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Cited by 1,617Sirtuins and Resveratrol in MedicineBiochemical and Molecular ResearchGenetics, Aging, and Longevity in Model Organisms

NAD+ metabolism and its roles in cellular processes during ageing

Open access
Covarrubias, Anthony J., Perrone, Rosalba, Grozio, Alessia, Verdin, Eric·2021·Nature Reviews Molecular Cell Biology
DOI 10.1038/s41580-020-00313-xPMC PMC7963035
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Abstract

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions, making it central to energy metabolism. NAD+ is also an essential cofactor for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ can directly and indirectly influence many key cellular functions, including metabolic pathways, DNA repair, chromatin remodelling, cellular senescence and immune cell function. These cellular processes and functions are critical for maintaining tissue and metabolic homeostasis and for healthy ageing. Remarkably, ageing is accompanied by a gradual decline in tissue and cellular NAD+ levels in multiple model organisms, including rodents and humans. This decline in NAD+ levels is linked causally to numerous ageing-associated diseases, including cognitive decline, cancer, metabolic disease, sarcopenia and frailty. Many of these ageing-associated diseases can be slowed down and even reversed by restoring NAD+ levels. Therefore, targeting NAD+ metabolism has emerged as a potential therapeutic approach to ameliorate ageing-related disease, and extend the human healthspan and lifespan. However, much remains to be learnt about how NAD+ influences human health and ageing biology. This includes a deeper understanding of the molecular mechanisms that regulate NAD+ levels, how to effectively restore NAD+ levels during ageing, whether doing so is safe and whether NAD+ repletion will have beneficial effects in ageing humans.

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Crossref · 10.1038/s41580-020-00313-x

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  • Findingown data

    In ageing mouse models and mice treated with doxorubicin, accumulation of senescent cells in metabolic tissues such as visceral fat and liver can directly activate CD38 expression in tissue-resident macrophages.

    “we showed in ageing mouse models and mice treated with the senescence-inducing chemotherapeutic reagent doxorubicin that accumulation of senescent cells in metabolic tissues, such as the visceral fat and liver, can directly activate the expression of CD38 in tissue-resident macrophages45.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • 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). source

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  • Findingown data

    The authors' laboratory detected no evidence of DNA damage or PARP1 activation during M1 macrophage polarization.

    “recently published results from our laboratory detected no evidence of DNA damage or PARP1 activation during M1 macropahge polarization45”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • 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). source

      Not checked in the free run.

  • Premisecitation

    Ageing is accompanied by a gradual decline in tissue and cellular NAD+ levels in multiple model organisms, including rodents and humans.

    “Remarkably, ageing is accompanied by a gradual decline in tissue and cellular NAD+ levels in multiple model organisms, including rodents and humans.”
    • Also stated in: § Abstract · boosted
      “lower NAD+ levels are now known to correlate with ageing in rodents and humans”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Verdin, E. NAD+ in aging, metabolism, and neurodegeneration. Science 350, 1208–1213 (2015). source

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  • Premisereasoning

    NAD+-consuming enzymes use NAD+ as a substrate or cofactor and generate nicotinamide as a by-product.

    “These utilize NAD+ as a substrate or cofactor and generate nicotinamide (NAM) as a by-product (FIG. 1).”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Some sirtuin family members mediate non-acetyl lysine acylations, such as succinylation, malonylation and fatty acid acylation, whose cellular functions are poorly understood.

    “Additionally, some members of the sirtuin family mediate non-acetyl lysine acylations (for example, succinylation, malonylation and fatty acid acylation)13–15, the cellular functions of which are so far poorly understood16.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [13] Feldman, J. L., Baeza, J. & Denu, J. M. Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins. J. Biol. Chem. 288, 31350–31356 (2013). source

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    • cites [14] Jiang, H. et al. SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine. Nature 496, 110–113 (2013). source

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    • cites [15] He, W., Newman, J. C., Wang, M. Z., Ho, L. & Verdin, E. Mitochondrial sirtuins: regulators of protein acylation and metabolism. Trends Endocrinol. Metab. 23, 467–476 (2012). source

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    • cites [16] Choudhary, C., Weinert, B. T., Nishida, Y., Verdin, E. & Mann, M. The growing landscape of lysine acetylation links metabolism and cell signalling. Nat. Rev. Mol. Cell Biol. 15, 536–550 (2014). source

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  • May combine two claims. 96
  • Classified as probably not a substantial claim. 16

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    Findingcitation

    Macrophages co-cultured in or exposed to conditioned media from senescent cells have enhanced expression of the NAD+-consuming enzyme CD38 and increased proliferation.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • 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). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    During ageing, the balance between NAD+ catabolism and anabolism can shift, and NAD+ degradation can outpace the ability of cells to make NAD+ de novo or to recycle or salvage NAM.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    PARP-mediated cleavage of NAD+ produces NAM and ADP-ribose, and 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.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Among all PARPs, only PARP1, PARP2 and PARP3 localize to the nucleus in response to early DNA damage and have a key role in DNA damage repair.

