NAD+ in Brain Aging and Neurodegenerative Disorders

In the paper

“The ambient levels of these metabolites are determined by different enzymes, which in the brain are preferentially localized in microglia and astrocytes, suggesting necessary glial cell-neuron communication (Schwarcz and Pellicciari, 2002).”

What the sources say

• Not checked yetcites Schwarcz and Pellicciari, 2002

In the paper

“The NAD+ salvage pathway starts from the recycling of nicotinamide (NAM) to nicotinamide mononucleotide (NMN) by intracellular nicotinamide phosphoribosyltransferase (iNAMPT), followed by the conversion of NMN into NAD+ via the NMNATs (Bogan and Brenner, 2008; Verdin, 2015).”

What the sources say

• Not checked yetcites Bogan and Brenner, 2008 source
• Not checked yetcites Verdin, 2015 source

In the paper

“Experimental evidence suggests that blood NA and NAM are able to cross the plasma membrane, while blood NAD+ cannot be taken up by cells directly but needs to be converted to smaller uncharged molecules to enter the cells (Hara et al., 2007; Ratajczak et al., 2016).”

What the sources say

• Not checked yetcites Hara et al., 2007 source
• Not checked yetcites Ratajczak et al., 2016 source

In the paper

“While kynurenic acid is an NMDA receptor antagonist, quinolinic acid is an NMDA receptor agonist (Vécsei et al., 2013).”

What the sources say

• Not checked yetcites Vécsei et al., 2013 source

In the paper

“While NMNAT1 and NMNAT3 are ubiquitously expressed, NMNAT2 is enriched in the brain, and adequate levels of NMNAT2 seem to be essential for axon development and survival (Gilley et al., 2019).”

What the sources say

• Not checked yetcites Gilley et al., 2019 source

In the paper

“The kynurenine pathway modulates neuronal functions as it is involved in the synthesis of two fundamental neuro-transmitters (glutamate and acetylcholine) as well as regulates N-methyl-D-aspartate (NMDA) receptor activity and free radical production (Vécsei et al., 2013).”

What the sources say

• Not checked yetcites Vécsei et al., 2013 source

In the paper

“Additionally, nicotinamide riboside (NR) integrates in this pathway via the conversion of NR into NMN by nicotinamide riboside kinase 1 (NRK1) or NRK2 (Bieganowski and Brenner, 2004; Ratajczak et al., 2016).”

What the sources say

• Not checked yetcites Bieganowski and Brenner, 2004 source
• Not checked yetcites Ratajczak et al., 2016 source

In the paper

“NAD+ is a vital redox cofactor for metabolism and ATP production, and a key substrate for at least four families of enzymes involved in healthspan and longevity (Fang et al., 2017; Gomes et al., 2013; Verdin, 2015).”

What the sources say

• Not checked yetcites Fang et al., 2017 source
• Not checked yetcites Gomes et al., 2013 source
• Not checked yetcites Verdin, 2015 source

In the paper

“The ratio of NAD+/NADH is important in various bioenergetic reactions in different subcellular compartments, and increased activity of one of these reactions can influence the metabolic homeostasis via changes in the NAD+/NADH ratio (Ying, 2008).”

What the sources say

• Not checked yetcites Ying, 2008 source

In the paper

“NAD+ plays an essential role in glycolysis and the citric acid (TCA) cycle, by its ability to accept hydride equivalents, forming NADH during ATP production (Krebs, 1970; Wallace, 2012).”

What the sources say

• Not checked yetcites Krebs, 1970 source
• Not checked yetcites Wallace, 2012 source

In the paper

“Extracellularly, NAD+ can be digested to NAM by the membrane-bound CD38 and CD157, with NAM further metabolized into NMN by extracellular NAMPT (eNAMPT); however, NAD+ can also be converted directly into NMN by CD73 (Bogan and Brenner, 2008; Verdin, 2015).”

What the sources say

• Not checked yetcites Bogan and Brenner, 2008 source
• Not checked yetcites Verdin, 2015 source

In the paper

“A newly reported NMN transporter, the Slc12a8, is highly expressed and regulated by NAD+, in the murine small intestine, and Slc12a8 deficiency abrogates the uptake of NMN in vitro and in vivo (Grozio et al., 2019).”

What the sources say

• Not checked yetcites Grozio et al., 2019 source

In the paper

“Additionally, the conversion of NAD+ to NADP+/NADPH is important in the involvement of different cellular functions, including antioxidation and generation of oxidative stress, calcium homeostasis, and cell survival or death (Ying, 2008).”

What the sources say

• Not checked yetcites Ying, 2008 source

In the paper

“NADH is one of the central electron donors in oxidative phosphorylation (OXPHOS) in the mitochondria, providing electrons to the electron transport chain (ETC) to generate ATP (Krebs, 1970; Wallace, 2012).”

What the sources say

• Not checked yetcites Krebs, 1970 source
• Not checked yetcites Wallace, 2012 source

In the paper

“Studies in mice and humans indicate that NR supplementation dramatically upregulates intracellular NAAD, suggesting unknown NAD+ metabolic pathways, including possibilities of NAD+ conversion to NAAD and/or NMN to nicotinic acid mononucleotide (NAMN) (Trammell et al., 2016a).”

