Skip to main content
SpringerLink
Log in

NAD+ as a Pharmacological Tool to Boost Sirtuin Activity

  • Chapter
  • First Online:
Sirtuins

Part of the book series: Proteins and Cell Regulation ((PROR,volume 10))

  • 855 Accesses

Abstract

NAD+ is long known as a redox cofactor, but in recent years also emerged as a substrate for sirtuins, which thereby regulates many cellular activities. The NAD+ levels dictate sirtuin activity and allow this metabolite to integrate metabolic cues into adaptive responses, for instance through inducing mitochondrial biogenesis. With this in mind, strategies to increase the cellular or mitochondrial NAD+ levels were developed as a treatment for metabolic diseases. In this chapter, I will discuss the NAD+ synthesis and breakdown pathways as their combined action determines NAD+ levels. Furthermore, I will outline the pharmacological ways to boost NAD+ levels and treat inherited and acquired metabolic diseases.

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

Access this chapter

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 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
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

Institutional subscriptions

References

  • Aksoy P, Escande C, White TA, Thompson M, Soares S, Benech JC, Chini EN (2006a) Regulation of SIRT 1 mediated NAD dependent deacetylation: a novel role for the multifunctional enzyme CD38. Biochem Biophys Res Commun 349:353–359

    Article  CAS  PubMed  Google Scholar 

  • Aksoy P, White TA, Thompson M, Chini EN (2006b) Regulation of intracellular levels of NAD: a novel role for CD38. Biochem Biophys Res Commun 345:1386–1392

    Article  CAS  PubMed  Google Scholar 

  • Andreux PA, Houtkooper RH, Auwerx J (2013) Pharmacological approaches to restore mitochondrial function. Nat Rev Drug Discov 12:465–483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bai P, Canto C, Brunyanszki A, Huber A, Szanto M, Cen Y, Yamamoto H, Houten SM, Kiss B, Oudart H et al (2011a) PARP-2 regulates SIRT1 expression and whole-body energy expenditure. Cell Metab 13:450–460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bai P, Nagy L, Fodor T, Liaudet L, Pacher P (2015) Poly(ADP-ribose) polymerases as modulators of mitochondrial activity. Trends Endocrinol Metab 26:75–83

    Article  CAS  PubMed  Google Scholar 

  • Barbosa MT, Soares SM, Novak CM, Sinclair D, Levine JA, Aksoy P, Chini EN (2007) The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity. Faseb J 21:3629–3639

    Article  CAS  PubMed  Google Scholar 

  • Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K et al (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Blander G, Guarente L (2004) The Sir2 family of protein deacetylases. Annu Rev Biochem 73:417–435

    Article  CAS  PubMed  Google Scholar 

  • Bleeker JC, Houtkooper RH (2016) Sirtuin activation as a therapeutic approach against inborn errors of metabolism. J Inherit Metab Dis 39:565–572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burnett C, Valentini S, Cabreiro F, Goss M, Somogyvari M, Piper MD, Hoddinott M, Sutphin GL, Leko V, McElwee JJ et al (2011) Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 477:482–485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Canto 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  CAS  PubMed  PubMed Central  Google Scholar 

  • Cerutti R, Pirinen E, Lamperti C, Marchet S, Sauve AA, Li W, Leoni V, Schon EA, Dantzer F, Auwerx J et al (2014) NAD(+)-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease. Cell Metab 19:1042–1049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chalkiadaki A, Guarente L (2012) Sirtuins mediate mammalian metabolic responses to nutrient availability. Nat Rev Endocrinol 8:287–296

    Article  CAS  PubMed  Google Scholar 

  • Curtin NJ, Szabo C (2013) Therapeutic applications of PARP inhibitors: anticancer therapy and beyond. Mol Aspects Med 34:1217–1256

    Article  CAS  PubMed  Google Scholar 

  • D’Amours D, Desnoyers S, D’Silva I, Poirier GG (1999) Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem J 342(Pt 2):249–268

    Article  PubMed  PubMed Central  Google Scholar 

  • Du J, Zhou Y, Su X, Yu J, Khan S, Jiang H, Kim J, Woo J, Kim JH, Choi BH et al (2011) Sirt5 Is an NAD-dependent protein lysine demalonylase and desuccinylase. Science 334:806–809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elvehjem C, Madden R, Strong F, Woolley D (1937) Relation of nicotinic acid and nicotinic acid amide to canine black tongue. J Am Chem Soc 59:1767–1768

    Article  Google Scholar 

  • Escande C, Nin V, Price NL, Capellini V, Gomes AP, Barbosa MT, O’Neil L, White TA, Sinclair DA, Chini EN (2013) Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes 62:1084–1093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guarente L (2013) Calorie restriction and sirtuins revisited. Genes Dev 27:2072–2085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haigis MC, Sinclair DA (2010) Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol 5:253–295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, Valenzuela DM, Yancopoulos GD, Karow M, Blander G et al (2006) SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 126:941–954

    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. Carbon-nitrogen hydrolase domain confers glutamine dependency. J Biol Chem 278:10914–10921

