NAD+ metabolism and its roles in cellular processes during ageing

In the paper

“However, since PARP1 has lower Km and higher Vmax with regard to NAD+ than SIRT1, PARP1 likely outcompetes SIRT1 for NAD+ as a result of its greater binding affinity and faster kinetics34.”

What the sources say

• Supported

  Section 2.2 states that PARP-1 has a fivefold lower Km and a much stronger Vmax than SIRT1, supporting the cited sentence’s proposed advantage in competing for NAD+. Section 2.1 also describes competition for a limited NAD+ pool. The verbatim citing sentence does not make the additional same-compartment assertion included in the supplied paraphrase. (LLM, conf=0.91)

  cites [34] Cantó, C., Sauve, A. A. & Bai, P. Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes. Mol. Asp. Med. 34, 1168–1201 (2013). source

In the paper

“Although this observation was initially disregarded, there is now growing evidence that ageing not only leads to increased macrophage abundance but is also accompanied by altered macrophage polarization state and function, which is emerging as a key driver of inflammageing98,99.”

What the sources say

• Partly supported

  The ‘Macrophage lineage cells in metabolic control’ section reports a shift toward proinflammatory M1 macrophages in aged mouse visceral fat and higher cytokine expression, while the ‘Perspectives’ section links changes in macrophage phenotype and function to inflammaging. Those passages support the polarization and function parts of the claim, but the retrieved passages do not establish a general increase in macrophage abundance with age; the reported increase in visceral-fat cell numbers concerns T cells. (LLM, conf=0.85)

  cites [98] Oishi, Y. & Manabe, I. Macrophages in age-related chronic inflammatory diseases. NPJ Aging Mech. Dis. 2, 16018 (2016). sourceExperimental — accuracy not yet measured
• Not checked yetcites [99] van Beek, A. A., Van den Bossche, J., Mastroberardino, P. G., de Winther, M. P. J. & Leenen, P. J. M. Metabolic alterations in aging macrophages: ingredients for inflammaging? Trends Immunol. 40, 113–127 (2019). source

In the paper

“Additionally, higher NAD+ levels can promote the deacetylase and deacylase activity of both nuclear SIRT1 and mitochondrial SIRT3, which regulate mitochondrial function and protect from high-fat diet-induced metabolic disease42,81,85–88.”

What the sources say

• Not checked yetcites [42] Camacho-Pereira, J. et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 23, 1127–1139 (2016). This study demonstrates that CD38 expression increases in multiple tissues during aging and that CD38 is a major NADase involved in the ageing-related tissue decline of NAD+ levels. source
• Partly supported

  The Results (‘NR enhances sirtuin activity in vivo’; page unavailable) report increased NAD+ alongside deacetylation of SIRT1 and SIRT3 targets in tissues where NAD+ rose. The Discussion links NR-driven NAD+ increases to activity in nuclear and mitochondrial compartments, and the Results link this tissue-specific response to mitochondrial function and protection against metabolic damage. The paper does not establish deacylase activity beyond deacetylation, so that additional part of the claim is unsupported. (LLM, conf=0.86)

  cites [81] Cantó, C. et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 15, 838–847 (2012). sourceExperimental — accuracy not yet measured
• Partly supported

  The paper’s Abstract says SIRT3 requires NAD+ and would be more active at a high NAD+/NADH ratio; it also reports that SIRT3 deacetylates LCAD and regulates mitochondrial fatty-acid oxidation during fasting. It does not establish SIRT1 activity, deacylase activity, or protection from high-fat diet-induced metabolic disease. (LLM, conf=0.87)

  cites [85] Hirschey, M. D. et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464, 121–125 (2010). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (page not provided) identifies sirtuins as NAD+-dependent deacetylases and SIRT3 as mitochondrial. The Results report NAD+-dependent SIRT3 deacetylase activity, while the Discussion links SIRT3 loss to worse high-fat-diet metabolic outcomes. The paper does not establish the claimed effects of higher NAD+ levels on SIRT1, address deacylase activity, or show that raising NAD+ protects against metabolic disease. (LLM, conf=0.88)

  cites [86] Hirschey, M. D. et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol. Cell 44, 177–190 (2011). sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page unavailable) reports that resveratrol facilitates SIRT1-mediated deacetylation, improves mitochondrial function, and protects mice on a high-fat diet from obesity and insulin resistance. It does not establish that higher NAD+ levels produce those effects, or address mitochondrial SIRT3 or deacylase activity. (LLM, conf=0.88)

  cites [87] Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127, 1109–1122 (2006). sourceExperimental — accuracy not yet measured
• Not checked yetcites [88] Pfluger, P. T., Herranz, D., Velasco-Miguel, S., Serrano, M. & Tschöp, M. H. Sirt1 protects against high-fat diet-induced metabolic damage. Proc. Natl Acad. Sci. USA 105, 9793–9798 (2008). source

In the paper

“Ageing is associated with increased activation of the NLRP3 inflammasome45,107, which is primarily expressed by myeloid immune cells107,108, and a subsequent increase in the expression of IL-1β, which is a major cytokine implicated in promoting ageing-related disease107.”

What the sources say

• Partly supported

  The Results section on ageing adipose tissue reports increased Il1b mRNA and greater inflammasome activation in old mice, indicated by processed caspase-1. It does not identify that inflammasome as NLRP3, establish that NLRP3 is primarily expressed by myeloid immune cells, or show that its activation caused the increase in Il1b. The cited passage also does not link IL-1β specifically to ageing-related disease. (LLM, conf=0.88)

  cites [45] Covarrubias, A. J. et al. Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. Nat. Metab. 2, 1265–1283 (2020). sourceExperimental — accuracy not yet measured
• Supported

  The Results sections report age-related Nlrp3-dependent caspase-1 activation and increased IL-1β expression in adipose tissue and the hippocampus. The CNS Results section also states that the inflammasome is expressed in myeloid-lineage cells; the Introduction links IL-1 to age-related degenerative disease. Page numbers are unavailable in our copy. (LLM, conf=0.89)

  cites [107] Youm, Y.-H. et al. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab. 18, 519–532 (2013). source
• ?Could not verify

  The Abstract describes a single-cell dataset from 3-month-old mice, not an analysis of ageing. Searches for NLRP3, myeloid-cell expression, and IL-1β found no passage in our copy addressing the claimed inflammasome activation or subsequent cytokine increase. (LLM, conf=0.76)

  cites [108] Tabula Muris Consortium et al. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 562, 367–372 (2018). This is a compendium of single-cell transcriptomic data that comprises more than 100,000 cells from 20 mouse organs and tissues. sourceExperimental — accuracy not yet measured

In the paper

“We showed that macrophages co-cultured in or exposed to conditioned media from senescent cells have enhanced expression of the NAD+-consuming enzyme CD38 and increased proliferation45.”

