Skip to main content
SpringerLink
Log in
Book cover

Aging Mechanisms II pp 141–156Cite as

NAD+ Metabolism in Aging

  • Chapter
  • First Online:

  • 878 Accesses

Abstract

Nicotinamide adenine dinucleotide (NAD+) is an essential molecule found in all living cells, which is involved in fundamental biological processes such as energy metabolism, DNA repair, epigenetic regulation, and neuronal axon homeostasis. Several studies have shown that tissue NAD+ levels decrease with aging. This age-related NAD+ decline has been associated with hallmarks of aging and the development and progression of a wide range of age-related diseases, such as metabolic disorders, cancer, and neurodegenerative diseases. Preclinical studies have largely shown that boosting NAD+ levels by oral administration of NAD+ precursors, such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), can ameliorate age-associated pathologies and extend health span. Early clinical trial results suggest that NR and NMN are safe and bioavailable in humans and certain effectiveness has been demonstrated. Thus, NAD+ metabolism is an exciting field whose modulation can provide beneficial effects and may improve human health.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Airhart SE, Shireman LM, Risler LJ, Anderson GD, Gowda GAN, 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:e0186459

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bai P, Canto C, Oudart H, Brunyanszki A, Cen Y, Thomas C, Yamamoto H, Huber A, Kiss B, Houtkooper RH et al (2011) PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab 13:461–468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bertoldo MJ, Listijono DR, Ho WJ, Riepsamen AH, Goss DM, Richani D, Jin XL, Mahbub S, Campbell JM, Habibalahi A (2020) NAD+ repletion rescues female fertility during reproductive aging. Cell Rep 30:1670–1681.e1677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bird JG, Zhang Y, Tian Y, Panova N, Barvík I, Greene L, Liu M, Buckley B, Krásný L, Lee JK et al (2016) The mechanism of RNA 5′ capping with NAD+, NADH and desphospho-CoA. Nature 535:444–447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Camacho-Pereira J, Tarrago MG, Chini CC, Nin V, Escande C, Warner GM, Puranik AS, Schoon RA, Reid JM, Galina A et al (2016) CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab 23:1127–1139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cantó C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, Fernandez-Marcos PJ, Yamamoto H, Andreux PA, Cettour-Rose P et al (2012) The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet induced obesity. Cell Metab 15:838–847

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chini CCS, Peclat TR, Warner GM, Kashyap S, Espindola-Netto JM, de Oliveira GC, Gomez LS, Hogan KA, Tarragó MG, Puranik AS et al (2020) CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. Nat Metab 2:1284–1304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clement J, Wong M, Poljak A, Sachdev P, Braidy N (2019) The plasma NAD+ metabolome is dysregulated in “normal” aging. Rejuvenation Res 22:121–130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cohen MS (2020) Interplay between compartmentalized NAD+ synthesis and consumption: a focus on the PARP family. Genes Dev 34:254–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Demontis F, Piccirillo R, Goldberg AL, Perrimon N (2013) Mechanisms of skeletal muscle aging: insights from Drosophila and mammalian models. Dis Model Mech 6:1339–1352

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ding R, Bao J, Deng C (2017) Emerging roles of SIRT1 in fatty liver diseases. Int J Biol Sci 13:852–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dollerup OL, Christensen B, Svart M, Schmidt MS, Sulek K, Ringgaard S, Stødkilde-Jørgensen H, Møller N, Brenner C, Jonas T, Treebak JT et al (2018) 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

    Article  PubMed  Google Scholar 

  • Elhassan YS, Kluckova K, Fletcher RS, Schmidt MS, Garten A, Doig CL, Cartwright DM, Oakey L, Burley CV, Jenkinson N et al (2019) Nicotinamide riboside augments the aged human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures. Cell Rep 28:1717–1728.e6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 23:899–916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Figley MD, Gu W, Nanson JD, Shi Y, Sasaki Y, Cunnea K, Malde AK, Jia X, Luo Z, Saikot FK (2021) SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration. Neuron 109:1118–1136.e11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frederick DW, Loro E, Liu L, Davila A, Chellappa K, Silverman IM, Quinn WJ, Gosai SJ, Tichy ED, Davis JG, Mourkioti F et al (2016) Loss of NAD homeostasis leads to progressive and reversible degeneration of skeletal muscle. Cell Metab 24:269–282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gill DM (1975) Involvement of nicotinamide adenine dinucleotide in the action of cholera toxin in vitro. Proc Natl Acad Sci U S A 72:2064–2068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gomes AP, Price NL, Ling AJY, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP et al (2013) Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155:1624–1638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hajer GR, van Haeften TW, Visseren FLJ (2008) Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J 29:2959–2971

