The role of NAD+ metabolism and its modulation of mitochondria in aging and disease

0
The role of NAD+ metabolism and its modulation of mitochondria in aging and disease
  • Chini, C. C. S., Zeidler, J. D., Kashyap, S., Warner, G. & Chini, E. N. Evolving concepts in NAD+ metabolism. Cell Metab. 33, 1076–1087 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Judge, A. & Dodd, M. S. Metabolism. Essays Biochem. 64, 607–647 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kalyanaraman, B. et al. A review of the basics of mitochondrial bioenergetics, metabolism, and related signaling pathways in cancer cells: therapeutic targeting of tumor mitochondria with lipophilic cationic compounds. Redox Biol. 14, 316–327 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Xie, N. et al. NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential. Signal Transduct. Target. Ther. 5, 227 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ying, W. NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid. Redox Signal. 10, 179–206 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Dasovich, M. & Leung, A. K. L. PARPs and ADP-ribosylation: Deciphering the complexity with molecular tools. Mol. Cell 83, 1552–1572 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zeidler, J. D. et al. The CD38 glycohydrolase and the NAD sink: implications for pathological conditions. Am. J. Physiol. Cell Physiol. 322, C521–C545 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Encyclopedia of Food and Health (Elsevier, 2016).

  • Brody, T. Nutritional Biochemistry (Academic Press, San Diego, 1999).

  • Fernández-Vizarra, E., Enríquez, J. A., Pérez-Martos, A., Montoya, J. & Fernández-Silva, P. Tissue-specific differences in mitochondrial activity and biogenesis. Mitochondrion 11, 207–213 (2011).

    Article 
    PubMed 

    Google Scholar 

  • Mori, V. et al. Metabolic profiling of alternative NAD biosynthetic routes in mouse tissues. PLoS ONE 9, e113939 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • McLaughlin, K. L. et al. Novel approach to quantify mitochondrial content and intrinsic bioenergetic efficiency across organs. Sci. Rep. 10, 17599 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sorrentino, V., Menzies, K. J. & Auwerx, J. Repairing mitochondrial dysfunction in disease. Annu. Rev. Pharmacol. Toxicol. 58, 353–389 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Stein, L. R. & Imai, S. The dynamic regulation of NAD metabolism in mitochondria. Trends Endocrinol. Metab. 23, 420–428 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pittelli, M. et al. Pharmacological effects of exogenous NAD on mitochondrial bioenergetics, DNA repair, and apoptosis. Mol. Pharm. 80, 1136–1146 (2011).

    Article 
    CAS 

    Google Scholar 

  • Fiers, W., Beyaert, R., Declercq, W. & Vandenabeele, P. More than one way to die: apoptosis, necrosis and reactive oxygen damage. Oncogene 18, 7719–7730 (1999).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Juan, C. A., Pérez de la Lastra, J. M., Plou, F. J. & Pérez-Lebeña, E. The chemistry of reactive oxygen species (ROS) revisited: outlining their role in biological macromolecules (DNA, lipids and proteins) and induced pathologies. Int. J. Mol. Sci. 22, 4642 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ma, K. et al. Mitophagy, mitochondrial homeostasis, and cell fate. Front. Cell Dev. Biol. 8, 467 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Shpilka, T. & Haynes, C. M. The mitochondrial UPR: mechanisms, physiological functions and implications in ageing. Nat. Rev. Mol. Cell Biol. 19, 109–120 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Combs, G. F. The Vitamins: Fundamental Aspects in Nutrition and Health (Elsevier/AP, Amsterdam, 2012).

  • Hove-Jensen, B. et al. Phosphoribosyl diphosphate (PRPP): biosynthesis, enzymology, utilization, and metabolic significance. Microbiol Mol. Biol. Rev. 81, e00040–16 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Hara, N., Yamada, K., Shibata, T., Osago, H. & Tsuchiya, M. Nicotinamide phosphoribosyltransferase/visfatin does not catalyze nicotinamide mononucleotide formation in blood plasma. PLoS ONE 6, e22781 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pinson, B., Ceschin, J., Saint-Marc, C. & Daignan-Fornier, B. Dual control of NAD+ synthesis by purine metabolites in yeast. eLife 8, e43808 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tsui, M. et al. Purine nucleoside phosphorylase deficiency induces p53-mediated intrinsic apoptosis in human induced pluripotent stem cell-derived neurons. Sci. Rep. 12, 9084 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kropotov, A. et al. Purine nucleoside phosphorylase controls nicotinamide riboside metabolism in mammalian cells. J. Biol. Chem. 298, 102615 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bender, D. A. & Olufunwa, R. Utilization of tryptophan, nicotinamide and nicotinic acid as precursors for nicotinamide nucleotide synthesis in isolated rat liver cells. Br. J. Nutr. 59, 279–287 (1988).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Bieganowski, P. & Brenner, C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans. Cell 117, 495–502 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Preiss, J. & Handler, P. Biosynthesis of diphosphopyridine nucleotide. I. Identification of intermediates. J. Biol. Chem. 233, 488–492 (1958).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Preiss, J. & Handler, P. Biosynthesis of diphosphopyridine nucleotide. II. Enzymatic aspects. J. Biol. Chem. 233, 493–500 (1958).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Zhang, X. et al. Structural characterization of a human cytosolic NMN/NaMN adenylyltransferase and implication in human NAD biosynthesis. J. Biol. Chem. 278, 13503–13511 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Efimov, I. et al. Heme-containing dioxygenases. In Advances in Inorganic Chemistry Vol. 64 33–51 (Elsevier, 2012).

  • Han, Q., Robinson, H. & Li, J. Biochemical identification and crystal structure of kynurenine formamidase from Drosophila melanogaster. Biochem. J. 446, 253–260 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Revollo, J. R., Grimm, A. A. & Imai, S. I. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J. Biol. Chem. 279, 50754–50763 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Lau, C., Niere, M. & Ziegler, M. The NMN/NaMN adenylyltransferase (NMNAT) protein family. Front. Biosci. Landmark Ed. 14, 410–431 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Zapata-Pérez, R. et al. Reduced nicotinamide mononucleotide is a new and potent NAD+ precursor in mammalian cells and mice. FASEB J. 35, e21456 (2021).