What the sources say

• Not checked yetcites [45] Covarrubias, A. J. et al. Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. Nat. Metab. 2, 1265–1283 (2020). source

In the paper

“However, during ageing, this balance between catabolic and anabolic processes can shift, and NAD+ degradation can outpace the ability of cells to make NAD+ de novo or their ability to effectively recycle or salvage NAM.”

In the paper

“Briefly, the PARP-mediated cleavage of NAD+ produces NAM and ADP-ribose as by-products, in which ADP-ribose is added as single or covalently linked polymers to PARP itself and other acceptor proteins, in a process called ‘poly(ADP-ribosyl)ation’ (PARylation) (FIG. 2b).”

In the paper

“Among all the PARPs, only PARP1, PARP2 and PARP3 localize to the nucleus (FIG. 1b) in response to early DNA damage and have a key role in DNA damage repair25–27 (Supplementary Box 2).”

What the sources say

• Not checked yetcites [25] Bai, P. & Cantó, C. The role of PARP-1 and PARP-2 enzymes in metabolic regulation and disease. Cell Metab. 16, 290–295 (2012). source
• Not checked yetcites [26] Oliver, A. W. et al. Crystal structure of the catalytic fragment of murine poly(ADP-ribose) polymerase-2. Nucleic Acids Res. 32, 456–464 (2004). source
• Not checked yetcites [27] Boehler, C. et al. Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression. Proc. Natl Acad. Sci. USA 108, 2783–2788 (2011). source

In the paper

“Early studies in yeast demonstrated roles of sirtuins in gene silencing, which in 2000 was attributed to their activity as NAD+-dependent deacetylases12.”

What the sources say

• Not checked yetcites [12] Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000). This study is the first to demonstrates that sirtuin function is dependent on NAD+. source

In the paper

“The human PARP protein family is composed of 17 proteins characterized by poly(ADP-ribosyl) polymerase or mono(ADP-ribosyl) polymerase activity24.”

What the sources say

• Not checked yetcites [24] Hottiger, M. O., Hassa, P. O., Lüscher, B., Schüler, H. & Koch-Nolte, F. Toward a unified nomenclature for mammalian ADP-ribosyltransferases. Trends Biochem. Sci. 35, 208–219 (2010). source

In the paper

“Thus, besides the liver, the de novo biosynthetic pathway seems to be a more indirect mechanism contributing to system-wide NAD+ levels, with most NAD+ coming from the NAM salvage pathway (BOX 1).”

What the sources say

• Not checked yetcites [5] Liu, L. et al. Quantitative analysis of NAD synthesis-breakdown fluxes. Cell Metab. 27, 1067–1080.e5 (2018). This study demonstrates that NAD+ synthesis breakdown fluxes differ widely across tissues, suggesting a tissue-specific NAD+ metabolism. source

In the paper

“While enhancing the activation of sirtuins has emerged as a way to increase lifespan and healthspan, aberrant activation of PARPs and NAD+ glycohydrolases, such as CD38, may exert the opposite effect and exacerbate ageing phenotypes (see later).”

In the paper

“In apparent contrast with its role in promoting mitochondrial biogenesis through peroxisome proliferator-activated receptor-γ co-activator 1α deacetylation19–21, SIRT1 has also been implicated in turnover of defective mitochondria by mitophagy22,23.”

What the sources say

• Not checked yetcites [19] Amat, R. et al. SIRT1 controls the transcription of the peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) gene in skeletal muscle through the PGC-1α Autoregulatory Loop and Interaction with MyoD. J. Biol. Chem. 284, 21872–21880 (2009). source
• Not checked yetcites [20] Nemoto, S., Fergusson, M. M. & Finkel, T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. J. Biol. Chem. 280, 16456–16460 (2005). source
• Not checked yetcites [21] Gurd, B. J. Deacetylation of PGC-1α by SIRT1: importance for skeletal muscle function and exercise-induced mitochondrial biogenesis. Appl. Physiol. Nutr. Metab. 36, 589–597 (2011). source
• Not checked yetcites [22] Kang, H. T. & Hwang, E. S. Nicotinamide enhances mitochondria quality through autophagy activation in human cells. Aging Cell 8, 426–438 (2009). source
• Not checked yetcites [23] Jang, S.-Y., Kang, H. T. & Hwang, E. S. Nicotinamide-induced mitophagy: event mediated by high NAD+/NADH ratio and SIRT1 protein activation. J. Biol. Chem. 287, 19304–19314 (2012). source

In the paper

“Most tryptophan is metabolized to NAM in the liver, where it is released into the serum, taken up by peripheral cells and converted to NAD+ by the NAM salvage pathway5.”

What the sources say

• Not checked yetcites [5] Liu, L. et al. Quantitative analysis of NAD synthesis-breakdown fluxes. Cell Metab. 27, 1067–1080.e5 (2018). This study demonstrates that NAD+ synthesis breakdown fluxes differ widely across tissues, suggesting a tissue-specific NAD+ metabolism. source

In the paper

“Specifically, recent evidence has shown that nuclear SIRT1, SIRT6 and SIRT7 are critical regulators of DNA repair and genome stability and that mitochondrial SIRT3, SIRT4 and SIRT5 and nuclear SIRT1 regulate mitochondrial homeostasis and metabolism7.”

What the sources say

• Not checked yetcites [7] Carrico, C., Meyer, J. G., He, W., Gibson, B. W. & Verdin, E. The mitochondrial acylome emerges: proteomics, regulation by sirtuins, and metabolic and disease implications. Cell Metab. 27, 497–512 (2018). source

In the paper

“NAD+ can be made de novo from l-tryptophan via the kynurenine pathway or from vitamin precursors, such as nicotinic acid (NA), via the Preiss–Handler pathway (FIG. 1a).”

In the paper

“In addition, SIRT1 and a key enzyme of the NAD+ salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT) (BOX 1), are key players in the circadian regulation of NAD+ levels, and NAMPT is regulated by the circadian clock, which provides a feedback loop, resulting in circadian oscillation of NAD+ levels10,11.”

What the sources say

• Not checked yetcites [10] Ramsey, K. M. et al. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science 324, 651–654 (2009). source
• Not checked yetcites [11] Nakahata, Y., Sahar, S., Astarita, G., Kaluzova, M. & Sassone-Corsi, P. Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science 324, 654–657 (2009). This study demonstrates that intracellular NAD+ levels are regulated by the core circadian regulator CLOCK–BMAL1 through the modulation of NAMPT expression. source

In the paper

“Additionally, some cells, mostly in the liver, can synthesize NAD+ de novo from multiple dietary sources.”