    Article  CAS  PubMed  Google Scholar 

  • Hara N, Yamada K, Terashima M, Osago H, Shimoyama M, Tsuchiya M (2003) Molecular identification of human glutamine- and ammonia-dependent NAD synthetases. J Biol Chem 278:10914–10921

    Article  CAS  PubMed  Google Scholar 

  • Hara N, Yamada K, Shibata T, Osago H, Hashimoto T, Tsuchiya M (2007) Elevation of cellular NAD levels by nicotinic acid and involvement of nicotinic acid phosphoribosyl transferase in human cells. J Biol Chem 282:24574–24582

    Article  CAS  PubMed  Google Scholar 

  • Harden A, Young WJ (1906) The alcoholic ferment of yeast-juice. Proc Biol Sci 77:405–420

    CAS  Google Scholar 

  • Igarashi M, Miura M, Williams E, Jaksch F, Kadowaki T, Yamauchi T, Guarente L (2019) NAD+ supplementation rejuvenates aged gut adult stem cells. Aging Cell 18:e12935

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Imai S, Guarente L (2014) NAD+ and sirtuins in aging and disease. Trends Cell Biol 24:464–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Irie J, Inagaki E, Fujita M, Nakaya H, Mitsuishi M, Yamaguchi S, Yamashita K, Shigaki S, Ono T, Yukioka H et al (2020) Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocr J 67:153–160

    Article  CAS  PubMed  Google Scholar 

  • Kaslow HR, Groppi VE, Abood ME, Bourne HR (1981) Cholera toxin can catalyze ADP-ribosylation of cytoskeletal proteins. J Cell Biol 91:410–413

    Article  CAS  PubMed  Google Scholar 

  • Katsyuba E, Mottis A, Zietak M, De Franco F, van der Velpen V, Gariani K, Ryu D, Cialabrini L, Matilainen O, Liscio P et al (2018) De novo NAD+ synthesis enhances mitochondrial function and improves health. Nature 563:354–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin CW, Liu HY, Chen CY, Hsueh YP (2014) Neuronally-expressed Sarm1 regulates expression of inflammatory and antiviral cytokines in brains. Innate Immun 20:161–172

    Article  PubMed  CAS  Google Scholar 

  • Liu C, Yu X (2015) ADP-ribosyltransferases and poly ADP-ribosylation. Curr Protein Pept Sci 16:491–501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu L, Su X, Quinn WJ, Hui S, Krukenberg K, Frederick DW, Redpath P, Zhan L, Chellappa K, White E et al (2018) Quantitative analysis of NAD synthesis-breakdown fluxes. Cell Metab 27:1067–1080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lombard DB, Tishkoff DX, Bao J (2011) Mitochondrial sirtuins in the regulation of mitochondrial activity and metabolic adaptation. Handb Exp Pharmacol 206:163–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR et al (2018) Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun 9:1286

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Massudi H, Grant R, Braidy N, Guest J, Farnsworth B, Guillemin GJ, Polymenis M (2012) Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS ONE 7(7):e42357. https://doi.org/10.1371/journal.pone.0042357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McReynolds M, Chellappa K, Chiles E, Jankowski C, Shen Y, Chen L, Descamps H, Mukherjee S, Bhat Y, Lingala SR et al (2021) NAD+ flux is maintained in aged mice despite lower tissue concentrations. Cell Syst 12:1160–1172

    Article  CAS  PubMed  Google Scholar 

  • Mehmel M, Jovanović N, Spitz U (2020) Nicotinamide riboside—the current state of research and therapeutic uses. Nutrients 12:1616