    Article 
    PubMed 

    Google Scholar 

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Orlandi, I., Alberghina, L. & Vai, M. Nicotinamide, nicotinamide riboside and nicotinic acid-emerging roles in replicative and chronological aging in yeast. Biomolecules 10, 604 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Belenky, P., Christensen, K. C., Gazzaniga, F., Pletnev, A. A. & Brenner, C. Nicotinamide riboside and nicotinic acid riboside salvage in fungi and mammals. Quantitative basis for Urh1 and purine nucleoside phosphorylase function in NAD+ metabolism. J. Biol. Chem. 284, 158–164 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liu, L. et al. Quantitative analysis of NAD synthesis-breakdown fluxes. Cell Metab. 27, 1067–1080.e5 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Katsyuba, E., Romani, M., Hofer, D. & Auwerx, J. NAD+ homeostasis in health and disease. Nat. Metab. 2, 9–31 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Wagner, S., Manickam, R., Brotto, M. & Tipparaju, S. M. NAD+ centric mechanisms and molecular determinants of skeletal muscle disease and aging. Mol. Cell Biochem. 477, 1829–1848 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sonntag, T. et al. Nicotinamide riboside kinases regulate skeletal muscle fiber-type specification and are rate-limiting for metabolic adaptations during regeneration. Front. Cell Dev. Biol. 10, 1049653 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Revollo, J. R. et al. Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell Metab. 6, 363–375 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lundt, S. & Ding, S. NAD+ metabolism and diseases with motor dysfunction. Genes12, 1776 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wen, F. et al. Drug discovery targeting nicotinamide phosphoribosyltransferase (NAMPT): updated progress and perspectives. Bioorg. Med. Chem. 99, 117595 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Yoshida, M. et al. Extracellular vesicle-contained eNAMPT delays aging and extends lifespan in mice. Cell Metab. 30, 329–342.e5 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Covarrubias, A. J., Perrone, R., Grozio, A. & Verdin, E. NAD+ metabolism and its roles in cellular processes during ageing. Nat. Rev. Mol. Cell Biol. 22, 119–141 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Nikiforov, A., Dölle, C., Niere, M. & Ziegler, M. Pathways and subcellular compartmentation of NAD biosynthesis in human cells: from entry of extracellular precursors to mitochondrial NAD generation. J. Biol. Chem. 286, 21767–21778 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Canto, C. NAD+ precursors: a questionable redundancy. Metabolites 12, 630 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chini, E. N., Chini, C. C. S., Espindola Netto, J. M., de Oliveira, G. C. & van Schooten, W. The pharmacology of CD38/NADase: an emerging target in cancer and diseases of aging. Trends Pharmacol. Sci. 39, 424–436 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Shi, B. et al. Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis. iScience 24, 101902 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Hopkins, E. L., Gu, W., Kobe, B. & Coleman, M. P. A novel NAD signaling mechanism in axon degeneration and its relationship to innate immunity. Front. Mol. Biosci. 8, 703532 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Loreto, A., Antoniou, C., Merlini, E., Gilley, J. & Coleman, M. P. NMN: The NAD precursor at the intersection between axon degeneration and anti-ageing therapies. Neurosci. Res. 197, 18–24 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Bitterman, K. J., Anderson, R. M., Cohen, H. Y., Latorre-Esteves, M. & Sinclair, D. A. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J. Biol. Chem. 277, 45099–45107 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Domínguez-Gómez, G. et al. Nicotinamide sensitizes human breast cancer cells to the cytotoxic effects of radiation and cisplatin. Oncol. Rep. 33, 721–728 (2015).

    Article 
    PubMed 

    Google Scholar 

  • Roberti, A., Fernández, A. F. & Fraga, M. F. Nicotinamide N-methyltransferase: At the crossroads between cellular metabolism and epigenetic regulation. Mol. Metab. 45, 101165 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Migaud, M. E., Ziegler, M. & Baur, J. A. Regulation of and challenges in targeting NAD+ metabolism. Nat. Rev. Mol. Cell Biol. 25, 822–840 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Gazzaniga, F., Stebbins, R., Chang, S. Z., McPeek, M. A. & Brenner, C. Microbial NAD metabolism: lessons from comparative genomics. Microbiol. Mol. Biol. Rev. 73, 529–541 (2009). Table of Contents.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Magnúsdóttir, S., Ravcheev, D., de Crécy-Lagard, V. & Thiele, I. Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes. Front. Genet. 6, 148 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lozada-Fernández, V. V. et al. Nicotinamide riboside-conditioned microbiota deflects high-fat diet-induced weight gain in mice. mSystems 7, e0023021 (2022).

    Article 
    PubMed 

    Google Scholar 

  • Yu, X. et al. Effect of nicotinamide riboside on lipid metabolism and gut microflora-bile acid axis in alcohol-exposed mice. Food Sci. Nutr. 9, 429–440 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Peluso, A. A. et al. Oral supplementation of nicotinamide riboside alters intestinal microbial composition in rats and mice, but not humans. NPJ Aging 9, 7 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bruzzone, S., Guida, L., Zocchi, E., Franco, L. & De Flora, A. Connexin 43 hemi channels mediate Ca2+-regulated transmembrane NAD+ fluxes in intact cells. FASEB J. 15, 10–12 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Wei, W., Graeff, R. & Yue, J. Roles and mechanisms of the CD38/cyclic adenosine diphosphate ribose/Ca(2+) signaling pathway. World J. Biol. Chem. 5, 58–67 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Grant, R. et al. A pilot study investigating changes in the human plasma and urine NAD+ metabolome during a 6 h intravenous infusion of NAD. Front. Aging Neurosci. 11, 257 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Grozio, A. et al. CD73 protein as a source of extracellular precursors for sustained NAD+ biosynthesis in FK866-treated tumor cells. J. Biol. Chem. 288, 25938–25949 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ratajczak, J. et al. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat. Commun. 7, 13103 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sauve, A. A. et al. Triple-Isotope Tracing for Pathway Discernment of NMN-Induced NAD+ Biosynthesis in Whole Mice. Int. J. Mol. Sci. 24, 11114 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Grozio, A. et al. Slc12a8 is a nicotinamide mononucleotide transporter. Nat. Metab. 1, 47–57 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kanai, Y. et al. Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). J. Biol. Chem. 273, 23629–23632 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Pillai, S. M. & Meredith, D. SLC36A4 (hPAT4) is a high affinity amino acid transporter when expressed in Xenopus laevis oocytes. J. Biol. Chem. 286, 2455–2460 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Chen, M. et al. SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters. Nat. Commun. 16, 1181 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ohkubo, M., Ohta, K., Inoue, K. & Yuasa, H. Nicotinate uptake by two kinetically distinct Na÷-dependent carrier-mediated transport systems in the rat small intestine. Drug Metab. Pharmacokinet. 27, 255–262 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Bahn, A. et al. Identification of a new urate and high affinity nicotinate transporter, hOAT10 (SLC22A13). J. Biol. Chem. 283, 16332–16341 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Alano, C. C. et al. Differences among cell types in NAD(+) compartmentalization: a comparison of neurons, astrocytes, and cardiac myocytes. J. Neurosci. Res. 85, 3378–3385 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Cambronne, X. A. et al. Biosensor reveals multiple sources for mitochondrial NAD+. Science 352, 1474–1477 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kory, N. et al. MCART1/SLC25A51 is required for mitochondrial NAD transport. Sci. Adv. 6, eabe5310 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Luongo, T. S. et al. SLC25A51 is a mammalian mitochondrial NAD+ transporter. Nature 588, 174–179 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Berger, F., Lau, C., Dahlmann, M. & Ziegler, M. Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms. J. Biol. Chem. 280, 36334–36341 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Yamamoto, M. et al. Nmnat3 is dispensable in mitochondrial NAD level maintenance in vivo. PLoS ONE 11, e0147037 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhu, Y., Liu, J., Park, J., Rai, P. & Zhai, R. G. Subcellular compartmentalization of NAD+ and its role in cancer: A sereNADe of metabolic melodies. Pharmacol. Ther. 200, 27–41 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fletcher, R. S. et al. Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells. Mol. Metab. 6, 819–832 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Svoboda, P. et al. Nuclear transport of nicotinamide phosphoribosyltransferase is cell cycle-dependent in mammalian cells, and its inhibition slows cell growth. J. Biol. Chem. 294, 8676–8689 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chen, L. et al. Quantitative dynamics of intracellular NMN by genetically encoded biosensor. Biosens. Bioelectron. 267, 116842 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Michishita, E., Park, J. Y., Burneskis, J. M., Barrett, J. C. & Horikawa, I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol. Biol. Cell 16, 4623–4635 (2005).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Nolfi-Donegan, D., Braganza, A. & Shiva, S. Mitochondrial electron transport chain: Oxidative phosphorylation, oxidant production, and methods of measurement. Redox Biol. 37, 101674 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gorman, G. S. et al. Mitochondrial diseases. Nat. Rev. Dis. Prim. 2, 16080 (2016).