    “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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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

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    • cites [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

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    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

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

    “Early studies in yeast demonstrated roles of sirtuins in gene silencing, which in 2000 was attributed to their activity as NAD+-dependent deacetylases12.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

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

    “The human PARP protein family is composed of 17 proteins characterized by poly(ADP-ribosyl) polymerase or mono(ADP-ribosyl) polymerase activity24.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Interpretationreasoning

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Interpretationnone given

    Enhancing sirtuin activation can increase lifespan and healthspan, whereas aberrant activation of PARPs and NAD+ glycohydrolases such as CD38 may exacerbate ageing phenotypes.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    SIRT1 has been implicated in turnover of defective mitochondria by mitophagy, in addition to its role in promoting mitochondrial biogenesis.

    “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.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [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

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    • cites [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

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    • cites [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

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    • cites [22] Kang, H. T. & Hwang, E. S. Nicotinamide enhances mitochondria quality through autophagy activation in human cells. Aging Cell 8, 426–438 (2009). source

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    • cites [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

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  • May combine two claims.

    Premisecitation

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

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nuclear SIRT1, SIRT6 and SIRT7 are critical regulators of DNA repair and genome stability, and mitochondrial SIRT3, SIRT4 and SIRT5 and nuclear SIRT1 regulate mitochondrial homeostasis and metabolism.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    NAD+ can be made de novo from l-tryptophan via the kynurenine pathway or from vitamin precursors such as nicotinic acid via the Preiss-Handler pathway.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    SIRT1 and NAMPT are key players in the circadian regulation of NAD+ levels, and NAMPT is regulated by the circadian clock, forming a feedback loop that results in circadian oscillation of NAD+ levels.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] Ramsey, K. M. et al. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science 324, 651–654 (2009). source

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    • cites [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

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Some cells, mostly in the liver, can synthesize NAD+ de novo from multiple dietary sources.

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

  • May combine two claims.

    Interpretationreasoning

    Targeting NAD+ metabolism is a potential therapeutic approach to ameliorate ageing-related disease and extend human healthspan and lifespan.

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

  • May combine two claims.

    Premisereasoning

    Critical cellular processes mediated by NAD+ include metabolic pathways, redox homeostasis, maintenance and repair of DNA, epigenetic regulation and chromatin remodelling, and autophagy.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    PARP1 likely outcompetes SIRT1 for NAD+ because PARP1 has lower Km and higher Vmax for NAD+ than SIRT1, and they are localized to the same cellular compartment.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • 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

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    NAD+ is a mediator of key cellular functions and adaptation to metabolic needs.

    “Accordingly, NAD+ is a mediator of key cellular functions and adaptation to metabolic needs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

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

    “PARP3 is important in DNA repair as well27, suggesting a large overlap and potential redundancy in PARP1, PARP2 and PARP3.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CD38 performs a base-exchange reaction, swapping the NAM of NAD(P)+ for NA under acidic conditions and generating NAAD(P).

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

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

    “SARM1 was only very recently assigned to the NAD+ glycohydrolase and cyclase family along with CD38 and CD157.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The CD38-CD31 axis seems to promote a proliferative response in chronic lymphocytic leukaemia lymphocytes, suggesting a detrimental role of CD38 in blood cancers.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [53] Vallario, A. et al. Human myeloma cells express the CD38 ligand CD31. Br. J. Haematol. 105, 441–444 (1999). source

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    • cites [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

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  • May combine two claims.

    Premisereasoning

    The glycohydrolysis of NAD+ by CD38 and CD157 cleaves the glycosidic bond within NAD+ to generate NAM and ADP-ribose, whereas the ADP-ribosyl cyclase activity generates cyclic ADP-ribose.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    SARM1 is primarily expressed in neurons and promotes neuronal morphogenesis and inflammation, and is also expressed by immune cells such as macrophages and T lymphocytes, where it regulates their functions.

    “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.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [61] Wang, Q. et al. Sarm1/Myd88-5 regulates neuronal intrinsic immune response to traumatic axonal injuries. Cell Rep. 23, 716–724 (2018). source

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    • cites [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).

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    • cites [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

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    • cites [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

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    • cites [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

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  • May combine two claims.

    Premisecitation

    CD157 is upregulated in ageing tissues and may have a role in ageing-related diseases such as rheumatoid arthritis and cancer.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • 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). source

      Not checked in the free run.

    • cites [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

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    SARM1 was originally discovered as a negative regulator of the innate immune response via direct interaction with TRIF downstream of Toll-like receptor signalling.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    NMN is emerging as an alternative substrate of CD38, whereas CD157 consumes NR as an alternative substrate.