    Article  CAS  PubMed  Google Scholar 

  • Houtkooper RH, Canto C, Wanders RJ, Auwerx J (2010) The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr Rev 31:194–223

    Article  CAS  PubMed  Google Scholar 

  • Houtkooper RH, Pirinen E, Auwerx J (2012) Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 13:225–238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL et al (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191–196

    Article  CAS  PubMed  Google Scholar 

  • Imai S, Armstrong CM, Kaeberlein M, Guarente L (2000) Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403:795–800

    Article  CAS  PubMed  Google Scholar 

  • Ivy JM, Klar AJ, Hicks JB (1986) Cloning and characterization of four SIR genes of Saccharomyces cerevisiae. Mol Cell Biol 6:688–702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jackson DG, Bell JI (1990) Isolation of a cDNA encoding the human CD38 (T10) molecule, a cell surface glycoprotein with an unusual discontinuous pattern of expression during lymphocyte differentiation. J Immunol 144:2811–2815

    CAS  PubMed  Google Scholar 

  • Jiang H, Khan S, Wang Y, Charron G, He B, Sebastian C, Du J, Kim R, Ge E, Mostoslavsky R et al (2013) SIRT6 regulates TNF-alpha secretion through hydrolysis of long-chain fatty acyl lysine. Nature 496:110–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaeberlein M, McVey M, Guarente L (1999) The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 13:2570–2580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khan NA, Auranen M, Paetau I, Pirinen E, Euro L, Forsstrom S, Pasila L, Velagapudi V, Carroll CJ, Auwerx J et al (2014) Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3. EMBO Mol Med 6:721–731

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P et al (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127:1109–1122

    Article  CAS  PubMed  Google Scholar 

  • Lee HC (2006) Structure and enzymatic functions of human CD38. Mol Med 12:317–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee HC (2012) Cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate (NAADP) as messengers for calcium mobilization. J Biol Chem 287:31633–31640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin SJ, Defossez PA, Guarente L (2000) Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289:2126–2128

    Article  CAS  PubMed  Google Scholar 

  • Lin SJ, Kaeberlein M, Andalis AA, Sturtz LA, Defossez PA, Culotta VC, Fink GR, Guarente L (2002) Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418:344–348

    Article  CAS  PubMed  Google Scholar 

  • Magni G, Amici A, Emanuelli M, Orsomando G, Raffaelli N, Ruggieri S (2004) Enzymology of NAD+ homeostasis in man. Cell Mol Life Sci 61:19–34

    Article  CAS  PubMed  Google Scholar 

  • Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, Vaisitti T, Aydin S (2008) Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev 88:841–886

    Article  CAS  PubMed  Google Scholar 

  • Menzies KJ, Zhang H, Katsyuba E, Auwerx J (2016) Protein acetylation in metabolism – metabolites and cofactors. Nat Rev Endocrinol 12:43–60

    Article  CAS  PubMed  Google Scholar 

  • Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D, Canto 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peng C, Lu Z, Xie Z, Cheng Z, Chen Y, Tan M, Luo H, Zhang Y, He W, Yang K et al (2011) The first identification of lysine malonylation substrates and its regulatory enzyme. Mol Cell Proteomics 10:M111.012658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pirinen E, Lo Sasso G, Auwerx J (2012) Mitochondrial sirtuins and metabolic homeostasis. Best Pract Res Clin Endocrinol Metab 26:759–770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pirinen E, Canto C, Jo YS, Morato L, Zhang H, Menzies KJ, Williams EG, Mouchiroud L, Moullan N, Hagberg C et al (2014) Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle. Cell Metab 19:1034–1041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rine J, Herskowitz I (1987) Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae. Genetics 116:9–22

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rogina B, Helfand SL (2004) Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci U S A 101:15998–16003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG (2010) PARP inhibition: PARP1 and beyond. Nat Rev Cancer 10:293–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan M, Peng C, Anderson KA, Chhoy P, Xie Z, Dai L, Park J, Chen Y, Huang H, Zhang Y et al (2014) Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab 19:605–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tissenbaum HA, Guarente L (2001) Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410:227–230

    Article  CAS  PubMed  Google Scholar 

  • van de Weijer T, Phielix E, Bilet L, Williams EG, Ropelle ER, Bierwagen A, Livingstone R, Nowotny P, Sparks LM, Paglialunga S et al (2015) Evidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans. Diabetes 64:1193–1201

    Article  CAS  PubMed  Google Scholar 

  • 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 14:528–536

    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 

  • Zhao YJ, Lam CM, Lee HC (2012) The membrane-bound enzyme CD38 exists in two opposing orientations. Sci Signal 5:ra67

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands

    Riekelt H. Houtkooper

Authors
  1. Riekelt H. Houtkooper
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Riekelt H. Houtkooper .

Editor information

Editors and Affiliations

  1. Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands

    Riekelt H. Houtkooper

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Houtkooper, R.H. (2016). NAD+ as a Pharmacological Tool to Boost Sirtuin Activity. In: Houtkooper, R. (eds) Sirtuins. Proteins and Cell Regulation, vol 10. Springer, Dordrecht. https://doi.org/10.1007/978-94-024-0962-8_2

Download citation

Publish with us

Policies and ethics

Search

Navigation