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Abstract and Figures

Nicotinamide adenine dinucleotide (NAD⁺) has been described as central coenzyme of redox reactions and is a key regulator of stress resistance and longevity. Aging is a multifactorial and irreversible process that is characterized by a gradual diminution in physiological functions in an organism over time, leading to development of age-associated pathologies and eventually increasing the probability of death. Ischemia is the lack of nutritive blood flow that causes damage and mortality that mostly occurs in various organs during aging. During the process of aging and related ischemic conditions, NAD⁺ levels decline and lead to nuclear and mitochondrial dysfunctions, resulting in age-related pathologies. The majority of studies have shown that restoring of NAD⁺ using supplementation with intermediates such as nicotinamide mononucleotide and nicotinamide riboside can be a valuable strategy for recovery of ischemic injury and age-associated defects. This review summarizes the molecular mechanisms responsible for the reduction in NAD⁺ levels during ischemic disorders and aging, as well as a particular focus is given to the recent progress in the understanding of NAD⁺ precursor’s effects on aging and ischemia.
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REVIEW ARTICLE
Nicotinamide adenine dinucleotide emerges as a therapeutic
target in aging and ischemic conditions
Leila Hosseini .Manouchehr S. Vafaee .Javad Mahmoudi .Reza Badalzadeh
Received: 17 December 2018 / Accepted: 27 February 2019 / Published online: 5 March 2019
ÓSpringer Nature B.V. 2019
Abstract Nicotinamide adenine dinucleotide
(NAD
?
) has been described as central coenzyme of
redox reactions and is a key regulator of stress
resistance and longevity. Aging is a multifactorial
and irreversible process that is characterized by a
gradual diminution in physiological functions in an
organism over time, leading to development of age-
associated pathologies and eventually increasing the
probability of death. Ischemia is the lack of nutritive
blood flow that causes damage and mortality that
mostly occurs in various organs during aging. During
the process of aging and related ischemic conditions,
NAD
?
levels decline and lead to nuclear and mito-
chondrial dysfunctions, resulting in age-related
pathologies. The majority of studies have shown that
restoring of NAD
?
using supplementation with inter-
mediates such as nicotinamide mononucleotide and
nicotinamide riboside can be a valuable strategy for
recovery of ischemic injury and age-associated
defects. This review summarizes the molecular mech-
anisms responsible for the reduction in NAD
?
levels
during ischemic disorders and aging, as well as a
particular focus is given to the recent progress in the
understanding of NAD
?
precursor’s effects on aging
and ischemia.
L. Hosseini
Drug Applied Research Center, Department of
Physiology, Tabriz University of Medical Sciences,
Tabriz, Iran
L. Hosseini M. S. Vafaee R. Badalzadeh (&)
Aging Research Institute, Tabriz University of Medical
Sciences, Tabriz, Iran
e-mail: badalzadehr@tbzmed.ac.ir
M. S. Vafaee
Department of Nuclear Medicine, Odense University
Hospital, Odense, Denmark
M. S. Vafaee
Department of Clinical Research, BRIDGE: Brain
Research-Inter-Disciplinary Guided Excellence,
University of Southern Denmark, Odense, Denmark
M. S. Vafaee J. Mahmoudi
Neuroscience Research Centre, Tabriz University of
Medical Sciences, Tabriz, Iran
R. Badalzadeh
Molecular Medicine Research Centre, Tabriz University
of Medical Sciences, Tabriz, Iran
123
Biogerontology (2019) 20:381–395
https://doi.org/10.1007/s10522-019-09805-6(0123456789().,-volV)(0123456789().,-volV)
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Additionally, NAD + takes part in vital processes not involving hydride transfer such as signaling [1,5], post-translational modification [1,3,6], transcription regulation [1], DNA repair, circadian activity modulation [7,8], and in the regulation of protein-protein interactions. Decreased levels of NAD + are associated with the nuclear and mitochondrial dysfunctions associated with aging [1,2,4,7,9,10] as well as pathophysiological conditions such as ischemia [11][12][13], obesity [2,4,[14][15][16], type 2 diabetes [2,[17][18][19], metabolic syndrome [2,4,19], non-alcoholic fatty liver disease [2,19], and neurodegenerative disorders [2,4,20,21]. The understanding of the mechanisms and roles of decreased NAD + levels during aging and age-related diseases is of great interest to the scientific community. ...