In the paper

“Therefore, targeting NAD+ metabolism has emerged as a potential therapeutic approach to ameliorate ageing-related disease, and extend the human healthspan and lifespan.”

In the paper

“Some of these critical cellular processes include metabolic pathways, redox homeostasis, maintenance and repair of DNA to safeguard genomic stability, epigenetic regulation and chromatin remodelling, and autophagy.”

In the paper

“Accordingly, NAD+ is a mediator of key cellular functions and adaptation to metabolic needs.”

In the paper

“PARP3 is important in DNA repair as well27, suggesting a large overlap and potential redundancy in PARP1, PARP2 and PARP3.”

What the sources say

• Not checked yetcites [27] Boehler, C. et al. Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression. Proc. Natl Acad. Sci. USA 108, 2783–2788 (2011). source

In the paper

“CD38 also performs a base-exchange reaction, by swapping the NAM of NAD(P)+ for NA in acidic conditions and generating nicotinic acid adenine dinucleotide (phosphate) (NAAD(P))37 (FIG. 2c).”

What the sources say

• Not checked yetcites [37] Liu, Q., Kriksunov, I. A., Hao, Q., Graeff, R. & Lee, H. C. Acidic residues at the active sites of CD38 and ADP-ribosyl cyclase determine NAAPD synthesis and hydrolysis activities. J. Biol. Chem. https://doi.org/10.2210/pdb2hct/pdb (2006). source

In the paper

“SARM1 was only very recently assigned to the NAD+ glycohydrolase and cyclase family along with CD38 and CD157.”

In the paper

“The CD38–CD31 axis seems to promote a proliferative response in chronic lymphocytic leukaemia lymphocytes, suggesting a detrimental role of CD38 in blood cancers53,54 (see Supplementary Box 3).”

What the sources say

• Not checked yetcites [53] Vallario, A. et al. Human myeloma cells express the CD38 ligand CD31. Br. J. Haematol. 105, 441–444 (1999). source
• Not checked yetcites [54] Deaglio, S. et al. CD38/CD31 interactions activate genetic pathways leading to proliferation and migration in chronic lymphocytic leukemia cells. Mol. Med. 16, 87–91 (2010). source

In the paper

“The glycohydrolysis of NAD+ is the primary catalytic reaction that cleaves the glycosidic bond within NAD+ to generate NAM and ADP-ribose, whereas the ADP-ribosyl cyclase activity generates cyclic ADP-ribose (FIG. 2c).”

In the paper

“Despite its controversial role in immune cells, SARM1 plays an undisputed key role in axonal degeneration and is emerging as a therapeutic target to prevent or ameliorate neurodegenerative diseases and traumatic brain injuries (as discussed in the section Neurodegeneration).”

What the sources say

• Not checked yetcites [60] Gerdts, J., Brace, E. J., Sasaki, Y., DiAntonio, A. & Milbrandt, J. SARM1 activation triggers axon degeneration locally via NAD destruction. Science 348, 453–457 (2015). source

In the paper

“SARM1 is primarily expressed in neurons and promotes neuronal morphogenesis and inflammation61,62; however, SARM1 is also expressed by immune cells such as macrophages and T lymphocytes, and regulates their functions63–65.”

What the sources say

• Not checked yetcites [61] Wang, Q. et al. Sarm1/Myd88-5 regulates neuronal intrinsic immune response to traumatic axonal injuries. Cell Rep. 23, 716–724 (2018). source
• Not checked yetcites [62] Lin, C.-W., Chen, C.-Y., Cheng, S.-J., Hu, H.-T. & Hsueh, Y.-P. Sarm1 deficiency impairs synaptic function and leads to behavioral deficits, which can be ameliorated by an mGluR allosteric modulator. Front. Cell. Neurosci. 8, 87 (2014).
• Not checked yetcites [63] Carty, M. et al. The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nat. Immunol. 7, 1074–1081 (2006). source
• Not checked yetcites [64] Panneerselvam, P. et al. T-cell death following immune activation is mediated by mitochondria-localized SARM. Cell Death Differ. 20, 478–489 (2013). source
• Not checked yetcites [65] Zhao, Z. Y. et al. A cell-permeant mimetic of NMN activates SARM1 to produce cyclic ADP-ribose and induce non-apoptotic cell death. iScience 15, 452–466 (2019). source

In the paper

“However, recent evidence shows that, like CD38, CD157 is upregulated in ageing tissues45 and may have a role in ageing-related diseases, such as rheumatoid arthritis and cancer46.”

What the sources say

• Not checked yetcites [45] Covarrubias, A. J. et al. Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. Nat. Metab. 2, 1265–1283 (2020). source
• Not checked yetcites [46] Ortolan, E., Augeri, S., Fissolo, G., Musso, I. & Funaro, A. CD157: from immunoregulatory protein to potential therapeutic target. Immunol. Lett. 205, 59–64 (2019). source

In the paper

“SARM1 was originally discovered as a negative regulator of the innate immune response via direct interaction with TRIF (TIR domain-containing adapter protein inducing interferon-β), downstream of Toll-like receptor signalling63.”

What the sources say

• Not checked yetcites [63] Carty, M. et al. The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nat. Immunol. 7, 1074–1081 (2006). source

In the paper

“Importantly, other than NAD+ and NADP+, NMN is emerging as an alternative substrate of CD38 (REFS41,42), whereas CD157 consumes NR as an alternative substrate43,44 (FIG. 2c).”

What the sources say

• Not checked yetcites [41] Torti, M., Bertoni, A., Canobbio, I., Sinigaglia, F. & Balduini, C. Hydrolysis of NADP by platelet CD38 in the absence of synthesis and degradation of cyclic ADP-ribose 2′-phosphate. FEBS Lett. 455, 359–363 (1999). source
• Not checked yetcites [42] Camacho-Pereira, J. et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 23, 1127–1139 (2016). This study demonstrates that CD38 expression increases in multiple tissues during aging and that CD38 is a major NADase involved in the ageing-related tissue decline of NAD+ levels. source
• Not checked yetcites [43] Aomatsu, E. et al. Novel SCRG1/BST1 axis regulates self-renewal, migration, and osteogenic differentiation potential in mesenchymal stem cells. Sci. Rep. 4, 3652 (2014). source
• Not checked yetcites [44] Preugschat, F. et al. A pre-steady state and steady state kinetic analysis of the N-ribosyl hydrolase activity of hCD157. Arch. Biochem. Biophys. 564, 156–163 (2014). source

In the paper

“CD38 is a transmembrane protein with a type ii orientation and/or a type III orientation identified in the late 1970s as a T cell activation marker but now known to be ubiquitously expressed, particularly during inflammation47,48.”

