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Emerging strategies, applications and challenges of targeting NAD+ in the clinic

Nature Aging volume 5, pages 1704–1731 (2025)Cite this article

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Abstract

Beyond their classical functions as redox cofactors, recent fundamental and clinical research has expanded our understanding of the diverse roles of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) in signaling pathways, epigenetic regulation and energy homeostasis. Moreover, NAD and NADP influence numerous diseases as well as the processes of aging, and are emerging as targets for clinical intervention. Here, we summarize safety, bioavailability and efficacy data from NAD+-related clinical trials, focusing on aging and neurodegenerative diseases. We discuss the established NAD+ precursors nicotinic acid and nicotinamide, newer compounds such as nicotinamide riboside and nicotinamide mononucleotide, and emerging precursors. We also discuss technological advances including in industrial-scale production and real-time detection, which are facilitating NAD+ research and clinical translation. Finally, we emphasize the need for further large-scale studies to determine optimal dose, administration routes and frequency, as well as long-term safety and interindividual variability in response.

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Fig. 1: NAD+ biosynthetic pathways: subcellular interactions and NAD+ metabolites as disease markers.
Fig. 2: NAD+ augmentation and systematic benefits by evidence from in vitro, animal model and human clinical studies.
Fig. 3: Mechanisms of NAD+ reduction in premature aging syndromes (HGPS, A-T, WS, XPA and CS).
Fig. 4: NAD+ metabolism intersects with hallmarks of aging.

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References

  1. Navas, L. E. & Carnero, A. NAD+ metabolism, stemness, the immune response, and cancer. Signal Transduct. Target. Ther. 6, 2 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Xiao, W., Wang, R. S., Handy, D. E. & Loscalzo, J. NAD(H) and NADP(H) redox couples and cellular energy metabolism. Antioxid. Redox Signal. 28, 251–272 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Braidy, N. et al. Role of nicotinamide adenine dinucleotide and related precursors as therapeutic targets for age-related degenerative diseases: rationale, biochemistry, pharmacokinetics, and outcomes. Antioxid. Redox Signal. 30, 251–294 (2019).

    Article  CAS  PubMed  Google Scholar 

  4. Verdin, E. NAD+ in aging, metabolism, and neurodegeneration. Science 350, 1208–1213 (2015).

    Article  CAS  PubMed  Google Scholar 

  5. 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 

  6. 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 

  7. 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 

  8. Canto, C., Menzies, K. J. & Auwerx, J. NAD+ metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab. 22, 31–53 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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 

  10. Lautrup, S. et al. Decreased mitochondrial NAD+ in WRN deficient cells links to dysfunctional proliferation. Aging 17, 937–959 (2025).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 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 

  12. 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 

  13. 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 

  14. Basse, A. L. et al. NAMPT-dependent NAD+ biosynthesis controls circadian metabolism in a tissue-specific manner. Proc. Natl Acad. Sci. USA 120, e2220102120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bonkowski, M. S. & Sinclair, D. A. Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat. Rev. Mol. Cell Biol. 17, 679–690 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yaku, K., Okabe, K. & Nakagawa, T. NAD metabolism: implications in aging and longevity. Ageing Res. Rev. 47, 1–17 (2018).

    Article  CAS  PubMed  Google Scholar 

  17. McReynolds, M. R., Chellappa, K. & Baur, J. A. Age-related NAD+ decline. Exp. Gerontol. 134, 110888 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Peluso, A., Damgaard, M. V., Mori, M. A. S. & Treebak, J. T. Age-dependent decline of NAD+-universal truth or confounded consensus? Nutrients https://doi.org/10.3390/nu14010101 (2021).

  19. Wang, H. L. et al. Meeting Summary of The NYO3 5th NO-Age/AD Meeting and the 1st Norway-UK Joint Meeting on Aging and Dementia: recent progress on the mechanisms and interventional strategies. J. Gerontol. A Biol. Sci. Med. Sci. https://doi.org/10.1093/gerona/glae029 (2024).

  20. Zhang, J., Wang, H. L. & Fang, E. F. in Molecular, Cellular, and Metabolic Fundamentals of Human Aging. (eds. E. F. Fang et al.) Ch. 5, 107–119 (Elsevier/Academic Press, 2022).

  21. Guo, C., Sun, L., Chen, X. & Zhang, D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen. Res 8, 2003–2014 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Fang, E. F. Mitophagy and NAD+ inhibit Alzheimer disease. Autophagy 15, 1112–1114 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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 

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

    Article  PubMed  PubMed Central  Google Scholar 

  25. Toker, L. et al. Genome-wide histone acetylation analysis reveals altered transcriptional regulation in the Parkinson’s disease brain. Mol. Neurodegener. 16, 31 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hoyland, L. E. et al. Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD. Nat. Metab. 6, 2319–2337 (2024).

    Article  PubMed  Google Scholar 

  28. Yoshino, J., Baur, J. A. & Imai, S. I. NAD+ intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab. 27, 513–528 (2018).

    Article  CAS  PubMed  Google Scholar 

  29. Mills, K. F. et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 24, 795–806 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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 

  31. Bai, P. et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab. 13, 461–468 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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 

  33. Bogan, K. L. & Brenner, C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu. Rev. Nutr. 28, 115–130 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Zapata-Perez, R., Wanders, R. J. A., van Karnebeek, C. D. M. & Houtkooper, R. H. NAD+ homeostasis in human health and disease. EMBO Mol. Med. 13, e13943 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lautrup, S., Hou, Y., Fang, E. F. & Bohr, V. A. Roles of NAD+ in health and aging. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a041193 (2024).

  36. Kerr, J. S. et al. Mitophagy and Alzheimer’s disease: cellular and molecular mechanisms. Trends Neurosci. 40, 151–166 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fang, E. F. et al. Mitophagy inhibits amyloid-beta 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 

  38. Veverova, K. et al. Alterations of human CSF and serum-based mitophagy biomarkers in the continuum of Alzheimer disease. Autophagy https://doi.org/10.1080/15548627.2024.2340408 (2024).

  39. Zhang, J., Wang, H. L., Veverova, K., Vyhnalek, M. & Fang, E. F. Identification and potential clinical applications of novel autophagy/mitophagy proteins in the biofluids of Alzheimer’s disease patients. Ageing Res. Rev. 99, 102378 (2024).

    Article  CAS  PubMed  Google Scholar 

  40. Mattson, M. P. & Arumugam, T. V. Hallmarks of brain aging: adaptive and pathological modification by metabolic states. Cell Metab. 27, 1176–1199 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wilson, D. M. III et al. Hallmarks of neurodegenerative diseases. Cell 186, 693–714 (2023).

    Article  CAS  PubMed  Google Scholar 

  42. Hou, Y. et al. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. 15, 565–581 (2019).

    Article  PubMed  Google Scholar 

  43. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Xie, C. et al. Amelioration of Alzheimer’s disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow. Nat. Biomed. Eng. 6, 76–93 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhao, N. et al. Effect of alternating nicotinamide phosphoribosyltransferase expression levels on mitophagy in Alzheimer’s disease mouse models. Biochim. Biophys. Acta Mol. Basis Dis. 1870, 167288 (2024).