What the sources say

• Not checked yetcites Trammell et al., 2016a

In the paper

“Furthermore, SIRT1 has been shown to promote neurite outgrowth and axon development, in addition to regulating dendritic arborization, long-term potentiation and learning, and memory (Gao et al., 2010).”

What the sources say

• Not checked yetcites Gao et al., 2010 source

In the paper

“Experimental evidence supports that PARP1 transfers the first ADP-ribose moiety from NAD+ to lysine, arginine, glutamate, aspartate, and serine residues on an acceptor protein, followed by addition of multiple ADP-ribose units to the preceding ones, thereby forming poly(ADP-ribose) (PAR) chains (Bonfiglio et al., 2017; Daniels et al., 2014).”

What the sources say

• Not checked yetcites Bonfiglio et al., 2017 source
• Not checked yetcites Daniels et al., 2014 source

In the paper

“In mammals, there are seven SIRTs, which regulate a large number of cellular pathways, including neuronal survival, stem cell rejuvenation, cancer, and healthy longevity (Chalkiadaki and Guarente, 2015).”

What the sources say

• Not checked yetcites Chalkiadaki and Guarente, 2015

In the paper

“The majority of PARylation is executed by PARP1, which participates in a number of necessary cellular processes, such as DNA repair, DNA/RNA metabolism, and cellular stress response.”

In the paper

“PARP1 is critical in the stabilization of DNA repair forks, with its catalytic activity necessary for multiple DNA repair pathways, such as the repair of single-strand breaks, bulky lesions, and double-strand breaks (DSBs) (Ray Chaudhuri and Nussenzweig, 2017).”

What the sources say

• Not checked yetcites Ray Chaudhuri and Nussenzweig, 2017 source

In the paper

“Notably, excessive PARP1 activation induces ATP depletion through PAR-dependent inhibition of hexokinase activity, resulting in dysfunctional glycolysis, a mechanism likely independent of NAD+ depletion (Andrabi et al., 2014; Fouquerel et al., 2014).”

What the sources say

• Not checked yetcites Andrabi et al., 2014 source
• Not checked yetcites Fouquerel et al., 2014 source

In the paper

“Among the 17 PARPs, only four of them are capable of adding multiple ADP-ribose units (poly[ADP-ribosyl]ation) or PARylation; they are PARP1, PARP2, PARP5a (tankyrase 1), and PARP5b (tankyrase 2) (Leung, 2017; Rouleau et al., 2010).”

What the sources say

• Not checked yetcites Leung, 2017 source
• Not checked yetcites Rouleau et al., 2010 source

In the paper

“While a small fraction of NAMPT has been shown to co-purify with mitochondria in liver extracts (Yang et al., 2007), results from mitochondrial purification and immunofluorescence in cell lines suggested an exclusion of NAMPT from the mitochondrial matrix, suggesting the lack of NAM recycling to NAD+ in the mitochondria (Pittelli et al., 2010).”

What the sources say

• Not checked yetcites Yang et al., 2007 source
• Not checked yetcites Pittelli et al., 2010 source

In the paper

“SARM1 is a newly recognized class of NADase that cleaves NAD+ into NAM, ADPR, and cADPR via its TIR domain. It is expressed in both brain and non-brain tissues, including the liver (Essuman et al., 2017; Pan and An, 2018).”

What the sources say

• Not checked yetcites Essuman et al., 2017 source
• Not checked yetcites Pan and An, 2018 source

In the paper

“Despite CD38 being a lymphocyte differentiation antigen, it is also expressed in the brain (Mizuguchi et al., 1995), and CD38 knockout mice show significant protection against ischemic brain damage (Long et al., 2017).”

What the sources say

• Not checked yetcites Mizuguchi et al., 1995 source
• Not checked yetcites Long et al., 2017 source

In the paper

“CD38 catalyzes the synthesis of the Ca2+-responsive messenger cyclic ADP-ribose (cADPR) by use of NAD+ and plays a key role in multiple physiological processes such as immunity, metabolism, inflammation, and even social behaviors (Jin et al., 2007).”

What the sources say

• Not checked yetcites Jin et al., 2007 source

In the paper

“SIRTS, PARPs, CD38/CD157, and SARM1 compete with each other to consume cellular NAD+; thus, the hyperactivation of one enzyme can impair the activities of other NAD+-dependent enzymes.”

What the sources say

• Not checked yetcites Bonkowski and Sinclair, 2016
• Not checked yetcites Fang et al., 2017 source
• Not checked yetcites Verdin, 2015 source

In the paper

“Two major mechanisms are involved in the regulation of subcellular balance of NAD+, including the expression of subcellular-specific NAD+-synthetic enzymes and subcellular transporters for NAD+ and related metabolites.”

In the paper

“NAD+ is in constant equilibrium between synthesis, consumption, and recycling in various subcellular compartments, including the cytoplasm, nucleus, mitochondria, and Golgi apparatus.”

In the paper

“The three mammalian NMNATs include the nuclear NMNAT1, the cytoplasmic NMNAT2, and the mitochondrial NMNAT3, which is also present in the cytosol (Berger et al., 2005).”

What the sources say

• Not checked yetcites Berger et al., 2005 source

In the paper

“Similarly, NAMPT (Figure 1) is primarily localized in the nucleus and cytoplasm, where it regulates subcellular NAD+ levels.”