    Article 
    PubMed 

    Google Scholar 

  • Yusri, K., Kumar, S., Fong, S., Gruber, J. & Sorrentino, V. Towards healthy longevity: comprehensive insights from molecular targets and biomarkers to biological clocks. Int. J. Mol. Sci. 25, 6793 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Alano, C. C. et al. NAD+ depletion is necessary and sufficient for poly(ADP-ribose) polymerase-1-mediated neuronal death. J. Neurosci. 30, 2967–2978 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yang, H. et al. Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell 130, 1095–1107 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Titov, D. V. et al. Complementation of mitochondrial electron transport chain by manipulation of the NAD+/NADH ratio. Science 352, 231–235 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liu, Y., Hu, L., Ma, T., Yang, J. & Ding, J. Insights into the inhibitory mechanisms of NADH on the αγ heterodimer of human NAD-dependent isocitrate dehydrogenase. Sci. Rep. 8, 3146 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cuenoud, B. et al. Brain NAD is associated with ATP energy production and membrane phospholipid turnover in humans. Front. Aging Neurosci. 12, 609517 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Jang, S., 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yuan, X. et al. NAD+/NADH redox alterations reconfigure metabolism and rejuvenate senescent human mesenchymal stem cells in vitro. Commun. Biol. 3, 774 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wang, H. et al. Nicotinamide mononucleotide supplementation improves mitochondrial dysfunction and rescues cellular senescence by NAD+/Sirt3 pathway in mesenchymal stem cells. Int. J. Mol. Sci. 23, 14739 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Meng, H. et al. SIRT3 regulation of mitochondrial quality control in neurodegenerative diseases. Front. Aging Neurosci. 11, 313 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Huang, L. et al. Effect of Sirt3 on retinal pigment epithelial cells in high glucose through Foxo3a/ PINK1-Parkin pathway mediated mitophagy. Exp. Eye Res. 218, 109015 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Tseng, A. H. H., Shieh, S.-S. & Wang, D. L. SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage. Free Radic. Biol. Med. 63, 222–234 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Mohrin, M. et al. Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 347, 1374–1377 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wang, C.-L. et al. The mitochondrial unfolded protein response regulates hippocampal neural stem cell aging. Cell Metab. 35, 996–1008.e7 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhou, Y., Wang, S., Li, Y., Yu, S. & Zhao, Y. SIRT1/PGC-1α signaling promotes mitochondrial functional recovery and reduces apoptosis after intracerebral hemorrhage in rats. Front. Mol. Neurosci. 10, 443 (2017).

    Article 
    PubMed 

    Google Scholar 

  • Lemos, V. et al. The NAD+-dependent deacetylase SIRT2 attenuates oxidative stress and mitochondrial dysfunction and improves insulin sensitivity in hepatocytes. Hum. Mol. Genet. 26, 4105–4117 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Cha, Y. et al. SIRT2 regulates mitochondrial dynamics and reprogramming via MEK1-ERK-DRP1 and AKT1-DRP1 axes. Cell Rep. 37, 110155 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fasano, C., Disciglio, V., Bertora, S., Lepore Signorile, M. & Simone, C. FOXO3a from the nucleus to the mitochondria: a round trip in cellular stress response. Cells 8, 1110 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sundaresan, N. R. et al. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J. Clin. Invest. 119, 2758–2771 (2009).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, H. et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352, 1436–1443 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Mouchiroud, L. et al. The NAD(+)/Sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154, 430–441 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 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).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Klimova, N., Long, A. & Kristian, T. Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3-dependent mechanism in male mice. J. Neurosci. Res. 97, 975–990 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Romani, M. et al. NAD+ boosting reduces age-associated amyloidosis and restores mitochondrial homeostasis in muscle. Cell Rep. 34, 108660 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Song, S. B. et al. Modulation of mitochondrial membrane potential and ROS generation by nicotinamide in a manner independent of SIRT1 and mitophagy. Mol. Cells 40, 503–514 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Braıdy, N. Intravenous NAD+ effectively increased the NAD metabolome, reduced oxidative stress and inflammation, and increased expression of longevity genes safely in elderly humans. J. Cell. Neurosci. Oxid. Stress 10, 779–779 (2018).

    Article 

    Google Scholar 

  • Gibson, S. B., Mestayer, R., Berg, J., Grant, R. & Dyess, G. Intravenous administration of nicotinamide adenine dinucleotide improves cognitive performance in human subjects: implications for clinical populations. Arch. Phys. Med. Rehabil. 102, e42 (2021).

    Article 

    Google Scholar 

  • Munk, S. H. N. et al. NAD+ regulates nucleotide metabolism and genomic DNA replication. Nat. Cell Biol. 25, 1774–1786 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Radenkovic, D., Reason & Verdin, E. Clinical evidence for targeting NAD therapeutically. Pharmaceuticals 13, 247 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Song, Q. et al. The safety and antiaging effects of nicotinamide mononucleotide in human clinical trials: an update. Adv. Nutr. 14, 1416–1435 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Damgaard, M. V. & Treebak, J. T. What is really known about the effects of nicotinamide riboside supplementation in humans. Sci. Adv. 9, eadi4862 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Henderson, J. D., Quigley, S. N. Z., Chachra, S. S., Conlon, N. & Ford, D. The use of a systems approach to increase NAD+ in human participants. NPJ Aging 10, 7 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bodor, E. T. & Offermanns, S. Nicotinic acid: an old drug with a promising future. Br. J. Pharmacol. 153, S68–S75 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Membrez, M. et al. Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia. Nat. Metab. 6, 433–447 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chellappa, K. et al. NAD precursors cycle between host tissues and the gut microbiome. Cell Metab. 34, 1947–1959.e5 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yaku, K. et al. BST1 regulates nicotinamide riboside metabolism via its glycohydrolase and base-exchange activities. Nat. Commun. 12, 6767 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yang, Y., Mohammed, F. S., Zhang, N. & Sauve, A. A. Dihydronicotinamide riboside is a potent NAD+ concentration enhancer in vitro and in vivo. J. Biol. Chem. 294, 9295–9307 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liu, Y. et al. Reduced nicotinamide mononucleotide (NMNH) potently enhances NAD+ and suppresses glycolysis, the TCA cycle, and cell growth. J. Proteome Res. 20, 2596–2606 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Aktar, S., Ferdousi, F., Kondo, S., Kagawa, T. & Isoda, H. Transcriptomics and biochemical evidence of trigonelline ameliorating learning and memory decline in the senescence-accelerated mouse prone 8 (SAMP8) model by suppressing proinflammatory cytokines and elevating neurotransmitter release. GeroScience (2023).