    Article  CAS  PubMed  Google Scholar 

  46. Gulaj, E., Pawlak, K., Bien, B. & Pawlak, D. Kynurenine and its metabolites in Alzheimer’s disease patients. Adv. Med Sci. 55, 204–211 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Giil, L. M. et al. Kynurenine pathway metabolites in Alzheimer’s disease. J. Alzheimers Dis. 60, 495–504 (2017).

    Article  CAS  PubMed  Google Scholar 

  48. 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 

  49. Knapskog, A. B. et al. Higher concentrations of kynurenic acid in CSF are associated with the slower clinical progression of Alzheimer’s disease. Alzheimers Dement. 19, 5573–5582 (2023).

    Article  CAS  PubMed  Google Scholar 

  50. Knapskog, A. B. et al. Sex-specific associations of kynurenic acid with neopterin in Alzheimer’s disease. Alzheimers Res. Ther. 16, 167 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. González-Sánchez, M. et al. Kynurenic acid levels are increased in the CSF of Alzheimer’s disease patients. Biomolecules https://doi.org/10.3390/biom10040571 (2020).

  52. Jacobs, K. R. et al. Correlation between plasma and CSF concentrations of kynurenine pathway metabolites in Alzheimer’s disease and relationship to amyloid-β and tau. Neurobiol. Aging 80, 11–20 (2019).

    Article  CAS  PubMed  Google Scholar 

  53. Wennström, M. et al. Kynurenic acid levels in cerebrospinal fluid from patients with Alzheimer’s disease or dementia with lewy bodies. Int. J. Tryptophan Res. 7, 1–7 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  54. van der Velpen, V. et al. Systemic and central nervous system metabolic alterations in Alzheimer’s disease. Alzheimers Res. Ther. 11, 93 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Xue, C. et al. Tryptophan metabolism in health and disease. Cell Metab. 35, 1304–1326 (2023).

    Article  CAS  PubMed  Google Scholar 

  56. Schwarcz, R., Bruno, J. P., Muchowski, P. J. & Wu, H. Q. Kynurenines in the mammalian brain: when physiology meets pathology. Nat. Rev. Neurosci. 13, 465–477 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Yulug, B. et al. Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial. Transl. Neurodegener. 12, 4 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 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 

  59. Orr, M. E. et al. Results from a pilot study: the effects of nicotinamide riboside on mild cognitive impairment. Alzheimer’s Dement. 16, e044746 (2020).

    Article  Google Scholar 

  60. Grill, J. D. et al. A Phase 2a proof‐of‐concept double‐blind, randomized, placebo‐controlled trial of nicotinamide in early Alzheimer’s disease. In Alzheimer’s Association International Conference, abstract: 77979 (AAIC, 2023).

  61. Bloem, B. R., Okun, M. S. & Klein, C. Parkinson’s disease. Lancet 397, 2284–2303 (2021).

    Article  CAS  PubMed  Google Scholar 

  62. Dickson, D. W. Parkinson’s disease and parkinsonism: neuropathology. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a009258 (2012).

  63. Dickson, D. W. Neuropathology of Parkinson disease. Parkinsonism Relat. Disord. 46, S30–S33 (2018).

    Article  PubMed  Google Scholar 

  64. Kalia, L. V. & Lang, A. E. Parkinson’s disease. Lancet 386, 896–912 (2015).

    Article  CAS  PubMed  Google Scholar 

  65. Wallings, R. L., Humble, S. W., Ward, M. E. & Wade-Martins, R. Lysosomal dysfunction at the centre of Parkinson’s disease and frontotemporal dementia/amyotrophic lateral sclerosis. Trends Neurosci. 42, 899–912 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Navarro-Romero, A., Montpeyo, M. & Martinez-Vicente, M. The emerging role of the lysosome in Parkinson’s disease. Cells https://doi.org/10.3390/cells9112399 (2020).

  67. Hirsch, E. C. & Hunot, S. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. 8, 382–397 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. 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 

  69. SenGupta, T. et al. Base excision repair causes age-dependent accumulation of single-stranded DNA breaks that contribute to Parkinson disease pathology. Cell Rep. 36, 109668 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Schondorf, 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 

  71. Chang, K. H. et al. Alternations of metabolic profile and kynurenine metabolism in the plasma of Parkinson’s disease. Mol. Neurobiol. 55, 6319–6328 (2018).

    Article  CAS  PubMed  Google Scholar 

  72. Heilman, P. L. et al. Tryptophan metabolites are associated with symptoms and nigral pathology in Parkinson’s disease. Mov. Disord. 35, 2028–2037 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 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 (2022).

    Article  CAS  PubMed  Google Scholar 

  74. Gaare, J. J. et al. Nicotinamide riboside supplementation is not associated with altered methylation homeostasis in Parkinson’s disease. iScience 26, 106278 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 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 

  76. Feldman, E. L. et al. Amyotrophic lateral sclerosis. Lancet 400, 1363–1380 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lombardo, F. L. et al. A randomized double-blind clinical trial on safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS): the statistical analysis plan of TUDCA-ALS trial. Trials 24, 792 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Wang, X. et al. Deletion of nampt in projection neurons of adult mice leads to motor dysfunction, neurodegeneration, and death. Cell Rep. 20, 2184–2200 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Harlan, B. A. et al. Enhancing NAD+ salvage pathway reverts the toxicity of primary astrocytes expressing amyotrophic lateral sclerosis-linked mutant superoxide dismutase 1 (SOD1). J. Biol. Chem. 291, 10836–10846 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Blacher, E. et al. Potential roles of gut microbiome and metabolites in modulating ALS in mice. Nature 572, 474–480 (2019).

    Article  CAS  PubMed  Google Scholar 

  81. Li, J. Y. et al. Alterations in metabolic biomarkers and their potential role in amyotrophic lateral sclerosis. Ann. Clin. Transl. Neurol. 9, 1027–1038 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 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).

    Article  PubMed  Google Scholar 

  83. Han, S., Choi, J. R., Soon Shin, K. & Kang, S. J. Resveratrol upregulated heat shock proteins and extended the survival of G93A-SOD1 mice. Brain Res. 1483, 112–117 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Korner, S. et al. Differential sirtuin expression patterns in amyotrophic lateral sclerosis (ALS) postmortem tissue: neuroprotective or neurotoxic properties of sirtuins in ALS? Neurodegener. Dis. 11, 141–152 (2013).

    Article  PubMed  Google Scholar 

  85. 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 

  86. Fan, L., Cacicedo, J. M. & Ido, Y. Impaired nicotinamide adenine dinucleotide (NAD+) metabolism in diabetes and diabetic tissues: Implications for nicotinamide-related compound treatment. J. Diabetes Investig. 11, 1403–1419 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Galderisi, A. et al. Metabolomics reveals new metabolic perturbations in children with type 1 diabetes. Pediatr. Diabetes 19, 59–67 (2018).

    Article  CAS  PubMed  Google Scholar 

  88. Gürcü, S. et al. Neopterin and biopterin levels and tryptophan degradation in patients with diabetes. Sci. Rep. 10, 17025 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Oxenkrug, G., van der Hart, M. & Summergrad, P. Elevated anthranilic acid plasma concentrations in type 1 but not type 2 diabetes mellitus. Integr. Mol. Med. 2, 365–368 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Orabona, C. et al. Deficiency of immunoregulatory indoleamine 2,3-dioxygenase 1in juvenile diabetes. JCI Insight https://doi.org/10.1172/jci.insight.96244 (2018).