What the sources say

• Not checked yetcites [47] Reinherz, E. L., Kung, P. C., Goldstein, G., Levey, R. H. & Schlossman, S. F. Discrete stages of human intrathymic differentiation: analysis of normal thymocytes and leukemic lymphoblasts of T-cell lineage. Proc. Natl Acad. Sci. USA 77, 1588–1592 (1980). source
• Not checked yetcites [48] Shubinsky, G. & Schlesinger, M. The CD38 lymphocyte differentiation marker: new insight into its ectoenzymatic activity and its role as a signal transducer. Immunity 7, 315–324 (1997). source

In the paper

“Several lines of evidence suggest that CD157 activation by specific monoclonal antibodies promotes trafficking of neutrophils and monocytes58.”

What the sources say

• Not checked yetcites [58] Funaro, A. et al. CD157 is an important mediator of neutrophil adhesion and migration. Blood 104, 4269–4278 (2004). source

In the paper

“CD157 is a glycophosphatidylinositol-anchored protein, which was first identified in the myeloid compartment of the haematopoietic system49. However, CD157 is also expressed by other cells, including B cell progenitors, Paneth cells and endothelial cells in the gut, pancreas and kidney50.”

What the sources say

• Not checked yetcites [49] Todd, R. F. 3rd, Roach, J. A. & Arnaout, M. A. The modulated expression of Mo5, a human myelomonocytic plasma membrane antigen. Blood 65, 964–973 (1985).
• Not checked yetcites [50] Quarona, V. et al. CD38 and CD157: a long journey from activation markers to multifunctional molecules. Cytometry B Clin. Cytom. 84, 207–217 (2013). source

In the paper

“Although SARM1 was originally reported to be required for chemokine CCL5 production in macrophages66, recent evidence revealed that SARM1 is not expressed in macrophages and that the observed chemokine phenotype was due to a background effect of the Sarm1-knockout mouse strain67.”

What the sources say

• Not checked yetcites [66] Gürtler, C. et al. SARM regulates CCL5 production in macrophages by promoting the recruitment of transcription factors and RNA polymerase II to the Ccl5 promoter. J. Immunol. 192, 4821–4832 (2014). source
• Not checked yetcites [67] Uccellini, M. B. et al. Passenger mutations confound phenotypes of SARM1-deficient mice. Cell Rep. 31, 107498 (2020). source

In the paper

“Of note, cyclic ADP-ribose, NAAD(P) and ADP-ribose are all key Ca2+-mobilizing second messengers, illustrating the pivotal role of CD38 in activating Ca2+ signalling and modulating essential cell processes, such as immune cell activation, survival and metabolism38–40.”

What the sources say

• Not checked yetcites [38] Ernst, I. M. A., Fliegert, R. & Guse, A. H. Adenine dinucleotide second messengers and T-lymphocyte calcium signaling. Front. Immunol. 4, 259 (2013).
• Not checked yetcites [39] Yu, P. et al. Direct gating of the TRPM2 channel by cADPR via specific interactions with the ADPR binding pocket. Cell Rep. 27, 3684–3695.e4 (2019). source
• Not checked yetcites [40] Mao, S. Architecture of the human TRPM2 channel. Science 362, 1372.12–1374 (2018). source

In the paper

“For example, CD38 is an adhesion receptor interacting with CD31 to mediate immune cell trafficking and extravasation through the endothelium51,52.”

What the sources say

• Not checked yetcites [51] Deaglio, S. et al. Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, an Ig superfamily member. J. Immunol. 160, 395–402 (1998). source
• Not checked yetcites [52] Deaglio, S. et al. Human CD38 and its ligand CD31 define a unique lamina propria T lymphocyte signaling pathway. FASEB J. 15, 580–582 (2001). source

In the paper

“Like Parp1-knockout mice, Parp2-knockout mice show enhanced SIRT1 activity and improved metabolic function, and are protected from high-fat diet-induced obesity36.”

What the sources say

• Not checked yetcites [36] Bai, P. et al. PARP-2 regulates SIRT1 expression and whole-body energy expenditure. Cell Metab. 13, 450–460 (2011). source

In the paper

“For example, in mice fed a high-fat diet, those that were treated with PARP inhibitors or lacking PARP1 and PARP2 had increased NAD+ levels, increased SIRT1 activity and improved mitochondrial function, and were protected from insulin resistance31,32.”

What the sources say

• Not checked yetcites [31] Bai, P. et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab. 13, 461–468 (2011). source
• Not checked yetcites [32] Pirinen, E. et al. Pharmacological inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle. Cell Metab. 19, 1034–1041 (2014). source

In the paper

“PARP2 is structurally related to PARP1. They share a similar catalytic domain required for several cellular processes, including DNA repair and transcriptional regulation, and account for about 10% of PARP activity35.”

What the sources say

• Not checked yetcites [35] Gui, B. et al. Selective targeting of PARP-2 inhibits androgen receptor signaling and prostate cancer growth through disruption of FOXA1 function. Proc. Natl Acad. Sci. USA 116, 14573–14582 (2019). source

In the paper

“Moreover, CD157 interacts with integrins to form a receptor recognized by scrapie-responsive gene 1 protein (SCRG1), promoting self-renewal, migration and osteogenic differentiation of human mesenchymal stem cells43.”

What the sources say

• Not checked yetcites [43] Aomatsu, E. et al. Novel SCRG1/BST1 axis regulates self-renewal, migration, and osteogenic differentiation potential in mesenchymal stem cells. Sci. Rep. 4, 3652 (2014). source

In the paper

“Unfortunately, while NR could effectively increase NAD+ levels in these individuals94, participants in neither study showed any signs of weight loss, increased insulin sensitivity or enhanced mitochondrial function, among other metabolic parameters studied.”

What the sources say

• Not checked yetcites [93] Dollerup, O. L. et al. Effects of nicotinamide riboside on endocrine pancreatic function and incretin hormones in nondiabetic men with obesity. J. Clin. Endocrinol. Metab. 104, 5703–5714 (2019). source
• Not checked yetcites [94] Remie, C. M. E. et al. Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans. Am. J. Clin. Nutr. https://doi.org/10.1093/ajcn/nqaa072 (2020). source

In the paper

“Accordingly, obesity accelerates and exacerbates ageing, and has been associated with shortened lifespan71.”