... Increased levels of NAD + can be achieved by supplementation with its precursors, and have great potential in the treatment of pathophysiological conditions involving decreased NAD + levels [4,9,[22][23][24]. For this reason, the scientific community has recently been focusing on the roles of NAD + key precursors, with emphasis on nicotinamide riboside (NR + ) ( Figure 1) [11,[22][23][24]. NR + is a niacin equivalent and a form of vitamin B3 naturally present in milk [25,26]. ...
... NR + is converted into NAD + by NR + kinase [30], or by the nucleoside phosphorylase and the nicotinamide (NAM) (Figure 1) salvage pathway [9]. When orally supplemented, a preventive and therapeutic effect in numerous diseases has been observed in association with increased NAD + levels [9,11,[22][23][24]30,31]. NR + is preferred over other NAD + precursors because its use is not related to serious side effects or flushing, as has been observed with other NAD + precursors [26,32]. ...
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NR+ is a highly effective vitamin B3 type supplement due to its unique ability to replenish NAD+ levels. While NR+ chloride is already on the market as a nutritional supplement, its synthesis is challenging, expensive, and low yielding, making it cumbersome for large-scale industrial production. Here we report the novel crystalline NR+ salts, d/l/dl-hydrogen tartrate and d/l/dl-hydrogen malate. Their high-yielding, one-pot manufacture does not require specific equipment and is suitable for multi-ton scale production. These new NR+ salts seem ideal for nutritional applications due to their bio-equivalence compared to the approved NR+ chloride. In addition, the crystal structures of all stereoisomers of NR+ hydrogen tartrate and NR+ hydrogen malate and a comparison to the known NR+ halogenides are presented.
... Supported by previous studies, nicotinamide adenine dinucleotide (NAD) was confirmed to be effective at improving cognitive function after insults [4][5][6]. NAD + is essential for many mitochondrial enzymatic reactions and appropriate bioenergetic metabolism. Under normal conditions, the loss of NAD + inhibits cellular respiration, resulting in reduced mitochondrial adenosine triphosphate (ATP) production and potentially cell death [6]. ...
... NAD + is essential for many mitochondrial enzymatic reactions and appropriate bioenergetic metabolism. Under normal conditions, the loss of NAD + inhibits cellular respiration, resulting in reduced mitochondrial adenosine triphosphate (ATP) production and potentially cell death [6]. NAD + is used as a substrate by several NAD + -dependent enzymes, including poly (ADP ribose) polymerase 1 (PARP1), Sirtuin-1 (Sirt1), and ADP ribosyl cyclase (CD38). ...
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Nicotinamide adenine dinucleotide (NAD) is a critical cosubstrate for enzymes involved in supplying energy to the brain. Nicotinamide riboside (NR), an NAD⁺ precursor, emerges as a neuroprotective factor after chronic brain insults. However, researchers have not determined whether it improves cognition after acute ischemia. In the present study, mice with middle cerebral artery occlusion were treated with NR chloride (NRC, 300 mg/kg, IP., 20 min after reperfusion). The results of the Morris water maze test revealed better recovery of learning and memory function in the NRC-treated group. Acute NRC treatment decreased hippocampal infarct volume, reduced neuronal loss and apoptosis in the hippocampus. Western blot and high-performance liquid chromatography assays of hippocampal tissues revealed that the activation of Sirtin-1 and adenosine 5′ monophosphate-activated protein kinase was increased, the NAD content was elevated, and the production of adenosine triphosphate was strengthened by NRC. Collectively, acute NRC treatment increased the energy supply, reduced the neuronal loss and apoptosis, protected the hippocampus and ultimately promoted the recovery of cognitive function after brain ischemia.