    “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).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CD38 is a transmembrane protein that was identified as a T cell activation marker but is now known to be ubiquitously expressed, particularly during inflammation.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CD157 activation by specific monoclonal antibodies promotes trafficking of neutrophils and monocytes.

    “Several lines of evidence suggest that CD157 activation by specific monoclonal antibodies promotes trafficking of neutrophils and monocytes58.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Funaro, A. et al. CD157 is an important mediator of neutrophil adhesion and migration. Blood 104, 4269–4278 (2004). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CD157 is a glycophosphatidylinositol-anchored protein first identified in the myeloid compartment of the haematopoietic system, and is also expressed by other cells including B cell progenitors, Paneth cells and endothelial cells in the gut, pancreas and kidney.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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).

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    • cites [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

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  • May combine two claims.

    Premisecitation

    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 strain.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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

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    • cites [67] Uccellini, M. B. et al. Passenger mutations confound phenotypes of SARM1-deficient mice. Cell Rep. 31, 107498 (2020). source

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  • May combine two claims.

    Premisecitation

    Cyclic ADP-ribose, NAAD(P) and ADP-ribose are key Ca2+-mobilizing second messengers, illustrating a pivotal role of CD38 in activating Ca2+ signalling and modulating immune cell activation, survival and metabolism.

    “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.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [40] Mao, S. Architecture of the human TRPM2 channel. Science 362, 1372.12–1374 (2018). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CD38 is an adhesion receptor interacting with CD31 to mediate immune cell trafficking and extravasation through the endothelium.

    “For example, CD38 is an adhesion receptor interacting with CD31 to mediate immune cell trafficking and extravasation through the endothelium51,52.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

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  • May combine two claims.

    Premisecitation

    Parp2-knockout mice show enhanced SIRT1 activity, improved metabolic function, and protection from high-fat diet-induced obesity.

    “Like Parp1-knockout mice, Parp2-knockout mice show enhanced SIRT1 activity and improved metabolic function, and are protected from high-fat diet-induced obesity36.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Bai, P. et al. PARP-2 regulates SIRT1 expression and whole-body energy expenditure. Cell Metab. 13, 450–460 (2011). source

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  • May combine two claims.

    Premisecitation

    In mice fed a high-fat diet, treatment with PARP inhibitors or lack of PARP1 and PARP2 increased NAD+ levels, increased SIRT1 activity, improved mitochondrial function, and protected from insulin resistance.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [31] Bai, P. et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab. 13, 461–468 (2011). source

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    • cites [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

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  • May combine two claims.

    Premisecitation

    PARP2 is structurally related to PARP1, shares a similar catalytic domain, and accounts for about 10% of PARP activity.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CD157 interacts with integrins to form a receptor recognized by SCRG1, promoting self-renewal, migration and osteogenic differentiation of human mesenchymal stem cells.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Participants in neither study showed any signs of weight loss, increased insulin sensitivity or enhanced mitochondrial function, among other metabolic parameters studied.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Obesity accelerates and exacerbates ageing and has been associated with shortened lifespan.

    “Accordingly, obesity accelerates and exacerbates ageing, and has been associated with shortened lifespan71.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Salvestrini, V., Sell, C. & Lorenzini, A. Obesity may accelerate the aging process. Front. Endocrinol. 10, 266 (2019). source

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  • May combine two claims.

    Premisecitation

    Ageing leads to increased macrophage abundance and is accompanied by altered macrophage polarization state and function, which is emerging as a key driver of inflammageing.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [98] Oishi, Y. & Manabe, I. Macrophages in age-related chronic inflammatory diseases. NPJ Aging Mech. Dis. 2, 16018 (2016). source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In macrophages, blocking NAMPT and lowering NAD+ reduced secretion of proinflammatory cytokines such as TNF and produced morphological changes including less spreading.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

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    • cites [101] Venter, G. et al. NAMPT-mediated salvage synthesis of NAD+ controls morphofunctional changes of macrophages. PLoS ONE 9, e97378 (2014).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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 supplementation.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    NAD+ lies at the heart of metabolism and regulates metabolic flux of multiple metabolic pathways.

    “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).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Inflammageing is recognized as a hallmark of ageing and a key driver of disease, including ageing-associated diseases, and is a prominent risk factor for morbidity and death.

    “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.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [96] Hotamisligil, G. S. Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177–185 (2017). source

      Not checked in the free run.

    • cites [97] Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25, 1822–1832 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Higher NAD+ levels promote the deacetylase and deacylase activity of nuclear SIRT1 and mitochondrial SIRT3, which regulate mitochondrial function and protect from high-fat diet-induced metabolic disease.

    “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.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [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 in the free run.

    • 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). source

      Not checked in the free run.

    • cites [85] Hirschey, M. D. et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464, 121–125 (2010). source

      Not checked in the free run.

    • 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). source

      Not checked in the free run.