What the sources say

• Not checked yetcites [71] Salvestrini, V., Sell, C. & Lorenzini, A. Obesity may accelerate the aging process. Front. Endocrinol. 10, 266 (2019). source

In the paper

“inhibition of NAMPT and subsequent depletion of NAD+ pools in macrophages decreased the secretion of proinflammatory cytokines, such as TNF, and caused morphological changes, such as reduced spreading in these cells100,101”

What the sources say

• Not checked yetcites [100] Van Gool, F. et al. Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner. Nat. Med. 15, 206–210 (2009). This study is one of the first to demonstrate that NAD+ levels can influence innate immune cell function. source
• Not checked yetcites [101] Venter, G. et al. NAMPT-mediated salvage synthesis of NAD+ controls morphofunctional changes of macrophages. PLoS ONE 9, e97378 (2014).

In the paper

“In line with this mechanism, mice with adipocyte-specific deletion of NAMPT have lower levels of NAD+ in their fat tissues, increased insulin resistance and increased metabolic dysfunction, which can be rescued with NMN supplementation92.”

What the sources say

• Not checked yetcites [92] Stromsdorfer, K. L. et al. NAMPT-mediated NAD+ biosynthesis in adipocytes regulates adipose tissue function and multi-organ insulin sensitivity in mice. Cell Rep. 16, 1851–1860 (2016). source

In the paper

“We now know that NAD+ lies at the heart of metabolism and regulates metabolic flux of multiple metabolic pathways (for details see BOX 1 and Supplementary Box 2).”

In the paper

“Inflammageing is now being recognized as a hallmark of ageing and a key driver of disease (FIG. 3Aa), including ageing-associated diseases, and has been described as a prominent risk factor for morbidity and death95–97.”

What the sources say

• Not checked yetcites [95] Franceschi, C., Garagnani, P., Parini, P., Giuliani, C. & Santoro, A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 14, 576–590 (2018). source
• Not checked yetcites [96] Hotamisligil, G. S. Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177–185 (2017). source
• Not checked yetcites [97] Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25, 1822–1832 (2019). source

In the paper

“This switch in macrophage polarization states in the visceral fat is accompanied by enhanced expression of proinflammatory cytokines, insulin resistance and reduced rates of lipolysis.”

In the paper

“Taken together, these key studies have provided strong evidence and the rationale that targeting NAD+ degradation pathways or boosting NAD+ levels can influence metabolic processes and can be protective against metabolic disease.”

In the paper

“In further support of this model, numerous studies have now shown that mouse models including Parp1-knockout and Cd38-knockout mice, or mice treated with PARP or CD38 inhibitors, have supraphysiological levels of NAD+. They are also protected from obesity, have increased metabolic rates and have (relatively) normal glucose metabolism during high-fat diet conditions and during ageing42,89–91.”

What the sources say

• Not checked yetcites [42] Camacho-Pereira, J. et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 23, 1127–1139 (2016). This study demonstrates that CD38 expression increases in multiple tissues during aging and that CD38 is a major NADase involved in the ageing-related tissue decline of NAD+ levels. source
• Not checked yetcites [89] Barbosa, M. T. P. et al. The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity. FASEB J. 21, 3629–3639 (2007). source
• Not checked yetcites [90] Szántó, M. & Bai, P. The role of ADP-ribose metabolism in metabolic regulation, adipose tissue differentiation, and metabolism. Genes Dev. 34, 321–340 (2020). source
• Not checked yetcites [91] Tarragó, M. G. et al. A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD decline. Cell Metab. 27, 1081–1095.e10 (2018). This study demonstrates that the pharmacological inhibition of CD38 reverses age-related NAD+ level decline, improving several physiological and metabolic features. source

In the paper

“In support of this hypothesis, it has now been demonstrated in mammalian systems that lifespan-extending metabolic manipulations, such as exercise75–77, caloric restriction78, time-restricted feeding and a ketogenic diet79, as well as healthy circadian rhythms1,11 (including regular sleep patterns80), work in part by increasing NAD+ levels, which leads to the activation of sirtuins.”

What the sources say

• Not checked yetcites [75] Fukuwatari, T., Shibata, K., Ishihara, K., Fushiki, T. & Sugimoto, E. Elevation of blood NAD level after moderate exercise in young women and mice. J. Nutr. Sci. Vitaminol. 47, 177–179 (2001). source
• Not checked yetcites [76] de Guia, R. M. et al. Aerobic and resistance exercise training reverses age-dependent decline in NAD salvage capacity in human skeletal muscle. Physiol. Rep. 7, e14139 (2019). source
• Not checked yetcites [77] Cantó, C. et al. AMPK regulates energy expenditure by modulating NAD metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009). source
• Not checked yetcites [78] Mitchell, S. J. et al. Effects of sex, strain, and energy intake on hallmarks of aging in mice. Cell Metab. 23, 1093–1112 (2016). source
• Not checked yetcites [79] Elamin, M., Ruskin, D. N., Masino, S. A. & Sacchetti, P. Ketogenic diet modulates NAD-dependent enzymes and reduces DNA damage in hippocampus. Front. Cell. Neurosci. 12, 263 (2018). source

In the paper

“Conversely, increasing cellular NAD+ levels has recently been shown to reduce reductive stress and drive the directionailty of metabolic reactions84.”

What the sources say

• Not checked yetcites [84] Goodman, R. P. et al. Hepatic NADH reductive stress underlies common variation in metabolic traits. Nature https://doi.org/10.1038/s41586-020-2337-2 (2020). source

In the paper

“Additionally, mice receiving a high-fat diet have increased inflammation, which drives decreased expression of NAMPT, and reduced activity of the NAD+ salvage pathway82 (BOX 1), providing a potential mechanistic explanation for why NAD+ levels decline during obesity.”

What the sources say

• Not checked yetcites [82] Yoshino, J., Mills, K. F., Yoon, M. J. & Imai, S.-I. Nicotinamide mononucleotide, a key NAD intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 14, 528–536 (2011). This study demonstrates that NAMPT expression can be dampened in inflammatory settings such as ageing and obesity. source

In the paper

“senescent cells upregulate the expression of the NAM salvage enzyme NAMPT (BOX 1) and that the SASP of senescent cells depends on NAD+ levels131”

What the sources say

• Not checked yetcites [131] Nacarelli, T. et al. NAD metabolism governs the proinflammatory senescence-associated secretome. Nat. Cell Biol. 21, 397–407 (2019). This article demonstrates that the NAD+ salvage pathway is upregulated during cellular senescence and regulates the expression of inflammatory SASP genes. source

In the paper

“This study and another recent report6,102 suggest that this NAD+ turnover, particularly during the first few hours of macrophage M1 polarization, depends on reactive oxygen species-induced DNA damage and activation of PARP1.”