In the paper

“While CD38 molecules are expressed in both a type II form(i.e., large extracellular C-terminal) and a type III form (with its catalytic domain facing the cytosol) (Liu et al., 2017, 2008), there is an age-dependent increase of CD38, which may contribute to cellular NAD+ depletion and impaired mitochondrial function (Camacho-Pereira et al., 2016).”

What the sources say

• Not checked yetcites Camacho-Pereira et al., 2016 source

In the paper

“The NADase activity of SARM1 may contribute to its role in axonal degeneration (Essuman et al., 2017) and is therefore a potential target for therapeutic intervention in neurodegenerative diseases.”

What the sources say

• Not checked yetcites Essuman et al., 2017 source

In the paper

“SARM1 exhibits both cyclase and glycohydrolase activities, and the estimated Michaelis constant (Km) is 24 μM, which is similar to that of the other known NAD+-consumers (PARP1, 50–97 μM; SIRT1, 94–96 μM; CD38, 15–25 μM) (Cantó et al., 2015).”

What the sources say

• Not checked yetcites Cantó et al., 2015 source

In the paper

“While the existence of mitochondrial NAD+ transporters is well documented in yeast and plants, a mammalian counterpart has yet to be identified.”

In the paper

“Furthermore, some NAD+ transporters (SLC25A17) localize in peroxisomes, where NAD+ participates in b-oxidation like in mitochondria (Agrimi et al., 2012).”

What the sources say

• Not checked yetcites Agrimi et al., 2012 source

In the paper

“Peroxisomes have recently been shown to have a shared mitochondrial and endoplasmic reticulum (ER) origin, further linking the function of mitochondria and peroxisomes (Sugiura et al., 2017).”

What the sources say

• Not checked yetcites Sugiura et al., 2017 source

In the paper

“Recent studies have demonstrated that both NMN and NAD+/NADH can be transported into the mitochondria by unknown systems, and that NMN is converted to NAD+ by NMNAT3 within the mitochondrial matrix, whereas NR is likely converted to NMN or NAD+ in the cytoplasm before transport into mitochondria (Davila et al., 2018; Nikiforov et al., 2011).”

What the sources say

• Not checked yetcites Davila et al., 2018 source
• Not checked yetcites Nikiforov et al., 2011 source

In the paper

“In addition to a role in mitophagy, USP30 was recently demonstrated to be involved in the peroxisome-specific degradation process, pexophagy. Peroxisomes have a half-life of 1.5–2.5 days, though pexophagy can be regulated by the metabolic state of the cells. This suggests a role for NAD+ in pexophagy regulation (Marcassa et al., 2018).”

What the sources say

• Not checked yetcites Marcassa et al., 2018 source

In the paper

“Furthermore, in the pentose phosphate pathway (PPP), glucose-6-phosphate (G6P) dehydrogenase (G6PD) converts G6P to 6-p-gluconate, when the NAD+-dependent SIRT2 deacetylates and activates G6PD. The PPP pathway converts NADP+ to NADPH and regenerates the antioxidant glutathione (GSH), thus promoting cell survival during oxidative stress (Wu and Sinclair, 2014).”

What the sources say

• Not checked yetcites Wu and Sinclair, 2014

In the paper

“Possible explanations for reduced cellular NAD+ during aging include increased NAD+ consumption by PARPs and CD38 (Camacho-Pereira et al., 2016; Fang et al., 2014) and reduced NAD+ production, such as that evidenced by reduced eNAMPT in the aged mice and humans (Yoshida et al., 2019).”

What the sources say

• Not checked yetcites Camacho-Pereira et al., 2016 source
• Not checked yetcites Fang et al., 2014 source
• Not checked yetcites Yoshida et al., 2019 source

In the paper

“The mechanism underlying the benefits of NAD+ augmentation likely involves reduced levels of DNA damage, leading to decreased PARP1 activity.”

What the sources say

• Not checked yetcites Fang et al., 2016b

In the paper

“Additionally, increased SIRT1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) activities were observed after NAD+ augmentation, which, when combined with enhanced DNA repair, suggest improved nuclear-to-mitochondrial communication (Fang et al., 2016b).”

What the sources say

• Not checked yetcites Fang et al., 2016b

In the paper

“Furthermore, adding extracellular vesicles containing eNAMPT improved cognitive/neuronal function and extended lifespan in WT mice (Yoshida et al., 2019).”

What the sources say

• Not checked yetcites Yoshida et al., 2019 source

In the paper

“Moreover, NAD+ augmentation restores mitochondrial function and bioenergetics, leading to enhanced neuronal survival and improved cognitive function in premature aging animal models.”

In the paper

“During aging, the cellular milieu of the brain exhibits mitochondrial dysfunction, intracellular accumulation of oxidatively damaged macromolecules (DNA, lipids, and proteins), dysregulated energy metabolism, impaired cellular “waste disposal” mechanisms, impaired adaptive stress response signaling, compromised DNA repair, aberrant neuronal network activity, dysregulated neuronal Ca2+ handling,”

What the sources say

• Not checked yetcites Mattson and Arumugam, 2018

In the paper

“NMN treatment improved cognition in this Nampt-knockdown (CA1) mouse model, partially through upregulation of calcium/calmodulin-dependent serine protein kinase (Cask), a potential downstream effector, in a SIRT1-dependent manner (Johnson et al., 2018).”