    • 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). source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

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

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Targeting NAD+ degradation pathways or boosting NAD+ levels can influence metabolic processes and be protective against metabolic disease.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mouse models including Parp1-knockout and Cd38-knockout mice, or mice treated with PARP or CD38 inhibitors, have supraphysiological levels of NAD+, are protected from obesity, have increased metabolic rates, and have relatively normal glucose metabolism during high-fat diet conditions and during ageing.

    “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.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mammalian systems, lifespan-extending metabolic manipulations such as exercise, caloric restriction, time-restricted feeding, a ketogenic diet, and healthy circadian rhythms work in part by increasing NAD+ levels, which leads to activation of sirtuins.

    “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.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [77] Cantó, C. et al. AMPK regulates energy expenditure by modulating NAD metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009). source

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    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increasing cellular NAD+ levels reduces reductive stress and drives the directionality of metabolic reactions.

    “Conversely, increasing cellular NAD+ levels has recently been shown to reduce reductive stress and drive the directionailty of metabolic reactions84.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice receiving a high-fat diet have increased inflammation, which drives decreased expression of NAMPT and reduced activity of the NAD+ salvage pathway, providing a potential mechanistic explanation for why NAD+ levels decline during obesity.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescent cells upregulate expression of the NAM salvage enzyme NAMPT, and the SASP of senescent cells depends on NAD+ levels.

    “senescent cells upregulate the expression of the NAM salvage enzyme NAMPT (BOX 1) and that the SASP of senescent cells depends on NAD+ levels131”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    NAD+ turnover during the first few hours of M1 macrophage polarization depends on reactive oxygen species-induced DNA damage and PARP1 activation.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ageing macrophages are characterized by impaired de novo synthesis of NAD+, which may impact macrophage function during ageing.

    “ageing macrophages are characterized by impaired de novo synthesis of NAD+, which in itself may impact macrophage function during ageing6”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Interpretationreasoning

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

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Macrophage polarization can be tumour promoting (M2) or tumour inhibitory (M1).

    “macrophage polarization can be either tumour promoting (M2) or tumour inhibitory (M1)109”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Pathria, P., Louis, T. L. & Varner, J. A. Targeting tumor-associated macrophages in cancer. Trends Immunol. 40, 310–327 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Supplementation with NR partially rescued this multimorbidity syndrome, in part by reducing inflammation and senescent cell burden.

    “supplementation with NR was able to partially rescue this multimorbidity syndrome, in part by reducing inflammation and senescent cell burden132”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    NAD+ depletion is reported in several models of accelerated ageing that exhibit neurodegeneration, as well as in neurodegenerative diseases including Alzheimer disease, Parkinson disease and amyotrophic lateral sclerosis.

    “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.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cells with dysfunctional mitochondria initiate a proinflammatory programme with secretion of proinflammatory cytokines, associated with greater senescent cell burden, increased metabolic and physical dysfunction, and premature ageing.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

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

    “Ageing is strongly associated with most neurodegenerative diseases and is accompanied by decreased cellular NAD+ levels in the mammalian brain133.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ageing is associated with increased activation of the NLRP3 inflammasome, which is primarily expressed by myeloid immune cells, and a subsequent increase in IL-1β expression.

    “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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • 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). source

      Not checked in the free run.

    • 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

      Not checked in the free run.

    • 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. source

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  • May combine two claims.

    Premisecitation

    A major phenotype of senescent cells is increased expression of inflammatory mediators, mostly cytokines and chemokines, known as SASP, which contributes to impaired tissue homeostasis by interfering with stem cell regeneration, tissue and wound repair and inflammageing.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    M1 macrophage polarization is associated with enhanced NAD+ degradation, and inhibiting NAMPT blocks glycolytic shifts in M1 macrophages, limiting proinflammatory responses in vitro and reducing systemic inflammation in vivo in response to sepsis.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescent cells and their SASP activate CD38 expression and promote CD38-dependent NADase activity in macrophages.

    “another group has also independently shown that senescent cells and their SASP activate CD38 expression and promote CD38-dependent NADase activity in macrophages105,106.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

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    • cites [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

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  • May combine two claims.

    Premisecitation

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

    “Treating senescent cells with NMN can heighten the SASP, leading to increased chronic inflammation, and can promote the development of inflammation-driven cancers.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    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 ageing.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

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    • cites [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

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  • May combine two claims.

    Interpretationcitation

    CD38 is emerging as a key enzyme involved in inflammageing and senescence, which are strongly associated with neurodegenerative diseases.

    “CD38 is emerging as a key enzyme involved in inflammageing and senescence45,105,106, which are strongly associated with neurodegenerative diseases124,128,168,169.”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • 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). source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

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  • May combine two claims.

    Premisecitation

    During axon degeneration, NMNAT2 axonal transport is blocked, and the axonal pool of the protein is rapidly degraded, leading to critical depletion of NAD+ in the axon.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

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  • May combine two claims.