What the sources say

• Not checked yetcites [6] Minhas, P. S. et al. Macrophage de novo NAD synthesis specifies immune function in aging and inflammation. Nat. Immunol. 20, 50–63 (2019). source
• Not checked yetcites [102] Cameron, A. M. et al. Inflammatory macrophage dependence on NAD salvage is a consequence of reactive oxygen species-mediated DNA damage. Nat. Immunol. 20, 420–432 (2019). source

In the paper

“ageing macrophages are characterized by impaired de novo synthesis of NAD+, which in itself may impact macrophage function during ageing6”

What the sources say

• Not checked yetcites [6] Minhas, P. S. et al. Macrophage de novo NAD synthesis specifies immune function in aging and inflammation. Nat. Immunol. 20, 50–63 (2019). source

In the paper

“Enhanced expression of proinflammatory cytokines may drive a vicious cycle of inflammageing, leading to greater inflammation, enhanced tissue and DNA damage, further activation of major consumers of NAD+, such as CD38 and PARPs, and accelerated physiological age-related decline.”

In the paper

“suggesting that NAD+ is a critical metabolite for general macrophage activation, and its metabolism is differentially regulated to control distinct biological processes and functions in M1 and M2 macrophages.”

In the paper

“macrophage polarization can be either tumour promoting (M2) or tumour inhibitory (M1)109”

What the sources say

• Not checked yetcites [109] Pathria, P., Louis, T. L. & Varner, J. A. Targeting tumor-associated macrophages in cancer. Trends Immunol. 40, 310–327 (2019). source

In the paper

“supplementation with NR was able to partially rescue this multimorbidity syndrome, in part by reducing inflammation and senescent cell burden132”

What the sources say

• Not checked yetcites [132] Desdín-Micó, G. et al. T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science https://doi.org/10.1126/science.aax0860 (2020). source

In the paper

“NAD+ depletion is reported in several models of accelerated ageing which exhibit neurodegeneration33,134,135, as well as in neuro-degenerative diseases, including Alzheimer disease136, Parkinson disease137,138 and amyotrophic lateral sclerosis (ALS)139.”

What the sources say

• Not checked yetcites [33] Scheibye-Knudsen, M. et al. A high-fat diet and NAD+ activate Sirt1 to rescue premature aging in cockayne syndrome. Cell Metab. 20, 840–855 (2014). source
• Not checked yetcites [134] Fang, E. F. et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD+/SIRT1 reduction. Cell 157, 882–896 (2014). source
• Not checked yetcites [135] Fang, E. F. et al. NAD replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab. 24, 566–581 (2016). source
• Not checked yetcites [136] Gong, B. et al. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer’s mouse models. Neurobiol. Aging 34, 1581–1588 (2013). source
• Not checked yetcites [137] Schöndorf, D. C. et al. The NAD+ precursor nicotinamide riboside rescues mitochondrial defects and neuronal loss in iPSC and fly models of Parkinson’s disease. Cell Rep. 23, 2976–2988 (2018). source
• Not checked yetcites [138] Birkmayer, J. G., Vrecko, C., Volc, D. & Birkmayer, W. Nicotinamide adenine dinucleotide (NADH)–a new therapeutic approach to Parkinson’s disease. Comparison of oral and parenteral application. Acta Neurol. Scand. Suppl. 146, 32–35 (1993). source

In the paper

“a recent study in mice has also shown that cells with dysfunctional mitochondria initiate a proinflammatory programme, with the secretion of proinflammatory cytokines. This was associated with greater senescent cell burden, increased metabolic and physical dysfunction, and premature ageing132.”

What the sources say

• Not checked yetcites [132] Desdín-Micó, G. et al. T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science https://doi.org/10.1126/science.aax0860 (2020). source

In the paper

“Ageing is strongly associated with most neurodegenerative diseases and is accompanied by decreased cellular NAD+ levels in the mammalian brain133.”

What the sources say

• Not checked yetcites [133] Zhu, X.-H., Lu, M., Lee, B.-Y., Ugurbil, K. & Chen, W. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proc. Natl Acad. Sci. 112, 2876–2881 (2015). source

In the paper

“One major phenotype of senescent cells and how they are thought to promote disease is the increased expression of inflammatory mediators, mostly cytokines and chemokines, known as the senescence-associated secretory phenotype (SASP), which contributes to impaired tissue homeostasis by interfering with stem cell regeneration, tissue and wound repair and inflammageing125,126”

What the sources say

• Not checked yetcites [125] Coppé, J.-P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008).
• Not checked yetcites [126] Basisty, N. et al. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol. 18, e3000599 (2020). This article presents a comprehensive proteomic database of soluble proteins and exosomal SASP factors originating from multiple senescence inducers and cell types. source

In the paper

“a recent study found that M1 macrophage polarization is associated with enhanced degradation of NAD+ and that inhibiting NAMPT blocks glycolytic shifts in M1 macrophages, limiting proinflammatory responses in vitro and reducing systemic inflammation in vivo in response to sepsis102.”

What the sources say

• Not checked yetcites [102] Cameron, A. M. et al. Inflammatory macrophage dependence on NAD salvage is a consequence of reactive oxygen species-mediated DNA damage. Nat. Immunol. 20, 420–432 (2019). source

In the paper

“another group has also independently shown that senescent cells and their SASP activate CD38 expression and promote CD38-dependent NADase activity in macrophages105,106.”

What the sources say

• Not checked yetcites [105] Chini, C. C. S. et al. CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. Nat. Metab. 2, 1284–1304 (2020). This study, along with Covarrubias et al. (2020), demonstrated that senescent cell burden is linked to tissue NAD+ level decline via CD38+ immune cells. source
• Not checked yetcites [106] Chini, C. et al. The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD decline. Biochem. Biophys. Res. Commun. 513, 486–493 (2019). source

In the paper

“Treating senescent cells with NMN can heighten the SASP, leading to increased chronic inflammation, and can promote the development of inflammation-driven cancers.”

What the sources say

• Not checked yetcites [131] Nacarelli, T. et al. NAD metabolism governs the proinflammatory senescence-associated secretome. Nat. Cell Biol. 21, 397–407 (2019). This article demonstrates that the NAD+ salvage pathway is upregulated during cellular senescence and regulates the expression of inflammatory SASP genes. source

In the paper

“Recently, it was shown that CD38 levels increase in mammalian tissues with age, and CD38 has been proposed to be the major NAD+-consuming enzyme responsible for the decline in NAD+ levels during ageing42,91.”