  • Farid, M. M., Yang, X., Kuboyama, T. & Tohda, C. Trigonelline recovers memory function in Alzheimer’s disease model mice: evidence of brain penetration and target molecule. Sci. Rep. 10, 16424 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sauve, A. A. & Schramm, V. L. Mechanism-based inhibitors of CD38: a mammalian cyclic ADP-ribose synthetase. Biochemistry 41, 8455–8463 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Sauve, A. A., Munshi, C., Lee, H. C. & Schramm, V. L. The reaction mechanism for CD38. A single intermediate is responsible for cyclization, hydrolysis, and base-exchange chemistries. Biochemistry 37, 13239–13249 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Hogan, K. A., Chini, C. C. S. & Chini, E. N. The multi-faceted ecto-enzyme CD38: Roles In Immunomodulation, Cancer, Aging, and Metabolic Diseases. Front. Immunol. 10, 1187 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Aksoy, P., White, T. A., Thompson, M. & Chini, E. N. Regulation of intracellular levels of NAD: a novel role for CD38. Biochem. Biophys. Res. Commun. 345, 1386–1392 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Piedra-Quintero, Z. L., Wilson, Z., Nava, P. & Guerau-de-Arellano, M. CD38: An Immunomodulatory Molecule In Inflammation And Autoimmunity. Front. Immunol. 11, 597959 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liu, Q. et al. Covalent and noncovalent intermediates of an NAD utilizing enzyme, human CD38. Chem. Biol. 15, 1068–1078 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 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).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Peclat, T. R. et al. CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell 21, e13589 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kellenberger, E., Kuhn, I., Schuber, F. & Muller-Steffner, H. Flavonoids as inhibitors of human CD38. Bioorg. Med. Chem. Lett. 21, 3939–3942 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Wang, H., Li, S., Zhang, G., Wu, H. & Chang, X. Potential therapeutic effects of cyanidin-3-O-glucoside on rheumatoid arthritis by relieving inhibition of CD38+ NK cells on Treg cell differentiation. Arthritis Res. Ther. 21, 220 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tang, D., Chen, K., Huang, L. & Li, J. Pharmacokinetic properties and drug interactions of apigenin, a natural flavone. Expert Opin. Drug Metab. Toxicol. 13, 323–330 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ogura, Y., Kitada, M., Xu, J., Monno, I. & Koya, D. CD38 inhibition by apigenin ameliorates mitochondrial oxidative stress through restoration of the intracellular NAD+/NADH ratio and Sirt3 activity in renal tubular cells in diabetic rats. Aging 12, 11325–11336(2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Adamia, S. et al. Combination therapy targeting Erk1/2 and CDK4/6i in relapsed refractory multiple myeloma. Leukemia 36, 1088–1101 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gozzetti, A. et al. Anti CD38 monoclonal antibodies for multiple myeloma treatment. Hum. Vaccin Immunother. 18, 2052658 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sanchez, L., Wang, Y., Siegel, D. S. & Wang, M. L. Daratumumab: a first-in-class CD38 monoclonal antibody for the treatment of multiple myeloma. J. Hematol. Oncol. 9, 51 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • van de Donk, N. W. C. J. et al. Monoclonal antibodies targeting CD38 in hematological malignancies and beyond. Immunol. Rev. 270, 95–112 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Abadier, M., Estevam, J., Berg, D. & Fedyk, E. R. Mezagitamab induces immunomodulatory effect in patients with relapsed/refractory multiple myeloma (RRMM). Blood 136, 9–9 (2020).

    Article 

    Google Scholar 

  • Dwivedi, S., Rendón-Huerta, E. P., Ortiz-Navarrete, V. & Montaño, L. F. CD38 and regulation of the immune response cells in cancer. J. Oncol. 2021, 6630295 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Raab, M. S. et al. MOR202, a novel anti-CD38 monoclonal antibody, in patients with relapsed or refractory multiple myeloma: a first-in-human, multicentre, phase 1-2a trial. Lancet Haematol. 7, e381–e394 (2020).

    Article 
    PubMed 

    Google Scholar 

  • Romano, A. et al. Mechanisms of action of the new antibodies in use in multiple myeloma. Front. Oncol. 11, 684561 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Franssen, L. E., Stege, C. A. M., Zweegman, S., van de Donk, N. W. C. J. & Nijhof, I. S. Resistance mechanisms towards CD38-Directed antibody therapy in multiple myeloma. J. Clin. Med. 9, 1195 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Jiao, Y. et al. CD38: targeted therapy in multiple myeloma and therapeutic potential for solid cancers. Expert Opin. Investig. Drugs 29, 1295–1308 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Ugamraj, H. S. et al. TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity. MAbs 14, 2095949 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Qian, M. et al. Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria. eLife 7, e34836 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hu, Y. et al. Aβ promotes CD38 expression in senescent microglia in Alzheimer’s disease. Biol. Res. 55, 10 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zha, S., Li, Z., Cao, Q., Wang, F. & Liu, F. PARP1 inhibitor (PJ34) improves the function of aging-induced endothelial progenitor cells by preserving intracellular NAD+ levels and increasing SIRT1 activity. Stem Cell Res. Ther. 9, 224 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Min, A. & Im, S.-A. PARP inhibitors as therapeutics: beyond modulation of PARylation. Cancers12, 394 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Singh, N., Pay, S. L., Bhandare, S. B., Arimpur, U. & Motea, E. A. Therapeutic strategies and biomarkers to modulate PARP activity for targeted cancer therapy. Cancers12, 972 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Paldino, E. et al. Modulation of inflammasome and pyroptosis by olaparib, a PARP-1 inhibitor, in the R6/2 mouse model of Huntington’s disease. Cells 9, 2286 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kovacs, K. et al. PARP inhibitor protects against chronic hypoxia/reoxygenation-induced retinal injury by regulation of MAPKs, HIF1α, Nrf2, and NFκB. Invest. Ophthalmol. Vis. Sci. 60, 1478–1490 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Gariani, K. et al. Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease. J. Hepatol. 66, 132–141 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Bridges, K. A. et al. Niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase inhibitor, radiosensitizes human lung and breast cancer cells. Oncotarget 5, 5076–5086 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mogol, A. N., Kaminsky, A. Z., Dutton, D. J. & Madak Erdogan, Z. Targeting NAD+ metabolism: preclinical insights into potential cancer therapy strategies. Endocrinology 165, bqae043 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Jones, P., Wilcoxen, K., Rowley, M. & Toniatti, C. Niraparib: a poly(ADP-ribose) polymerase (PARP) inhibitor for the treatment of tumors with defective homologous recombination. J. Med. Chem. 58, 3302–3314 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Martin-Oliva, D. et al. Inhibition of poly(ADP-ribose) polymerase modulates tumor-related gene expression, including hypoxia-inducible factor-1 activation, during skin carcinogenesis. Cancer Res. 66, 5744–5756 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Wang, G. et al. PARP-1 inhibitor, DPQ, attenuates LPS-induced acute lung injury through inhibiting NF-κB-mediated inflammatory response. PLoS ONE 8, e79757 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Damiani, R. M. et al. Influence of PARP-1 inhibition in the cardiotoxicity of the topoisomerase 2 inhibitors doxorubicin and mitoxantrone. Toxicol. Vitr. 52, 203–213 (2018).

    Article 
    CAS 

    Google Scholar 

  • Caldini, R. et al. Low doses of 3-aminobenzamide, a poly(ADP-ribose) polymerase inhibitor, stimulate angiogenesis by regulating expression of urokinase type plasminogen activator and matrix metalloprotease 2. Vasc. Cell 3, 12 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Woodhouse, B. C. & Dianov, G. L. Poly ADP-ribose polymerase-1: an international molecule of mystery. DNA Repair7, 1077–1086 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Lo, E. H., Bosque-Hamilton, P. & Meng, W. Inhibition of poly(ADP-ribose) polymerase: reduction of ischemic injury and attenuation of N-methyl-D-aspartate-induced neurotransmitter dysregulation. Stroke 29, 830–836 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Liaudet, L. et al. Suppression of poly (ADP-ribose) polymerase activation by 3-aminobenzamide in a rat model of myocardial infarction: long-term morphological and functional consequences. Br. J. Pharmacol. 133, 1424–1430 (2001).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Krishnan Muthaiah, V. P., Kaliyappan, K. & Mahajan, S. D. Poly ADP-ribose polymerase-1 inhibition by 3-aminobenzamide recuperates HEI-OC1 auditory hair cells from blast overpressure-induced cell death. Front. Cell Dev. Biol. 11, 1047308 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ohmoto, A. & Yachida, S. Current status of poly(ADP-ribose) polymerase inhibitors and future directions. Onco Targets Ther. 10, 5195–5208 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kaci, F. N. & Daglioglu, C. 3-Aminobenzamide-linked multifunctional nanoparticles enhances anticancer activity of low-dose cisplatin chemotherapy in lung adenocarcinoma. J. Drug Deliv. Sci. Technol. 100, 106038 (2024).

