NAD+ in Brain Aging and Neurodegenerative Disorders
Open accessAbstract
NAD+ is a pivotal metabolite involved in cellular bioenergetics, genomic stability, mitochondrial homeostasis, adaptive stress responses, and cell survival. Multiple NAD+-dependent enzymes are involved in synaptic plasticity and neuronal stress resistance. Here, we review emerging findings that reveal key roles for NAD+ and related metabolites in the adaptation of neurons to a wide range of physiological stressors and in counteracting processes in neurodegenerative diseases, such as those occurring in Alzheimer's, Parkinson's, and Huntington diseases, and amyotrophic lateral sclerosis. Advances in understanding the molecular and cellular mechanisms of NAD+-based neuronal resilience will lead to novel approaches for facilitating healthy brain aging and for the treatment of a range of neurological disorders.
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TL;DR
This review argues that NAD+ availability declines with brain aging and in Alzheimer’s, Parkinson’s, Huntington’s, and ALS, while NAD+-boosting strategies improve pathology and function in many preclinical models. It also surveys human trial evidence and cautions that causal human data, optimal precursors, and long-term safety remain unresolved.
Key findings
- NAD+ depletion is reported across species and tissues: human brain NAD+ and NAD+/NADH decline with age by non-invasive 31P MR assay; mouse hippocampus shows nearly 40% lower NAD+ at 10–12 months versus 1 month; aged worms also show lower organismal NAD+.
- The review links NAD+ loss to the 10 hallmarks of brain aging, including mitochondrial dysfunction, oxidative damage, impaired autophagy/proteasome function, disturbed calcium handling, weakened adaptive stress responses, reduced network plasticity, defective DNA repair, inflammation, impaired neurogenesis, and senescence/telomere changes.
- In neurodegenerative disease models, NAD+ augmentation with precursors such as NR, NMN, NAM, or NA, or by PARP inhibition/SIRT activation, reduces pathology and improves behavior. Examples include a 30% NAD+ reduction in LRRK2 G2019S dopaminergic neurons, 69% lower NAD+ in PINK1 mutant flies, 78% lower NAD+ in parkin mutant flies, and about 50% lower total NAD+ in Fbxo7-deficient cells or patient fibroblasts.
- Human trials show bioavailability and some safety signals: oral NR at 1,000 mg/day for 7 days raised blood NAD+ up to 2.7-fold and NAAD 45-fold; NRPT raised whole-blood NAD+ by 90%; however, a phase II NAM trial in 15 mild-to-moderate AD patients showed no significant benefit, and NAD+ precursors may carry cancer-related concerns in some contexts.
Methods
- Narrative review synthesizing mechanistic, preclinical, and clinical literature on NAD+ synthesis, metabolism, subcellular balance, brain aging, and neurodegenerative disorders.
- Evidence discussed includes animal models (mice, C. elegans, Drosophila, rhesus monkeys), human postmortem tissue, patient-derived cells/iPSCs, and clinical trials; no new primary data are generated.
- Main analysis is conceptual synthesis, including a proposed model connecting NAD+ depletion to the hallmarks of brain aging and disease-specific pathologies, with tables summarizing preclinical and clinical findings.
Limitations
- The paper states that human data on NAD+ changes during normal aging are sparse and require large, well-controlled population studies; a direct causal role for impaired NAD+-dependent processes in human neurodegenerative disease remains to be established.
- The paper notes unresolved questions about mechanisms upstream/downstream of NAD+ depletion, whether NAD+ precursors increase cancer risk in the general population, and the lack of direct human comparisons among NR, NMN, NA, and NAM.
- Evident from the text: as a review, it does not perform a systematic search or meta-analysis, and many cited clinical trials are small or short (for example, 15 AD patients in the NAM phase II trial and 20 ALS patients in the EH301 pilot), with mixed outcomes.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 273 cited sources checked · 0 supported · 0 flagged
- Premisecitation
In mammals, the kynurenine pathway is the sole de novo route for NAD+ synthesis.
“While the aspartate pathway is the de novo NAD+ pathway in most photosynthetic eukaryotes, the kynurenine pathway is the only de novo NAD+ synthetic pathway in mammals.”
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- Premisecitation
NMNATs show neuroprotective effects in mouse and Drosophila models.
“Three mammalian NMNATs exist, NMNAT1–3, showing neuroprotective effects in both mice and D. melanogaster models (Ali et al., 2013).”
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- Premisecitation
The kynurenine pathway has both neuroprotective metabolites and neurotoxic intermediates.
“The kynurenine pathway exhibits “double-edged sword” effects on neurons with both neuroprotective metabolites (tryptophan, kynurenic acid, and picolinic acid) and neurotoxic intermediates, including 3-hydroxykynure-nine (3-HK) that generates free radicals, 3-hydroxyanthranilic acid (3-HAA), and quinolinic acid (that induces glutamate receptor excitotoxicity) (Figure 1).”
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- Premisecitation
Hyperactivation of PARP1-induced NAD+ depletion can induce neuronal loss and accelerated aging.
“In addition to ATP loss, hyperactivation of PARP1-induced NAD+ depletion can induce neuronal loss and accelerated aging (Fang et al., 2016a).”
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- Premisecitation
Excessive PARP1 activation can trigger parthanatos through PAR formation that releases mitochondrial AIF, which translocates to the nucleus and activates MIF, leading to MIF-dependent chromatinolysis and cell death.
“However, excessive PARP1 activation can trigger cell death, termed parthanatos, through a mechanism in which PAR formation triggers the release of mitochondrial apoptosis-inducing factor (AIF) from the cytosolic side of the mitochondrial outer membrane. AIF is then translocated to the nucleus to activate macrophage migration inhibitory factor (MIF, a nuclease), which finally results in MIF-depend”
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- Premisenone given
NAD+ is a substrate for NAD+-consuming proteins SIRTs, PARPs, CD38/CD157, and SARM1, which catabolize NAD+ to NAM.
“In addition to cellular bioenergetics, NAD+ is also a substrate for different NAD+-consuming proteins, which catabolize NAD+ to NAM. They are class III histone deacetylases sirtuins (SIRTs), poly (ADP-ribose) polymerases (PARPs), ADP ribosyl-cyclases (CD38/CD157), and NADase sterile alpha and TIR motif-containing 1 (SARM1) (Figure 1).”
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SIRT1 consumes NAD+ to regulate glycolysis, gluconeogenesis, and mitochondrial homeostasis via balancing mitochondrial biogenesis and mitophagy and adaptive neuronal responses to exercise and metabolic/excitatory challenges.
“For example, SIRT1 consumes NAD+ to regulate glycolysis, gluconeogenesis, and mitochondrial homeostasis via the balance between mitochondrial biogenesis and mitophagy and adaptive responses of neurons to exercise and metabolic/excitatory challenges (Bonkowski and Sinclair, 2016; Cheng et al., 2016; Fang, 2019).”
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- Premisecitation
In neurons, NMNAT2 localizes to Golgi and Rab7-containing late endosomes as well as synaptic terminals and axons.
“In neurons, NMNAT2 localizes to Golgi and Rab7-containing late endosomes as well as to both synaptic terminals and axons (Gilley and Coleman, 2010; Mayer et al., 2010).”
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CA1-region-specific knockdown of Nampt to reduce brain NAD+ production recapitulates hippocampal cognitive phenotypes of old mice.
“In line with the role of NAD+ in maintaining healthy brain function, genetic approaches to reduce brain NAD+ production via CA1-region-specific knockdown of Nampt recapitulate hippocampal cognitive phenotypes of old mice (Johnson et al., 2018).”
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- Premisecitation
In mice, hippocampal NAD+ levels decrease by nearly 40% in 10- to 12-month-old mice compared with 1-month-old mice.
“In mice, there was a nearly 40% decrease of NAD+ levels in the hippocampus in 10- to 12-month-old mice compared with 1-month-old mice (Stein and Imai, 2014).”