  91. Oxenkrug, G. F. Increased plasma levels of xanthurenic and kynurenic acids in type 2 diabetes. Mol. Neurobiol. 52, 805–810 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Vangipurapu, J., Fernandes Silva, L., Kuulasmaa, T., Smith, U. & Laakso, M. Microbiota-related metabolites and the risk of type 2 diabetes. Diabetes Care 43, 1319–1325 (2020).

    Article  CAS  PubMed  Google Scholar 

  93. Qi, Q. et al. Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies. Gut 71, 1095–1105 (2022).

    Article  CAS  PubMed  Google Scholar 

  94. Abedi, S., Vessal, M., Asadian, F. & Takhshid, M. A. Association of serum kynurenine/tryptophan ratio with poor glycemic control in patients with type2 diabetes. J. Diabetes Metab. Disord. 20, 1521–1527 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Moon, J. Y. et al. Gut microbiota and plasma metabolites associated with diabetes in women with, or at high risk for, HIV infection. EBioMedicine 37, 392–400 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  96. 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 

  97. 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 

  98. 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 

  99. 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 

  100. Dunaif, A. et al. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 41, 1257–1266 (1992).

    Article  CAS  PubMed  Google Scholar 

  101. Polderman, K. H., Gooren, L. J., Asscheman, H., Bakker, A. & Heine, R. J. Induction of insulin resistance by androgens and estrogens. J. Clin. Endocrinol. Metab. 79, 265–271 (1994).

    CAS  PubMed  Google Scholar 

  102. Kane, A. E. et al. Long-term NMN treatment increases lifespan and healthspan in mice in a sex dependent manner. Preprint at bioRxiv https://doi.org/10.1101/2024.06.21.599604 (2024).

  103. 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 

  104. Qiu, Y. et al. NAD+ exhaustion by CD38 upregulation contributes to blood pressure elevation and vascular damage in hypertension. Signal Transduct. Target. Ther. 8, 353 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lund, A. et al. Plasma kynurenines and prognosis in patients with heart failure. PLoS ONE 15, e0227365 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Pedersen, E. R. et al. Associations of plasma kynurenines with risk of acute myocardial infarction in patients with stable angina pectoris. Arterioscler. Thromb. Vasc. Biol. 35, 455–462 (2015).

    Article  CAS  PubMed  Google Scholar 

  107. Shi, B. et al. Targeting gut microbiota-derived kynurenine to predict and protect the remodeling of the pressure-overloaded young heart. Sci. Adv. 9, eadg7417 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Konishi, M. et al. Impact of plasma kynurenine level on functional capacity and outcome in heart failure - results from Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF). Circ. J. 81, 52–61 (2016).

    Article  PubMed  Google Scholar 

  109. de Picciotto, N. E. et al. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell 15, 522–530 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Abdellatif, M., Bugger, H., Kroemer, G. & Sedej, S. NAD+ and vascular dysfunction: from mechanisms to therapeutic opportunities. J. Lipid Atheroscler. 11, 111–132 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Abdellatif, M., Sedej, S. & Kroemer, G. NAD+ metabolism in cardiac health, aging, and disease. Circulation 144, 1795–1817 (2021).

    Article  CAS  PubMed  Google Scholar 

  112. 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 

  113. Fang, E. F. & Tao, J. Targeting on the NAD+-mitophagy axis to treat cardiovascular disease. Aging Med. 3, 151–152 (2020).

    Article  Google Scholar 

  114. Canner, P. L. et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J. Am. Coll. Cardiol. 8, 1245–1255 (1986).

    Article  CAS  PubMed  Google Scholar 

  115. Maher, V. M. et al. Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a). JAMA 274, 1771–1774 (1995).

    Article  CAS  PubMed  Google Scholar 

  116. Matthan, N. R., Giovanni, A., Schaefer, E. J., Brown, B. G. & Lichtenstein, A. H. Impact of simvastatin, niacin, and/or antioxidants on cholesterol metabolism in CAD patients with low HDL. J. Lipid Res. 44, 800–806 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Phan, B. A. et al. Effects of niacin on glucose levels, coronary stenosis progression, and clinical events in subjects with normal baseline glucose levels (<100 mg/dl): a combined analysis of the Familial Atherosclerosis Treatment Study (FATS), HDL-Atherosclerosis Treatment Study (HATS), Armed Forces Regression Study (AFREGS), and Carotid Plaque Composition by MRI during lipid-lowering (CPC) study. Am. J. Cardiol. 111, 352–355 (2013).

    Article  CAS  PubMed  Google Scholar 

  118. Haynes, R. et al. Serious adverse effects of extended-release niacin/laropiprant: results from the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Trial. Clin. Ther. 41, 1767–1777 (2019).

    Article  CAS  PubMed  Google Scholar 

  119. Group, H. T. C. HPS2-THRIVE randomized placebo-controlled trial in 25,673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur. Heart J. 34, 1279–1291 (2013).

    Article  Google Scholar 

  120. Teo, K. K. et al. Extended-release niacin therapy and risk of ischemic stroke in patients with cardiovascular disease: the Atherothrombosis Intervention in Metabolic Syndrome with low HDL/High Triglycerides: Impact on Global Health Outcome (AIM-HIGH) trial. Stroke 44, 2688–2693 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Cheung, M. C., Zhao, X. Q., Chait, A., Albers, J. J. & Brown, B. G. Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary artery disease and low HDL. Arterioscler. Thromb. Vasc. Biol. 21, 1320–1326 (2001).

    Article  CAS  PubMed  Google Scholar 

  122. McDermott, M. M. et al. Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial. Nat. Commun. 15, 5046 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Abdellatif, M. et al. Nicotinamide for the treatment of heart failure with preserved ejection fraction. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.abd7064 (2021).

  124. 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 

  125. Dellinger, R. W. et al. Nicotinamide riboside and pterostilbene reduces markers of hepatic inflammation in NAFLD: a double-blind, placebo-controlled clinical trial. Hepatology 78, 863–877 (2023).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  127. Mukherjee, S. et al. Nicotinamide adenine dinucleotide biosynthesis promotes liver regeneration. Hepatology 65, 616–630 (2017).

    Article  CAS  PubMed  Google Scholar 

  128. Dall, M. et al. Hepatocyte-specific perturbation of NAD+ biosynthetic pathways in mice induces reversible nonalcoholic steatohepatitis-like phenotypes. J. Biol. Chem. 297, 101388 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Li, D. J. et al. NAD+-boosting therapy alleviates nonalcoholic fatty liver disease via stimulating a novel exerkine Fndc5/irisin. Theranostics 11, 4381–4402 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Zhang, C. et al. The acute effect of metabolic cofactor supplementation: a potential therapeutic strategy against non-alcoholic fatty liver disease. Mol. Syst. Biol. 16, e9495 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 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 

  132. 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 

  133. Chubanava, S. et al. NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging. Cell Metab. https://doi.org/10.1016/j.cmet.2025.04.002 (2025).