What the sources say

• Not checked yetcites Johnson et al., 2018 source

In the paper

“Two hallmarks of aging in proliferative tissues, including cellular senescence and telomere damage, may also apply in some types of glial cells and neural progenitor cells in the brain, but this remains elusive (Mattson and Arumugam, 2018).”

What the sources say

• Not checked yetcites Mattson and Arumugam, 2018

In the paper

“Mitochondria generate ATP to support neuronal activities including neurotransmission and Ca2+ homeostasis and are a source of signals that regulate nuclear-mitochondrial communication and even the arbitration of neuronal survival and death (Mattson et al., 2008).”

What the sources say

• Not checked yetcites Mattson et al., 2008 source

In the paper

“NAD+ is central to mitochondrial homeostasis, including in mitochondrial biogenesis, mitophagy, the mitochondrial unfolded protein response (UPRmt), and nuclear-mitochondrial communication (Fang et al., 2014; Gomes et al., 2013; Mouchiroud et al., 2013).”

What the sources say

• Not checked yetcites Fang et al., 2014 source
• Not checked yetcites Gomes et al., 2013 source
• Not checked yetcites Mouchiroud et al., 2013 source

In the paper

“Mitochondria isolated from animal and post-mortem human brain tissues show an age-dependent rise in mitochondrial functional heterogeneity, increased oxidative damage, reduced function of the ETC, disrupted membrane potential, impaired Ca2+ handling, and/or an accumulation of dysfunctional mitochondria (Lin and Beal, 2006; Mattson et al., 2008; Sorrentino et al., 2017).”

What the sources say

• Not checked yetcites Lin and Beal, 2006
• Not checked yetcites Mattson et al., 2008 source
• Not checked yetcites Sorrentino et al., 2017 source

In the paper

“During aging, neurons accumulate dysfunctional proteins and subcellular organelles as a result of the actions of reactive oxygen species (ROS). This has been exemplified by the observed increase in oxidative damage to DNA, proteins, and lipids in the aging brain (Mattson and Arumugam, 2018).”

What the sources say

• Not checked yetcites Mattson and Arumugam, 2018

In the paper

“Superoxide produced during mitochondrial electron transport and via the activity of NADPH oxidase are the two major routes of cellular ROS production, and both NAD+/NADH and NADP+/NADPH play key roles in cellular antioxidant systems (Ying, 2008).”

What the sources say

• Not checked yetcites Ying, 2008 source

In the paper

“In quiescent NSCs from old mice, an age-dependent reduction of lysosome activity with accumulated protein aggregates was observed.”

What the sources say

• Not checked yetcites Leeman et al., 2018 source

In the paper

“In the adult brain, the autophagy-lysosome pathway keeps healthy brain function via the maintenance of the survival and function of mature neurons and keeping a “youthful state” of NSC pool.”

In the paper

“Accordingly, long-lived animals, including the naked mole-rat, rodents maintained on calorie restricted (CR) and intermittent fasting (IF) diets, and long-lived daf-2 mutant worms exhibit decreased levels of oxidative damage and are more resistant to oxidative stress (Fontana and Partridge, 2015; Guarente and Kenyon, 2000; Pérez et al., 2009).”

What the sources say

• Not checked yetcites Fontana and Partridge, 2015 source
• Not checked yetcites Guarente and Kenyon, 2000
• Not checked yetcites Pérez et al., 2009 source

In the paper

“Reduced NAD+ levels play a pivotal role in brain aging and neurodegenerative disorders because NAD+ replenishment improves mitochondrial function and mitochondrial biogenesis and reduces accumulation of damaged mitochondria in both premature aging models and Alzheimer’s disease (AD) models (Fang et al., 2014, 2016a; Scheibye-Knudsen et al., 2014).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Fang et al., 2014, 2016a
• Not checked yetcites Scheibye-Knudsen et al., 2014 source

In the paper

“As we age, levels of autophagy and proteasomal degradation gradually decline, leading to proteinopathies, a result of aberrant protein misfolding and aggregation (Menzies et al., 2015; Nixon, 2013).”

What the sources say

• Not checked yetcites Menzies et al., 2015 source
• Not checked yetcites Nixon, 2013 source

In the paper

“Genetic (expression of the transcription factor EB/TFEB, a master regulator of autophagy and lysosome biogenesis) or pharmacological (feeding with the mTOR inhibitor rapamycin) enhancement of the lysosome activity in old quiescent NSCs cleared protein aggregates and inhibited the NSCs’ activation to maintain the “youthful state” (Leeman et al., 2018).”

What the sources say

• Not checked yetcites Leeman et al., 2018 source

In the paper

“Similar to age-dependent reduction of autophagy, evidence of impaired UPS in the aging brain arises from studies showing age-dependent accumulation of polyubiquitinated proteins in neurons and a brain region-specific reduction of age-dependent proteasome activity in the hippocampus and cerebral cortex (Keller et al., 2002; Mattson and Arumugam, 2018).”