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- Premisecitation
In intact human brain from healthy volunteers, NAD+ levels, NAD+/NADH, and total NAD(H) contents decline with age as measured by 31P MR.
“Using a non-invasive 31P magnetic resonance (MR)-based in vivo NAD assay, Zhu et al. demonstrated an age-dependent reduction of NAD+ levels, NAD+/NADH, and total NAD(H) contents in intact human brain from healthy volunteers (Zhu et al., 2015).”
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- Premisecitation
During normal aging, lower NAD+ levels are observed in tissues of humans, mice, and C. elegans.
“During normal aging, lower NAD+ levels are observed in tissues of various organisms including humans, mice, and C. elegans.”
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Organismal NAD+ decreases with age in wild-type worms.
“Similarly, an age-dependent reduction of organismal NAD+ in wild-type (WT) worms has been shown (Fang et al., 2014).”
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- Premisecitation
NAD+ augmentation strategies, including NR or NMN, PARP1 inhibitor, or SIRT1 activator, improve healthspan and lifespan in accelerated aging animal models.
“In line with the importance of NAD+ depletion in neurodegeneration, multiple NAD+ augmentation strategies (including treatment with the NAD+ precursors NR or NMN, or treatment with a PARP1 inhibitor or a SIRT1 activator) improved healthspan and lifespan in the accelerated aging animal models (Fang et al., 2014, 2016a; Scheibye-Knudsen et al., 2014).”
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- Premisecitation
NAD+ depletion occurs in accelerated aging diseases with neurodegeneration, including ataxia telangiectasia, xeroderma pigmentosum group A, and Cockayne syndrome.
“Several accelerated aging diseases exhibit neurodegeneration, including ataxia telangiectasia (AT), xeroderma pigmentosum group A (XPA), and Cockayne syndrome (CS). NAD+ depletion has been shown in both C. elegans and brain tissues from mouse models of AT, XPA, and CS.”
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In brain tissues from old normal mice and accelerated aging mice, declining NAD+ contributes to age-associated decline in mitochondrial biogenesis via impaired SIRT1-PGC-1a signaling.
“In brain tissues from old normal mice and accelerated aging mice, a decline in NAD+ levels contributes to the age-associated decline of mitochondrial biogenesis via impaired SIRT1-PGC-1a signaling (Fang et al., 2014; Mouchiroud et al., 2013; Stein and Imai, 2014).”
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Age-dependent reduction in cellular ability to clear damaged mitochondria via mitophagy/macroautophagy has been shown.
“Furthermore, an age-dependent reduction in the cellular ability to clear damaged mitochondria via mitophagy/macro-autophagy has been shown (Fang et al., 2019; Hansen et al., 2018; Palikaras et al., 2015).”
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Age-related NAD+ depletion is positively related to the 10 hallmarks of brain aging.
“Emerging findings are revealing linkages by which age-related NAD+ depletion is positively related to the 10 hallmarks of brain aging.”
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- cites Lou et al., 2019
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- cites Mattson and Arumugam, 2018
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- Interpretationnone given
Reduced NAD+ levels contribute to most, if not all, hallmarks of brain aging.
“As described in the following sections, reduced NAD+ levels contribute to most, if not all, of the hallmarks of brain aging.”
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NAD+ depletion induces a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication, contributing to age-related mitochondrial decline.
“Furthermore, NAD+ depletion induces a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication, which contributes to the decline in mitochondrial function with age (Gomes et al., 2013).”
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- Interpretationreasoning
NAD+ is critical for coupling mitochondrial biogenesis and mitophagy to maintain mitochondrial homeostasis in neurons.
“Thus, NAD+ is critical for the coupling of mitochondrial biogenesis and mitophagy to maintain mitochondrial homeostasis in neurons.”
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Aging in rats is associated with decreased NAD+ levels correlated with increased lipid and protein oxidation and increased DNA damage in heart, lung, kidney, and liver.
“The aging of rats has been associated with a decrease in NAD+ levels that is correlated with increased lipid and protein oxidation as well as increased DNA damage in the heart, lung, kidney, and liver (Braidy et al., 2011).”
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- Premisecitation
NAD+ augmentation decreases elevated ROS in cell and animal models of premature aging through reduced ROS production, improved mitochondrial function, and possibly increased ROS detoxification.
“Moreover, NAD+ augmentation decreases the elevated levels of ROS in cell and animal models of premature aging diseases through reduced ROS production, improved mitochondrial function, and possibly also increased ROS detoxification (Fang et al., 2016a, 2019; Scheibye-Knudsen et al., 2014).”
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- cites Scheibye-Knudsen et al., 2014 source
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Genetic and pharmacological restoration of autophagic/mitophagic clearance in animal models of neurodegenerative diseases ameliorates disease-defining pathologies and behavioral deficits.
“Genetic and pharmacological restorations of autophagic/mitophagic clearance in animal models of these diseases ameliorate disease-defining pathologies and behavioral deficits (Fang et al., 2019; Ravikumar et al., 2004; Sliter et al., 2018).”
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Key proteins involved in UPS and memory include 19S/20S/26S proteasomes, SUMO-I, USP14, and CaMKII.
“Some key proteins involved in UPS and memory are 19S/20S/26S proteasomes, small ubiquitin-related modifier I (SUMO-I), ubiquitin-specific protein 14 (USP14), and the proteasome phosphorylation-regulating protein CaMKII (Jarome and Devulapalli, 2018; Jarome et al., 2013, 2016).”
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NAD+-dependent proteins involved in stimulating autophagy/mitophagy include SIRT1, SIRT3, SIRT6, SIRT7, CD38, SARM1, and IL10-dependent upregulation of autophagic/mitophagic proteins.
“NAD+-dependent proteins involved in stimulation of autophagy/mitophagy include SIRT1, SIRT3, SIRT6, SIRT7, CD38, SARM1, and IL10-dependent upregulation of the expression of autophagic/mitophagic proteins (Fang, 2019).”
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Evidence suggests an important role for the ubiquitin-proteasome system in brain function.
“In addition to the autophagy-lysosome pathway, experimental evidence suggests an important role for the ubiquitin-proteasome system (UPS)-mediated protein degradation in brain function.”
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Three major initiators of adaptive cellular stress responses in neurons are ATP consumption, ROS production, and Ca2+ signaling.
“Three major initiators of adaptive cellular stress responses in neurons are ATP consumption, ROS production, and Ca2+ signaling.”
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Studies in aged mice show CASK is a potential downstream effector responding to age-related NAD+ depletion in hippocampus.
“Additionally, studies in aged mice show that calcium/calmodulin-dependent serine protein kinase (CASK) is a potential downstream effector in response to age-related NAD+ depletion in the hippocampus (Johnson et al., 2018).”
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- Premisecitation
During synaptic activity, transient Ca2+ influx affects glutamate receptor trafficking, cytoskeletal remodeling, and local protein synthesis through activation of kinases, phosphatases, and transcription factors PGC-1α and CREB.
“During synaptic activity, the transient Ca2+ influx affects glutamate receptor trafficking, cytoskeletal remodeling, and local protein synthesis through activation of cytosolic kinases, phosphatases, and the major neuronal transcription factors, including PGC-1α and cyclic AMP response element-binding protein (CREB) (Mattson and Arumugam, 2018; Tsien et al., 1988).”
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Perturbed Ca2+ signaling is implicated in the aging brain and age-related neurodegenerative diseases.
“Perturbed Ca2+ signaling is implicated in the aging brain and age-related neurodegenerative diseases.”
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In vitro cell culture and in vivo rodent studies suggest that reduced mitochondrial NAD+ may be more detrimental to cell death than other subcellular NAD+ pools.
“Among the different subcellular pools of NAD+, in vitro cell culture and in vivo rodent studies suggest that reduced mitochondrial NAD+ might be more detrimental to cell death than the other subcellular NAD+ pools (Yang et al., 2007).”
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- Interpretationreasoning
With advancing age, NAD+ depletion can compromise the neuronal protective functions of CD38.