    Article 
    CAS 

    Google Scholar 

  • Chung, S. et al. Regulation of SIRT1 in cellular functions: role of polyphenols. Arch. Biochem. Biophys. 501, 79–90 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Iside, C., Scafuro, M., Nebbioso, A. & Altucci, L. SIRT1 activation by natural phytochemicals: an overview. Front. Pharmacol. 11, 1225 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Łanoszka, K. & Vlčková, N. Natural Sirtuin1 activators and atherosclerosis: an overview. Curr. Atheroscler. Rep. 25, 979–994 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kim, J. E. et al. Mitochondrial SIRT3 as a protective factor against cyclosporine A-induced nephrotoxicity. Sci. Rep. 14, 10143 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Trinh, D., Al Halabi, L., Brar, H., Kametani, M. & Nash, J. E. The role of SIRT3 in homeostasis and cellular health. Front. Cell Neurosci. 18, 1434459 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Harris, P. S., Gomez, J. D., Backos, D. S. & Fritz, K. S. Characterizing Sirtuin 3 deacetylase affinity for aldehyde dehydrogenase 2. Chem. Res. Toxicol. 30, 785–793 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li, Y. et al. Role of SIRT3 in neurological diseases and rehabilitation training. Metab. Brain Dis. 38, 69–89 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Ma, S., Fan, L. & Cao, F. Combating cellular senescence by sirtuins: implications for atherosclerosis. Biochim. Biophys. Acta Mol. Basis Dis. 1865, 1822–1830 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Troelsen, K. S. et al. Mitochondria-targeted inhibitors of the human SIRT3 lysine deacetylase. RSC Chem. Biol. 2, 627–635 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pillai, V. B. et al. Honokiol, an activator of Sirtuin-3 (SIRT3) preserves mitochondria and protects the heart from doxorubicin-induced cardiomyopathy in mice. Oncotarget 8, 34082–34098 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Peng, F. et al. 2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis. Signal Transduct. Target Ther. 9, 133 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lee, J. H., Yun, C. W., Hur, J. & Lee, S. H. Fucoidan rescues p-cresol-induced cellular senescence in mesenchymal stem cells via FAK-Akt-TWIST axis. Mar. Drugs 16, 121 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lin, Y. et al. The anti-cancer effects of fucoidan: a review of both in vivo and in vitro investigations. Cancer Cell Int. 20, 154 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li, J.-J. et al. Nicotinamide N-methyltransferase (NNMT): a new hope for treating aging and age-related conditions. Metabolites 14, 343 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rahnasto-Rilla, M. K. et al. The identification of a SIRT6 activator from brown algae Fucus distichus. Mar. Drugs 15, 190 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, L. et al. Fucoidans are novel senotherapeutics that enhance sirt6 and DNA repair activity. Innov. Aging 6, 732–732 (2022).

    Article 
    PubMed Central 

    Google Scholar 

  • Kim, S. et al. Sirtuin 7 inhibitor attenuates colonic mucosal immune activation in mice-potential therapeutic target in inflammatory bowel disease. Biomedicines 10, 2693 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sun, W.-D. et al. Nicotinamide N-methyltransferase (NNMT): a novel therapeutic target for metabolic syndrome. Front. Pharmacol. 15, 1410479 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liu, M. et al. Serum N(1)-methylnicotinamide is associated with obesity and diabetes in Chinese. J. Clin. Endocrinol. Metab. 100, 3112–3117 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ruf, S. et al. Novel tricyclic small molecule inhibitors of Nicotinamide N-methyltransferase for the treatment of metabolic disorders. Sci. Rep. 12, 15440 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kannt, A. et al. A small molecule inhibitor of Nicotinamide N-methyltransferase for the treatment of metabolic disorders. Sci. Rep. 8, 3660 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chen, D. et al. Novel propargyl-linked bisubstrate analogues as tight-binding inhibitors for nicotinamide N-methyltransferase. J. Med. Chem. 62, 10783–10797 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Policarpo, R. L. et al. High-affinity alkynyl bisubstrate inhibitors of nicotinamide N-methyltransferase (NNMT). J. Med. Chem. 62, 9837–9873 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Meng, Y., Iyamu, I. D., Ahmed, N. A. M. & Huang, R. Comparative analysis of two NNMT bisubstrate inhibitors through chemoproteomic studies: uncovering the role of unconventional SAM analogue moiety for improved selectivity. ACS Chem. Biol. 19, 89–100 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lee, H.-Y. et al. Covalent inhibitors of nicotinamide N-methyltransferase (NNMT) provide evidence for target engagement challenges in situ. Bioorg. Med. Chem. Lett. 28, 2682–2687 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Neelakantan, H. et al. Selective and membrane-permeablesmall molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice. Biochem Pharmacol. 147, 141–152 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Neelakantan, H. et al. Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle. Biochem. Pharmacol. 163, 481–492 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Dimet-Wiley, A. L. et al. Nicotinamide N-methyltransferase inhibition mimics and boosts exercise-mediated improvements in muscle function in aged mice. Sci. Rep. 14, 15554 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ahmed-Belkacem, R., Debart, F. & Vasseur, J. Bisubstrate strategies to target methyltransferases. Eur. J. Org. Chem. 2022, e202101481 (2022).

    Article 
    CAS 

    Google Scholar 

  • Gao, Y., Martin, N. I. & Van Haren, M. J. Nicotinamide N-methyl transferase (NNMT): an emerging therapeutic target. Drug Discov. Today 26, 2699–2706 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Sampson, C. M. et al. Combined nicotinamide N-methyltransferase inhibition and reduced-calorie diet normalizes body composition and enhances metabolic benefits in obese mice. Sci. Rep. 11, 5637 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Xu, Q. et al. Mechanism research and treatment progress of NAD pathway related molecules in tumor immune microenvironment. Cancer Cell Int. 22, 242 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhu, Y. et al. From rate-limiting enzyme to therapeutic target: the promise of NAMPT in neurodegenerative diseases. Front. Pharmacol. 13, 920113 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Garten, A. et al. Physiological and pathophysiological roles of NAMPT and NAD metabolism. Nat. Rev. Endocrinol. 11, 535–546 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • van der Veer, E. et al. Extension of human cell lifespan by nicotinamide phosphoribosyltransferase. J. Biol. Chem. 282, 10841–10845 (2007).

    Article 
    PubMed 

    Google Scholar 

  • Song, J. et al. Nicotinamide phosphoribosyltransferase is required for the calorie restriction-mediated improvements in oxidative stress, mitochondrial biogenesis, and metabolic adaptation. J. Gerontol. A Biol. Sci. Med. Sci. 69, 44–57 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Wei, Y., Xiang, H. & Zhang, W. Review of various NAMPT inhibitors for the treatment of cancer. Front. Pharmacol. 13, 970553 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Xu, T.-Y. et al. Discovery and characterization of novel small-molecule inhibitors targeting nicotinamide phosphoribosyltransferase. Sci. Rep. 5, 10043 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, S.-L. et al. Crystal structure-based comparison of two NAMPT inhibitors. Acta Pharm. Sin. 39, 294–301 (2018).

    Article 
    CAS 

    Google Scholar 

  • Ghanem, M. S. et al. Identification of NAPRT inhibitors with anti-cancer properties by in silico drug discovery. Pharmaceuticals 15, 848 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Parisotto, M. et al. The NAMPT inhibitor FK866 increases metformin sensitivity in pancreatic cancer cells. Cancers14, 5597 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zeng, M. et al. Nicotinamide phosphoribosyltransferase inhibitor ameliorates mouse aging-induced cognitive impairment. J. Cereb. Blood Flow. Metab. 41, 2510–2523 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Holen, K., Saltz, L. B., Hollywood, E., Burk, K. & Hanauske, A.-R. The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor. Invest. N. Drugs 26, 45–51 (2008).

    Article 
    CAS 

    Google Scholar 

  • Akiu, M. et al. Discovery of DS68702229 as a potent, orally available NAMPT (nicotinamide phosphoribosyltransferase) activator. Chem. Pharm. Bull.69, 1110–1122 (2021).

