NAD+ in Brain Aging and Neurodegenerative Disorders

In the paper

“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).”

What the sources say

• Not checked yetcites Bonkowski and Sinclair, 2016
• Partly supported

  The Introduction says SIRT1 regulates gene expression in response to bioenergetic challenges, and the Discussion says SIRT1 is NAD+-dependent. But the paper's findings on neuronal responses to exercise and metabolic or excitatory challenges concern SIRT3, not SIRT1. The cited passages do not support the claims about SIRT1 regulating glycolysis, gluconeogenesis, or a balance between mitochondrial biogenesis and mitophagy. Page numbers are not provided in our copy. (LLM, conf=0.88)

  cites Cheng et al., 2016 sourceExperimental — accuracy not yet measured
• Not checked yetcites Fang, 2019

In the paper

“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.”

What the sources say

• Supported

  The Results section (‘A Mitochondrially Targeted NAMPT Increases Total and Mitochondrial NAD+ Content in Astrocytes’) reports that overexpressing either NAMPT or mitochondria-targeted NAMPT increased total NAD+ and mitochondrial NAD+ in spinal cord astrocytes. The paper also describes NAMPT as catalyzing the conversion of NAM to NMN. The claim is supported in the studied cell setting. (LLM, conf=0.95)

  cites Harlan et al., 2016 source

In the paper

“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.”

What the sources say

• Not checked yetcites Vécsei et al., 2013 source

In the paper

“Three mammalian NMNATs exist, NMNAT1–3, showing neuroprotective effects in both mice and D. melanogaster models (Ali et al., 2013).”

What the sources say

• Not checked yetcites Ali et al., 2013 source

In the paper

“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).”

What the sources say

• Not checked yetcites Vécsei et al., 2013 source

In the paper

“In addition to ATP loss, hyperactivation of PARP1-induced NAD+ depletion can induce neuronal loss and accelerated aging (Fang et al., 2016a).”

What the sources say

• Not checked yetcites Fang et al., 2016a

In the paper

“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”

What the sources say

• ?Not matched

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

  cites Wang et al., 2011, 2016
• ?Not matched

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

  cites Yu et al., 2002

In the paper

“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).”

In the paper

“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).”

What the sources say

• Not checked yetcites Gilley and Coleman, 2010 source
• Not checked yetcites Mayer et al., 2010 source

In the paper

“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).”

What the sources say

• Not checked yetcites Johnson et al., 2018 source

In the paper

“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).”

What the sources say

• Not checked yetcites Stein and Imai, 2014

In the paper

“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).”

What the sources say

• Not checked yetcites Zhu et al., 2015 source

In the paper

“During normal aging, lower NAD+ levels are observed in tissues of various organisms including humans, mice, and C. elegans.”

What the sources say

• Not checked yetcites Zhu et al., 2015 source
• Not checked yetcites Stein and Imai, 2014
• Not checked yetcites Fang et al., 2014 source

In the paper

“Similarly, an age-dependent reduction of organismal NAD+ in wild-type (WT) worms has been shown (Fang et al., 2014).”

What the sources say

• Not checked yetcites Fang et al., 2014 source

In the paper

“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).”

What the sources say

• ?Not matched

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

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

In the paper

“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.”

What the sources say

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

In the paper

“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).”

What the sources say

• Not checked yetcites Fang et al., 2014 source
• Not checked yetcites Mouchiroud et al., 2013 source
• Not checked yetcites Stein and Imai, 2014

In the paper

“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).”

What the sources say

• Not checked yetcites Fang et al., 2019
• Not checked yetcites Hansen et al., 2018 source
• Not checked yetcites Palikaras et al., 2015 source

In the paper

“Emerging findings are revealing linkages by which age-related NAD+ depletion is positively related to the 10 hallmarks of brain aging.”

What the sources say

• Not checked yetcites Fang et al., 2017 source
• Not checked yetcites Lou et al., 2019
• Not checked yetcites Mattson and Arumugam, 2018

In the paper

“As described in the following sections, reduced NAD+ levels contribute to most, if not all, of the hallmarks of brain aging.”

In the paper

“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).”

What the sources say

• Not checked yetcites Gomes et al., 2013 source

In the paper

“Thus, NAD+ is critical for the coupling of mitochondrial biogenesis and mitophagy to maintain mitochondrial homeostasis in neurons.”

