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The role of nicotinamide mononucleotide (NMN) in anti-aging, longevity, and its potential for treating chronic conditions

Abstract

Biosynthesis and regulation of nicotinamide adenine dinucleotide (NAD+) has recently gained a lot of attention. A systemic decline in NAD+ across many tissues is associated with all the hallmarks of aging. NAD+ can affect a variety of cellular processes, including metabolic pathways, DNA repair, and immune cell activity, both directly and indirectly. These cellular processes play a vital role in maintaining homeostasis, but as people get older, their tissue and cellular NAD+ levels decrease, and this drop in NAD+ levels has been connected to a number of age-related disorders. By restoring NAD+ levels, several of these age-related disorders can be delayed or even reversed. Some of the new studies conducted in mice and humans have targeted the NAD+ metabolism with NAD+ intermediates. Of these, nicotinamide mononucleotide (NMN) has been shown to offer great therapeutic potential with promising results in age-related chronic conditions such as diabetes, cardiovascular issues, cognitive impairment, and many others. Further, human interventions are required to study the long-term effects of supplementing NMN with varying doses. The paper focuses on reviewing the importance of NAD+ on human aging and survival, biosynthesis of NAD+ from its precursors, key clinical trial findings, and the role of NMN on various health conditions.

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References

  1. Martin JA, Hamilton BE, Osterman MJK, Driscoll AK (2021) Births: final data for 2019. Natl Vital Stat Rep 70(2):1–51 (PMID: 33814033)

    PubMed  Google Scholar 

  2. United States Census Bureau. Population Data. Retrieved 1 January 2022 from https://www.census.gov/topics/population/data.html

  3. Moon S, Choi M (2018) The effect of usual source of care on the association of annual healthcare expenditure with patients’ age and chronic disease duration. Int J Environ Res Public Health 15(9):1844. https://doi.org/10.3390/ijerph15091844

    Article  PubMed Central  Google Scholar 

  4. Fang EF, Lautrup S, Hou Y, Demarest TG, Croteau DL, Mattson MP, Bohr VA (2017) NAD+ in aging: molecular mechanisms and translational implications. Trends Mol Med 23(10):899–916

    CAS  Article  Google Scholar 

  5. Poljsak B, Milisav I (2018) Vitamin B3 forms as precursors to NAD+: are they safe? Trends Food Sci Technol 79:198–203. https://doi.org/10.1016/j.tifs.2018.07.020

    CAS  Article  Google Scholar 

  6. Rajman L, Chwalek K, Sinclair DA (2018) Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab 27(3):529–547. https://doi.org/10.1016/j.cmet.2018.02.011

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Johnson S, Imai SI (2018) NAD+ biosynthesis, aging, and disease. F1000Res 7:132

    Article  Google Scholar 

  8. Kincaid JW, Berger NA (2020) NAD metabolism in aging and cancer. Exp Biol Med (Maywood) 245(17):1594–1614

    CAS  Article  Google Scholar 

  9. Sas K, Szabó E, Vécsei L (2018) Mitochondria, oxidative stress and the kynurenine system, with a focus on ageing and neuroprotection. Molecules 23(1):191. https://doi.org/10.3390/molecules23010191

    CAS  Article  PubMed Central  Google Scholar 

  10. Kane AE, Sinclair DA (2018) Sirtuins and NAD+ in the development and treatment of metabolic and cardiovascular diseases. Circ Res 123(7):868–885

    CAS  Article  Google Scholar 

  11. Cui H, Kong Y, Zhang H (2012) Oxidative stress, mitochondrial dysfunction, and aging. J Signal Transduct 2012:646354. https://doi.org/10.1155/2012/646354

    CAS  Article  PubMed  Google Scholar 

  12. Leadsham JE, Sanders G, Giannaki S, Bastow EL, Hutton R, Naeimi WR, Breitenbach M, Gourlay CW (2013) Loss of cytochrome c oxidase promotes RAS-dependent ROS production from the ER resident NADPH oxidase, Yno1p, in yeast. Cell Metab 18(2):279–286. https://doi.org/10.1016/j.cmet.2013.07.005

    CAS  Article  PubMed  Google Scholar 

  13. Nicolson GL (2014) Mitochondrial dysfunction and chronic disease: treatment with natural supplements. Integr Med (Encinitas) 13(4):35–43

    Google Scholar 

  14. Fang EF, Hou Y, Lautrup S, Jensen MB, Yang B, SenGupta T, Caponio D, Khezri R, Demarest TG, Aman Y, Figueroa D, Morevati M, Lee HJ, Kato H, Kassahun H, Lee JH, Filippelli D, Okur MN, Mangerich A, Croteau DL, Maezawa Y, Lyssiotis CA, Tao J, Yokote K, Rusten TE, Mattson MP, Jasper H, Nilsen H, Bohr VA (2019) NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome. Nat Commun 10(1):5284. https://doi.org/10.1038/s41467-019-13172-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Valentin-Vega YA, Maclean KH, Tait-Mulder J, Milasta S, Steeves M, Dorsey FC, Cleveland JL, Green DR, Kastan MB (2012) Mitochondrial dysfunction in ataxia-telangiectasia. Blood 119(6):1490–1500. https://doi.org/10.1182/blood-2011-08-373639

