Niacinamide therapy for joint mobility; therapeutic reversal of a common clinical manifestation of the normal aging process.

    KAUFMAN W.

    PMID: 13060032

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