In the paper

“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).”

What the sources say

• Not checked yetcites Braidy et al., 2011 source

In the paper

“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).”

What the sources say

• Not checked yetcites Fang et al., 2016a, 2019
• Not checked yetcites Scheibye-Knudsen et al., 2014 source

In the paper

“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).”

What the sources say

• Not checked yetcites Fang et al., 2019
• Not checked yetcites Ravikumar et al., 2004 source
• Not checked yetcites Sliter et al., 2018 source

In the paper

“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).”

What the sources say

• Not checked yetcites Jarome and Devulapalli, 2018
• Not checked yetcites Jarome et al., 2013, 2016

In the paper

“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).”

What the sources say

• Not checked yetcites Fang, 2019

In the paper

“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.”

In the paper

“Three major initiators of adaptive cellular stress responses in neurons are ATP consumption, ROS production, and Ca2+ signaling.”

In the paper

“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).”

What the sources say

• Not checked yetcites Johnson et al., 2018 source

In the paper

“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).”

What the sources say

• Not checked yetcites Mattson and Arumugam, 2018
• Not checked yetcites Tsien et al., 1988 source

In the paper

“Perturbed Ca2+ signaling is implicated in the aging brain and age-related neurodegenerative diseases.”

In the paper

“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).”

What the sources say

• Not checked yetcites Yang et al., 2007 source

In the paper

“Thus, with advancing age, a depletion of NAD+ levels can compromise these neuronal protective functions of CD38.”

In the paper

“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).”

What the sources say

• Not checked yetcites Hou et al., 2018 source
• Not checked yetcites McKinnon, 2013 source

In the paper

“In summary, NAD+ plays an important role in the maintenance and structural and functional plasticity of neuronal circuits.”

In the paper

“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).”

What the sources say

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

In the paper

“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).”

What the sources say

• Not checked yetcites Fang et al., 2019
• Not checked yetcites Lautrup et al., 2019 source

In the paper

“NR treatment also improved neurogenesis and proliferation of neural progenitor cells in a BER-defective 3xTg AD mouse model (Hou et al., 2018).”

What the sources say

• Not checked yetcites Hou et al., 2018 source

In the paper

“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).”

What the sources say

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

In the paper

“Emerging evidence points to a key role for NAD+ depletion and impairment of NAD+-dependent pathways in AD pathophysiology (Figure 4; Table 1).”

What the sources say

• Not checked yetcites Figure 4
• Not checked yetcites Table 1

In the paper

“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).”

What the sources say

• Not checked yetcites Zhang et al., 2016 source

In the paper

“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).”

What the sources say

• Not checked yetcites Dong and Brewer, 2019
• Not checked yetcites Hou et al., 2018 source

In the paper

“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).”

What the sources say

• Not checked yetcites Das et al., 2018
• Not checked yetcites Vannini et al., 2019 source
• Not checked yetcites Zhang et al., 2016 source

In the paper

“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).”

What the sources say

• Not checked yetcites Moreno-Jiménez et al., 2019 source

In the paper

“Third, NAD+ augmentation restores neurogenesis in AD mice by promoting the proliferation of neural progenitor cells (Hou et al., 2018).”

What the sources say

• Not checked yetcites Hou et al., 2018 source

In the paper

“This provides strong support for the contribution of NAD+ depletion to AD progression.”

In the paper

“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).”

What the sources say

• Not checked yetcites Hou et al., 2018 source

In the paper

“Exposure of cultured rat cortical neurons to aggregating Aβ results in reduced NAD+ levels (Liu et al., 2013).”

What the sources say

• Not checked yetcites Liu et al., 2013 source

In the paper

“Second, NAD+ augmentation inhibits neuroinflammation in AD mice (Hou et al., 2018).”

What the sources say

• Not checked yetcites Hou et al., 2018 source

In the paper

“The stem cell rejuvenating activity of NR/NMN may therefore contribute to amelioration of hippocampus-dependent learning and memory deficits.”

In the paper

“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).”

What the sources say

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

In the paper

“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).”

What the sources say

• Not checked yetcites Fang et al., 2019

In the paper

“Emerging evidence suggests that neurons affected in PD experience a deficit of NAD+ (Table 1; Figure 4).”