What the sources say

• Not checked yetcites [42] Camacho-Pereira, J. et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 23, 1127–1139 (2016). This study demonstrates that CD38 expression increases in multiple tissues during aging and that CD38 is a major NADase involved in the ageing-related tissue decline of NAD+ levels. source
• Not checked yetcites [91] Tarragó, M. G. et al. A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD decline. Cell Metab. 27, 1081–1095.e10 (2018). This study demonstrates that the pharmacological inhibition of CD38 reverses age-related NAD+ level decline, improving several physiological and metabolic features. source

In the paper

“CD38 is emerging as a key enzyme involved in inflammageing and senescence45,105,106, which are strongly associated with neurodegenerative diseases124,128,168,169.”

What the sources say

• Not checked yetcites [45] Covarrubias, A. J. et al. Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. Nat. Metab. 2, 1265–1283 (2020). source
• Not checked yetcites [105] Chini, C. C. S. et al. CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. Nat. Metab. 2, 1284–1304 (2020). This study, along with Covarrubias et al. (2020), demonstrated that senescent cell burden is linked to tissue NAD+ level decline via CD38+ immune cells. source
• Not checked yetcites [106] Chini, C. et al. The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD decline. Biochem. Biophys. Res. Commun. 513, 486–493 (2019). source
• Not checked yetcites [124] Chen, L. et al. CD38-mediated immunosuppression as a mechanism of tumor cell escape from PD-1/PD-L1 blockade. Cancer Discov. 8, 1156–1175 (2018). source
• Not checked yetcites [128] Bussian, T. J. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578–582 (2018). source
• Not checked yetcites [168] Franceschi, C. & Campisi, J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med. Sci. 69, S4–S9 (2014). source
• Not checked yetcites [169] Zhang, P. et al. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat. Neurosci. 22, 719–728 (2019). source

In the paper

“during axon degeneration, NMNAT2 axonal transport is blocked, and the axonal pool of the protein is rapidly degraded, leading to a critical depletion of NAD+ in the axon142,143.”

What the sources say

• Not checked yetcites [142] Gilley, J. & Coleman, M. P. Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. PLoS Biol. 8, e1000300 (2010). source
• Not checked yetcites [143] Loreto, A. et al. Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration. Neurobiol. Dis. 134, 104678 (2020). source

In the paper

“Multiple cells in the brain, including microglia, astrocytes, neurons and endothelial cells, express CD38 (REFS108,160), and treating microglia and astrocytes with inflammatory cytokines induces CD38 expression163,164.”

What the sources say

• Not checked yetcites [108] Tabula Muris Consortium et al. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 562, 367–372 (2018). This is a compendium of single-cell transcriptomic data that comprises more than 100,000 cells from 20 mouse organs and tissues. source
• Not checked yetcites [160] Mrdjen, D. et al. High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity 48, 599 (2018). source
• Not checked yetcites [163] Mayo, L. et al. Dual role of CD38 in microglial activation and activation-induced cell death. J. Immunol. 181, 92–103 (2008). source
• Not checked yetcites [164] Banerjee, S. et al. CD38/cyclic ADP-ribose regulates astrocyte calcium signaling: implications for neuroinflammation and HIV-1-associated dementia. J. Neuroimmune Pharmacol. 3, 154–164 (2008). source

In the paper

“the NAD+-consuming enzyme SARM1 is activated by axonal injury and mediates axonal degeneration by promoting NAD+ degradation60.”

What the sources say

• Not checked yetcites [60] Gerdts, J., Brace, E. J., Sasaki, Y., DiAntonio, A. & Milbrandt, J. SARM1 activation triggers axon degeneration locally via NAD destruction. Science 348, 453–457 (2015). source

In the paper

“an Alzheimer disease mouse model lacking CD38 (Cd38-knockout mice), which results in elevated NAD+ levels in their brains, shows a milder disease phenotype159.”

What the sources say

• Not checked yetcites [159] Blacher, E. et al. Alzheimer’s disease pathology is attenuated in a CD38-deficient mouse model. Ann. Neurol. 78, 88–103 (2015). source

In the paper

“Overall, Wlds mouse studies largely show the neuro protective function of the biosynthetic enzymes NMNAT1, NMNAT2 and NMNAT3 (REFS142,150–152) and their protective role in several neurodegenerative disorders, including Parkinson disease153–155.”

What the sources say

• Not checked yetcites [142] Gilley, J. & Coleman, M. P. Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. PLoS Biol. 8, e1000300 (2010). source
• Not checked yetcites [150] Kitaoka, Y. et al. Axonal protection by Nmnat3 overexpression with involvement of autophagy in optic nerve degeneration. Cell Death Dis. 4, e860 (2013). source
• Not checked yetcites [151] Yahata, N., Yuasa, S. & Araki, T. Nicotinamide mononucleotide adenylyltransferase expression in mitochondrial matrix delays Wallerian degeneration. J. Neurosci. 29, 6276–6284 (2009). source
• Not checked yetcites [152] Pellegatta, M. & Taveggia, C. The complex work of proteases and secretases in wallerian degeneration: beyond neuregulin-1. Front. Cell. Neurosci. 13, 93 (2019). source
• Not checked yetcites [153] Conforti, L., Gilley, J. & Coleman, M. P. Wallerian degeneration: an emerging axon death pathway linking injury and disease. Nat. Rev. Neurosci. 15, 394–409 (2014). source
• Not checked yetcites [154] Williams, P. A. et al. Nicotinamide and WLD act together to prevent neurodegeneration in glaucoma. Front. Neurosci. 11, 232 (2017). source
• Not checked yetcites [155] Brown, K. D. et al. Activation of SIRT3 by the NAD+ precursor nicotinamide riboside protects from noise-induced hearing loss. Cell Metab. 20, 1059–1068 (2014). source

In the paper

“During normal physiological conditions, the NAD+ biosynthetic enzyme nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) (FIG. 1; BOX 1) is a survival factor in axons, in which it needs to be constantly replenished via anterograde axonal transport due to its rapid turnover142.”

What the sources say

• Not checked yetcites [142] Gilley, J. & Coleman, M. P. Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. PLoS Biol. 8, e1000300 (2010). source

In the paper

“Wallerian degeneration slow (Wlds) mice, which are protected from axonal degeneration, showing absence of SARM1 expression144 and higher neuronal NAD+ levels, owing to the overexpression of a chimeric fusion protein of NMNAT1, which allows its redistribution from the nucleus to the axon, where it can substitute for the activity of NMNAT2 (REFS145,146).”