“Thus, with advancing age, a depletion of NAD+ levels can compromise these neuronal protective functions of CD38.”
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In neurons, base excision repair, the main pathway for repairing oxidative DNA damage, is reduced in elderly humans and in Alzheimer's disease patients.
“In neurons, BER, the primary pathway for the repair of oxidative DNA damage, is reduced in elderly humans and in AD patients (Hou et al., 2018; McKinnon, 2013).”
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NAD+ plays an important role in maintaining the structural and functional plasticity of neuronal circuits.
“In summary, NAD+ plays an important role in the maintenance and structural and functional plasticity of neuronal circuits.”
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In Alzheimer's disease mouse models, supplementation with NAD+ precursors improves synaptic plasticity and neuronal morphology.
“Supplementation with NAD+ precursors has been shown to improve synaptic plasticity and neuronal morphology in AD mouse models (Fang et al., 2019; Hou et al., 2018).”
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The molecular mechanism by which NAD+ suppresses neuroinflammation involves elimination of damaged pro-inflammatory mitochondria and inhibition of the NLRP3 inflammasome.
“The underlying molecular mechanism by which NAD+ suppresses neuroinflammation involves the elimination of damaged pro-inflammatory mitochondria and inhibition of the major inflammasome NLRP3 (Fang et al., 2019; Lautrup et al., 2019).”
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Nicotinamide riboside treatment also improved neurogenesis and proliferation of neural progenitor cells in a BER-defective 3xTg Alzheimer's disease mouse model.
“NR treatment also improved neurogenesis and proliferation of neural progenitor cells in a BER-defective 3xTg AD mouse model (Hou et al., 2018).”
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Emerging evidence suggests that senescent cells, including p16INK4A-positive senescent astrocytes and microglia and Aβ plaque-associated p16INK4A-positive oligodendrocyte progenitor cells, have a detrimental impact on neuronal loss and cognitive impairment in Alzheimer's disease mouse models.
“Emerging evidence suggests a detrimental impact of senescent cells, including p16INK4A-positive senescent astrocytes and microglia, and Aβ plaque-associated Olig2- and NG2-expressing p16INK4A-positive oligodendrocyte progenitor cells (OPCs) in neuronal loss and cognitive impairment in mouse models of AD (Bussian et al., 2018; Zhang et al., 2019).”
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Emerging evidence points to a key role for NAD+ depletion and impairment of NAD+-dependent pathways in Alzheimer's disease pathophysiology.
“Emerging evidence points to a key role for NAD+ depletion and impairment of NAD+-dependent pathways in AD pathophysiology (Figure 4; Table 1).”
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In aged mice, nicotinamide riboside treatment increased proliferation and neurogenesis in both the subventricular zone and the dentate gyrus of the hippocampus.
“Similarly, NR treatment of aged mice resulted in increased proliferation and increased neurogenesis in both the subventricular zone and the dentate gyrus of the hippocampus in aged mice (Zhang et al., 2016).”
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- Premisecitation
In rodent models of early-onset familial Alzheimer's disease, brain NAD+ depletion and metabolic dysfunction have been demonstrated.
“In rodent models of early-onset familial AD, brain NAD+ depletion and metabolic dysfunction have been demonstrated (Dong and Brewer, 2019; Hou et al., 2018).”
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- cites Hou et al., 2018 source
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Mounting evidence supports a critical role for NAD+ in stem cell rejuvenation, including in hematopoietic stem cells, endothelial stem cells, muscle stem cells, and melanocyte stem cells.
“Mounting evidence supports a critical role for NAD+ in stem cell rejuvenation, including in HSCs, endothelial stem cells, muscle stem cells, and melanocyte stem cells (Das et al., 2018; Vannini et al., 2019; Zhang et al., 2016).”
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Studies in large numbers of human brain samples indicate that hippocampal neurogenesis progressively declines as Alzheimer's disease advances.
“In line with this, studies in large numbers of human brain samples indicate that hippocampal neurogenesis progressively declines as AD advances (Moreno-Jiménez et al., 2019).”
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Third, NAD+ augmentation restores neurogenesis in Alzheimer's disease mice by promoting the proliferation of neural progenitor cells.
“Third, NAD+ augmentation restores neurogenesis in AD mice by promoting the proliferation of neural progenitor cells (Hou et al., 2018).”
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- Interpretationreasoning
This provides strong support for the contribution of NAD+ depletion to Alzheimer's disease progression.
“This provides strong support for the contribution of NAD+ depletion to AD progression.”
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In a BER-defective 3xTgAD/Polβ+/− mouse model, nicotinamide riboside supplementation reduced DNA damage, as evidenced by reduced γH2AX staining (marking DNA double-strand breaks) in the hippocampus.
“In a BER-defective 3xTgAD/Polβ+/− mouse model, NR supplementation reduced DNA damage as evidenced by reduced γH2AX staining (marking DNA DSBs) in the hippocampus (Hou et al., 2018).”
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- Premisecitation
Exposure of cultured rat cortical neurons to aggregating Aβ results in reduced NAD+ levels.
“Exposure of cultured rat cortical neurons to aggregating Aβ results in reduced NAD+ levels (Liu et al., 2013).”
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Second, NAD+ augmentation inhibits neuroinflammation in Alzheimer's disease mice.
“Second, NAD+ augmentation inhibits neuroinflammation in AD mice (Hou et al., 2018).”
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- Interpretationreasoning
The stem cell rejuvenating activity of nicotinamide riboside/nicotinamide mononucleotide may therefore contribute to amelioration of hippocampus-dependent learning and memory deficits.
“The stem cell rejuvenating activity of NR/NMN may therefore contribute to amelioration of hippocampus-dependent learning and memory deficits.”
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On the basis of evidence from post-mortem brain tissues from Alzheimer's disease patients and different AD mouse models, damaged mitochondria and increased oxidative stress are common features of Alzheimer's disease.
“On the basis of evidence from post-mortem brain tissues from AD patients as well as different AD mouse models, damaged mitochondria and increased oxidative stress are common features of AD (Lin and Beal, 2006; Mattson et al., 2008).”
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It was recently reported that treatment with the NAD+ precursor NMN and mitophagy-inducing chemicals can reduce the accumulation of dysfunctional mitochondria in human Alzheimer's disease patient iPSC-derived neurons and in AD mouse and C. elegans models.
“It was recently reported that treatment with the NAD+ precursor NMN and mitophagy-inducing chemicals can reduce the accumulation of dysfunctional mitochondria in human AD patient iPSC-derived neurons and in AD mouse and C. elegans models (Fang et al., 2019).”
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- Interpretationcitation
Emerging evidence suggests that neurons affected in Parkinson's disease experience a deficit of NAD+.
“Emerging evidence suggests that neurons affected in PD experience a deficit of NAD+ (Table 1; Figure 4).”
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Recent studies suggest that there is an accumulation of damaged mitochondria in Alzheimer's disease caused by defective mitophagy.
“Additionally, recent studies suggest that there is an accumulation of damaged mitochondria in AD caused by defective mitophagy (Cummins et al., 2019; Fang et al., 2019).”
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NAM supplementation markedly improves behavioral and pathological phenotypes in ALS-prone SOD1-Tg mice.
“NAM supplementation dramatically improved both behavioral and pathological phenotypes in the ALS-prone SOD1-Tg mice”
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Overexpression of NAMPT or mitochondria-targeted NAMPT raises NAD+ levels, including the mitochondrial NAD+ fraction.
“overexpression of NAMPT, the protein converting NAM to NMN, or overexpression of a mitochondria-targeted NAMPT results in increased levels of NAD+, including the mitochondrial NAD+ fraction.”
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The kynurenine pathway is impaired in ALS patients.
“Similar to that in HD patients, the kynurenine pathway is also impaired in ALS.”
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NAM levels are lower in serum and CSF from ALS patients than in healthy controls.