  134. 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 

  135. de Zelicourt, 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 

  136. 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 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Ito, K. & Barnes, P. J. COPD as a disease of accelerated lung aging. Chest 135, 173–180 (2009).

    Article  PubMed  Google Scholar 

  138. Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. Hallmarks of aging: an expanding universe. Cell 186, 243–278 (2023).

    Article  CAS  PubMed  Google Scholar 

  139. Norheim, K. L. et al. Effect of nicotinamide riboside on airway inflammation in COPD: a randomized, placebo-controlled trial. Nat. Aging https://doi.org/10.1038/s43587-024-00758-1 (2024).

  140. Ghosh, T. S., Shanahan, F. & O’Toole, P. W. The gut microbiome as a modulator of healthy ageing. Nat. Rev. Gastroenterol. Hepatol. 19, 565–584 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Shats, I. et al. Bacteria boost mammalian host NAD metabolism by engaging the deamidated biosynthesis pathway. Cell Metab. 31, 564–579 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Kim, L. J. et al. Host-microbiome interactions in nicotinamide mononucleotide (NMN) deamidation. FEBS Lett. 597, 2196–2220 (2023).

    Article  CAS  PubMed  Google Scholar 

  144. 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 

  145. Rodionov, D. A. et al. Transcriptional regulation of NAD metabolism in bacteria: genomic reconstruction of NiaR (YrxA) regulon. Nucleic Acids Res. 36, 2032–2046 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Biagi, E. et al. Gut microbiota and extreme longevity. Curr. Biol. 26, 1480–1485 (2016).

    Article  CAS  PubMed  Google Scholar 

  147. Chu, X. et al. Nicotinamide adenine dinucleotide supplementation drives gut microbiota variation in Alzheimer’s mouse model. Front. Aging Neurosci. 14, 993615 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Fang, E. F. et al. Nuclear DNA damage signalling to mitochondria in ageing. Nat. Rev. Mol. Cell Biol. 17, 308–321 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Fang, E. F. et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD+/SIRT1 reduction. Cell 157, 882–896 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. 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 

  151. Scheibye-Knudsen, M. et al. Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA. Proc. Natl Acad. Sci. USA 113, 12502–12507 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. 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 

  153. Maynard, S. et al. Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1α and the NAMPT-NAD+ pathway. Nucleic Acids Res. 50, 9948–9965 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Rothblum-Oviatt, C. et al. Ataxia telangiectasia: a review. Orphanet J. Rare Dis. 11, 159 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Khanna, K. K., Lavin, M. F., Jackson, S. P. & Mulhern, T. D. ATM, a central controller of cellular responses to DNA damage. Cell Death Differ. 8, 1052–1065 (2001).

    Article  CAS  PubMed  Google Scholar 

  156. 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 

  157. Veenhuis, S. J. G. et al. Nicotinamide riboside improves ataxia scores and immunoglobulin levels in ataxia telangiectasia. Mov. Disord. 36, 2951–2957 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Steinbrucker, K., Tiefenthaler, E., Schernthaner, E. M., Jungwirth, J. & Wortmann, S. B. Nicotinamide riboside for ataxia telangiectasia: a report of an early treated individual. Neuropediatrics 54, 78–81 (2023).

    Article  PubMed  Google Scholar 

  159. Chen, L. & Oshima, J. Werner syndrome. J. Biomed. Biotechnol. 2, 46–54 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Shamanna, R. A., Croteau, D. L., Lee, J. H. & Bohr, V. A. Recent advances in understanding Werner syndrome. F1000Res 6, 1779 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Tian, Y. et al. WRN loss accelerates abnormal adipocyte metabolism in Werner syndrome. Cell Biosci. 14, 7 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Shoji, M. et al. Nicotinamide riboside supplementation benefits in patients with Werner syndrome: a double-blind randomized crossover placebo-controlled trial. Aging Cell https://doi.org/10.1111/acel.70093 (2025).

  163. Huang, A. R., Jiang, K., Lin, F. R., Deal, J. A. & Reed, N. S. Hearing loss and dementia prevalence in older adults in the US. JAMA 329, 171–173 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Okur, M. N. et al. Long-term NAD+ supplementation prevents the progression of age-related hearing loss in mice. Aging Cell 22, e13909 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Okur, M. N. et al. Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome. NPJ Aging Mech. Dis. 6, 1 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Williams, P. A. et al. Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science 355, 756–760 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Pang, H. et al. Aberrant NAD+ metabolism underlies Zika virus-induced microcephaly. Nat. Metab. 3, 1109–1124 (2021).

    Article  CAS  PubMed  Google Scholar 

  168. Jiang, Y. et al. Treatment of SARS-CoV-2-induced pneumonia with NAD+ and NMN in two mouse models. Cell Discov. 8, 38 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Chen, P. M. et al. CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy. Sci. Adv. 8, eabo4271 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Kontani, K., Nishina, H., Ohoka, Y., Takahashi, K. & Katada, T. NAD glycohydrolase specifically induced by retinoic acid in human leukemic HL-60 cells. Identification of the NAD glycohydrolase as leukocyte cell surface antigen CD38. J. Biol. Chem. 268, 16895–16898 (1993).

    Article  CAS  PubMed  Google Scholar 

  171. 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 

  172. Young, G. S., Choleris, E., Lund, F. E. & Kirkland, J. B. Decreased cADPR and increased NAD+ in the Cd38-/- mouse. Biochem. Biophys. Res. Commun. 346, 188–192 (2006).

    Article  CAS  PubMed  Google Scholar 

  173. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. 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 

  176. Jin, D. et al. CD38 is critical for social behaviour by regulating oxytocin secretion. Nature 446, 41–45 (2007).

    Article  CAS  PubMed  Google Scholar 

  177. Migaud, M. E. et al. Efficient and scalable syntheses of nicotinoyl ribosides and reduced nicotinoyl ribosides, modified derivatives thereof, phosphorylated analogs thereof, adenylyl dinucleotide conjugates thereof, and novel crystalline forms thereof. Patent PCT WO2018089830A1 (2021).

  178. Brenner, C., Belenky, P. & Bogan, K. L. Yeast strain and method for using the same to produce nicotinamide riboside. Patent US8114626B2 (2012).

  179. Zhang, N. & Sauve, A. A. Synthesis of beta-nicotinamide riboside using an efficient two-step methodology. Curr. Protoc. Nucleic Acid Chem. 71, 14.14.1–14.14.9 (2017).

    Article  PubMed  Google Scholar 

  180. Zhang, M., Jiang, Y., Su, Z., Sun, W. & Zhan, L. Novel synthesis method of nicotinamide ribose. Patent CN111892635A (2020).

  181. Sinclair, D. A. & Ear, P. H. Biological production of NAD precursors and analogs. WO Patent 2015/069860 (2015).

  182. Jin, C. & Wang, J. Carriers for enzyme or cell immobilization and immobilization method using the carriers. Patent US8486676B2 (2013).

  183. Kameda, A. et al. A novel ATP regeneration system using polyphosphate-AMP phosphotransferase and polyphosphate kinase. J. Biosci. Bioeng. 91, 557–563 (2001).