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Scheibye-Knudsen M, Mitchell SJ, Fang EF, Iyama T, Ward T, Wang J, Dunn CA, Singh N, Veith S, Hasan-Olive MM, Mangerich A, Wilson MA, Mattson MP, Bergersen LH, Cogger VC, Warren A, Le Couteur DG, Moaddel R, Wilson DM 3rd, Croteau DL, de Cabo R, Bohr VA (2014) A high-fat diet and NAD(+) activate Sirt1 to rescue premature aging in cockayne syndrome. Cell Metab 20(5):840–855. https://doi.org/10.1016/j.cmet.2014.10.005

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Fang EF, Kassahun H, Croteau DL, Scheibye-Knudsen M, Marosi K, Lu H, Shamanna RA, Kalyanasundaram S, Bollineni RC, Wilson MA, Iser WB, Wollman BN, Morevati M, Li J, Kerr JS, Lu Q, Waltz TB, Tian J, Sinclair DA, Mattson MP, Nilsen H, Bohr VA (2016) NAD+ replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab 24(4):566–581. https://doi.org/10.1016/j.cmet.2016.09.004

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Fang EF, Scheibye-Knudsen M, Brace LE, Kassahun H, SenGupta T, Nilsen H, Mitchell JR, Croteau DL, Bohr VA (2014) Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell 157(4):882–896. https://doi.org/10.1016/j.cell.2014.03.026

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Shade C (2020) The science behind NMN-A stable, reliable NAD+ activator and anti-aging molecule. Integr Med (Encinitas) 19(1):12–14

    Google Scholar 

  20. Covarrubias AJ, Perrone R, Grozio A, Verdin E (2021) NAD+ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol 22(2):119–141. https://doi.org/10.1038/s41580-020-00313-x

    CAS  Article  PubMed  Google Scholar 

  21. Yoshino M, Yoshino J, Kayser BD, Patti GJ, Franczyk MP, Mills KF, Sindelar M, Pietka T, Patterson BW, Imai SI, Klein S (2021) Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science 372(6547):1224–1229. https://doi.org/10.1126/science.abe9985

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Fan L, Cacicedo JM, Ido Y (2020) Impaired nicotinamide adenine dinucleotide (NAD+) metabolism in diabetes and diabetic tissues: Implications for nicotinamide-related compound treatment. J Diabetes Investig 11(6):1403–1419. https://doi.org/10.1111/jdi.13303

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Yoshino J, Mills KF, Yoon MJ, Imai S (2011) Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab 14(4):528–536. https://doi.org/10.1016/j.cmet.2011.08.014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Chandrasekaran K, Choi J, Arvas MI, Salimian M, Singh S, Xu S, Gullapalli RP, Kristian T, Russell JW (2020) Nicotinamide mononucleotide administration prevents experimental diabetes-induced cognitive impairment and loss of hippocampal neurons. Int J Mol Sci 21(11):3756. https://doi.org/10.3390/ijms21113756

    CAS  Article  PubMed Central  Google Scholar 

  25. Zhang R, Shen Y, Zhou L, Sangwung P, Fujioka H, Zhang L, Liao X (2017) Short-term administration of nicotinamide mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure. J Mol Cell Cardiol 112:64–73. https://doi.org/10.1016/j.yjmcc.2017.09.001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Liao B, Zhao Y, Wang D, Zhang X, Hao X, Hu M (2021) Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study. J Int Soc Sports Nutr 18(1):54. https://doi.org/10.1186/s12970-021-00442-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Alzheimer’s Disease (2021) Centers for Disease Control and Prevention (CDC). https://www.cdc.gov/dotw/alzheimers/ Accessed 12 Dec 2021.