“the NAM level was decreased in both serum and CSF samples from ALS patients (n = 60 for serum and 14 for CSF) compared with healthy controls (n = 33 for serum and 17 for CSF)”
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ALS-prone SOD1-Tg mice have lower NAM levels because the gut microbiome is impaired through loss of Akkermansia muciniphila.
“lower NAM levels in the ALS-prone SOD1-Tg mice due to impairment of the gut microbiome via diminution of the protective bacterium Akkermansia muciniphila”
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SIRT1 activators, including resveratrol, slow disease progression in ALS animal models.
“treatment with SIRT1 activators, including resveratrol, ameliorates the disease progress in ALS animal models”
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- Interpretationcitation
A preliminary EH301 trial, using an NAD+ precursor plus a SIRT1 activator, supports the importance of NAD+ metabolism and SIRT1 activation.
“The importance of NAD+ metabolism and SIRT1 activation has been supported by a recent preliminary clinical trial with EH301, consisting of an NAD+ precursor and a SIRT1 activator”
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The lack of NAM efficacy in the AD trial may have been due to the small sample size and relatively short treatment period.
“the lack of efficacy may have been due to several contributing factors, such as small sample size and a relatively short treatment period”
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NR is safe in diabetic men even at 2,000 mg/day taken twice daily for 12 weeks.
“NR was safe even at 2,000 mg/day (twice a day) for 12 weeks”
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A follow-up clinical study with a similar design found no cognitive improvements in AD patients.
“a follow-up clinical study with similar design did not result in any cognitive improvements”
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NADH has shown beneficial effects on movement in PD.
“With relation to PD, NADH has shown beneficial effects on movement.”
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An open-label study in 17 AD patients reported that NADH ingestion at a total of 10 mg/day for 8-12 weeks improved cognitive effects.
“an open-label study in 17 AD patients (33–84 years, mean age 67.7) reported that NADH ingestion (twice a day with a total 10 mg/day) for 8–12 weeks improved cognitive effects”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Rainer et al., 2000 source
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- Premisecitation
Multiple clinical trials of NAD+ precursors NAM, NR, and NMN in neurological disorders are in progress.
“Multiple clinical trials of NAD+ precursors, including NAM, NR, and NMN, in neurological disorders are in progress”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Table 2
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- Study design and conductcitation
The Dizdar et al. PD study was double-blinded.
“double-blinded study on 5 clinically moderate PD patients”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Dizdar et al., 1994 source
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- Premisecitation
In an early study, intravenous NADH at 25 mg/day for 4 days in 34 PD patients produced dramatic benefits in 21 patients (61.7%) and moderate motor improvement in the remaining 13.
“An early study using NADH (intravenous administration, 25 mg/day) in 34 PD patients for 4 days, reported that 21 patients (61.7%) showed dramatic benefits, while the remaining 13 PD patients showed moderate improvement of motor deficits”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Birkmayer et al., 1989 source
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- Premisecitation
High NAD+ levels may promote cancer, at least pancreatic cancer, through changes in senescent cell secretory activity that release pro-inflammatory cytokines.
“high NAD+ levels may lead to cancer promotion (at least in pancreatic cancer) through changes in the secretory activity of senescent cells to release pro-inflammatory cytokines”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Nacarelli et al., 2019 source
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- Premisecitation
NAD+ replenishment delays cellular senescence, including mitochondrial dysfunction-associated senescence.
“NAD+ replenishment delays cellular senescence (including mitochondrial dysfunction-associated senescence)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wiley et al., 2016 source
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- Premisecitation
A later study with 885 PD patients confirmed similar benefits for parenteral and oral NADH.
“The benefits were confirmed in a following study with 885 PD patients, also showing similar benefits between parenteral and oral applications”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Birkmayer et al., 1993 source
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- Premisecitation
A double-blinded study of 5 clinically moderate PD patients found no benefit from NADH given intravenously at 25 mg once daily for 4 days and then intramuscularly after 2 and 4 weeks.
“benefits were not seen in a double-blinded study on 5 clinically moderate PD patients treated with NADH (25 mg) given intravenously once a day for 4 days followed by NADH (25 mg) given intramuscularly after 2 and 4 weeks”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Dizdar et al., 1994 source
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- Premisecitation
Major NAD+ metabolic enzymes iNAMPT, eNAMPT, and/or NMNAT2 are overexpressed in many cancers, including breast, pancreatic, prostate, and colorectal cancers.
“Major NAD+ metabolic enzymes, e.g., iNAMPT, eNAMPT, and/or NMNAT2, are overexpressed in a broad variety of cancers including breast, pancreatic, prostate, and colorectal cancers”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Demarest et al., 2019 source
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- Premisecitation
In some cases, NAD+/NADH and its metabolites can inhibit cancer growth and metastasis.
“in some cases NAD+/NADH and its metabolites can inhibit cancer growth and metastasis”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Birkmayer, 1995
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- cites Chen et al., 2015 source
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- Premisecitation
β-hydroxybutyrate protects dopaminergic neurons in an animal model of PD.
“also protects dopaminergic neurons in an animal model of PD”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Tieu et al., 2003 source
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- Premisecitation
Clinical case reports suggest that NADH inhibits metastasis of invasive duct carcinoma, liver cancer, and breast cancer.
“a clinical case reports suggest that NADH inhibits the metastasis of invasive duct carcinoma, liver cancer, and breast cancer”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Birkmayer, 1995
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- Premisecitation
NMN may worsen axon degeneration in vitro caused by the chemotherapeutic agent vincristine.
“NMN may exacerbate axon degeneration in vitro induced by the chemotherapeutic agent vincristine”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Liu et al., 2018 source
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- Interpretationnone given
Raising brain NAD+ with NAD+, NADH, or NAD+ precursors can be limited by cell impermeability, administration route, stability, and side effects.
“Increasing NAD+ levels in the brain using NAD+, NADH, or NAD+ precursors can be limited by their cell impermeability, the different routes of administration, stability, and side effects.”
Quote in the paperNot a substantial claim - Premisecitation
Intermittent bioenergetic challenges such as exercise, fasting, and intellectual challenges may protect the human brain against age-related dysfunction and disease.
“intermittent bioenergetic challenges, as exemplified by exercise, fasting, and intellectual challenges may protect the human brain against age-related dysfunction and disease”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Mattson and Arumugam, 2018
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- cites Mattson et al., 2018
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- Premisecitation
Mouse studies show that NR has unique oral bioavailability compared with NA and NAM.
“mouse studies show that NR exhibits a unique oral bioavailability compared to NA and NAM”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Trammell et al., 2016a
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- Premisecitation
Modern, sedentary, and overindulgent lifestyles contribute to brain aging and age-related neurodegenerative diseases.
“modern, sedentary, and overindulgent lifestyles contribute to brain aging and age-related neurodegenerative diseases”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Mattson and Arumugam, 2018
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- cites Mattson et al., 2018
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- May combine two claims. 123
- Classified as probably not a substantial claim. 25
- The quote only partly states this claim. 1
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PremisecitationIn brain, enzymes that determine ambient levels of kynurenine metabolites are preferentially localized in microglia and astrocytes, suggesting glial-neuron communication.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Schwarcz and Pellicciari, 2002
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PremisecitationThe NAD+ salvage pathway recycles NAM to NMN via iNAMPT and then converts NMN to NAD+ via NMNATs.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationBlood NA and NAM can cross the plasma membrane, whereas blood NAD+ cannot be taken up directly and must be converted to smaller uncharged molecules.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationKynurenic acid antagonizes NMDA receptors, whereas quinolinic acid agonizes them.
“While kynurenic acid is an NMDA receptor antagonist, quinolinic acid is an NMDA receptor agonist (Vécsei et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Vécsei et al., 2013 source
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PremisecitationNMNAT2 is enriched in brain, and adequate levels appear essential for axon development and survival.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Gilley et al., 2019 source
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PremisecitationThe kynurenine pathway affects neuronal function by contributing to glutamate and acetylcholine synthesis and by regulating NMDA receptor activity and free radical production.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Vécsei et al., 2013 source
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PremisecitationNR enters the salvage pathway by being converted to NMN by NRK1 or NRK2.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationNAD+ is a vital redox cofactor for metabolism and ATP production and a key substrate for at least four enzyme families involved in healthspan and longevity.