... CLP + N100 group: Sepsis was induced using the CLP method under general anesthesia as in the CLP group. In addition, the rats in this group were given Nicotinamide i.p. at a dose of 100 mg/kg, after dissolution in 0.09% NaCl for 5 days before the CLP procedure and 6 h after the operation [12] . ...
... CLP+N300 group: Sepsis was induced using the CLP method under general anesthesia as in the CLP group. Nicotinamide was given i.p. after dissolution in 0.09% NaCl at a dose of 300 mg/kg for 5 days before the CLP procedure and 6 h after the operation [12] . ...
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The aim of this study is to determine the antioxidant and anti-inflammatory effects of Nicotinamide Adenine Dinucleotide (NAD+) in preventing multi-organ damage caused by sepsis. Twenty-eight male Wistar-albino rats were randomly divided into four groups. The study groups comprised Sham group, sepsis group (CLP), sepsis + 100 mg/kg NAD+ (CLP+N100) and sepsis + 300 mg/kg NAD+ group (CLP+N300). Sepsis was induced by the cecum ligation perforation (CLP) method. NAD+ was administered intraperitoneally for five days before cecum perforation and 6 h after operation. Serum, liver and kidney tissues were taken from the rats 24 h after the operation. MDA, GSH, CAT, TNF-α, IL-6, IL-1β, and caspase-3 parameters were measured in tissue samples with biochemical and immunohistochemical methods. In the histopathological and immunohistochemical examination, increases in TNF-α, IL-6, IL-1β, and caspase-3 expressions were observed in the liver and kidney tissues of the CLP group and severe damage was seen in tissue morphology (P<0.001). Hepatorenal injury was significantly decreased in the treatment groups. Sepsis increased MDA levels in all tissues, but significantly decreased GSH and CAT activities. While NAD+ administration significantly increased GSH and CAT activity in the liver and kidney tissues, it caused a significant decrease in MDA levels. This study shows that nicotinamide may be a potent therapeutic agent for the treatment of sepsis.
... Besides, the NMN administration also exerts a pleiotropic effect on acute heart failure and renal injury. 23,613,614 It is worth noting that clinical trials of NAM have been initiated in patients with cancers including bladder cancer, non-small-cell lung carcinoma, non-melanoma skin cancer, non-Hodgkin's lymphoma and multiple myeloma ( Table 1). ...
... NMN may be directly taken up by specific transporters, as the NAD + content in peripheral organs, such as the gut, is immediately increased by NMN administration. 23,614 However, in vitro studies demonstrate that Nrk1/2 depletion abandons the incorporation of NMN into NAD + synthesis. Moreover, NMN administration can significantly elevate NAD + biosynthesis in white adipose tissue, heart and the liver, but not the NAD + content in brown adipose tissue and kidney, suggesting a tissue-and cell-type-specific transportation of NMN to cells or tissues for NAD + biosynthesis presumably due to the deferent expression pattern of NRK1. ...
Article
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Nicotinamide adenine dinucleotide (NAD+) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics. These effects are mainly achieved by the driving effect of NAD+ on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple NAD+-dependent enzymes are involved in physiology either by post-synthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP+. Prolonged disequilibrium of NAD+ metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. In this review, we summarize recent advances in our understanding of the molecular mechanisms of NAD+-regulated physiological responses to stresses, the contribution of NAD+ deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention.
... Overproduction of ROS activates oxidative DNA damage signaling and PARP1, leading to decreased intracellular ATP and NAD +.218,219 NAD + is a cosubstrate for sirtuin family proteins (SIRT1-7), all of which play a critical role in regulating redox homeostasis and are associated with CVDs. 220,221 Intracellular depletion of NAD + attenuates the activity of SIRT1 222 and SIRT3, 223 further disturbing mitochondrial biogenesis and antioxidant defense, which leads to mitochondrial dysfunction, one of the hallmarks of IRI. 224 Numerous investigations have confirmed the correlation between myocardial IRI and ROS-induced oxidative DNA damage. ...