  28. Cai Q, Jeong YY (2020) Mitophagy in Alzheimer’s disease and other age-related neurodegenerative diseases. Cells 9(1):150. https://doi.org/10.3390/cells9010150

    CAS  Article  PubMed Central  Google Scholar 

  29. Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, Lautrup S, Hasan-Olive MM, Caponio D, Dan X, Rocktäschel P, Croteau DL, Akbari M, Greig NH, Fladby T, Nilsen H, Cader MZ, Mattson MP, Tavernarakis N, Bohr VA (2019) Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci 22(3):401–412. https://doi.org/10.1038/s41593-018-0332-9

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Yao Z, Yang W, Gao Z, Jia P (2017) Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease. Neurosci Lett 647:133–140. https://doi.org/10.1016/j.neulet.2017.03.027

    CAS  Article  PubMed  Google Scholar 

  31. Ungvari Z, Tarantini S, Donato AJ, Galvan V, Csiszar A (2018) Mechanisms of vascular aging. Circ Res 123(7):849–867. https://doi.org/10.1161/CIRCRESAHA.118.311378

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Toth P, Tarantini S, Csiszar A, Ungvari Z (2017) Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging. Am J Physiol Heart Circ Physiol 312(1):H1–H20. https://doi.org/10.1152/ajpheart.00581.2016

    Article  PubMed  Google Scholar 

  33. Kisler K, Nelson AR, Montagne A, Zlokovic BV (2017) Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci 18(7):419–434. https://doi.org/10.1038/nrn.2017.48

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Kiss T, Giles CB, Tarantini S, Yabluchanskiy A, Balasubramanian P, Gautam T, Csipo T, Nyúl-Tóth Á, Lipecz A, Szabo C, Farkas E, Wren JD, Csiszar A, Ungvari Z (2019) Nicotinamide mononucleotide (NMN) supplementation promotes anti-aging miRNA expression profile in the aorta of aged mice, predicting epigenetic rejuvenation and anti-atherogenic effects. Geroscience 41(4):419–439. https://doi.org/10.1007/s11357-019-00095-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Lv H, Lv G, Chen C, Zong Q, Jiang G, Ye D, Cui X, He Y, Xiang W, Han Q, Tang L, Yang W, Wang H (2021) NAD+ metabolism maintains inducible PD-L1 expression to drive tumor immune evasion. Cell Metab 33(1):110-127.e5. https://doi.org/10.1016/j.cmet.2020.10.021

    CAS  Article  PubMed  Google Scholar 

  36. Takeda K, Okumura K (2021) Nicotinamide mononucleotide augments the cytotoxic activity of natural killer cells in young and elderly mice. Biomed Res 42(5):173–179. https://doi.org/10.2220/biomedres.42.173

    CAS  Article  PubMed  Google Scholar 

  37. Chen X, Amorim JA, Moustafa GA, Lee JJ, Yu Z, Ishihara K, Iesato Y, Barbisan P, Ueta T, Togka KA, Lu L, Sinclair DA, Vavvas DG (2020) Neuroprotective effects and mechanisms of action of nicotinamide mononucleotide (NMN) in a photoreceptor degenerative model of retinal detachment. Aging 12(24):24504–24521

    CAS  Article  Google Scholar 

  38. Sauer MV (2015) Reproduction at an advanced maternal age and maternal health. Fertil Steril 103(5):1136–1143. https://doi.org/10.1016/j.fertnstert.2015.03.004

    Article  PubMed  Google Scholar 

  39. Bertoldo MJ, Listijono DR, Ho WJ, Riepsamen AH, Goss DM, Richani D, Jin XL, Mahbub S, Campbell JM, Habibalahi A, Loh WN, Youngson NA, Maniam J, Wong ASA, Selesniemi K, Bustamante S, Li C, Zhao Y, Marinova MB, Kim LJ, Lau L, Wu RM, Mikolaizak AS, Araki T, Le Couteur DG, Turner N, Morris MJ, Walters KA, Goldys E, O’Neill C, Gilchrist RB, Sinclair DA, Homer HA, Wu LE (2020) NAD+ repletion rescues female fertility during reproductive aging. Cell Rep 30(6):1670-1681.e7. https://doi.org/10.1016/j.celrep.2020.01.058

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Makris K, Spanou L (2016) Acute kidney injury: definition, pathophysiology and clinical phenotypes. Clin Biochem Rev 37(2):85–98

    PubMed  PubMed Central  Google Scholar 

  41. Levey AS, James MT (2017) Acute Kidney Injury. Ann Intern Med 167(9):ITC66–ITC80

    Article  Google Scholar 

  42. Jia Y, Kang X, Tan L, Ren Y, Qu L, Tang J, Liu G, Wang S, Xiong Z, Yang L (2021) Nicotinamide mononucleotide attenuates renal interstitial fibrosis after AKI by suppressing tubular DNA damage and senescence. Front Physiol 12:649547. https://doi.org/10.3389/fphys.2021.649547

    Article  PubMed  PubMed Central  Google Scholar 

  43. Katayoshi T, Nakajo T, Tsuji-Naito K (2021) Restoring NAD+ by NAMPT is essential for the SIRT1/p53-mediated survival of UVA- and UVB-irradiated epidermal keratinocytes. J Photochem Photobiol B 221:112238. https://doi.org/10.1016/j.jphotobiol.2021.112238