    Article 
    CAS 

    Google Scholar 

  • Pinkerton, A. B. et al. Optimization of a urea-containing series of nicotinamide phosphoribosyltransferase (NAMPT) activators. Bioorg. Med. Chem. Lett. 41, 128007 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Tang, S. et al. Chemistry-led investigations into the mode of action of NAMPT activators, resulting in the discovery of non-pyridyl class NAMPT activators. Acta Pharm. Sin. B 13, 709–721 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Yao, H. et al. Discovery of small-molecule activators of nicotinamide phosphoribosyltransferase (NAMPT) and their preclinical neuroprotective activity. Cell Res. 32, 570–584 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hong, W., Mo, F., Zhang, Z., Huang, M. & Wei, X. Nicotinamide mononucleotide: a promising molecule for therapy of diverse diseases by targeting NAD+ metabolism. Front. Cell Dev. Biol. 8, 246 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liang, J. et al. Impact of NAD+ metabolism on ovarian aging. Immun. Ageing 20, 70 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kim, M. et al. Discovery of a novel NAMPT inhibitor that selectively targets NAPRT-deficient EMT-subtype cancer cells and alleviates chemotherapy-induced peripheral neuropathy. Theranostics 13, 5075–5098 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Olesen, U. H., Thougaard, A. V., Jensen, P. B. & Sehested, M. A preclinical study on the rescue of normal tissue by nicotinic acid in high-dose treatment with APO866, a specific nicotinamide phosphoribosyltransferase inhibitor. Mol. Cancer Ther. 9, 1609–1617 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Piacente, F. et al. Nicotinic acid phosphoribosyltransferase regulates cancer cell metabolism, susceptibility to NAMPT inhibitors, and DNA repair. Cancer Res. 77, 3857–3869 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Franco, J. et al. Structure-based identification and biological characterization of new NAPRT inhibitors. Pharmaceuticals 15, 855 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Baldassarri, C. et al. Properly substituted benzimidazoles as a new promising class of nicotinate phosphoribosyltransferase (NAPRT) modulators. Pharmaceuticals 16, 189 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sporny, M. et al. Structural basis for SARM1 inhibition and activation under energetic stress. eLife 9, e62021 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chen, J. & Li, H. Characterization of novel SARM1 inhibitors for the treatment of chemotherapy-induced peripheral neuropathy. Biomedicines 12, 2123 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yoshino, J. ACMSD: a novel target for modulating NAD+ homeostasis. Trends Endocrinol. Metab. 30, 229–232 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Katsyuba, E. et al. De novo NAD+ synthesis enhances mitochondrial function and improves health. Nature 563, 354–359 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cianci, M. et al. Structural Basis of Human Dimeric α-Amino-β-Carboxymuconate-ε-Semialdehyde Decarboxylase Inhibition With TES-1025. Front Mol Biosci. 9, 834700 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yang, Y. et al. Diflunisal derivatives as modulators of ACMS decarboxylase targeting the tryptophan-kynurenine pathway. J. Med. Chem. 64, 797–811 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Balakrishnan, K. et al. Phase 2 and pharmacodynamic study of oral forodesine in patients with advanced, fludarabine-treated chronic lymphocytic leukemia. Blood 116, 886–892 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Dummer, R. et al. Final results of a multicenter phase II study of the purine nucleoside phosphorylase (PNP) inhibitor forodesine in patients with advanced cutaneous T-cell lymphomas (CTCL) (Mycosis fungoides and Sézary syndrome). Ann. Oncol. 25, 1807–1812 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Feuz, M. B., Meyer-Ficca, M. L. & Meyer, R. G. Beyond pellagra-research models and strategies addressing the enduring clinical relevance of NAD deficiency in aging and disease. Cells 12, 500 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fang, E. F. et al. NAD+ in aging: molecular mechanisms and translational implications. Trends Mol. Med. 23, 899–916 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

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

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pirinen, E. et al. Niacin cures systemic NAD+ deficiency and improves muscle performance in adult-onset mitochondrial myopathy. Cell Metab. 31, 1078–1090.e5 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Ferrell, M. et al. A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk. Nat. Med. 30, 424–434 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Orr, M. E. et al. A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment. Geroscience 46, 665–682 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Schmeisser, K. et al. Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide. Nat. Chem. Biol. 9, 693–700 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Beltrà, M. et al. NAD+ repletion with niacin counteracts cancer cachexia. Nat. Commun. 14, 1849 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Migliavacca, E. et al. Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities. Nat. Commun. 10, 5808 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hiona, A. & Leeuwenburgh, C. The role of mitochondrial DNA mutations in aging and sarcopenia: implications for the mitochondrial vicious cycle theory of aging. Exp. Gerontol. 43, 24–33 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Askanas, V. & Engel, W. K. Sporadic inclusion-body myositis: conformational multifactorial ageing-related degenerative muscle disease associated with proteasomal and lysosomal inhibition, endoplasmic reticulum stress, and accumulation of amyloid-β42 oligomers and phosphorylated tau. Presse Med. 40, e219–e235 (2011).

    Article 
    PubMed 

    Google Scholar 

  • Joshi, P. R. et al. Functional relevance of mitochondrial abnormalities in sporadic inclusion body myositis. J. Clin. Neurosci. 21, 1959–1963 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Aguennouz, M. et al. Telomere shortening is associated to TRF1 and PARP1 overexpression in Duchenne muscular dystrophy. Neurobiol. Aging 32, 2190–2197 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Ryu, D. et al. NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation. Sci. Transl. Med. 8, 361ra139 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Frederick, D. W. et al. Loss of NAD homeostasis leads to progressive and reversible degeneration of skeletal muscle. Cell Metab. 24, 269–282 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Argilés, J. M., Busquets, S., Stemmler, B. & López-Soriano, F. J. Cancer cachexia: understanding the molecular basis. Nat. Rev. Cancer 14, 754–762 (2014).

    Article 
    PubMed 

    Google Scholar 

  • Park, J. M., Han, Y. M., Lee, H. J., Park, Y. J. & Hahm, K. B. Nicotinamide riboside vitamin B3 mitigated C26 adenocarcinoma-induced cancer cachexia. Front. Pharmacol. 12, 665493 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Campelj, D. G. et al. The paradoxical effect of PARP inhibitor BGP-15 on irinotecan-induced cachexia and skeletal muscle dysfunction. Cancers12, 3810 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sorensen, J. C. et al. BGP-15 protects against oxaliplatin-induced skeletal myopathy and mitochondrial reactive oxygen species production in mice. Front. Pharmacol. 8, 137 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Basse, A. L. et al. Nampt controls skeletal muscle development by maintaining Ca2+ homeostasis and mitochondrial integrity. Mol. Metab. 53, 101271 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kim, H.-J., Jung, D.-W. & Williams, D. R. Age is just a number: progress and obstacles in the discovery of new candidate drugs for sarcopenia. Cells 12, 2608 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tsai, S.-Y. Lost in translation: challenges of current pharmacotherapy for sarcopenia. Trends Mol. Med. 30, 1047–1060 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Duan, D., Goemans, N., Takeda, S., Mercuri, E. & Aartsma-Rus, A. Duchenne muscular dystrophy. Nat. Rev. Dis. Prim. 7, 13 (2021).