    Article  CAS  PubMed Central  Google Scholar 

  • Mehr AP, Tran MT, Ralto KM, Leaf DE, Washco V, Messmer J, Lerner A, Kher A, Kim SH, Khoury CC et al (2018) De novo NAD+ biosynthetic impairment in acute kidney injury in humans. Nat Med 24:1351–1359

    Article  PubMed Central  CAS  Google Scholar 

  • Michels J, Vitale I, Saparbaev M, Castedo M, Kroemer G (2014) Predictive biomarkers for cancer therapy with PARP inhibitors. Oncogene 33:3894–3907

    Article  CAS  PubMed  Google Scholar 

  • Migliavacca E, Tay SKH, Patel HP, Sonntag T, Civiletto G, McFarlane C, Forrester T, Barton SJ, Leow MK, Antoun E et al (2019) Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities. Nat Commun 10:5808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K et al (2016) Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab 24:795–806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minhas PS, Liu L, Moon PK, Joshi AU, Dove C, Mhatre S, Contrepois K, Wang Q, Lee BA, Coronado M et al (2019) Macrophage de novo NAD+ synthesis specifies immune function in aging and inflammation. Nat Immunol 20:50–63

    Article  CAS  PubMed  Google Scholar 

  • Miranda MX, van Tits LJ, Lohmann C, Arsiwala T, Winnik S, Tailleux A, Stein S, Gomes AP, Suri V, Ellis JL et al (2014) The Sirt1 activator SRT3025 provides atheroprotection in Apoe-/- mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression. Eur Heart J 36:51–59

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D, Cantó C, Mottis A, Jo YS, Viswanathan M, Schoonjans K et al (2013) The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154:430–441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mukherjee S, Chellappa K, Moffitt A, Ndungu J, Dellinger RW, Davis JG, Agarwal B, Baur JA (2017) Nicotinamide adenine dinucleotide biosynthesis promotes liver regeneration. Hepatology 65:616–630

    Article  CAS  PubMed  Google Scholar 

  • Muraoka H, Hasegawa K, Sakamaki Y, Minakuchi H, Kawaguchi T, Yasuda I, Kanda T, Tokuyama H, Wakino S, Itoh H (2019) Role of Nampt-Sirt6 axis in renal proximal tubules in extracellular matrix deposition in diabetic nephropathy. Cell Rep 27:199–212.e5

    Article  CAS  PubMed  Google Scholar 

  • Nitta K, Okada K, Yanai M, Takahashi S (2013) Aging and chronic kidney disease. Kidney Blood Press Res 38:109–120

    Article  PubMed  Google Scholar 

  • Okabe K, Yaku K, Tobe K, Nakagawa T (2019) Implications of altered NAD metabolism in metabolic disorders. J Biomed Sci 26:34

    Article  PubMed  PubMed Central  Google Scholar 

  • Okabe K, Nawaz A, Nishida Y, Yaku K, Usui I, Tobe K, Nakagawa T (2020) NAD+ metabolism regulates preadipocyte differentiation by enhancing α-ketoglutarate-mediated histone H3K9 demethylation at the PPARγ promoter. Front Cell Dev Biol 8:586179

    Article  PubMed  PubMed Central  Google Scholar 

  • Parker R, Schmidt MS, Cain O, Gunson B, Brenner C (2020) Nicotinamide adenine dinucleotide metabolome is functionally depressed in patients undergoing liver transplantation for alcohol-related liver disease. Hepatol Commun 4:1183–1192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Piedra-Quintero ZL, Wilson Z, Nava P, Guerau-de-Arellano M (2020) CD38: an immunomodulatory molecule in inflammation and autoimmunity. Front Immunol 11:597959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pirinen E, Auranen M, Khan NA, Brilhante V, Urho N, Pessia A, Hakkarainen A, Kuula J, Heinonen U, Schmidt MS et al (2020) Niacin cures systemic NAD+ deficiency and improves muscle performance in adult-onset mitochondrial myopathy. Cell Metab 31:1078–1090.e5