What the sources say

• Not checked yetcites Keller et al., 2002 source
• Not checked yetcites Mattson and Arumugam, 2018

In the paper

“Impaired UPS can be caused by the global aging process and by intracellular proteinopathies, such as Ab and tau aggregates (Saez and Vilchez, 2014).”

What the sources say

• Not checked yetcites Saez and Vilchez, 2014

In the paper

“NAD+ levels are reduced in many neurodegenerative diseases, and NAD+ augmentation forestalls pathologies in animal and cell culture models of AD, PD, and HD, at least partially through induction of autophagy/mitophagy (detailed in the next section).”

In the paper

“Impaired autophagy with accumulated proteinopathies are common pathological features in many age-predisposed neurodegenerative diseases, including AD, Parkinson’s disease (PD), Huntington disease (HD), and tauopathies. Importantly, impaired lysosome function and autophagy/mitophagy are common features among them (Kerr et al., 2017; Lou et al., 2019; Menzies et al., 2015; Nixon, 2013).”

What the sources say

• Not checked yetcites Kerr et al., 2017 source
• Not checked yetcites Lou et al., 2019
• Not checked yetcites Menzies et al., 2015 source

In the paper

“Recently, it was shown that knockdown of any of three mitophagy-related genes (pink1, pdr-1, and dct-1) in a C. elegans AD model eliminated benefits of NAD+ augmentation on behavioral deficits, and a similar pivotal role for mitophagy was demonstrated in AD mice and AD patient-derived induced pluripotent stem cells (iPSCs) (Fang et al., 2019).”

What the sources say

• Not checked yetcites Fang et al., 2019

In the paper

“Accordingly, enhancement of UPS can improve healthy aging as well as longevity in disease and aged animals, although the specific benefits to neurons and brain function are still elusive (Saez and Vilchez, 2014; Walther et al., 2015).”

What the sources say

• Not checked yetcites Saez and Vilchez, 2014
• Not checked yetcites Walther et al., 2015 source

In the paper

“With advancing age, these stress responses might become impaired, which will render the neurons more vulnerable to various forms of stress of either endogenous or exogenous origin (Mattson et al., 2018). This will in turn compromise synaptic function due to reduced expression and activity of neurotrophic factors and decreased mitochondrial function.”

What the sources say

• Not checked yetcites Mattson et al., 2018

In the paper

“Interestingly, the reduced form of NAD+, NADH, binds and stabilizes 26S proteasomes, and may also regulate the function of 20S proteasomes, the two main proteolytic complexes (Asher et al., 2005; Tsvetkov et al., 2014).”

What the sources say

• Not checked yetcites Asher et al., 2005 source
• Not checked yetcites Tsvetkov et al., 2014 source

In the paper

“During aging, the neurons suffer impaired proteostasis and energy production as well as increased oxidative damage, resulting in compromised subcellular Ca2+ handling, which may lead to caspase-regulated apoptosis and PARP1-mediated neuronal death (Bezprozvanny and Mattson, 2008; Mairet-Coello et al., 2013).”

What the sources say

• Not checked yetcites Bezprozvanny and Mattson, 2008 source
• Not checked yetcites Mairet-Coello et al., 2013 source

In the paper

“Collectively, there is a strong link between impaired autophagy-lysosome and UPS pathways in the aging brain, while detailed linkages between NAD+ levels and such pathways in the aging brain remain to be further studied.”

In the paper

“As previously mentioned, the strong links between NAD+ and mitochondrial function (ATP production), ROS, and Ca2+ signaling suggest that bolstering cellular NAD+ levels can improve adaptive cellular stress responses in neurons.”

In the paper

“NAD(P) is a precursor of nicotinic acid adenine dinucleotide phosphate (NAADP), cADPR, and ADPR, which are key regulators of Ca2+ signaling and are synthesized by CD38 and CD157 by the use of NAD+ (Figure 1) (Guse, 2015).”

What the sources say

• Not checked yetcites Guse, 2015 source

In the paper

“NAADP and cADPR stimulate the release of Ca2+ from ER stores, whereas cADPR regulates the entry of Ca2+ from the extracellular space.”

In the paper

“In neurons, SIRT3 mediates the adaptive responses of neurons to exercise, intermittent fasting, and excitatory challenges and helps prevent noise-induced hearing loss and spiral ganglia neurite degeneration (Brown et al., 2014; Cheng et al., 2016; Liu et al., 2019).”

What the sources say

• Not checked yetcites Brown et al., 2014 source
• Not checked yetcites Cheng et al., 2016 source
• Not checked yetcites Liu et al., 2019 source

In the paper

“Moreover, NAD+ depletion is evident as a phenotypic driver in many of these DNA damage-induced diseases, including at least CS, XPA, and A-T, since restoration of tissue NAD+ through PARPs inhibition ameliorates disease pathologies (Fang et al., 2014).”

What the sources say

• Not checked yetcites Fang et al., 2014 source

In the paper

“For example, mitochondrial NAD+ levels remain unchanged following genotoxic stress and can maintain cell viability in the conditions of depleted nuclear and cytoplasmic NAD+.”

What the sources say

• Not checked yetcites Yang et al., 2007 source

In the paper

“In AD mouse models, supplementation with the NAD+ precursor NR inhibited the disease-associated neuroinflammation, decreased the numbers of activated microglia and astrocytes, and reduced pro-inflammatory cytokines (Fang et al., 2019; Hou et al., 2018).”