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DNA damage response (DDR) signaling ensures genomic and proteomic homeostasis to maintain a healthy genome. Dysregulation either in the form of down‐ or upregulation in the DDR pathways correlates with various pathophysiological states, including cancer and cardiovascular diseases (CVDs). Impaired DDR is studied as a signature mechanism for cancer; however, it also plays a role in ischemia‐reperfusion injury (IRI), inflammation, cardiovascular function, and aging, demonstrating a complex and intriguing relationship between cancer and pathophysiology of CVDs. Accordingly, there are increasing number of reports indicating higher incidences of CVDs in cancer patients. In the present review, we thoroughly discuss (1) different DDR pathways, (2) the functional cross talk among different DDR mechanisms, (3) the role of DDR in cancer, (4) the commonalities and differences of DDR between cancer and CVDs, (5) the role of DDR in pathophysiology of CVDs, (6) interventional strategies for targeting genomic instability in CVDs, and (7) future perspective.
... Therefore, NAD + plays a central role in oxidative phosphorylation, making it an attractive target for interventions in cardiac diseases including AF. Indeed, accumulating studies have already shown that boosting NAD + levels improve mitochondrial function in cardiovascular diseases, such as heart failure and ischemic conditions [118][119][120], which has been reviewed in-depth [121]. Collectively, these findings suggest that NAD + homeostasis improves mitochondrial function by attenuation of oxidative stress and DNA damage [118]. ...
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Atrial fibrillation (AF) is the most prevalent and progressive cardiac arrhythmia worldwide and is associated with serious complications such as heart failure and ischemic stroke. Current treatment modalities attenuate AF symptoms and are only moderately effective in halting the arrhythmia. Therefore, there is an urgent need to dissect molecular mechanisms that drive AF. As AF is characterized by a rapid atrial activation rate, which requires a high energy metabolism, a role of mitochondrial dysfunction in AF pathophysiology is plausible. It is well known that mitochondria play a central role in cardiomyocyte function, as they produce energy to support the mechanical and electrical function of the heart. Details on the molecular mechanisms underlying mitochondrial dysfunction are increasingly being uncovered as a contributing factor in the loss of cardiomyocyte function and AF. Considering the high prevalence of AF, investigating the role of mitochondrial impairment in AF may guide the path towards new therapeutic and diagnostic targets. In this review, the latest evidence on the role of mitochondria dysfunction in AF is presented. We highlight the key modulators of mitochondrial dysfunction that drive AF and discuss whether they represent potential targets for therapeutic interventions and diagnostics in clinical AF.
... NAD + is also a rate-limiting co-substrate for sirtuin family proteins (SIRT1-7), which all serve as important regulators of redox homeostasis and are implicated in various cardiac diseases [189,190]. NAD + depletion will thus lead to reduction in the activity of SIRT1 [191] and SIRT3 [192], which impairs mitochondrial biogenesis and antioxidant defense, further enhancing mitochondrial dysfunction, one of the hallmarks of IRI [193] (Figure 4). . Schematic relation between oxidative stress-induced DNA damage and the pathophysiology of IRI in IHD and potential therapeutic role of antioxidants, vitamin B3, and enzymes involved in DNA repair pathways in IRI treatment. ...