“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).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe NAD+/NADH ratio is important in bioenergetic reactions across subcellular compartments, and increased activity of one reaction can alter metabolic homeostasis via changes in this ratio.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ying, 2008 source
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PremisecitationNAD+ is essential in glycolysis and the TCA cycle by accepting hydride equivalents to form NADH during ATP production.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationExtracellular NAD+ can be digested to NAM by CD38 and CD157, with NAM further metabolized to NMN by eNAMPT, or converted directly to NMN by CD73.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationSlc12a8 is an NMN transporter highly expressed and regulated by NAD+ in murine small intestine, and its deficiency abrogates NMN uptake in vitro and in vivo.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Grozio et al., 2019 source
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PremisecitationConversion of NAD+ to NADP+/NADPH is important for antioxidation, oxidative stress generation, calcium homeostasis, and cell survival or death.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ying, 2008 source
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PremisecitationNADH is a central electron donor in oxidative phosphorylation, supplying electrons to the electron transport chain to generate ATP.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationNR supplementation in mice and humans markedly increases intracellular NAAD, suggesting unknown NAD+ metabolic routes.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Trammell et al., 2016a
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PremisecitationSIRT1 promotes neurite outgrowth and axon development and regulates dendritic arborization, long-term potentiation, learning, and memory.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Gao et al., 2010 source
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PremisecitationPARP1 transfers the first ADP-ribose moiety from NAD+ to specific residues on an acceptor protein and then adds multiple ADP-ribose units to form PAR chains.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn mammals, seven SIRTs regulate many cellular pathways including neuronal survival, stem cell rejuvenation, cancer, and healthy longevity.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Chalkiadaki and Guarente, 2015
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Premisenone givenMost PARylation is carried out by PARP1, which participates in DNA repair, DNA/RNA metabolism, and cellular stress response.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPARP1 is critical for stabilizing DNA repair forks, and its catalytic activity is necessary for multiple DNA repair pathways including repair of single-strand breaks, bulky lesions, and double-strand breaks.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ray Chaudhuri and Nussenzweig, 2017 source
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PremisecitationExcessive PARP1 activation induces ATP depletion via PAR-dependent inhibition of hexokinase, causing dysfunctional glycolysis, likely independently of NAD+ depletion.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAmong 17 PARPs, only PARP1, PARP2, PARP5a, and PARP5b can add multiple ADP-ribose units (PARylation).
“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).”
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PremisecitationEvidence on mitochondrial NAMPT is debated; some liver extracts show a small fraction co-purifying with mitochondria, while other cell-line results suggest exclusion from mitochondrial matrix and lack of NAM recycling to NAD+ in mitochondria.
“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).”
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PremisecitationSARM1 cleaves NAD+ into NAM, ADPR, and cADPR via its TIR domain and is expressed in brain and non-brain tissues including liver.
“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).”
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PremisecitationCD38 is expressed in brain, and CD38 knockout mice show significant protection against ischemic brain damage.
“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).”
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PremisecitationCD38 uses NAD+ to synthesize cADPR and plays key roles in immunity, metabolism, inflammation, and social behaviors.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Jin et al., 2007 source
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PremisecitationSIRTs, PARPs, CD38/CD157, and SARM1 compete for cellular NAD+, so hyperactivation of one enzyme can impair other NAD+-dependent enzymes.
“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.”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisereasoningSubcellular NAD+ balance is regulated by expression of subcellular-specific NAD+-synthetic enzymes and by transporters for NAD+ and related metabolites.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenNAD+ is in constant equilibrium between synthesis, consumption, and recycling across subcellular compartments including cytoplasm, nucleus, mitochondria, and Golgi.
“NAD+ is in constant equilibrium between synthesis, consumption, and recycling in various subcellular compartments, including the cytoplasm, nucleus, mitochondria, and Golgi apparatus.”
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PremisecitationThe three mammalian NMNATs are nuclear NMNAT1, cytoplasmic NMNAT2, and mitochondrial NMNAT3, which is also present in cytosol.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Berger et al., 2005 source
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Premisenone givenNAMPT is primarily localized in nucleus and cytoplasm, where it regulates subcellular NAD+ levels.
“Similarly, NAMPT (Figure 1) is primarily localized in the nucleus and cytoplasm, where it regulates subcellular NAD+ levels.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationCD38 increases with age, which may contribute to cellular NAD+ depletion and impaired mitochondrial function.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Camacho-Pereira et al., 2016 source
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InterpretationcitationSARM1 NADase activity may contribute to axonal degeneration and is a potential target for therapeutic intervention in neurodegenerative diseases.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Essuman et al., 2017 source
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PremisecitationSARM1 has cyclase and glycohydrolase activities with an estimated Km of 24 μM, similar to other known NAD+ consumers.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Cantó et al., 2015 source
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Premisenone givenMitochondrial NAD+ transporters are well documented in yeast and plants, but a mammalian counterpart has not been identified.
“While the existence of mitochondrial NAD+ transporters is well documented in yeast and plants, a mammalian counterpart has yet to be identified.”
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PremisecitationSLC25A17 localizes in peroxisomes, where NAD+ participates in beta-oxidation as in mitochondria.
“Furthermore, some NAD+ transporters (SLC25A17) localize in peroxisomes, where NAD+ participates in b-oxidation like in mitochondria (Agrimi et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Agrimi et al., 2012 source
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PremisecitationPeroxisomes have a shared mitochondrial and endoplasmic reticulum origin.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sugiura et al., 2017 source
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PremisecitationNMN and NAD+/NADH can be transported into mitochondria by unknown systems; NMN is converted to NAD+ by NMNAT3 in the matrix, whereas NR is likely converted to NMN or NAD+ in cytoplasm before transport.
“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).”
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PremisecitationUSP30 is involved in pexophagy, peroxisomes have a half-life of 1.5-2.5 days, and pexophagy can be regulated by metabolic state, suggesting a role for NAD+ in pexophagy regulation.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Marcassa et al., 2018 source
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PremisecitationIn the pentose phosphate pathway, SIRT2 deacetylates and activates G6PD, which converts G6P to 6-p-gluconate; the pathway converts NADP+ to NADPH and regenerates glutathione, promoting survival during oxidative stress.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wu and Sinclair, 2014
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InterpretationcitationPossible causes of reduced cellular NAD+ during aging include increased consumption by PARPs and CD38 and reduced production, as evidenced by reduced eNAMPT in aged mice and humans.
“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).”
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InterpretationcitationThe benefits of NAD+ augmentation likely involve reduced DNA damage and decreased PARP1 activity.
“The mechanism underlying the benefits of NAD+ augmentation likely involves reduced levels of DNA damage, leading to decreased PARP1 activity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fang et al., 2016b
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InterpretationcitationAfter NAD+ augmentation, increased SIRT1 and PGC-1α activities and enhanced DNA repair suggest improved nuclear-to-mitochondrial communication.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fang et al., 2016b
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PremisecitationExtracellular vesicles containing eNAMPT improve cognitive/neuronal function and extend lifespan in wild-type mice.
“Furthermore, adding extracellular vesicles containing eNAMPT improved cognitive/neuronal function and extended lifespan in WT mice (Yoshida et al., 2019).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Yoshida et al., 2019 source
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PremisereasoningNAD+ augmentation restores mitochondrial function and bioenergetics, enhancing neuronal survival and improving cognitive function in premature aging animal models.
“Moreover, NAD+ augmentation restores mitochondrial function and bioenergetics, leading to enhanced neuronal survival and improved cognitive function in premature aging animal models.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationDuring aging, the brain cellular milieu exhibits mitochondrial dysfunction, oxidative macromolecule accumulation, dysregulated energy metabolism, impaired waste disposal, impaired adaptive stress signaling, compromised DNA repair, aberrant neuronal network activity, dysregulated Ca2+ handling, stem cell exhaustion, and inflammation (10 hallmarks).