    Article  CAS  PubMed  Google Scholar 

  184. Zheng, C., Li, Y., Wu, X., Gao, L. & Chen, X. Advances in the synthesis and physiological metabolic regulation of nicotinamide mononucleotide. Nutrients https://doi.org/10.3390/nu16142354 (2024).

  185. 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 

  186. 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 

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

    Article  CAS  PubMed  Google Scholar 

  188. 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 

  189. 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 

  190. 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 

  191. Ren, J. et al. Evidence of brain target engagement in Parkinson’s disease and multiple sclerosis by the investigational nanomedicine, CNM-Au8, in the REPAIR phase 2 clinical trials. J. Nanobiotechnology 21, 478 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Vucic, S. et al. Efficacy and safety of CNM-Au8 in amyotrophic lateral sclerosis (RESCUE-ALS study): a phase 2, randomised, double-blind, placebo-controlled trial and open label extension. EClinicalMedicine 60, 102036 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Writing Committee for the HEALEY ALS Platform Trial; Berryet al. CNM-Au8 in amyotrophic lateral sclerosis: the HEALEY ALS Platform Trial. JAMA 333, 1138–1149 (2025).

    Article  Google Scholar 

  194. Wang, H. L. et al. A luminescent-based protocol for NAD+/NADH detection in C. elegans, mice, and human whole blood. STAR Protoc. 5, 103428 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. 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. USA 112, 2876–2881 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Yu, Q. et al. A biosensor for measuring NAD+ levels at the point of care. Nat. Metab. 1, 1219–1225 (2019).

    Article  CAS  PubMed  Google Scholar 

  197. Cambronne, X. A. & Kraus, W. L. Location, location, location: compartmentalization of NAD+ synthesis and functions in mammalian cells. Trends Biochem. Sci. 45, 858–873 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Dziadosz, M. et al. Quantification of NAD+ in human brain with 1H MR spectroscopy at 3 T: comparison of three localization techniques with different handling of water magnetization. Magn. Reson. Med. 88, 1027–1038 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Peng, Y., Zhang, Z., He, L., Li, C. & Liu, M. NMR spectroscopy for metabolomics in the living system: recent progress and future challenges. Anal. Bioanal. Chem. 416, 2319–2334 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Mevenkamp, J. et al. Development of a 31P magnetic resonance spectroscopy technique to quantify NADH and NAD+ at 3 T. Nat. Commun. 15, 9159 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Matsuyama, R. et al. Stabilization and quantitative measurement of nicotinamide adenine dinucleotide in human whole blood using dried blood spot sampling. Anal. Bioanal. Chem. 415, 775–785 (2023).

    Article  CAS  PubMed  Google Scholar 

  202. 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 

  203. 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 

  204. 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 

  205. 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 

  206. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. 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 

  209. Mateuszuk, Ł. et al. Reversal of endothelial dysfunction by nicotinamide mononucleotide via extracellular conversion to nicotinamide riboside. Biochem. Pharmacol. 178, 114019 (2020).

    Article  CAS  PubMed  Google Scholar 

  210. 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 

  211. Sociali, G. et al. Antitumor effect of combined NAMPT and CD73 inhibition in an ovarian cancer model. Oncotarget 7, 2968–2984 (2016).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Damgaard, M. V. et al. Intravenous nicotinamide riboside elevates mouse skeletal muscle NAD+ without impacting respiratory capacity or insulin sensitivity. iScience 25, 103863 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Hawkins, J. et al. Randomized, placebo-controlled, pilot clinical study evaluating acute Niagen®+ IV and NAD+ IV in healthy adults. Preprint at medRxiv https://doi.org/10.1101/2024.06.06.24308565 (2024).

  215. Conlon, N. J. The Role of NAD+ in regenerative medicine. Plast. Reconstr. Surg. 150, 41s–48s (2022).

    Article  CAS  PubMed  Google Scholar 

  216. Lee, S. H. et al. Augmentation of NAD+ by dunnione ameliorates imiquimod-induced psoriasis-like dermatitis in mice. J. Inflamm. Res. 15, 4623–4636 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Han, K. et al. Boosting NAD preferentially blunts Th17 inflammation via arginine biosynthesis and redox control in healthy and psoriasis subjects. Cell Rep. Med. https://doi.org/10.1016/j.xcrm.2023.101157 (2023).

  218. Zhang, Z., Lu, Y., Qi, J. & Wu, W. An update on oral drug delivery via intestinal lymphatic transport. Acta Pharm. Sin. B 11, 2449–2468 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Sun, S. et al. Design and preparation of NMN nanoparticles based on protein-marine polysaccharide with increased NAD+ level in d-galactose induced aging mice model. Colloids Surf. B Biointerfaces 239, 113903 (2024).

    Article  CAS  PubMed  Google Scholar 

  220. Zhang, D. et al. Hydroxyapatite-based nano-drug delivery system for nicotinamide mononucleotide (NMN): significantly enhancing NMN bioavailability and replenishing in vivo nicotinamide adenine dinucleotide (NAD+) levels. J. Pharm. Pharmacol. 75, 1569–1580 (2023).

    Article  CAS  PubMed  Google Scholar 

  221. Trammell, S. A. et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat. Commun. 7, 12948 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  223. Guyton, J. R. & Bays, H. E. Safety considerations with niacin therapy. Am. J. Cardiol. 99, 22c–31c (2007).

    Article  CAS  PubMed  Google Scholar 

  224. Winter, S. L. & Boyer, J. L. Hepatic toxicity from large doses of vitamin B3 (nicotinamide). N. Engl. J. Med. 289, 1180–1182 (1973).

    Article  CAS  PubMed  Google Scholar 

  225. Rader, J. I., Calvert, R. J. & Hathcock, J. N. Hepatic toxicity of unmodified and time-release preparations of niacin. Am. J. Med 92, 77–81 (1992).

    Article  CAS  PubMed  Google Scholar 

  226. Knip, M. et al. Safety of high-dose nicotinamide: a review. Diabetologia 43, 1337–1345 (2000).

    Article  CAS  PubMed  Google Scholar 

  227. Jenkins, D. J. A. et al. Supplemental vitamins and minerals for CVD prevention and treatment. J. Am. Coll. Cardiol. 71, 2570–2584 (2018).

    Article  CAS  PubMed  Google Scholar 

  228. 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 

  229. Ferrell, M. et al. Publisher correction: a terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk. Nat. Med. 30, 1791 (2024).

    Article  CAS  PubMed  Google Scholar 

  230. Diguet, N. et al. Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy. Circulation 137, 2256–2273 (2018).

    Article  CAS  PubMed  Google Scholar 

  231. Lv, H. et al. NAD+ metabolism maintains inducible PD-L1 expression to drive tumor immune evasion. Cell Metab. 33, 110–127 (2021).

    Article  CAS  PubMed  Google Scholar 

  232. Bi, T. Q. & Che, X. M. Nampt/PBEF/visfatin and cancer. Cancer Biol. Ther. 10, 119–125 (2010).

    Article  CAS  PubMed  Google Scholar 

  233. Santidrian, A. F. et al. Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J. Clin. Invest. 123, 1068–1081 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Chen, A. C. et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N. Engl. J. Med. 373, 1618–1626 (2015).