    CAS  Article  PubMed  Google Scholar 

  44. Irie J, Inagaki E, Fujita M, Nakaya H, Mitsuishi M, Yamaguchi S, Yamashita K, Shigaki S, Ono T, Yukioka H, Okano H, Nabeshima YI, Imai SI, Yasui M, Tsubota K, Itoh H (2020) Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocr J 67(2):153–160. https://doi.org/10.1507/endocrj.EJ19-0313

    CAS  Article  PubMed  Google Scholar 

  45. Hong W, Mo F, Zhang Z, Huang M, Wei X (2020) Nicotinamide mononucleotide: a promising molecule for therapy of diverse diseases by targeting NAD+ metabolism. Front Cell Dev Biol 8:246. https://doi.org/10.3389/fcell.2020.00246

    Article  PubMed  PubMed Central  Google Scholar 

  46. Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, Imai SI (2016) Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab 24(6):795–806. https://doi.org/10.1016/j.cmet.2016.09.013

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Zhou Q, Zhu L, Qiu W, Liu Y, Yang F, Chen W, Xu R (2020) Nicotinamide riboside enhances mitochondrial proteostasis and adult neurogenesis through activation of mitochondrial unfolded protein response signaling in the brain of ALS SOD1G93A mice. Int J Biol Sci 16(2):284–297. https://doi.org/10.7150/ijbs.38487

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Okur MN, Mao B, Kimura R, Haraczy S, Fitzgerald T, Edwards-Hollingsworth K, Tian J, Osmani W, Croteau DL, Kelley MW, Bohr VA (2020) Short-term NAD+ supplementation prevents hearing loss in mouse models of cockayne syndrome. NPJ Aging Mech Dis 6:1. https://doi.org/10.1038/s41514-019-0040-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Gariani K, Menzies KJ, Ryu D, Wegner CJ, Wang X, Ropelle ER, Moullan N, Zhang H, Perino A, Lemos V, Kim B, Park YK, Piersigilli A, Pham TX, Yang Y, Ku CS, Koo SI, Fomitchova A, Cantó C, Schoonjans K, Sauve AA, Lee JY, Auwerx J (2016) Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology 63(4):1190–1204. https://doi.org/10.1002/hep.28245

    CAS  Article  PubMed  Google Scholar 

  50. Giroud-Gerbetant J, Joffraud M, Giner MP, Cercillieux A, Bartova S, Makarov MV, Zapata-Pérez R, Sánchez-García JL, Houtkooper RH, Migaud ME, Moco S, Canto C (2019) 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. https://doi.org/10.1016/j.molmet.2019.09.013

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. Schöndorf DC, Ivanyuk D, Baden P, Sanchez-Martinez A, De Cicco S, Yu C, Giunta I, Schwarz LK, Di Napoli G, Panagiotakopoulou V, Nestel S (2018) The NAD+ precursor nicotinamide riboside rescues mitochondrial defects and neuronal loss in iPSC and fly models of Parkinson’s disease. Cell Rep 23(10):2976–2988

    Article  Google Scholar 

  52. Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, Raftery D, Tian R, Shen DD, O’Brien KD (2017) 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(12):e0186459. https://doi.org/10.1371/journal.pone.0186459

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR (2018) Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun 9(1):1286. https://doi.org/10.1038/s41467-018-03421-7

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Remie CME, Roumans KHM, Moonen MPB, Connell NJ, Havekes B, Mevenkamp J, Lindeboom L, de Wit VHW, van de Weijer T, Aarts SABM, Lutgens E, Schomakers BV, Elfrink HL, Zapata-Pérez R, Houtkooper RH, Auwerx J, Hoeks J, Schrauwen-Hinderling VB, Phielix E, Schrauwen P (2020) Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans. Am J Clin Nutr 112(2):413–426. https://doi.org/10.1093/ajcn/nqaa072

    Article  PubMed  PubMed Central  Google Scholar 

  55. Reiten OK, Wilvang MA, Mitchell SJ, Hu Z, Fang EF (2021) Preclinical and clinical evidence of NAD+ precursors in health, disease, and ageing. Mech Ageing Dev 199:111567. https://doi.org/10.1016/j.mad.2021.111567

    CAS  Article  PubMed  Google Scholar 

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Mounica Soma and Satya Kumar Lalam contributed equally for all sections of the manuscript that includes design, conceptualization, writing, draft preparation, review, and editing. Both authors read and approved the final version of the manuscript.

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Soma, M., Lalam, S.K. The role of nicotinamide mononucleotide (NMN) in anti-aging, longevity, and its potential for treating chronic conditions. Mol Biol Rep 49, 9737–9748 (2022). https://doi.org/10.1007/s11033-022-07459-1

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Keywords

  • Nicotinamide adenine dinucleotide
  • NAD+
  • Nicotinamide mononucleotide
  • NMN
  • Anti-aging
  • Therapeutic potential
  • Age-related disorders