“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,”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Mattson and Arumugam, 2018
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PremisecitationNMN treatment improves cognition in the CA1 Nampt-knockdown mouse model, partly through upregulation of Cask in a SIRT1-dependent manner.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Johnson et al., 2018 source
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PremisecitationCellular senescence and telomere damage may also apply in some glial cells and neural progenitor cells in the brain, but this remains elusive.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mattson and Arumugam, 2018
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PremisecitationMitochondria generate ATP for neuronal activities including neurotransmission and Ca2+ homeostasis and provide signals regulating nuclear-mitochondrial communication and neuronal survival/death.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mattson et al., 2008 source
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PremisecitationNAD+ is central to mitochondrial homeostasis, including mitochondrial biogenesis, mitophagy, UPRmt, and nuclear-mitochondrial communication.
“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).”
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PremisecitationMitochondria from animal and post-mortem human brain tissues show age-dependent increases in functional heterogeneity, oxidative damage, reduced ETC function, disrupted membrane potential, impaired Ca2+ handling, and/or accumulation of dysfunctional mitochondria.
“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).”
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PremisecitationDuring aging, neurons accumulate dysfunctional proteins and organelles due to ROS, as shown by increased oxidative damage to DNA, proteins, and lipids in the aging brain.
“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).”
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PremisecitationSuperoxide from mitochondrial electron transport and NADPH oxidase are the two major routes of cellular ROS production, and NAD+/NADH and NADP+/NADPH play key roles in cellular antioxidant systems.
“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).”
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PremisecitationIn quiescent neural stem cells from old mice, lysosome activity decreases with age and protein aggregates accumulate.
“In quiescent NSCs from old mice, an age-dependent reduction of lysosome activity with accumulated protein aggregates was observed.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Leeman et al., 2018 source
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PremisecitationThe autophagy-lysosome pathway maintains healthy brain function by supporting survival and function of mature neurons and preserving a youthful state of the neural stem cell pool.
“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.”
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PremisecitationLong-lived animals including naked mole-rats, calorie-restricted/intermittent-fasting rodents, and long-lived daf-2 mutant worms have decreased oxidative damage and greater resistance to oxidative stress.
“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).”
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InterpretationcitationReduced NAD+ levels play a pivotal role in brain aging and neurodegenerative disorders because NAD+ replenishment improves mitochondrial function and biogenesis and reduces damaged mitochondria in premature aging and Alzheimer's disease models.
“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).”
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- cites Scheibye-Knudsen et al., 2014 source
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PremisecitationAs age increases, autophagy and proteasomal degradation decline, leading to proteinopathies from aberrant protein misfolding and aggregation.
“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).”
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PremisecitationEnhancing lysosome activity in old quiescent neural stem cells by TFEB expression or rapamycin clears protein aggregates and inhibits NSC activation to maintain a youthful state.
“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).”
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PremisecitationEvidence of impaired UPS in the aging brain includes age-dependent accumulation of polyubiquitinated proteins in neurons and brain-region-specific reduction of proteasome activity in hippocampus and cerebral cortex.
“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).”
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- cites Mattson and Arumugam, 2018
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PremisecitationImpaired UPS can be caused by global aging and by intracellular proteinopathies such as Ab and tau aggregates.
“Impaired UPS can be caused by the global aging process and by intracellular proteinopathies, such as Ab and tau aggregates (Saez and Vilchez, 2014).”
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PremisecitationNAD+ 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 partly through induction of autophagy/mitophagy.
“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).”
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PremisecitationImpaired autophagy with accumulated proteinopathies and impaired lysosome function/autophagy/mitophagy are common features of age-predisposed neurodegenerative diseases including AD, PD, HD, and tauopathies.
“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).”
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PremisecitationKnockdown of any of three mitophagy-related genes (pink1, pdr-1, dct-1) in a C. elegans AD model eliminated benefits of NAD+ augmentation on behavioral deficits, and mitophagy has a similar pivotal role in AD mice and AD patient-derived iPSCs.
“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).”
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PremisecitationEnhancement of UPS can improve healthy aging and longevity in disease and aged animals, although benefits to neurons and brain function remain elusive.
“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).”
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- cites Walther et al., 2015 source
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InterpretationcitationWith advancing age, these stress responses may become impaired, making neurons more vulnerable to endogenous or exogenous stress and compromising synaptic function via reduced neurotrophic factors and decreased mitochondrial function.
“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.”
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PremisecitationNADH binds and stabilizes 26S proteasomes and may also regulate 20S proteasomes.
“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).”
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PremisecitationDuring aging, impaired proteostasis and energy production plus increased oxidative damage compromise subcellular Ca2+ handling, which may lead to caspase-regulated apoptosis and PARP1-mediated neuronal death.
“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).”
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InterpretationreasoningThere is a strong link between impaired autophagy-lysosome and UPS pathways in the aging brain, while detailed linkages between NAD+ levels and these pathways remain to be studied.
“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.”
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InterpretationreasoningStrong links between NAD+ and mitochondrial function, ROS, and Ca2+ signaling suggest that increasing cellular NAD+ can improve adaptive cellular stress responses in neurons.
“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.”
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PremisecitationNAD(P) is a precursor of NAADP, cADPR, and ADPR, which are key regulators of Ca2+ signaling synthesized by CD38 and CD157 using NAD+.
“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).”
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Premisenone givenNAADP and cADPR stimulate Ca2+ release from ER stores, while cADPR regulates Ca2+ entry from extracellular space.
“NAADP and cADPR stimulate the release of Ca2+ from ER stores, whereas cADPR regulates the entry of Ca2+ from the extracellular space.”
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PremisecitationIn neurons, SIRT3 mediates adaptive responses to exercise, intermittent fasting, and excitatory challenges and helps prevent noise-induced hearing loss and spiral ganglia neurite degeneration.
“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).”
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PremisecitationNAD+ depletion acts as a phenotypic driver in several DNA damage-induced diseases, including at least Cockayne syndrome, XPA, and ataxia-telangiectasia, because restoring tissue NAD+ by inhibiting PARPs ameliorates disease pathologies.
“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).”
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PremisecitationMitochondrial NAD+ levels remain unchanged after genotoxic stress and can maintain cell viability when nuclear and cytoplasmic NAD+ are depleted.
“For example, mitochondrial NAD+ levels remain unchanged following genotoxic stress and can maintain cell viability in the conditions of depleted nuclear and cytoplasmic NAD+.”
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PremisecitationIn Alzheimer's disease mouse models, supplementation with the NAD+ precursor nicotinamide riboside inhibited disease-associated neuroinflammation, decreased numbers of activated microglia and astrocytes, and reduced pro-inflammatory cytokines.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Fang et al., 2019
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- cites Hou et al., 2018 source
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PremisecitationIn neurodegenerative mouse models including AD, HD, and premature aging A-T, NAD+ augmentation increases BDNF expression and activity, leading to enhanced synaptic plasticity and function.
“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).”
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PremisecitationBDNF is important in development, maintenance, and plasticity of the central and peripheral nervous system and protects the aging brain against injury and disease by stimulating glucose transport and mitochondrial biogenesis.
“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).”
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InterpretationreasoningImpaired DNA repair byproducts and intermediates accumulate in cells of the aging brain and may contribute to numerous human neurological diseases, at least partly through NAD+ depletion driven by PARP hyperactivation.
“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.”
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PremisecitationIn primary cell culture, nicotinamide riboside supplementation delays cellular senescence, and nicotinamide riboside treatment reduces the senescent state in neural stem cells and other stem cell types.
“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).”
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InterpretationreasoningThe available knowledge suggests an important role of reduced NAD+ levels in senescence, although further research is needed to understand the mechanisms upstream and downstream of NAD+ depletion in cell senescence in the aging brain.