    Article  CAS  PubMed  Google Scholar 

  235. Surjana, D., Halliday, G. M., Martin, A. J., Moloney, F. J. & Damian, D. L. Oral nicotinamide reduces actinic keratoses in phase II double-blinded randomized controlled trials. J. Invest. Dermatol. 132, 1497–1500 (2012).

    Article  CAS  PubMed  Google Scholar 

  236. Yiasemides, E., Sivapirabu, G., Halliday, G. M., Park, J. & Damian, D. L. Oral nicotinamide protects against ultraviolet radiation-induced immunosuppression in humans. Carcinogenesis 30, 101–105 (2009).

    Article  CAS  PubMed  Google Scholar 

  237. Nacarelli, T. et al. NAD+ metabolism governs the proinflammatory senescence-associated secretome. Nat. Cell Biol. 21, 397–407 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Fang, J. et al. NAD+ metabolism-based immunoregulation and therapeutic potential. Cell Biosci. 13, 81 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Morandi, F., Horenstein, A. L. & Malavasi, F. The key role of NAD+ in anti-tumor immune response: an update. Front. Immunol. 12, 658263 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Sun, C. et al. Re-equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction. EMBO J. 39, e103420 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Wang, H., Lautrup, S., Caponio, D., Zhang, J. & Fang, E. F. DNA damage-induced neurodegeneration in accelerated ageing and Alzheimer’s disease. Int. J. Mol. Sci. https://doi.org/10.3390/ijms22136748 (2021).

  242. Ummarino, S. et al. NAD Modulates DNA methylation and cell differentiation. Cells https://doi.org/10.3390/cells10112986 (2021).

  243. Tomita, T. et al. Sirt1-deficiency causes defective protein quality control. Sci. Rep. 5, 12613 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Levine, D. C. et al. NAD+ controls circadian reprogramming through PER2 nuclear translocation to counter aging. Mol. Cell 78, 835–849 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Aman, Y. et al. Autophagy in healthy aging and disease. Nat. Aging 1, 634–650 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  246. Ludewig, A. H. et al. Pheromone sensing regulates Caenorhabditis elegans lifespan and stress resistance via the deacetylase SIR-2.1. Proc. Natl Acad. Sci. USA 110, 5522–5527 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Lin, J., Handschin, C. & Spiegelman, B. M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 1, 361–370 (2005).

    Article  PubMed  Google Scholar 

  248. Miwa, S., Kashyap, S., Chini, E. & von Zglinicki, T. Mitochondrial dysfunction in cell senescence and aging. J. Clin. Invest. https://doi.org/10.1172/JCI158447 (2022).

  249. Allen, A. R., Jones, A., LoBianco, F. V., Krager, K. J. & Aykin-Burns, N. Effect of Sirt3 on hippocampal MnSOD activity, mitochondrial function, physiology, and cognition in an aged murine model. Behav. Brain Res. 444, 114335 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Chini, C. C. S., Cordeiro, H. S., Tran, N. L. K. & Chini, E. N. NAD metabolism: role in senescence regulation and aging. Aging Cell 23, e13920 (2024).

    Article  CAS  PubMed  Google Scholar 

  251. Pareja-Galeano, H., Sanchis-Gomar, F. & Lucia, A. p16INK4a, NAD+, and sestrins: new targets for combating aging-related chronic illness? J. Cell. Physiol. 229, 1575–1576 (2014).

    Article  CAS  PubMed  Google Scholar 

  252. 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 

  253. Gomes, A. P. et al. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624–1638 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Ying, X., Zheng, X., Zhang, X., Yin, Y. & Wang, X. Kynurenine in IDO1high cancer cell-derived extracellular vesicles promotes angiogenesis by inducing endothelial mitophagy in ovarian cancer. J. Transl. Med. 22, 267 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Hou, Y. et al. NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer’s disease via cGAS-STING. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2011226118 (2021).

  256. Schmidlin, C. J., Dodson, M. B., Madhavan, L. & Zhang, D. D. Redox regulation by NRF2 in aging and disease. Free Radic. Biol. Med. 134, 702–707 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Devereaux, J. et al. Alterations in tryptophan metabolism and de novo NAD+ biosynthesis within the microbiota-gut-brain axis in chronic intestinal inflammation. Front. Med. 11, 1379335 (2024).

    Article  Google Scholar 

  258. Dehhaghi, M., Kazemi Shariat Panahi, H. & Guillemin, G. J. Microorganisms, tryptophan metabolism, and kynurenine pathway: a complex interconnected loop influencing human health status. Int. J. Tryptophan Res. 12, 1178646919852996 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  259. Wellman, A. S. et al. Intestinal epithelial sirtuin 1 regulates intestinal inflammation during aging in mice by altering the intestinal microbiota. Gastroenterology 153, 772–786 (2017).

    Article  PubMed  Google Scholar 

  260. Minhas, P. S. et al. Restoring hippocampal glucose metabolism rescues cognition across Alzheimer’s disease pathologies. Science 385, eabm6131 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Dan, X. et al. Loss of smelling is an early marker of aging and is associated with inflammation and DNA damage in C57BL/6J mice. Aging Cell 22, e13793 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Hamilton, H. L. et al. Nicotinamide adenine dinucleotide precursor supplementation modulates neurite complexity and survival in motor neurons from amyotrophic lateral sclerosis models. Antioxid. Redox Signal. 41, 573–589 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Szot, J. O. et al. A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder. J. Clin. Invest. https://doi.org/10.1172/JCI174824 (2024).

  264. Gille, A., Bodor, E. T., Ahmed, K. & Offermanns, S. Nicotinic acid: pharmacological effects and mechanisms of action. Annu. Rev. Pharmacol. Toxicol. 48, 79–106 (2008).

    Article  CAS  PubMed  Google Scholar 

  265. Gindri, I. M. et al. Evaluation of safety and effectiveness of NAD in different clinical conditions: a systematic review. Am. J. Physiol. Endocrinol. Metab. 326, E417–E427 (2024).

    Article  PubMed  Google Scholar 

  266. Schiuma, G., Lara, D., Clement, J., Narducci, M. & Rizzo, R. Nicotinamide adenine dinucleotide: the redox sensor in aging-related disorders. Antioxid. Redox Signal. https://doi.org/10.1089/ars.2023.0375 (2024).

  267. 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).

    Article  CAS  PubMed  Google Scholar 

  268. Roos, J., Zinngrebe, J. & Fischer-Posovszky, P. Nicotinamide mononucleotide: a potential effective natural compound against insulin resistance. Signal Transduct. Target. Ther. 6, 310 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Zapata-Perez, R. et al. Biotechnological production of reduced and oxidized NAD+ precursors. Food Res. Int. 165, 112560 (2023).

    Article  CAS  PubMed  Google Scholar 

  270. Li, F., Wu, C. & Wang, G. Targeting NAD metabolism for the therapy of age-related neurodegenerative diseases. Neurosci. Bull. 40, 218–240 (2024).

    Article  CAS  PubMed  Google Scholar 

  271. Watne, L. O. et al. Cerebrospinal fluid quinolinic acid is strongly associated with delirium and mortality in hip-fracture patients. J. Clin. Invest. https://doi.org/10.1172/JCI163472 (2023).

  272. Suhs, K. W. et al. Kynurenine is a cerebrospinal fluid biomarker for bacterial and viral central nervous system infections. J. Infect. Dis. 220, 127–138 (2019).