    Article  CAS  PubMed  Google Scholar 

  • Ponugoti B, Kim D, Xiao Z, Smith Z, Miao J, Zang M, Wu S, Chiang C, Veenstra T, Kemper JK (2010) SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. J Biol Chem 285:33959–33970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rajman L, Chwalek K, Sinclair DA (2018) Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab 27:529–547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ratnayake D, Nguyen PD, Rossello FJ, Wimmer VC, Tan JL, Galvis LA, Julier Z, Wood AJ, Boudier T, Isiaku AI et al (2021) Macrophages provide a transient muscle stem cell niche via NAMPT secretion. Nature 591:281–287

    Article  CAS  PubMed  Google Scholar 

  • Ryu D, Zhang H, Ropelle ER, Sorrentino V, Mázala DAG, Mouchiroud L, Marshall PL, Campbell MD, Ali AS, Knowels GM et al (2016) NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation. Sci Transl Med 8:361ra139

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Stromsdorfer KL, Yamaguchi S, Yoon MJ, Moseley AC, Franczyk MP, Kelly SC, Qi N, Imai S, Yoshino J (2016) NAMPT-mediated NAD+ biosynthesis in adipocytes regulates adipose tissue function and multi-organ insulin sensitivity in mice. Cell Rep 16:1851–1860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sydenstricker VP (1958) The history of pellagra, its recognition as a disorder of nutrition and its conquest. Am J Clin Nutr 6:409–414

    Article  CAS  PubMed  Google Scholar 

  • Tang BL (2016) Sirt1 and the mitochondria. Mol Cells 39:87–95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tarragó MG, Chini CCS, Kanamori KS, Warner GM, Caride A, de Oliveira GC, Rud M, Samani A, Hein KZ, Huang R et al (2018) A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD+ decline. Cell Metab 27:1081–1095

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vassilopoulos A, Fritz KS, Petersen DR, Gius D (2011) The human sirtuin family: evolutionary divergences and functions. Hum Genomics 5:485–496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang L, Wang X, Huang C, Hu L, Xiao Y, Guan X, Qian Y, Deng K, Xin H (2017) Inhibition of NAMPT aggravates high fat diet-induced hepatic steatosis in mice through regulating Sirt1/AMPKα/SREBP1 signaling pathway. Lipids Health Dis 16:82

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Weidele K, Beneke S, Bürkle A (2017) The NAD+ precursor nicotinic acid improves genomic integrity in human peripheral blood mononuclear cells after X-irradiation. DNA Repair 52:12–23

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Yamaguchi S, Yoshino J (2017) Adipose tissue NAD+ biology in obesity and insulin resistance: from mechanism to therapy. BioEssays 39:10

    Article  PubMed Central  CAS  Google Scholar 

  • Yoshino M, Yoshino J, Kayser BD, Patti G, Franczyk MP, Mills KF, Sindelar M, Pietka T, Patterson BW, Imai S et al (2021) Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science 372:1224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, D’Amico D, Ropelle ER, Lutolf MP, Aebersold R et al (2016) NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352:1436–1443

    Article  CAS  PubMed  Google Scholar 

  • Zhou CC, Yang X, Hua X, Liu J, Fan MB, Li GQ, Song J, Xu T, Li Z, Guan Y et al (2016) Hepatic NAD+ deficiency as a therapeutic target for non-alcoholic fatty liver disease in ageing. Br J Pharmacol 173:2352–2368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu X, Shen W, Wang Y, Jaiswal A, Ju Z, Sheng Q (2017) Nicotinamide adenine dinucleotide replenishment rescues colon degeneration in aged mice. Signal Transduct Target Ther 2:17017

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular and Medical Pharmacology, Faculty of Medicine, University of Toyama, Toyama, Japan

    Sailesh Palikhe & Takashi Nakagawa

  2. Research Center for Pre-Disease Science, University of Toyama, Toyama, Japan

    Takashi Nakagawa

Authors
  1. Sailesh Palikhe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takashi Nakagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takashi Nakagawa .

Editor information

Editors and Affiliations

  1. Fukuoka International University of Health and Welfare, Fukuoka, Japan

    Nozomu Mori

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Palikhe, S., Nakagawa, T. (2022). NAD+ Metabolism in Aging. In: Mori, N. (eds) Aging Mechanisms II . Springer, Singapore. https://doi.org/10.1007/978-981-16-7977-3_8

Download citation

Publish with us

Policies and ethics

Search

Navigation