What the sources say

• Not checked yetcites Fang et al., 2019
• Not checked yetcites Hou et al., 2018 source

In the paper

“In different neurodegenerative mouse models including AD, HD, and the premature aging disease A-T, NAD+ augmentation increases the expression and activity of BDNF, leading to enhanced synaptic plasticity and function (Fang et al., 2016a; Hathorn et al., 2011; Liu et al., 2013).”

What the sources say

• Not checked yetcites Fang et al., 2016a
• Not checked yetcites Hathorn et al., 2011 source
• Not checked yetcites Liu et al., 2013 source

In the paper

“The neurotrophin brain-derived neurotrophic factor (BDNF) is important in the development, maintenance, and plasticity of the central and peripheral nervous system; it also protects the aging brain against injury and disease through stimulation of glucose transport and mitochondrial biogenesis (Marosi and Mattson, 2014).”

What the sources say

• Not checked yetcites Marosi and Mattson, 2014 source

In the paper

“Collectively, impaired DNA repair byproducts and intermediates accumulate in cells of the aging brain and may contribute to numerous human neurological diseases, at least partially through NAD+ depletion driven by hyperactivation of PARP.”

In the paper

“In primary cell culture, supplementation with NR delays cellular senescence (Wiley et al., 2016), and NR treatment also reduces the senescent state in both NSCs and other stem cell types (Zhang et al., 2016).”

What the sources say

• Not checked yetcites Wiley et al., 2016 source
• Not checked yetcites Zhang et al., 2016 source

In the paper

“Collectively, the knowledge so far suggests an important role of reduced NAD+ levels in senescence, though further research is needed to understand the mechanisms upstream and downstream of NAD+ depletion in cell senescence in the aging brain.”

In the paper

“Neurons affected by Aβ and p-Tau neurofibrillary pathology in AD exhibit oxidative damage, impaired Ca2+ handling, defective lysosome function and mitophagy, and reduced DNA repair (Canter et al., 2016; Fang et al., 2019; Mattson et al., 2018; Polanco et al., 2018).”

What the sources say

• Not checked yetcites Canter et al., 2016 source
• Not checked yetcites Fang et al., 2019
• Not checked yetcites Mattson et al., 2018

In the paper

“While Aβ, p-Tau, and inflammation are major contributors to AD pathogenesis, NAD+ augmentation can ameliorate cognitive deficits in AD mouse models by suppressing these pathologies.”

In the paper

“Knockdown of CD38 in APPswePS1ΔE9 (APP.PS) mice reduced Aβ plaques and soluble Aβ levels, and increased spatial learning, possibly through upregulation of brain NAD+ levels (Blacher et al., 2015).”

What the sources say

• Not checked yetcites Blacher et al., 2015 source

In the paper

“Accordingly, NAD+ augmentation inhibited AD-related pathology and cognitive decline in different AD animal models, including 3xTgAD mice treated with NAM (Liu et al., 2013), 3xTgAD/Polβ+/− mice treated with NR (Hou et al., 2018), and in neuronal Aβ1–42 and the neuronal Tau (pro-aggregant F3ΔK280 tau fragment) transgenic C. elegans models (Fang et al., 2019) (summarized in Table 1).”

What the sources say

• Not checked yetcites Liu et al., 2013 source
• Not checked yetcites Hou et al., 2018 source
• Not checked yetcites Fang et al., 2019

In the paper

“NAD+ augmentation inhibited Tau phosphorylation at different sites (Thr181, Ser202, Thr205, and Thr231) possibly through suppression of cyclin-dependent kinase 5 (Cdk5)-p25 complex activity (Fang et al., 2019; Green et al., 2008).”

What the sources say

• Not checked yetcites Fang et al., 2019
• Not checked yetcites Green et al., 2008 source

In the paper

“Consistent with NHEJ being bolstered by NAD+, NR treatment of ATM-deficient neurons improved neuronal NHEJ activity through deacetylation and activation of the key NHEJ protein Ku70 in addition to facilitating the chromatin binding of Ku70 and DNA-PKcs, an additional NHEJ repair protein (Fang et al., 2016a).”

What the sources say

• Not checked yetcites Fang et al., 2016a

In the paper

“Four months of NAM treatment increased the level of p25 2-fold, reduced p-TauThr231 levels, and improved cognitive function in 3xTgAD mice (Green et al., 2008).”

What the sources say

• Not checked yetcites Green et al., 2008 source

In the paper

“While LTP is impaired in the 3xTgAD mice, NR restores LTP, correlating with improvements in learning and memory (Hou et al., 2017).”

What the sources say

• Not checked yetcites Hou et al., 2017 source

In the paper

“In mice, the expression and activity of CD38 increase during aging, and CD38 contributes significantly to age-related NAD+ depletion and mitochondrial dysfunction at least in part via inhibition of NAD+/SIRT3 activity (Camacho-Pereira et al., 2016).”

What the sources say

• Not checked yetcites Camacho-Pereira et al., 2016 source

In the paper

“In summary, NAD+ augmentation enhances synaptic plasticity and improves memory in different AD mouse models possibly through the reduction of Aβ and p-Tau pathologies and suppression of inflammation (see below).”