“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.”
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PremisecitationNeurons affected by Aβ and p-Tau neurofibrillary pathology in Alzheimer's disease exhibit oxidative damage, impaired calcium handling, defective lysosome function and mitophagy, and reduced DNA repair.
“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).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Canter et al., 2016 source
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- cites Fang et al., 2019
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- cites Mattson et al., 2018
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InterpretationcitationWhile Aβ, p-Tau, and inflammation are major contributors to Alzheimer's disease pathogenesis, NAD+ augmentation can ameliorate cognitive deficits in AD mouse models by suppressing these pathologies.
“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.”
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PremisecitationKnockdown of CD38 in APPswePS1ΔE9 mice reduced Aβ plaques and soluble Aβ levels and increased spatial learning, possibly through upregulation of brain NAD+ levels.
“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).”
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PremisecitationNAD+ augmentation inhibited Alzheimer's disease-related pathology and cognitive decline in different AD animal models, including 3xTgAD mice treated with nicotinamide, 3xTgAD/Polβ+/− mice treated with nicotinamide riboside, and neuronal Aβ1-42 and Tau transgenic C. elegans models.
“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).”
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PremisecitationNAD+ augmentation inhibited Tau phosphorylation at Thr181, Ser202, Thr205, and Thr231, possibly through suppression of cyclin-dependent kinase 5 (Cdk5)-p25 complex activity.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Fang et al., 2019
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- cites Green et al., 2008 source
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PremisecitationConsistent with NHEJ being bolstered by NAD+, nicotinamide riboside treatment of ATM-deficient neurons improved neuronal NHEJ activity through deacetylation and activation of Ku70 and facilitated chromatin binding of Ku70 and DNA-PKcs.
“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).”
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PremisecitationFour months of NAM treatment increased p25 levels 2-fold, reduced p-TauThr231 levels, and improved cognitive function in 3xTgAD mice.
“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).”
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PremisecitationWhile long-term potentiation is impaired in 3xTgAD mice, nicotinamide riboside restores LTP, correlating with improvements in learning and memory.
“While LTP is impaired in the 3xTgAD mice, NR restores LTP, correlating with improvements in learning and memory (Hou et al., 2017).”
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PremisecitationIn mice, CD38 expression and activity 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.
“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).”
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InterpretationreasoningIn summary, NAD+ augmentation enhances synaptic plasticity and improves memory in different Alzheimer's disease mouse models, possibly through reduction of Aβ and p-Tau pathologies and suppression of inflammation.
“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).”
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PremisecitationSenolytic elimination of Aβ-associated senescent oligodendrocyte progenitor cells or Tau pathology-associated senescent glial cells ameliorates cognitive impairment in different Alzheimer's disease mouse models.
“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).”
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PremisecitationNicotinamide riboside supplementation delayed senescence of adult neural stem cells in 2-year-old mice, suggesting a role for a deficit in NAD+ or one or more of the enzymes it supports in neural-cell senescence.
“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.”
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InterpretationcitationALS is connected to NAD+ metabolism through impairment of the kynurenine pathway and possible changes in SIRT1 and SIRT3 activity.
“ALS has been linked to NAD+ metabolism via impairment of the kynurenine pathway and the potential involvement of altered SIRT1 and SIRT3 activities.”
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PremisecitationNeurons expressing the LRRK2 G2019S mutation exhibit mitochondrial dysfunction and a 30% reduction of NAD+ levels.
“As evidenced, neurons expressing the LRRK2 G2019S mutation exhibit mitochondrial dysfunction and a 30% reduction of NAD+ levels.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Schwab et al., 2017 source
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- cites Sison and Ebert, 2018
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PremisecitationNAD+-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.
“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).”
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PremisecitationNAD+ augmentation via nicotinamide riboside supplementation induced the ubiquitin-proteasome system in both the hippocampus and cortex of Tg2576 Alzheimer's disease mice and restored the mitochondrial unfolded protein response in APPswe/PSEN1dE9 AD mice.
“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.”
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PremisecitationKnockdown of PINK1 expression in primary neurons and neuroblastoma cells causes increased oxidative stress and a 50% reduction of NADH levels.
“Knockdown of PINK1 expression in primary neurons and neuroblastoma cells causes increased oxidative stress and 50% reduction of NADH levels (Gandhi et al., 2009).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Gandhi et al., 2009 source
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PremisecitationParkinson's disease is a progressive fatal neurological disorder of aging that profoundly impairs control of body movements due to loss of dopaminergic neurons in the substantia nigra, which exhibit abnormal accumulation of α-synuclein fibrils in their cell body and neurites.
“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).”
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PremisecitationDopaminergic neurons derived from iPSCs expressing mutant GBA exhibit a reduced cytosolic NAD+/NADH ratio, although no significant change in total cellular NAD+ was seen.
“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).”
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PremisecitationALS patients have higher CSF and serum levels of tryptophan, kynurenine, and quinolinic acid, and lower serum picolinic acid, than controls.
“In ALS patients, there were higher levels of CSF and serum tryptophan, kynurenine, and quinolinic acid, and decreased serum picolinic acid”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chen et al., 2010 source
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PremisecitationSIRT3 expression has been linked to ALS through a PGC-1α-dependent pathway, but the mechanism is unknown.
“SIRT3 expression has been linked to ALS in a PGC-1α-dependent pathway, though the mechanism remains unknown”
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InterpretationreasoningEven though NAD+ levels were not measured, the ALS data point to an inflammation-related excitotoxic-chelation defective mechanism.
“Though NAD+ levels were not reported, all the data suggest an inflammation-related excitotoxic-chelation defective mechanism in ALS patients.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningDifferences among findings on SIRT1 levels in ALS may result from the cell lines used or from changes in SIRT1 expression as the disease progresses.
“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.”
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PremisecitationALS patients show greater microglial inflammation and increased neuronal and microglial expression of indoleamine 2,3-dioxygenase and quinolinic acid in motor cortex and spinal cord tissues.
“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”
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InterpretationcitationImproved NAD+ salvage likely activates SIRT1, SIRT3, and/or SIRT6, reducing IDH2 acetylation and activating Nrf2, which improves motor neuron oxidative stress resistance and mitochondrial function.
“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”
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PremisecitationSIRT1 activity is altered in ALS mouse models and in postmortem ALS tissue, but the direction of the change is disputed.
“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”
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PremisecitationEnhancing the NAD+ salvage pathway protects astrocytes expressing ALS-linked mutant SOD1 and promotes motor neuron survival.
“enhancement of the NAD+ salvage pathway protects astrocytes expressing an ALS-linked mutant SOD1 and thereby promotes motor neuron survival”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Harlan et al., 2016 source
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PremisecitationTreatment with NAD+ precursors NMN or NR, or NAMPT overexpression, increases oxidative stress resistance in motor neurons and prevents toxicity from co-cultured SOD1-mutant astrocytes.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Harlan et al., 2016 source
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PremisecitationOral NR at 1,000 mg/day for 7 days increases human blood NAD+ up to 2.7-fold and the intermediate NAAD 45-fold.
“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)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Trammell et al., 2016a
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PremisecitationNR is orally bioavailable, well tolerated, and raises NAD+ in healthy middle-aged and older adults and in older diabetic males.
“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.”
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InterpretationreasoningCellular NAD+ depletion is involved in AD, PD, HD, and ALS, and treatments that raise NAD+ levels have potential therapeutic benefit in these disorders.
“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.”
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PremisecitationNR at 1,000 mg/day for 6 weeks in 24 healthy adults of average age 65 ± 7 is bioavailable and safe, with possible cardiovascular benefits.
“the data confirmed that NR was bioavailable and safe, with potential cardiovascular benefits”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Martens et al., 2018 source
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May combine two claims.
InterpretationreasoningAt least four independent clinical trials show that NR supplementation at 1-2 g/day for up to 3 months is orally bioavailable and relatively safe.