    Article  CAS  PubMed  Google Scholar 

  273. Quist-Paulsen, E. et al. High neopterin and IP-10 levels in cerebrospinal fluid are associated with neurotoxic tryptophan metabolites in acute central nervous system infections. J. Neuroinflammation 15, 327 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. De Pinto, V. Renaissance of VDAC: new insights on a protein family at the interface between mitochondria and cytosol. Biomolecules https://doi.org/10.3390/biom11010107 (2021).

  275. Magri, A. et al. AAV-mediated upregulation of VDAC1 rescues the mitochondrial respiration and sirtuins expression in a SOD1 mouse model of inherited ALS. Cell Death Discov. 10, 178 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Canto, C. NAD+ precursors: a questionable redundancy. Metabolites https://doi.org/10.3390/metabo12070630 (2022).

  278. Kropotov, A. et al. Equilibrative nucleoside transporters mediate the import of nicotinamide riboside and nicotinic acid riboside into human cells. Int. J. Mol. Sci. https://doi.org/10.3390/ijms22031391 (2021).

  279. MacKay, D., Hathcock, J. & Guarneri, E. Niacin: chemical forms, bioavailability, and health effects. Nutr. Rev. 70, 357–366 (2012).

    Article  PubMed  Google Scholar 

  280. 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 

  281. 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 

  282. Mathialagan, S. et al. Nicotinic acid transport into human liver involves organic anion transporter 2 (SLC22A7). Biochem. Pharmacol. 174, 113829 (2020).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

E.F.F. is supported by the Cure Alzheimer’s Fund (282952, 284930), HELSE SØR-ØST (2020001, 2021021, 2023093), the Research Council of Norway (262175, 334361), Molecule AG/VITADAO (282942), NordForsk Foundation (119986), the National Natural Science Foundation of China (81971327), Akershus University Hospital (269901, 261973, 262960), the Civitan Norges Forskningsfond for Alzheimers sykdom (281931), the Czech Republic-Norway KAPPA program (with M. Vyhnálek, TO01000215), the Rosa sløyfe/Norwegian Cancer Society & Norwegian Breast Cancer Society (207819), Wellcome Leap’s Dynamic Resilience Program (jointly funded by Temasek Trust; 104617) and the Alzheimer’s Association (PTC-Gene-25-1439553). E.F.F., M.S.K., C.C., E.P., M.D., S.B., G.E.J., R.Z.-P. and R.H.H. received funding from the European Union’s Horizon Europe research and innovation program through the NADIS project (101073251). H.L.W. is supported by the Norwegian Health Association (43080). H.L.N. is partially supported by the Research Council of Norway through its Centres of Excellence scheme (project number 332713), KLINBEFORSK (26044), the Research Council of Norway (302483) and the Michael J. Fox Foundation (022355). J.T.T. is supported by the Novo Nordisk Foundation Center for Basic Metabolic Research, which is an independent research center at the University of Copenhagen, partially funded by the Novo Nordisk Foundation (NNF23SA0084103). L.O.W. is funded by the South-Eastern Norway Regional Health Authorities (2017095), the Norwegian Health Association (19536, 1513) and by Wellcome Leap’s Dynamic Resilience Program (jointly funded by Temasek Trust) (104617). T.O. is supported by the Research Council of Norway (326461) and the South-Eastern Norway Regional Health Authority (272931). E.P. has received funding from the European Union’s Horizon Europe research and innovation program under a grant agreement (NADIS; GA-101073251, with R.Z.-P., C.C., M.D., G.E.J., M.S.K., E.F.F., S.B. and R.H.) and from Research Council of Finland Profi 6 funding (336449) awarded to the University of Oulu. M.Z. is supported by grants from the Research Council of Norway (325172, 309567, 302314). R.Z.-P. is supported by grants from Ministerio de Ciencia, Innovación y Universidades – Proyectos de Generación de Conocimiento 2023 (PID2023-147560OA-I00) and from Fundación Séneca – Agencia de Ciencia y Tecnología de la Región de Murcia (22011/JLI/22, Ayudas a Proyectos para la Gene-ración de Nuevo Liderazgo Científico Jóvenes Líderes en Investigación 2022). S.B. is supported by Marie Skłodowska-Curie HORIZON-MSCA-DN-2021 (NADIS; GA-101073251, with E.P., R.Z.-P., C.C., M.D., G.E.J., M.S.K., E.F.F. and RH), Fondazione Compagnia di San Paolo (Bando Trapezio) and the Italian Ministry of University and Research (PRIN 2022P9RM9M). M.D. is supported by ERC CoG (PD-GUT-101003329), AFM Telethon (28568), JPND (01ED2005B), Aligning Science Across Parkinson’s (ASAP-000420) and Fondation De France (00147852/WB-2023-51647). K.Y. is supported by the Japan Agency for Medical Research and Development (JP21bm0804016, JP21jm0210096, JP22ym0126066, JP23ek0109622) and the Ministry of Health, Labor and Welfare of Japan (JPMH21FC1016). C.T. is supported by grants from: The Research Council of Norway (288164), Bergen Research Foundation (BFS2017REK05), The KG Jebsen Foundation (SKGJ-MED-023) and the Western Norway Regional Health Authority (F-10229-D11661; IHF). J.Z. is supported by Akershus University Hospital (263928) and the national key clinical specialties program of Hunan Province (20230146). S.L. is supported by the Norwegian Health Association (281956). L.E.W. is funded by a Hevolution/American Federation for Aging Research (AFAR) New Investigator award.

Author information

Author notes

  1. These authors contributed equally: Jianying Zhang, He-Ling Wang.

Authors and Affiliations

  1. Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway

    Jianying Zhang, He-Ling Wang, Sofie Lautrup & Evandro Fei Fang

  2. Key Laboratory of Oral Health Research in Hunan Province, Xiangya School of Stomatology, Central South University, Hu’nan, China

    Jianying Zhang

  3. The Norwegian Centre on Healthy Ageing (NO-Age) and the Norwegian National anti-Alzheimer’s Disease (NO-AD) Networks, Oslo, Norway

    Jianying Zhang, He-Ling Wang, Sofie Lautrup & Evandro Fei Fang

  4. Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Hilde Loge Nilsen & Geir Selbæk