What the sources say

• Not checked yetcites [144] Wang, J. et al. A local mechanism mediates NAD-dependent protection of axon degeneration. J. Cell Biol. 170, 349–355 (2005). source
• Not checked yetcites [145] Araki, T., Sasaki, Y. & Milbrandt, J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science 305, 1010–1013 (2004). source
• Not checked yetcites [146] Sasaki, Y., Nakagawa, T., Mao, X., DiAntonio, A. & Milbrandt, J. NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD depletion. eLife 5, e19749 (2016). source

In the paper

“CD38 was also reported to affect social behaviour, as was its homologue CD157 (REFS166,167)”

What the sources say

• Not checked yetcites [166] Jin, D. et al. CD38 is critical for social behaviour by regulating oxytocin secretion. Nature 446, 41–45 (2007). source
• Not checked yetcites [167] Higashida, H. et al. An immunohistochemical, enzymatic, and behavioral study of CD157/BST-1 as a neuroregulator. BMC Neurosci. 18, 35 (2017). source

In the paper

“Sarm1-knockout mice are protected from axonal degeneration60 and can rescue the severe axon growth defects and perinatal death induced by lack of NMNAT2 (REFS147,148).”

What the sources say

• Not checked yetcites [60] Gerdts, J., Brace, E. J., Sasaki, Y., DiAntonio, A. & Milbrandt, J. SARM1 activation triggers axon degeneration locally via NAD destruction. Science 348, 453–457 (2015). source
• Not checked yetcites [147] Gilley, J., Adalbert, R., Yu, G. & Coleman, M. P. Rescue of peripheral and CNS axon defects in mice lacking NMNAT2. J. Neurosci. 33, 13410–13424 (2013). source
• Not checked yetcites [148] Gilley, J., Orsomando, G., Nascimento-Ferreira, I. & Coleman, M. P. Absence of SARM1 rescues development and survival of NMNAT2-deficient axons. Cell Rep. 10, 1974–1981 (2015). source

In the paper

“Restoration of NAD+ levels with NAD+ supplements and the overexpression of the two biosynthetic enzymes NAMPT and NMNAT1 were found to prevent axon degeneration60,146.”

What the sources say

• Not checked yetcites [60] Gerdts, J., Brace, E. J., Sasaki, Y., DiAntonio, A. & Milbrandt, J. SARM1 activation triggers axon degeneration locally via NAD destruction. Science 348, 453–457 (2015). source
• Not checked yetcites [146] Sasaki, Y., Nakagawa, T., Mao, X., DiAntonio, A. & Milbrandt, J. NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD depletion. eLife 5, e19749 (2016). source

In the paper

“NMN treatment significantly increased NAD+ levels and the maximum lifespan also in a mouse model of ataxia telangiectasia135.”

What the sources say

• Not checked yetcites [135] Fang, E. F. et al. NAD replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab. 24, 566–581 (2016). source

In the paper

“NMN enhances mitochondrial function in various organs, including skeletal muscle201, kidney202–204, liver203, heart205, eyes206, brain161 and the cardiovascular system207, and can mitigate oxidative stress in the vasculature208, including improvements in neurovascular coupling responses in the aged cortex of the brain209.”

What the sources say

• Not checked yetcites [201] Gomes, A. P. et al. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624–1638 (2013). source
• Not checked yetcites [202] Sims, C. A. et al. Nicotinamide mononucleotide preserves mitochondrial function and increases survival in hemorrhagic shock. JCI Insight 3, e120182 (2018).
• Not checked yetcites [203] Uddin, G. M., Youngson, N. A., Sinclair, D. A. & Morris, M. J. Head to head comparison of short-term treatment with the NAD+ precursor nicotinamide mononucleotide (NMN) and 6 weeks of exercise in obese female mice. Front. Pharmacol. 7, 258 (2016). source
• Not checked yetcites [204] Guan, Y. et al. Nicotinamide mononucleotide, an NAD precursor, rescues age-associated susceptibility to AKI in a sirtuin 1–dependent manner. J. Am. Soc. Nephrol. 28, 2337–2352 (2017). source

In the paper

“One potential explanation for this discrepancy is that NAM influences NAD+ functions directly and indirectly.”

In the paper

“there have been more phase I clinical trials using NR than those using NMN, and these have provided conflicting results.”

What the sources say

• Not checked yetcites TABLE 2

In the paper

“One trial showed that short-term NR administration has some beneficial effects in healthy elderly individuals185, and another showed positive results in patients with ALS93,186,187.”

What the sources say

• Not checked yetcites [185] Martens, C. R. et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD in healthy middle-aged and older adults. Nat. Commun. 9, 1286 (2018).
• Not checked yetcites [93] Dollerup, O. L. et al. Effects of nicotinamide riboside on endocrine pancreatic function and incretin hormones in nondiabetic men with obesity. J. Clin. Endocrinol. Metab. 104, 5703–5714 (2019). source
• Not checked yetcites [186] Dollerup, O. L. et al. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. Am. J. Clin. Nutr. 108, 343–353 (2018). source
• Not checked yetcites [187] de la Rubia, J. E. et al. Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled human pilot study. Amyotroph. Lateral Scler. Frontotemporal Degener. 20, 115–122 (2019). source

In the paper

“From the findings taken together, there is growing evidence that NAD+ is a central metabolite for maintaining a healthy nervous system and can impact the biology of multiple brain cell types”

In the paper

“long-term (1-year) feeding of mice with NMN starting at 5 months of age increased whole-body insulin sensitivity, energy metabolism and physical activity and improved lipid profiles with no obvious toxic effects199.”

What the sources say

• Not checked yetcites [199] Mills, K. F. et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 24, 795–806 (2016). source

In the paper

“Aside from being a direct NAD+ precursor in the salvage pathway, NAM is also a by-product of NAD+ catabolism, and at high millimolar concentrations it has been shown to act as a feedback inhibitor for NAD+-dependent enzymes, such as PARPs193 and sirtuins194 in vitro.”

What the sources say

• Not checked yetcites [193] Saldeen, J., Tillmar, L., Karlsson, E. & Welsh, N. Nicotinamide- and caspase-mediated inhibition of poly(ADP-ribose) polymerase are associated with p53-independent cell cycle (G2) arrest and apoptosis. Mol. Cell. Biochem. 243, 113–122 (2003). source
• Not checked yetcites [194] Avalos, J. L., Bever, K. M. & Wolberger, C. Mechanism of sirtuin inhibition by nicotinamide: altering the NAD+ cosubstrate specificity of a Sir2 enzyme. Mol. Cell 17, 855–868 (2005). source

In the paper

“Augmentation of NAD+ levels has shown efficacy in a variety of mouse models of human diseases (TABLE 1), leading to numerous clinical trials of NAD+ boosters in humans during ageing (TABLE 2).”

What the sources say

• Not checked yetcites TABLE 1
• Not checked yetcites TABLE 2