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The role of autophagy, neuroprotective mechanisms of nicotinamide adenine dinucleotide (NAD ⁺ ), and their relationship in spinal cord ischemic reperfusion injury (SCIR) was assessed. Forty-eight Sprague-Dawley rats were divided into four groups: sham, ischemia reperfusion (I/R), 10 mg/kg NAD ⁺ , and 75 mg/kg NAD ⁺ . Western blotting, immunofluorescence, and immunohistochemistry were used to assess autophagy and apoptosis. Basso, Beattie, and Bresnahan (BBB) scores were used to assess neurological function. Expression levels of Beclin-1, Atg12-Atg5, LC3B-II, cleaved caspase 3, and Bax were upregulated in the I/R group and downregulated in the 75 mg/kg NAD ⁺ group; p-mTOR, p-AKT, p62, and Bcl-2 were downregulated in the I/R group and upregulated in the 75 mg/kg NAD ⁺ group. Numbers of LC3B-positive, caspase 3-positive, Bax-positive, and TUNEL-positive cells were significantly increased in the I/R group and decreased in the 75 mg/kg NAD ⁺ group. The mean integrated option density of Bax increased and that of Nissl decreased in the I/R group, and it decreased and increased, respectively, in the 75 mg/kg NAD ⁺ group. BBB scores significantly increased in the 75 mg/kg NAD ⁺ group relative to the I/R group. No difference was observed between I/R and 10 mg/kg NAD ⁺ groups for these indicators. Therefore, excessive and sustained autophagy aggravates SCIR; administration of NAD ⁺ alleviates injury.
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Background and purpose: Tissue plasminogen activator (tPA) is the only approved pharmacological therapy for acute brain ischemia; however, a major limitation of tPA is the haemorrhagic transformation followed by tPA treatment. Here, we determine whether nicotinamide mononucleotide (NMN), a key intermediate of nicotinamide adenine dinucleotide biosynthesis, would affect tPA-induced haemorrhagic transformation. Experimental approach: Middle cerebral artery occlusion (MCAO) was achieved in CD1 mice by introducing a filament to the left MCA for 5 hours. When the filament was removed for reperfusion, tPA was infused from tail vein. NMN was injected intraperitoneally with a single dose (300 mg/kg). Mice were euthanized at 24 hours post ischemia and their brains were evaluated for brain infarction, edema, hemoglobin content, apoptosis, neuroinflammation, blood-brain barrier (BBB) permeability, tight junction proteins (TJPs) expression and matrix metalloproteinases (MMPs) activities/expression. Key results: In the mice infused with tPA at 5 hours post ischemia, there were significant increases in mortality, brain infarction, brain edema, brain hemoglobin level, neural apoptosis, Iba-1 staining (microglia activation) and MPO staining (neutrophil infiltration). All these tPA-induced alterations were significantly prevented by NMN administration. Mechanistically, the delayed tPA treatment induced BBB permeability by downregulating tight junction proteins, including claudin-1, occludin and ZO-1, and enhancing the activities and protein expression of MMP9 and MMP2. Similarly, NMN administration partly blocked these tPA-induced molecular changes. Conclusions and implications: Our results demonstrate that NMN ameliorates tPA-induced haemorrhagic transformation in brain ischemia by maintaining BBB integrity.
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Ripk3-required necroptosis and mitochondria-mediated apoptosis are the predominant types of cell death that largely account for the development of cardiac ischemia reperfusion injury (IRI). Here, we explored the effect of Ripk3 on mitochondrial apoptosis. Compared with wild-type mice, the infarcted area in Ripk3-deficient (Ripk3-/-) mice had a relatively low abundance of apoptotic cells. Moreover, the loss of Ripk3 protected the mitochondria against IRI and inhibited caspase9 apoptotic pathways. These protective effects of Ripk3 deficiency were relied on mitophagy activation. However, inhibition of mitophagy under Ripk3 deficiency enhanced cardiomyocyte and endothelia apoptosis, augmented infarcted area and induced microvascular dysfunction. Furthermore, ischemia activated mitophagy by modifying FUNDC1 dephosphorylation, which substantively engulfed mitochondria debris and cytochrome-c, thus blocking apoptosis signal. However, reperfusion injury elevated the expression of Ripk3 which disrupted FUNDC1 activation and abated mitophagy, increasing the likelihood of apoptosis. In summary, this study confirms the promotive effect of Ripk3 on mitochondria-mediated apoptosis via inhibition of FUNDC1-dependent mitophagy in cardiac IRI. These findings provide new insight into the roles of Ripk3-related necroptosis, mitochondria-mediated apoptosis and FUNDC1-required mitophagy in cardiac IRI.