  5. Centre for Embryology and Healthy Development (CRESCO), University of Oslo, Oslo, Norway

    Hilde Loge Nilsen

  6. Department of Microbiology, Oslo University Hospital, Oslo, Norway

    Hilde Loge Nilsen

  7. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Jonas T. Treebak

  8. Institute of Clinical Medicine, Campus Ahus, University of Oslo, Lørenskog, Norway

    Leiv Otto Watne

  9. Department of Geriatric Medicine, Akershus University Hospital, Lørenskog, Norway

    Leiv Otto Watne

  10. Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway

    Geir Selbæk

  11. Norwegian National Centre for Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway

    Geir Selbæk

  12. School of Biomedical Sciences, UNSW Sydney, Sydney, New South Wales, Australia

    Lindsay E. Wu

  13. Department of Cardiology, Akershus University Hospital, Lørenskog, Norway

    Torbjørn Omland

  14. K.G. Jebsen Center for Cardiac Biomarkers, University of Oslo, Oslo, Norway

    Torbjørn Omland

  15. Research Unit of Biomedicine and Internal Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland

    Eija Pirinen

  16. Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland

    Eija Pirinen

  17. Biocenter Oulu, University of Oulu, Oulu, Finland

    Eija Pirinen

  18. Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland

    Eija Pirinen

  19. Hong Kong Longevity Science Laboratory Limited, Hong Kong Science Park, Pak Shek Kok, Hong Kong SAR, China

    Tin Cho Cheung & Jun Wang

  20. Department of Biomedicine, University of Bergen, Bergen, Norway

    Mathias Ziegler

  21. Department of Clinical Medicine, University of Bergen, Bergen, Norway

    Ole-Bjørn Tysnes & Charalampos Tzoulis

  22. Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway

    Ole-Bjørn Tysnes & Charalampos Tzoulis

  23. Group of Metabolism and Gene Regulation, UCAM HiTech Sport & Health Innovation Hub, Universidad Católica de Murcia, Guadalupe de Maciascoque, Murcia, Spain

    Rubén Zapata-Pérez

  24. Department of Experimental Medicine, Section of Biochemistry, University of Genova, Genova, Italy

    Santina Bruzzone

  25. Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    Carles Canto

  26. Mechanisms and Therapy of Genetic Brain Diseases Institut Imagine, INSERM UMR 1163- Paris Cite’ University, Paris, France

    Michela Deleidi

  27. Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism (AGEM), Amsterdam Cardiovascular Sciences (ACS), Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

    Georges E. Janssens & Riekelt H. Houtkooper

  28. Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark

    Morten Scheibye-Knudsen & Vilhelm A. Bohr

  29. Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, Chiba, Japan

    Masaya Koshizaka & Koutaro Yokote

  30. Department of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, Chiba, Japan

    Masaya Koshizaka & Koutaro Yokote

  31. UCSF Department of Medicine, San Francisco, CA, USA

    Eric Verdin

  32. Buck Institute for Research on Aging, Novato, CA, USA

    Eric Verdin

  33. Section on DNA Repair, National Institute on Aging, Baltimore, MD, USA

    Vilhelm A. Bohr

  34. K.G. Jebsen Center for Translational Research in Parkinson’s disease, University of Bergen, Bergen, Norway

    Charalampos Tzoulis

  35. Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA, USA

    David A. Sinclair

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  1. Jianying Zhang
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  2. He-Ling Wang
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Contributions

Conceptualization: J.Z. and E.F.F. Writing—original draft preparation: J.Z., H.L.W., S.L., H.L.N., J.T.T., L.O.W., G.S., L.E.W., T.O., E.P., T.C.C., J.W., M.Z., O.-B.T., R.Z.-P., S.B., C.C., M.D., G.E.J., R.H.H., M.S.K., K.Y., M.K., C.T. and E.F.F. Writing—review and editing: J.Z., H.L.W., S.L., H.L.N., J.T.T., L.O.W., G.S., L.E.W., T.O., E.P., T.C.C., J.W., M.Z., O.-B.T., R.Z.-P., S.B., C.C., M.D., G.E.J., R.H.H., M.S.K., K.Y., M.K., E.V., V.B., C.T., D.A.S. and E.F.F. Visualization: J.Z. and H.L.W. Supervision: E.F.F.

Corresponding author

Correspondence to Evandro Fei Fang.

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Competing interests

E.F.F. is a co-owner of Fang-S Consultation AS (organization no. 931 410 717) and NO-Age AS (organization no. 933 219 127); has a material transfer agreement with LMITO Therapeutics (South Korea), a CRADA arrangement with ChromaDex (USA), a commercialization agreement with Molecule AG/VITADAO and material transfer agreements with GeneHarbor (Hong Kong) Biotechnologies Limited and Hong Kong Longevity Science Laboratory (Hong Kong); is a consultant for MindRank AI (China), NYO3 (Norway), AgeLab (Vitality Nordic AS, Norway) and Hong Kong Longevity Science Laboratory (Hong Kong). H.L.N. is an owner of NilsenRepairAge Consulting (organization no. 932146797) and NO-Age AS (organization no. 933219127); has a CRADA arrangement with ChromaDex (USA) and is a consultant for Ambr Institute (Norway), MitoTerapeutics (Norway) and AgeLab (Vitality Nordic AS, Norway). C.T. is listed as inventor on international patent applications relating to the use of NR as a treatment for PD. These patents have been filed by the Technology Transfer Office ‘Vestlandets Innovasjonsselskap As (VIS)’ on behalf of Haukeland University Hospital, Bergen, Norway (PCT/EP2022/067408, PCT/EP2022/067412 and PCT/EP2023/060962). G.S. has received honoraria for giving lectures at symposia sponsored by Eisai and Eli Lilly and has participated at advisory board meetings for Eisia, Roche and Eli Lilly concerning the manufacture of disease-modifying therapies for AD. T.O. has received institutional research support from ChromaDex (USA). E.P. reports a relationship with ChromaDex that includes speaking and lecture fees. M.Z. is chief scientist at Blue Helix Health AS. K.Y. and M.K. have received research support from ChromaDex (USA) via their institution. V.B. is a member of the Chromadex Scientific Advisory Board. T.C.C. and J.W. are inventors and consultants in the Hong Kong Longevity Science Laboratory. D.A.S. is a consultant, inventor, board member and, in some cases, an investor in Atai (2021–present) I; Galilei Biosciences SIRT6 activators (2014–present) F, I, E, A, B; InsideTracker (Segterra), Cambridge, MA I, A, IP (2011–present) B (2011–2017); Zymo Research Irvine, CA, molecular biology (2017–present) A; MetroBiotech, an EdenRoc company also known as Bauhaus; NAD boosters (2015–present) F, I, E, A, B (EdenRoc), IP; Life Biosciences Boston, and affiliates, Cantata Bio (formerly Dovetail Genomics and Arc Bio), Delavie Sciences (2017–present) F, I, E, A, B, IP; Levels (2021–present) E, A; Bold Capital (2021–present) E, A; Falcon Edge Capital (2021–present) E; AFAR (American Federation for Aging Research) B, A, F; Life Extension Advocacy Foundation (LEAF) A; Animal Biosciences (2017–present) I, E; Immetas (2018–present) F, I, E, A, B; Jumpstart Fertility, a Life Biosciences Company, F, I, E, A, B, IP; Fully Aligned Co, F, E, B, IP. F, founder; I, investor; E, equity; A, advisor/consultant; B, board of directors; IP, inventor on licensed patents; L, funding for laboratory (for further information about the affiliations of D.A.S., including those judged not relevant to this work, see https://sinclair.hms.harvard.edu/david-sinclairs-affiliations/). L.E.W. is a scientific advisor and shareholder in Metro Biotech and Jumpstart Fertility. The other authors declare no competing interests.

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Nature Aging thanks Eduardo Chini, Joseph Baur and Shinghua Ding for their contribution to the peer review of this work.

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Zhang, J., Wang, HL., Lautrup, S. et al. Emerging strategies, applications and challenges of targeting NAD+ in the clinic. Nat Aging 5, 1704–1731 (2025). https://doi.org/10.1038/s43587-025-00947-6

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