    Premisecitation

    Multiple cells in the brain, including microglia, astrocytes, neurons and endothelial cells, express CD38, and treating microglia and astrocytes with inflammatory cytokines induces CD38 expression.

    “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.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • 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. source

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    • cites [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

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    • cites [163] Mayo, L. et al. Dual role of CD38 in microglial activation and activation-induced cell death. J. Immunol. 181, 92–103 (2008). source

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    • cites [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

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  • May combine two claims.

    Premisecitation

    SARM1 is activated by axonal injury and mediates axonal degeneration by promoting NAD+ degradation.

    “the NAD+-consuming enzyme SARM1 is activated by axonal injury and mediates axonal degeneration by promoting NAD+ degradation60.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    An Alzheimer disease mouse model lacking CD38 has elevated brain NAD+ levels and shows a milder disease phenotype.

    “an Alzheimer disease mouse model lacking CD38 (Cd38-knockout mice), which results in elevated NAD+ levels in their brains, shows a milder disease phenotype159.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [159] Blacher, E. et al. Alzheimer’s disease pathology is attenuated in a CD38-deficient mouse model. Ann. Neurol. 78, 88–103 (2015). source

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  • May combine two claims.

    Premisecitation

    Wlds mouse studies largely show the neuroprotective function of NMNAT1, NMNAT2 and NMNAT3 and their protective role in several neurodegenerative disorders, including Parkinson disease.

    “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.”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [142] Gilley, J. & Coleman, M. P. Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. PLoS Biol. 8, e1000300 (2010). source

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    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

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    • cites [154] Williams, P. A. et al. Nicotinamide and WLD act together to prevent neurodegeneration in glaucoma. Front. Neurosci. 11, 232 (2017). source

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    • cites [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

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  • May combine two claims.

    Premisecitation

    Under normal physiological conditions, NMNAT2 is a survival factor in axons and must be constantly replenished via anterograde axonal transport due to its rapid turnover.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [142] Gilley, J. & Coleman, M. P. Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. PLoS Biol. 8, e1000300 (2010). source

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  • May combine two claims.

    Premisecitation

    Wlds mice are protected from axonal degeneration, show absence of SARM1 expression and higher neuronal NAD+ levels due to overexpression of a chimeric NMNAT1 fusion protein that redistributes to the axon and substitutes for NMNAT2.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [144] Wang, J. et al. A local mechanism mediates NAD-dependent protection of axon degeneration. J. Cell Biol. 170, 349–355 (2005). source

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    • cites [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 in the free run.

    • cites [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

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  • May combine two claims.

    Premisecitation

    CD38 affects social behaviour, as does its homologue CD157.

    “CD38 was also reported to affect social behaviour, as was its homologue CD157 (REFS166,167)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [166] Jin, D. et al. CD38 is critical for social behaviour by regulating oxytocin secretion. Nature 446, 41–45 (2007). source

      Not checked in the free run.

    • cites [167] Higashida, H. et al. An immunohistochemical, enzymatic, and behavioral study of CD157/BST-1 as a neuroregulator. BMC Neurosci. 18, 35 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sarm1-knockout mice are protected from axonal degeneration and can rescue severe axon growth defects and perinatal death induced by lack of NMNAT2.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Restoration of NAD+ levels with NAD+ supplements and overexpression of NAMPT and NMNAT1 prevents axon degeneration.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NMN treatment significantly increased NAD+ levels and maximum lifespan in a mouse model of ataxia telangiectasia.

    “NMN treatment significantly increased NAD+ levels and the maximum lifespan also in a mouse model of ataxia telangiectasia135.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    NMN enhances mitochondrial function in various organs, including skeletal muscle, kidney, liver, heart, eyes, brain and the cardiovascular system, and can mitigate oxidative stress in the vasculature, including improvements in neurovascular coupling responses in the aged cortex.

    “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.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [202] Sims, C. A. et al. Nicotinamide mononucleotide preserves mitochondrial function and increases survival in hemorrhagic shock. JCI Insight 3, e120182 (2018).

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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

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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    NAM influences NAD+ functions directly and indirectly.

    “One potential explanation for this discrepancy is that NAM influences NAD+ functions directly and indirectly.”
    Quote in the paperSubstantial claim

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    Premisecitation

    There have been more phase I clinical trials using NR than NMN, and these have provided conflicting results.

    “there have been more phase I clinical trials using NR than those using NMN, and these have provided conflicting results.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites TABLE 2

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  • May combine two claims.

    Premisecitation

    One trial showed short-term NR administration has some beneficial effects in healthy elderly individuals, and another showed positive results in patients with ALS.

    “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.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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

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    • cites [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 in the free run.

    • cites [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

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  • May combine two claims.

    Interpretationreasoning

    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.