In the paper

“Senolytic elimination of Aβ-associated senescent OPCs or Tau pathology-associated senescent glial cells ameliorates cognitive impairment in different AD mouse models (Bussian et al., 2018; Zhang et al., 2019).”

What the sources say

• Not checked yetcites Bussian et al., 2018 source
• Not checked yetcites Zhang et al., 2019 source

In the paper

“NR supplementation delayed senescence of adult NSCs in 2-year-old mice (Zhang et al., 2016), suggesting a role for a deficit in NAD+ or one or more of the enzymes it supports in neural-cell senescence.”

What the sources say

• Not checked yetcites Zhang et al., 2016 source

In the paper

“ALS has been linked to NAD+ metabolism via impairment of the kynurenine pathway and the potential involvement of altered SIRT1 and SIRT3 activities.”

In the paper

“As evidenced, neurons expressing the LRRK2 G2019S mutation exhibit mitochondrial dysfunction and a 30% reduction of NAD+ levels.”

What the sources say

• Not checked yetcites Schwab et al., 2017 source
• Not checked yetcites Sison and Ebert, 2018

In the paper

“NAD+-induced mitophagy likely plays a major role in the observed benefits, as mutation of key mitophagy genes (pink1, parkin/pdr-1, and nix/dct-1) abolishes NAD+- dependent memory improvement in Aβ and p-Tau C. elegans models (Fang et al., 2019).”

What the sources say

• Not checked yetcites Fang et al., 2019

In the paper

“NAD+ augmentation via NR supplementation induced UPS in both the hippocampus and cortex of Tg2576 AD mice (Gong et al., 2013) and restored UPRmt in APPswe/PSEN1dE9 AD mice.”

What the sources say

• Not checked yetcites Gong et al., 2013 source

In the paper

“Knockdown of PINK1 expression in primary neurons and neuroblastoma cells causes increased oxidative stress and 50% reduction of NADH levels (Gandhi et al., 2009).”

What the sources say

• Not checked yetcites Gandhi et al., 2009 source

In the paper

“PD is a progressive fatal neurological disorder of aging that profoundly impairs one’s ability to control body movements as the result of loss of dopaminergic neurons in the substantia nigra, which exhibit abnormal accumulation of α-synuclein fibrils in their cell body and neurites (Kam et al., 2018; Spillantini et al., 1997).”

What the sources say

• Not checked yetcites Kam et al., 2018 source
• Not checked yetcites Spillantini et al., 1997 source

In the paper

“Dopaminergic neurons derived from iPSCs expressing mutant GBA exhibit a reduced cytosolic NAD+/NADH ratio, although no significant change of total cellular NAD+ was seen (Schöndorf et al., 2018).”

What the sources say

• Not checked yetcites Schöndorf et al., 2018 source

In the paper

“In ALS patients, there were higher levels of CSF and serum tryptophan, kynurenine, and quinolinic acid, and decreased serum picolinic acid”

What the sources say

• Not checked yetcites Chen et al., 2010 source

In the paper

“SIRT3 expression has been linked to ALS in a PGC-1α-dependent pathway, though the mechanism remains unknown”

What the sources say

• Not checked yetcites Buck et al., 2017 source
• Not checked yetcites Harlan et al., 2016 source

In the paper

“Though NAD+ levels were not reported, all the data suggest an inflammation-related excitotoxic-chelation defective mechanism in ALS patients.”

In the paper

“The discrepancies between the findings on SIRT1 levels in ALS might be due to different cell lines used or altered expression of SIRT1 during disease progression.”

In the paper

“there was higher microglial inflammation and increased neuronal and microglial expression of indoleamine 2,3-dioxygenase and quinolinic acid in the motor cortex and spinal cord tissues from ALS patients”

What the sources say

• Not checked yetcites Chen et al., 2010 source

In the paper

“SIRT1, SIRT3, and/or SIRT6 are likely activated as a result of improved NAD+ salvage, leading to decreased acetylation of IDH2 and activation of Nrf2, thereby improving the resistance of motor neurons to oxidative stress and the mitochondrial function”

What the sources say

• Not checked yetcites Harlan et al., 2016 source
• Not checked yetcites Harlan et al., 2019 source

In the paper

“SIRT1 activity is altered in mouse models of ALS and in postmortem tissue samples from ALS patients; however, the direction of change has been debated”

What the sources say

• Not checked yetcites Kim et al., 2007 source
• Not checked yetcites Körner et al., 2013 source
• Not checked yetcites Lee et al., 2012 source

In the paper

“enhancement of the NAD+ salvage pathway protects astrocytes expressing an ALS-linked mutant SOD1 and thereby promotes motor neuron survival”

What the sources say

• Not checked yetcites Harlan et al., 2016 source

In the paper

“NAD+ precursor treatment (NMN or NR) or NAMPT overexpression results in increased oxidative stress resistance in motor neurons and prevents the toxicity of co-cultured SOD1-mutant astrocytes.”

What the sources say

• Not checked yetcites Harlan et al., 2016 source

In the paper

“up to 2.7-fold increased NAD+ levels and 45-fold increase in the intermediate NAAD in human blood after oral NR supplementation (1,000 mg/day for 7 days)”

What the sources say

• Not checked yetcites Trammell et al., 2016a

In the paper

“NR is orally bioavailable, and it is well tolerated and elevates NAD+ in healthy middle-aged and older adults as well as in old diabetic males.”