“at least four independent clinical trials indicate NR supplementation (1–2 g/day for up to 3 months) is orally bioavailable and relatively safe.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationClinical data show NAM is relatively safe at 1,000-2,000 mg/day and is readily absorbed from the gastrointestinal tract, with peak serum concentrations 1 h after oral ingestion.
“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”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationNRPT/EH301 treatment (500 mg NR plus 100 mg pterostilbene for 8 weeks in 40 people aged 60-80) raises whole blood NAD+ by 90% with no serious adverse events.
“NRPT treatment increased whole blood NAD+ levels by 90% with no serious adverse events”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dellinger et al., 2017 source
Not checked in the free run.
The quote only partly states this claim.
PremisecitationA phase II trial of NAM in 15 AD patients with mild to moderate dementia, using 1,500 mg twice daily for 24 weeks, found no significant effects.
“However, NAM did not show any significant effects”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Phelan et al., 2017
Not checked in the free run.
May combine two claims.
PremisecitationAfter 4 months, all patients in the EH301 group chose to continue treatment; after 1 year, no deterioration except in FVC was observed.
“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”
Quote in the paperSubstantial claim0 of 1 sources checked- cites de la Rubia et al., 2019 source
Not checked in the free run.
May combine two claims.
PremisecitationIncreased NAD+, through overexpressed NAD+ synthetic enzymes or NAD+ precursor supplementation, promotes cancer cell proliferation, migration, and resistance to anticancer chemo- or radiotherapy.
“increased NAD+, through either overexpressed NAD+ synthetic enzymes or supplementation with NAD+ precursors, promotes cancer cell proliferation, migration, and resistance to anticancer chemo-/radiotherapy”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Demarest et al., 2019 source
Not checked in the free run.
May combine two claims.
PremisecitationDepleting cellular NAD+ and inhibiting NAD+ synthetic enzymes can trigger cancer cell death.
“strategies to deplete cellular NAD+ and the inhibition of NAD+ synthetic enzymes can trigger cancer cell death”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Buonvicino et al., 2018 source
Not checked in the free run.
May combine two claims.
PremisecitationNRPT/EH301 treatment improved ALSFRS-R, increased the MRC grading scale index, forced vital capacity, and muscle electrical activity in ALS patients.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites de la Rubia et al., 2019 source
Not checked in the free run.
May combine two claims.
PremisecitationIn one 78-year-old male PD patient, 500 mg niacin twice daily improved rigidity and bradykinesia, while 1,000 mg twice daily caused severe nightmares and skin rash.
“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”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Alisky, 2005 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPainful flushing is a common side effect of high niacin doses.
“painful flushing is a common side effect of high NA doses”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites DiPalma and Thayer, 1991
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductcitationThe ALS EH301 trial was randomized and double-blind and included both males and females.
“The study was a randomized double-blind design and included both males and females.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites de la Rubia et al., 2019 source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
InterpretationcitationDespite the small number of participants, the EH301 trial supports the potential of NAD+ augmentation or SIRT1 activation as an ALS treatment and warrants larger trials.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites de la Rubia et al., 2019 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationcitationThe gut-to-brain axis may show effects of NAD+ augmentation and may provide a new target of interest in neurodegenerative diseases.
“the gut-to-brain axis may also show effects of NAD+ augmentation and, hereby, provide a new target of interest in neurodegenerative diseases”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Blacher et al., 2019 source
Not checked in the free run.
May combine two claims.
InterpretationcitationCancer cells and post-mitotic cells have completely different metabolism despite both being energy-demanding, which may explain why NAD+ augmentation and autophagy can be neuroprotective yet promote specific cancers such as pancreatic cancer.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sousa et al., 2016 source
Not checked in the free run.
- Rests on an assumption: Cancer cells and post-mitotic cells have fundamentally different metabolism despite both having high energy demand.
May combine two claims.
InterpretationreasoningEmerging findings reveal a critical role for NAD+ in neural resilience and in the molecular mechanisms of brain aging hallmarks.
“Emerging findings are revealing a critical role for NAD+ in neural resilience and in the molecular mechanisms of the hallmarks of brain aging.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationA phase-III randomized large clinical trial reported that oral NAM was safe and effective in reducing new nonmelanoma skin cancers and actinic keratosis in high-risk patients.
“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”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Chen et al., 2015 source
Not checked in the free run.
May combine two claims.
InterpretationcitationEmerging evidence suggests NAD+ depletion in brain cells is common during aging and is accentuated in AD, PD, HD, and ALS, and that NAD+ augmentation inhibits pathological features in animal models of these disorders.
“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”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Table 1
Not checked in the free run.
May combine two claims.
PremisecitationIn glaucoma, NAD+ depletion and mitochondrial abnormalities have been shown, and NAM treatment has beneficial effects in mouse models.
“NAD+ depletion and mitochondrial abnormalities have been shown, and beneficial effects of NAM treatment of mouse models have been reported”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Williams et al., 2017 source
Not checked in the free run.
May combine two claims.
PremisecitationThe ketone β-hydroxybutyrate raises NAD+ in neurons and suppresses Aβ and p-Tau pathologies and ameliorates behavioral deficits in a mouse model of AD.
“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”
Quote in the paperNot a substantial claim0 of 3 sources checked
The paper relies on this without support.
Mechanisms of NAD+ depletion and benefits of NAD+ augmentation observed in animal models apply to human brain aging and neurodegenerative disorders.
“While mounting evidence in animals shows age-dependent NAD+ depletion, similar data on NAD+ changes through normal aging in humans are sparse, and data from large, well-controlled population studies will be required.”
The paper relies on this without support.
Understanding NAD+-based neuronal resilience mechanisms will lead to novel approaches for healthy brain aging and treatment of neurological disorders.
“Advances in understanding the molecular and cellular mechanisms of NAD+-based neuronal resilience will lead to novel approaches for facilitating healthy brain aging and for the treatment of a range of neurological disorders.”
The paper relies on this without support.
Cancer cells and post-mitotic cells have fundamentally different metabolism despite both having high energy demand.
“Despite both being nutrition demanding, cancer cells and post-mitotic cells exhibit a completely different metabolism”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
NAD+ augmentation ameliorates both amyloid-β and p-tau pathologies and neuroinflammation.
“NAD+ augmentation ameliorates both Aβ and p-tau pathologies and neuroinflammation.125”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [125]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Opposite effects of lysosome activation on neural stem-cell activation
MinorThe review says enhancing lysosome activity inhibited activation of quiescent neural stem cells, but the cited reference's title says lysosome activation enhanced it.
“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).”
“Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging.”
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- Authors
- Lautrup, S., Sinclair, D. A., Mattson, M. P., & Fang, E. F.
- Affiliations
- University of Oslo (NO)
- Harvard University (US)
- Johns Hopkins University (US)
- Corresponding author
- Fang, Evandro F.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 30
- Issue
- 4
- Pages
- 630-655
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC6787556
- OpenAlex
- W2977367243
- Cited by
- 790
- References
- 233
- Citations by year
- 2026: 140 · 2025: 130 · 2024: 126 · 2023: 115 · 2022: 123 · 2021: 100 · 2020: 52 · 2019: 4
- FWCI
- 8.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- NORA - Norwegian Open Research Archives (submittedVersion, other-oa)
- Funders
- Mayo Clinic
- Glenn Foundation for Medical Research
- Harvard Medical School
- National Natural Science Foundation of China (207819, 269901, 81971327)
- Akershus Universitetssykehus
- Zhengzhou University
- Norges Forskningsråd (262175, 277813)
- Norges Idrettshøgskole (R01 AG019719, R01 DK100263, R37 AG028730)
- Sun Yat-sen University
- Jinan University
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- NAD+, brain aging, neurodegenerative diseases, neuronal resilience, NAD+ metabolism, neurological disease treatment
- MeSH terms
- Aging, Animals, Brain, Cell Line, Humans, NAD, Neurons, Neurodegenerative Diseases, Mice, Rats
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