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Long-term (1-year) NMN feeding in mice starting at 5 months increased whole-body insulin sensitivity, energy metabolism and physical activity and improved lipid profiles with no obvious toxic effects.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    Aside from being a direct NAD+ precursor in the salvage pathway, NAM is a by-product of NAD+ catabolism, and at high millimolar concentrations it acts as a feedback inhibitor for NAD+-dependent enzymes such as PARPs and sirtuins in vitro.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

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    • cites [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

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  • May combine two claims.

    Premisecitation

    Augmentation of NAD+ levels has shown efficacy in a variety of mouse models of human diseases, leading to numerous clinical trials of NAD+ boosters in humans during ageing.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites TABLE 1

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    • cites TABLE 2

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  • May combine two claims.

    Premisecitation

    Long-term NAM administration prevented high-fat diet-related disease, promoting healthspan, but did not significantly affect lifespan.

    “long-term administration of NAM prevented disease related to a high-fat diet, promoting healthspan, but it did not have significant effects on lifespan200.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [200] Mitchell, S. J. et al. Nicotinamide improves aspects of healthspan, but not lifespan, in mice. Cell Metab. 27, 667–676.e4 (2018). source

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  • May combine two claims.

    Interpretationreasoning

    An increase in NAM level leads to a proportional increase of NAM methylation, which affects cellular availability of methyl groups important for DNA methylation and gene expression modulation.

    “an increase in NAM level leads to a proportional increase of NAM methylation. This in turn affects cellular availability of methyl groups, which are important for DNA methylation and gene expression modulation (BOX 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Clinical trials evaluating pharmacokinetics and toxicology of NAD+ precursors have primarily demonstrated that NMN and NR administration is safe and can efficiently increase NAD+ levels in healthy volunteers.

    “to date the clinical trials evaluating the pharmacokinetics and toxicology of NAD+ precursors have primarily demonstrated that NMN and NR administration is safe and can efficiently increase NAD+ levels in healthy volunteers (TABLE 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites TABLE 2

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  • May combine two claims.

    Premisecitation

    NAD+ replenishment using NR and/or NMN delays progeroid phenotype and extends lifespan in C. elegans models of xeroderma pigmentosum group A, ataxia telangiectasia and Cockayne syndrome, and in a worm model of Werner syndrome.

    “NAD+ replenishment, using NR and/or NMN, has also been effective in delaying progeroid phenotype and extending lifespan in relevant C. elegans models of xeroderma pigmentosum group A, ataxia telangiectasia and Cockayne syndrome33,134,135 and in a worm model of Werner syndrome (a progeroid disease)196.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [196] Fang, E. F. et al. NAD augmentation restores mitophagy and limits accelerated aging in Werner syndrome. Nat. Commun. 10, 5284 (2019).

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  • May combine two claims.

    Premisecitation

    NAD+ precursors NR and NMN improve neuronal cell health, memory and cognitive function in rat and mouse models of Alzheimer disease, and show neuroprotective properties in Drosophila models of Parkinson disease and mouse models of ALS.

    “the NAD+ precursors NR and NMN improve neuronal cell health, memory and cognitive function in rat and mouse models of Alzheimer disease136,161,175–180, and also showed neuroprotective properties in Drosophila melanogaster models of Parkinson disease181,182 and in mouse models of ALS139.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [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 in the free run.

    • cites [161] Long, A. N. et al. Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model. BMC Neurol. 15, 19 (2015).

      Not checked in the free run.

    • cites [175] Hou, Y. et al. NAD supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc. Natl Acad. Sci. USA 115, E1876–E1885 (2018). source

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    • cites [176] Yao, Z., Yang, W., Gao, Z. & Jia, P. Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease. Neurosci. Lett. 647, 133–140 (2017). source

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    • cites [177] Wang, X., Hu, X., Yang, Y., Takata, T. & Sakurai, T. Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res. 1643, 1–9 (2016). source

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    • cites [178] Chi, Y. & Sauve, A. A. Nicotinamide riboside, a trace nutrient in foods, is a vitamin B3 with effects on energy metabolism and neuroprotection. Curr. Opin. Clin. Nutr. Metab. Care 16, 657–661 (2013). source

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    • cites [179] Sorrentino, V. et al. Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity. Nature 552, 187–193 (2017). source

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    • cites [180] Fang, E. F. et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat. Neurosci. 22, 401–412 (2019). source

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    • cites [181] Lehmann, S., Loh, S. H. Y. & Miguel Martins, L. Enhancing NAD salvage metabolism is neuroprotective in a PINK1 model of Parkinson’s disease. Biol. Open 6, 141–147 (2017). source

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    • cites [182] Jia, H. et al. High doses of nicotinamide prevent oxidative mitochondrial dysfunction in a cellular model and improve motor deficit in a Drosophila model of Parkinson’s disease. J. Neurosci. Res. 86, 2083–2090 (2008). source

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  • May combine two claims.

    Premisecitation

    NMN supplementation increased endothelial cell number and improved endothelial cell function by increasing blood flow and endurance in elderly mice via a SIRT1-dependent mechanism.