What the sources say

• Not checked yetcites Trammell et al., 2016a
• Not checked yetcites Martens et al., 2018 source
• Not checked yetcites Dollerup et al., 2018 source

In the paper

“The involvement of cellular NAD+ depletion and the potential therapeutic benefits of treatments that bolster NAD+ levels include, but are not limited to, AD, PD, HD, and ALS.”

In the paper

“the data confirmed that NR was bioavailable and safe, with potential cardiovascular benefits”

What the sources say

• Not checked yetcites Martens et al., 2018 source

In the paper

“at least four independent clinical trials indicate NR supplementation (1–2 g/day for up to 3 months) is orally bioavailable and relatively safe.”

In the paper

“the clinical data showing NAM is relatively safe (1,000–2,000 mg/day) and is readily absorbed from the gastrointestinal tract with peak serum concentrations in 1 h after oral ingestion”

What the sources say

• Not checked yetcites Chen et al., 2015 source
• Not checked yetcites Petley et al., 1995 source
• Not checked yetcites Phelan et al., 2017

In the paper

“NRPT treatment increased whole blood NAD+ levels by 90% with no serious adverse events”

What the sources say

• Not checked yetcites Dellinger et al., 2017 source

In the paper

“However, NAM did not show any significant effects”

What the sources say

• Not checked yetcites Phelan et al., 2017

In the paper

“All patients in the EH301 group choose to continue the treatment after 4 months, and thus the treatment was finalized after 1-year treatment, where no deterioration, except of FVC, was observed”

What the sources say

• Not checked yetcites de la Rubia et al., 2019 source

In the paper

“increased NAD+, through either overexpressed NAD+ synthetic enzymes or supplementation with NAD+ precursors, promotes cancer cell proliferation, migration, and resistance to anticancer chemo-/radiotherapy”

What the sources say

• Not checked yetcites Demarest et al., 2019 source

In the paper

“strategies to deplete cellular NAD+ and the inhibition of NAD+ synthetic enzymes can trigger cancer cell death”

What the sources say

• Not checked yetcites Buonvicino et al., 2018 source

In the paper

“NRPT/EH301 treatment improved ALS functional rating scale revised (ALSFRS-R), increased the MRC grading scale index (grades muscle power), and forced vital capacity (FVC, functional respiratory capacity test), as well as increased electrical activity in muscles.”

What the sources say

• Not checked yetcites de la Rubia et al., 2019 source

In the paper

“500 mg NA twice a day improved rigidity and bradykinesia, while a higher dose at 1,000 mg twice a day produced severe nightmares and skin rash”

What the sources say

• Not checked yetcites Alisky, 2005 source

In the paper

“painful flushing is a common side effect of high NA doses”

What the sources say

• Not checked yetcites DiPalma and Thayer, 1991

In the paper

“The study was a randomized double-blind design and included both males and females.”

What the sources say

• Not checked yetcites de la Rubia et al., 2019 source

In the paper

“Despite the low level of participants in this study, it sets the stage for the potential for NAD+ augmentation/SIRT1 activation as a treatment for ALS, and large-scale phase trials are warranted.”

What the sources say

• Not checked yetcites de la Rubia et al., 2019 source

In the paper

“the gut-to-brain axis may also show effects of NAD+ augmentation and, hereby, provide a new target of interest in neurodegenerative diseases”

What the sources say

• Not checked yetcites Blacher et al., 2019 source

In the paper

“cancer cells and post-mitotic cells exhibit a completely different metabolism, which may explain why the neuroprotective conditions of NAD+ augmentation and autophagy (Sousa et al., 2016) can also promote the growth of specific cancers (e.g., pancreatic cancer).”

What the sources say

• Not checked yetcites Sousa et al., 2016 source

In the paper

“Emerging findings are revealing a critical role for NAD+ in neural resilience and in the molecular mechanisms of the hallmarks of brain aging.”

In the paper

“A phase-III randomized large clinical trial reported that oral NAM was safe and effective in reducing the rates of new nonmelanoma skin cancers and actinic keratosis in high-risk patients”

What the sources say

• Not checked yetcites Chen et al., 2015 source

In the paper

“Emerging evidence suggests NAD+ depletion in brain cells is common during aging and is accentuated in many neurodegenerative disorders including AD, PD, HD, and ALS, and that NAD+ augmentation inhibits pathological features in animal models of these disorders”

What the sources say

• Not checked yetcites Table 1

In the paper

“NAD+ depletion and mitochondrial abnormalities have been shown, and beneficial effects of NAM treatment of mouse models have been reported”

What the sources say

• Not checked yetcites Williams et al., 2017 source

In the paper

“the ketone β-hydroxybutyrate, which elevates NAD+ levels in neurons and has been shown to suppress Aβ and p-Tau pathologies and ameliorate behavioral deficits in a mouse model of AD”

What the sources say

• Not checked yetcites Kashiwaya et al., 2013 source
• Not checked yetcites Marosi et al., 2016 source
• Not checked yetcites Pawlosky et al., 2017 source