    Article 
    PubMed 

    Google Scholar 

  • Cardoso, D., Barthélémy, I., Blot, S. & Muchir, A. Replenishing NAD+ content reduces aspects of striated muscle disease in a dog model of Duchenne muscular dystrophy. Skelet. Muscle 13, 20 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Frederick, D. W. et al. Complementary NAD+ replacement strategies fail to functionally protect dystrophin-deficient muscle. Skelet. Muscle 10, 30 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Amjad, S. et al. Role of NAD+ in regulating cellular and metabolic signaling pathways. Mol. Metab. 49, 101195 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bartman, S., Coppotelli, G. & Ross, J. M. Mitochondrial dysfunction: a key player in brain aging and diseases. Curr. Issues Mol. Biol. 46, 1987–2026 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lautrup, S., Sinclair, D. A., Mattson, M. P. & Fang, E. F. NAD+ in brain aging and neurodegenerative disorders. Cell Metab. 30, 630–655 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wang, X. et al. NAD+ in Alzheimer’s disease: molecular mechanisms and systematic therapeutic evidence obtained in vivo. Front. Cell Dev. Biol. 9, 668491 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yu, M., Sporns, O. & Saykin, A. J. The human connectome in Alzheimer disease – relationship to biomarkers and genetics. Nat. Rev. Neurol. 17, 545–563 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

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

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Blacher, E. et al. Alzheimer’s disease pathology is attenuated in a CD38-deficient mouse model. Ann. Neurol. 78, 88–103 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Maggiore, A. et al. Neuroprotective effects of PARP inhibitors in Drosophila models of Alzheimer’s disease. Cells 11, 1284 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fathi, M. et al. Dynamic changes in metabolites of the kynurenine pathway in Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease: a systematic Review and meta-analysis. Front. Immunol. 13, 997240 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gabrawy, M. M. et al. Dual treatment with kynurenine pathway inhibitors and NAD+ precursors synergistically extends life span in Drosophila. Aging Cell 23, e14102 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 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).

    Article 
    PubMed 

    Google Scholar 

  • Flønes, I. H. et al. Mitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease. Nat. Commun. 15, 3631 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • González-Rodríguez, P. et al. Disruption of mitochondrial complex I induces progressive Parkinsonism. Nature 599, 650–656 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Dölle, C. et al. Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease. Nat. Commun. 7, 13548 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lehmann, S., Costa, A. C., Celardo, I., Loh, S. H. Y. & Martins, L. M. Parp mutations protect against mitochondrial dysfunction and neurodegeneration in a PARKIN model of Parkinson’s disease. Cell Death Dis. 7, e2166 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

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

    CAS 
    PubMed 

    Google Scholar 

  • Caito, S. W. & Aschner, M. NAD+ Supplementation attenuates methylmercury dopaminergic and mitochondrial toxicity in Caenorhabditis elegans. Toxicol. Sci. 151, 139–149 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Shan, C. et al. Protective effects of β- nicotinamide adenine dinucleotide against motor deficits and dopaminergic neuronal damage in a mouse model of Parkinson’s disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 94, 109670 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Turconi, G. et al. Nicotinamide riboside first alleviates symptoms but later downregulates dopamine metabolism in proteasome inhibition mouse model of Parkinson’s disease. Heliyon 10, e34355 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yang, B. et al. NAD+ supplementation prevents STING-induced senescence in ataxia telangiectasia by improving mitophagy. Aging Cell 20, e13329 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hughes, R. O. et al. Small molecule SARM1 inhibitors recapitulate the SARM1-/- phenotype and allow recovery of a metastable pool of axons fated to degenerate. Cell Rep. 34, 108588 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Alexandris, A. S. et al. Protective effects of NAMPT or MAPK inhibitors and NaR on Wallerian degeneration of mammalian axons. Neurobiol. Dis. 171, 105808 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Takaso, Y. et al. Deletion of CD38 and supplementation of NAD+ attenuate axon degeneration in a mouse facial nerve axotomy model. Sci. Rep. 10, 17795 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chanvillard, L., Tammaro, A. & Sorrentino, V. NAD+ metabolism and interventions in premature renal aging and chronic kidney disease. Cells 12, 21 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cohen, J. J. Relationship between energy requirements for Na+ reabsorption and other renal functions. Kidney Int. 29, 32–40 (1986).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • van der Rijt, S., Leemans, J. C., Florquin, S., Houtkooper, R. H. & Tammaro, A. Immunometabolic rewiring of tubular epithelial cells in kidney disease. Nat. Rev. Nephrol. 18, 588–603 (2022).

    Article 
    PubMed 

    Google Scholar 

  • Takahashi, R. et al. The significance of NAD + metabolites and nicotinamide N-methyltransferase in chronic kidney disease. Sci. Rep. 12, 1–19 (2022).

    Article 

    Google Scholar 

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yasuda, I. et al. Pre-emptive short-term nicotinamide mononucleotide treatment in a mouse model of diabetic nephropathy. J. Am. Soc. Nephrol.32, 1355–1370 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cho, K., Kim, H., Rodriguez-Iturbe, B. & Vaziri, N. D. Niacin ameliorates oxidative stress, inflammation, proteinuria, and hypertension in rats with chronic renal failure. Am. J. Physiol. Ren. Physiol. 297, F106–F113 (2009).

    Article 
    CAS 

    Google Scholar 

  • Zhen, X. et al. Nicotinamide supplementation attenuates renal interstitial fibrosis via boosting the activity of sirtuins. Kidney Dis.7, 186–199 (2021).

    Article 

    Google Scholar 

  • Marjot, T., Moolla, A., Cobbold, J. F., Hodson, L. & Tomlinson, J. W. Nonalcoholic fatty liver disease in adults: current concepts in etiology, outcomes, and management. Endocr. Rev. 41, bnz009 (2020).

    Article 
    PubMed 

    Google Scholar 

  • Liu, Y. J. et al. ACMSD inhibition corrects fibrosis, inflammation, and DNA damage in MASLD/MASH. J. Hepatol. 82, 174–188 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Koltai, E. et al. Exercise alters SIRT1, SIRT6, NAD and NAMPT levels in skeletal muscle of aged rats. Mech. Ageing Dev. 131, 21–28 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Barth, P. G. et al. An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes. J. Neurol. Sci. 62, 327–355 (1983).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Damschroder, D. et al. Stimulating the sir2-spargel axis rescues exercise capacity and mitochondrial respiration in a Drosophila model of Barth syndrome. Dis. Model Mech. 15, dmm049279 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ji, J. et al. NAD supplementation improves mitochondrial performance of cardiolipin mutants. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1867, 159094 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, H., Zhang, Y., Zhang, J. & Jia, D. Exercise alleviates cardiovascular diseases by improving mitochondrial homeostasis. J. Am. Heart Assoc. 13, e036555 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Caldwell, C. C., Petzinger, G. M., Jakowec, M. W. & Cadenas, E. Treadmill exercise rescues mitochondrial function and motor behavior in the CAG140 knock-in mouse model of Huntington’s disease. Chem. Biol. Interact. 315, 108907 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Hokari, F. et al. Muscle contractile activity regulates Sirt3 protein expression in rat skeletal muscles. J. Appl. Physiol.109, 332–340 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Cantó, C. et al. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab. 11, 213–219 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 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).