    “NMN supplementation also increased the number of endothelial cells and improved endothelial cell function by increasing blood flow and endurance in elderly mice by a SIRT1-dependent mechanism210.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [210] Das, A. et al. Impairment of an endothelial NAD+-H2S signaling network is a reversible cause of vascular aging. Cell 173, 74–89.e20 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Beneficial effects of NAD+ precursors could possibly be relevant to humans and are currently being tested in clinical trials.

    “These beneficial effects of NAD+ precursors could possibly be relevant to humans and are currently being tested in clinical trials (TABLE 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites TABLE 2

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  • May combine two claims.

    Premisecitation

    Apigenin raises NAD+ levels in human cells and in mouse liver.

    “For example, apigenin, a naturally occurring flavonoid, enhances NAD+ levels in human cells and mouse liver tissue, and improves glucose and lipid homeostasis in mouse models of obesity226.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [226] Escande, C. et al. Flavonoid apigenin is an inhibitor of the NAD+ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes 62, 1084–1093 (2013). source

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  • May combine two claims.

    Premisecitation

    Compound 78c treatment activates the AMPK pathway, which is linked to longevity.

    “Although the study authors did not report lifespan changes directly, they did report activation of the prolongevity AMPK pathway and reduced activation of the mTOR–p70S6K and ERK pathways91.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pharmacological inhibition of ACMSD by TES-991 and TES-102524 boosts de novo NAD+ synthesis and SIRT1 activity, enhancing mitochondrial function in liver, kidneys and brain of mice.

    “pharmacological inhibition of ACMSD by TES-991 and TES-102524 boosts de novo NAD+ synthesis and SIRT1 activity, ultimately enhancing mitochondrial function in the liver, kidneys and brain of mice216.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [216] Katsyuba, E. et al. De novo NAD synthesis enhances mitochondrial function and improves health. Nature 563, 354–359 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A reduced form of NR, NRH, is more stable and potent than NR in increasing intracellular NAD+ content, through a pathway in which adenosine kinase converts NRH into NMNH, which is oxidized to NMN or metabolized by NMNATs to produce NADH and then NAD+.

    “a reduced form of NR, NRH, is more stable and potent than NR in increasing intracellular NAD+ content, which occurs through a new metabolic pathway in which adenosine kinase converts NRH into NMNH, which is then oxidized to NMN or further metabolized by NMNATs to produce NADH and then NAD+ (REFS211,212).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [211] Giroud-Gerbetant, J. et al. A reduced form of nicotinamide riboside defines a new path for NAD biosynthesis and acts as an orally bioavailable NAD precursor. Mol. Metab. 30, 192–202 (2019). source

      Not checked in the free run.

    • cites [212] Yang, Y., Zhang, N., Zhang, G. & Sauve, A. A. NRH salvage and conversion to NAD requires NRH kinase activity by adenosine kinase. Nat. Metab. 2, 364–379 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SBI-797812 is a potent NAMPT activator active in the nanomolar range; it increased NAMPT-mediated NMN production in vitro and NAD+ levels in cell lines and in vivo.

    “SBI-797812, was proposed as a potent NAMPT activator active in the nanomolar range. This compound increased NAMPT-mediated NMN production in vitro and, importantly, NAD+ levels in cell lines and in vivo214,215.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [214] Wang, G. et al. P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage. Cell 158, 1324–1334 (2014). source

      Not checked in the free run.

    • cites [215] Gardell, S. J. et al. Boosting NAD with a small molecule that activates NAMPT. Nat. Commun. 10, 3241 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Luteolin has neuroprotective effects in autistic children.

    “Clinically, luteolin has neuroprotective effects in children with autism229, although NAD+ levels were not directly assessed in this context.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [229] Taliou, A., Zintzaras, E., Lykouras, L. & Francis, K. An open-label pilot study of a formulation containing the anti-inflammatory flavonoid luteolin and its effects on behavior in children with autism spectrum disorders. Clin. Ther. 35, 592–602 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    P7C3 enhances NAMPT activity and boosts NAD+ levels in doxorubicin-treated human cells.

    “the neuroprotective agent P7C3 enhances NAMPT activity and boosts NAD+ levels in doxorubicin-treated human cells”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [214] Wang, G. et al. P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage. Cell 158, 1324–1334 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NQO1 was shown to be increased by caloric restriction, although it was not sufficient to mediate anti-ageing effects of this dietary intervention.

    “NQO1 was shown to be increased by caloric restriction (although it was not sufficient to mediate anti-ageing effects of this dietary intervention)217”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [217] Diaz-Ruiz, A. et al. Benefits of caloric restriction in longevity and chemical-induced tumorigenesis are transmitted independent of NQO1. J. Gerontol. A Biol. Sci. Med. Sci. 74, 155–162 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In C. elegans, PARP inhibition results in significant lifespan extension in wild-type worms, in a model of ataxia telangiectasia and under hyperglycaemic conditions.