What the sources say

• Not checked yetcites Table 1
• Not checked yetcites Figure 4

In the paper

“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).”

What the sources say

• Not checked yetcites Cummins et al., 2019 source
• Not checked yetcites Fang et al., 2019

In the paper

“NAM supplementation dramatically improved both behavioral and pathological phenotypes in the ALS-prone SOD1-Tg mice”

What the sources say

• Not checked yetcites Blacher et al., 2019 source

In the paper

“Similar to that in HD patients, the kynurenine pathway is also impaired in ALS.”

What the sources say

• Not checked yetcites Chen et al., 2010 source

In the paper

“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)”

What the sources say

• Not checked yetcites Blacher et al., 2019 source

In the paper

“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”

What the sources say

• Not checked yetcites Blacher et al., 2019 source

In the paper

“treatment with SIRT1 activators, including resveratrol, ameliorates the disease progress in ALS animal models”

What the sources say

• Not checked yetcites Tang, 2017 source

In the paper

“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”

What the sources say

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

In the paper

“the lack of efficacy may have been due to several contributing factors, such as small sample size and a relatively short treatment period”

What the sources say

• Not checked yetcites Phelan et al., 2017

In the paper

“NR was safe even at 2,000 mg/day (twice a day) for 12 weeks”

What the sources say

• Not checked yetcites Dollerup et al., 2018 source

In the paper

“a follow-up clinical study with similar design did not result in any cognitive improvements”

What the sources say

• Not checked yetcites Rainer et al., 2000 source

In the paper

“With relation to PD, NADH has shown beneficial effects on movement.”

What the sources say

• Not checked yetcites Birkmayer et al., 1989 source
• Not checked yetcites Birkmayer et al., 1993 source

In the paper

“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”

What the sources say

• Not checked yetcites Rainer et al., 2000 source

In the paper

“Multiple clinical trials of NAD+ precursors, including NAM, NR, and NMN, in neurological disorders are in progress”

What the sources say

• Not checked yetcites Table 2

In the paper

“double-blinded study on 5 clinically moderate PD patients”

What the sources say

• Not checked yetcites Dizdar et al., 1994 source

In the paper

“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”

What the sources say

• Not checked yetcites Birkmayer et al., 1989 source

In the paper

“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”

What the sources say

• Not checked yetcites Nacarelli et al., 2019 source

In the paper

“NAD+ replenishment delays cellular senescence (including mitochondrial dysfunction-associated senescence)”

What the sources say

• Not checked yetcites Wiley et al., 2016 source

In the paper

“The benefits were confirmed in a following study with 885 PD patients, also showing similar benefits between parenteral and oral applications”

What the sources say

• Not checked yetcites Birkmayer et al., 1993 source

In the paper

“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”

What the sources say

• Not checked yetcites Dizdar et al., 1994 source

In the paper

“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”

What the sources say

• Not checked yetcites Demarest et al., 2019 source

In the paper

“in some cases NAD+/NADH and its metabolites can inhibit cancer growth and metastasis”

What the sources say

• Not checked yetcites Birkmayer, 1995
• Not checked yetcites Chen et al., 2015 source

In the paper

“also protects dopaminergic neurons in an animal model of PD”

What the sources say

• Not checked yetcites Tieu et al., 2003 source

In the paper

“a clinical case reports suggest that NADH inhibits the metastasis of invasive duct carcinoma, liver cancer, and breast cancer”

What the sources say

• Not checked yetcites Birkmayer, 1995

In the paper

“NMN may exacerbate axon degeneration in vitro induced by the chemotherapeutic agent vincristine”

What the sources say

• Not checked yetcites Liu et al., 2018 source

In the paper

“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.”

In the paper

“intermittent bioenergetic challenges, as exemplified by exercise, fasting, and intellectual challenges may protect the human brain against age-related dysfunction and disease”

What the sources say

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

In the paper

“mouse studies show that NR exhibits a unique oral bioavailability compared to NA and NAM”

What the sources say

• Not checked yetcites Trammell et al., 2016a

In the paper

“modern, sedentary, and overindulgent lifestyles contribute to brain aging and age-related neurodegenerative diseases”

What the sources say

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