    Article 
    PubMed 

    Google Scholar 

  • Airhart, S. E. et al. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS ONE 12, e0186459 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lapatto, H. A. K. et al. Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study. Sci. Adv. 9, eadd5163 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Berven, H. et al. NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson’s disease. Nat. Commun. 14, 7793 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Elhassan, Y. S. et al. Nicotinamide riboside augments the aged human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures. Cell Rep. 28, 1717–1728.e6 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ahmadi, A. et al. Randomized crossover clinical trial of coenzyme Q10 and nicotinamide riboside in chronic kidney disease. JCI Insight 8, e167274 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Dollerup, O. L. et al. Nicotinamide riboside does not alter mitochondrial respiration, content or morphology in skeletal muscle from obese and insulin-resistant men. J. Physiol. 598, 731–754 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Zhou, B. et al. Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure. J. Clin. Invest. 130, 6054–6063 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wang, D. D. et al. Safety and tolerability of nicotinamide riboside in heart failure with reduced ejection fraction. JACC Basic Transl. Sci. 7, 1183–1196 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Brakedal, B. et al. The NADPARK study: a randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease. Cell Metab. 34, 396–407.e6 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Presterud, R. et al. Long-term nicotinamide riboside use improves coordination and eye movements in ataxia telangiectasia. Mov. Disord. 39, 360–369 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Connell, N. et al. NAD+-precursor supplementation with L-tryptophan, nicotinic acid, and nicotinamide does not affect mitochondrial function or skeletal muscle function in physically compromised older adults. J. Nutr. 151, 2917–2931 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kuerec, A. H. et al. Towards personalized nicotinamide mononucleotide (NMN) supplementation: nicotinamide adenine dinucleotide (NAD) concentration. Mech. Ageing Dev. 218, 111917 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Yi, L. et al. The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial. GeroScience 45, 29–43 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Yoshino, M. et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science 372, 1224–1229 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Igarashi, M. et al. Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men. NPJ Aging 8, 5 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Walzik, D. et al. Acute exercise boosts NAD+ metabolism of human peripheral blood mononuclear cells. Brain Behav. Immun. 123, 1011–1023 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • 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).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Olszanecka-Glinianowicz, M. et al. Relationship between circulating visfatin/NAMPT, nutritional status and insulin resistance in an elderly population – results from the PolSenior substudy. Metabolism 63, 1409–1418 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Lamb, D. A. et al. Resistance training increases muscle NAD+ and NADH concentrations as well as NAMPT protein levels and global sirtuin activity in middle-aged, overweight, untrained individuals. Aging12, 9447–9460 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Costford, S. R. et al. Skeletal muscle NAMPT is induced by exercise in humans. Am. J. Physiol. Endocrinol. Metab. 298, E117–E126 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Janssens, G. E. et al. Healthy aging and muscle function are positively associated with NAD+ abundance in humans. Nat. Aging 2, 254–263 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Benyó, Z. et al. GPR109A (PUMA-G/HM74A) mediates nicotinic acid–induced flushing. J. Clin. Invest. 115, 3634–3640 (2005).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Poynten, A. M. et al. Nicotinic acid-induced insulin resistance is related to increased circulating fatty acids and fat oxidation but not muscle lipid content. Metabolism 52, 699–704 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Chedere, A., Mishra, M., Kulkarni, O., Sriraman, S. & Chandra, N. Personalized quantitative models of NAD metabolism in hepatocellular carcinoma identify a subgroup with poor prognosis. Front. Oncol. 12, 954512 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 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. 112, 413–426 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Moore, M. P. & Mucinski, J. M. Impact of nicotinamide riboside supplementation on skeletal muscle mitochondria and whole-body glucose homeostasis: challenging the current hypothesis. J. Physiol. 598, 3327–3328 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Bird, J. G. et al. Highly efficient 5’ capping of mitochondrial RNA with NAD+ and NADH by yeast and human mitochondrial RNA polymerase. eLife 7, e42179 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Grudzien-Nogalska, E., Bird, J. G., Nickels, B. E. & Kiledjian, M. NAD-capQ’ detection and quantitation of NAD caps. RNA 24, 1418–1425 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wolfram-Schauerte, M. & Höfer, K. NAD-capped RNAs – a redox cofactor meets RNA. Trends Biochem. Sci. 48, 142–155 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Melkonian, E. A. & Schury, M. P. Biochemistry, anaerobic glycolysis. In StatPearls (StatPearls Publishing, Treasure Island, FL, 2025).

  • Luengo, A. et al. Increased demand for NAD+ relative to ATP drives aerobic glycolysis. Mol. Cell 81, 691–707.e6 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Cha, Y. et al. Metabolic control of primed human pluripotent stem cell fate and function by the miR-200c-SIRT2 axis. Nat. Cell Biol. 19, 445–456 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ma, R. et al. SIRT3 suppression resulting from the enhanced β-catenin signaling drives glycolysis and promotes hypoxia-induced cell growth in hepatocellular carcinoma cells. Cell Cycle 23, 435–447 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Finley, L. W. S. et al. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. Cancer Cell 19, 416–428 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Guo, J. et al. The role of NAD-dependent deacetylase sirtuin-2 in liver metabolic stress through regulating pyruvate kinase M2 ubiquitination. J. Transl. Med. 22, 656 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Nishida, Y. et al. SIRT5 Regulates both Cytosolic and Mitochondrial Protein Malonylation with Glycolysis as a Major Target. Mol Cell 59, 321–332 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yang, L. et al. Serine catabolism feeds NADH when respiration is impaired. Cell Metab. 31, 809–821.e6 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Khan, N. A. et al. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3. EMBO Mol. Med. 6, 721–731 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Myakala, K. et al. NAD metabolism modulates inflammation and mitochondria function in diabetic kidney disease. J. Biol. Chem. 299, 104975 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • de Castro, J. M., Stein, D. J., Medeiros, H. R., de Oliveira, C. & Torres, I. L. S. Nicotinamide riboside neutralizes hypothalamic inflammation and increases weight loss without altering muscle mass in obese rats under calorie restriction: a preliminary investigation. Front. Nutr. 8, 648893 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kim, M.-B. et al. Nicotinamide riboside supplementation exerts an anti-obesity effect and prevents inflammation and fibrosis in white adipose tissue of female diet-induced obesity mice. J. Nutr. Biochem. 107, 109058 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Wang, L., Chen, C., Zhou, H., Tao, L. & Xu, E. Nicotinamide riboside-driven modulation of SIRT3/mtROS/JNK signaling pathways alleviates myocardial ischemia-reperfusion injury. Int. J. Med. Sci. 21, 2139–2148 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Abdellatif, M. et al. Nicotinamide for the treatment of heart failure with preserved ejection fraction. Sci. Transl. Med. 13, eabd7064 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Xiong, X. et al. NAD+-boosting agent nicotinamide mononucleotide potently improves mitochondria stress response in Alzheimer’s disease via ATF4-dependent mitochondrial UPR. Cell Death Dis. 15, 744 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hasegawa, K., Sakamaki, Y., Tamaki, M. & Wakino, S. Nicotinamide mononucleotide ameliorates adriamycin-induced renal damage by epigenetically suppressing the NMN/NAD consumers mediated by Twist2. Sci. Rep. 12, 13712 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chandrasekaran, K. et al. NAD+ precursors repair mitochondrial function in diabetes and prevent experimental diabetic neuropathy. Int. J. Mol. Sci. 23, 4887 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

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

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • de Zélicourt, A. et al. CD38-NADase is a new major contributor to Duchenne muscular dystrophic phenotype. EMBO Mol. Med. 14, e12860 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gong, M. et al. Trigonelline inhibits tubular epithelial-mesenchymal transformation in diabetic kidney disease via targeting Smad7. Biomed. Pharmacother. 168, 115747 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Faivre, A. et al. Differential role of nicotinamide adenine dinucleotide deficiency in acute and chronic kidney disease. Nephrol. Dial. Transpl. 36, 60–68 (2021).

    Article 
    CAS 

    Google Scholar 

  • 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).

    Article 
    PubMed 

    Google Scholar 

  • Norheim, K. L. et al. Effect of nicotinamide riboside on airway inflammation in COPD: a randomized, placebo-controlled trial. Nat. Aging 4, 1772–1781 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Simic, P. et al. Nicotinamide riboside with pterostilbene (NRPT) increases NAD+ in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI. BMC Nephrol. 21, 342 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Dellinger, R. W. et al. Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study. NPJ Aging Mech. Dis. 3, 17 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • van Dijk, A. E. et al. Acute effects of decaffeinated coffee and the major coffee components chlorogenic acid and trigonelline on glucose tolerance. Diab. Care 32, 1023–1025 (2009).

    Article 

    Google Scholar 

  • link

    Leave a Reply

    Your email address will not be published. Required fields are marked *