    “In C. elegans, PARP inhibition results in a significant lifespan extension in wild-type worms190, in a model of ataxia telangiectasia135 and under hyperglycaemic conditions221.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [190] Mouchiroud, L. et al. The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154, 430–441 (2013). source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [221] Xia, Q. et al. PARP-1 inhibition rescues short lifespan in hyperglycemic C. elegans and improves GLP-1 secretion in human cells. Aging Dis. 9, 17 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NQO1 is commonly overexpressed in most solid tumours, in which β-lapachone administration induces imbalance of redox cycle and oxidative stresses.

    “NQO1 is commonly overexpressed in most solid tumours in which β-lapachone administration induces imbalance of redox cycle and oxidative stresses220”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [220] Morales, J. et al. Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Crit. Rev. Eukaryot. Gene Expr. 24, 15–28 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The authors of that study did not directly report changes in lifespan.

    “Although the study authors did not report lifespan changes directly, they did report activation of the prolongevity AMPK pathway and reduced activation of the mTOR–p70S6K and ERK pathways91.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Olaparib and rucaparib, which inhibit PARP1, are sold as cancer treatments either with chemotherapy or alone.

    “PARP1 inhibitors, such as olaparib and rucaparib, are marketed as adjuncts to chemotherapy or monotherapies for cancer222.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [222] Brown, J. S., Kaye, S. B. & Yap, T. A. PARP inhibitors: the race is on. Br. J. Cancer 114, 713–715 (2016). source

      Not checked in the free run.

107 of 107

  • The paper relies on this without support.

    Ageing reduces the ability to mount an effective adaptive immune response because adaptive immune cell functions change, a process called immunosenescence.

    “ageing is characterized by a reduced ability to build an effective adaptive immune response due to altered functions of adaptive immune cells, known as immunosenescence.”

  • The paper relies on this without support.

    Ageing skews immune cell populations, decreasing naive T and B cells, reducing T cell antigen receptor diversity, and increasing virtual memory T cells.

    “Ageing leads to an imbalance or skewing of immune cell populations, including decreased levels of naive T and B cells, loss of T cell antigen receptor diversity and an increase in levels of virtual memory T cells.”

  • The paper relies on this without support.

    NAD+-boosting strategies that extend healthspan and lifespan in animal models will also do so in humans.

    “The good news is that different NAD+-boosting strategies have been shown to be effective in extending healthspan and lifespan (see the section Therapeutic targeting of NAD+ level decline and TABLE 1).”
    “However, the translatability of NAD+-boosting therapies to humans remains the key question to be answered.”

  • The paper relies on this without support.

    Ageing-related diseases will impose substantial societal and economic costs in the coming decades.

    “This is particularly important as elderly populations are rising rapidly, and ageing-related diseases are predicted to cause a great deal of societal and economic burden in the coming decades.”
4 of 4

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?

  • Reduced NAD+ levels are associated with impaired mitochondrial function, immune cell metabolic reprogramming, and cell function.

    “Therapeutics targeting NAD+ metabolism have also been proposed as potential treatments for age-related immune decline, since reduced NAD+ levels are associated with impaired mitochondrial function, immune cell metabolic reprogramming, and cell function182.”

    From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [182]

  • NAD levels decline with ageing in both serum and tissues.

    “The levels of NAD decline with ageing in both serum and tissues218.”

    From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [218]

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.

  • Macrophage SARM1 expression is asserted and denied

    Minor

    One passage states that macrophages express SARM1; a later passage says recent evidence found that they do not. The discussion acknowledges disputed findings, but its two statements about expression are incompatible as written.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. 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). · DOI

Cited by

Sorted by citations

Authors
Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E.
Affiliations
Buck Institute for Research on Aging (US)
Corresponding author
Verdin, Eric
ORCID
Venue
Nature Reviews Molecular Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2020-12-22
Volume
22
Issue
2
Pages
119-141
ISSN
  • 1471-0072 (ISSN-L)
  • 1471-0080
DOI
10.1038/s41580-020-00313-x
PMC
PMC7963035
OpenAlex
W3115773653
Cited by
1,617
References
272
Citations by year
2026: 403 · 2025: 352 · 2024: 302 · 2023: 233 · 2022: 222 · 2021: 103 · 2020: 2
FWCI
17.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Molecular Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (T32AG000266)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R24DK085610)
Topics
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
NAD+ metabolism, aging, sirtuins, CD38, poly(ADP-ribose) polymerase, cellular senescence, DNA repair, chromatin remodeling, immune cell function, healthspan extension, lifespan extension, sarcopenia, frailty, metabolic disorders, cognitive decline
MeSH terms
Aging, Animals, Cell Physiological Phenomena, Energy Metabolism, Humans, Mitochondria, NAD, Metabolic Networks and Pathways

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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