Nicotinamide riboside is uniquely and orally bioavailable in mice and humans

Samuel A. J. Trammell; Mark S. Schmidt; Benjamin J. Weidemann; Philip Redpath; Frank Jaksch; Ryan W. Dellinger; Zhonggang LI; E. Dale Abel; Marie E. Migaud; Charles Brenner

doi:10.1038/ncomms12948

journal article Open Access Oct 10, 2016

Nicotinamide riboside is uniquely and orally bioavailable in mice and humans

Samuel A. J. Trammell Mark S. Schmidt

Benjamin J. Weidemann Philip Redpath Frank Jaksch Ryan W. Dellinger Zhonggang LI E. Dale Abel

Marie E. Migaud

Charles Brenner

Nature Communications Vol. 7 No. 1 · Springer Science and Business Media LLC

View at Publisher Save 10.1038/ncomms12948

Abstract

Abstract

Nicotinamide riboside (NR) is in wide use as an NAD
+
precursor vitamin. Here we determine the time and dose-dependent effects of NR on blood NAD
+
metabolism in humans. We report that human blood NAD
+
can rise as much as 2.7-fold with a single oral dose of NR in a pilot study of one individual, and that oral NR elevates mouse hepatic NAD
+
with distinct and superior pharmacokinetics to those of nicotinic acid and nicotinamide. We further show that single doses of 100, 300 and 1,000 mg of NR produce dose-dependent increases in the blood NAD
+
metabolome in the first clinical trial of NR pharmacokinetics in humans. We also report that nicotinic acid adenine dinucleotide (NAAD), which was not thought to be en route for the conversion of NR to NAD
+
, is formed from NR and discover that the rise in NAAD is a highly sensitive biomarker of effective NAD
+
repletion.

Topics

No keywords indexed for this article. Browse by subject →

References

57

[1]

NAD+ metabolism in health and disease

Peter Belenky, Katrina L. Bogan, Charles Brenner

Trends in Biochemical Sciences 2007 10.1016/j.tibs.2006.11.006

[2]

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). 10.1146/annurev.nutr.28.061807.155443

[3]

Bouchard, V. J., Rouleau, M. & Poirier, G. G. PARP-1, a determinant of cell survival in response to DNA damage. Exp. Hematol. 31, 446–454 (2003). 10.1016/s0301-472x(03)00083-3

[4]

Finkel, T., Deng, C. X. & Mostoslavsky, R. Recent progress in the biology and physiology of sirtuins. Nature 460, 587–591 (2009). 10.1038/nature08197

[5]

Okamoto, H., Takawasa, S. & Sugawara, A. The CD38-cyclic ADP-ribose system in mammals: historical background, pathophysiology and perspective. Messenger 3, 27–24 (2014). 10.1166/msr.2014.1032

[6]

Bieganowski, P. & Brenner, C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans. Cell 117, 495–502 (2004). 10.1016/s0092-8674(04)00416-7

[7]

Nicotinamide Riboside Is a Major NAD+ Precursor Vitamin in Cow Milk

Samuel AJ Trammell, Liping Yu, Philip Redpath et al.

The Journal of Nutrition 2016 10.3945/jn.116.230078

[8]

Evans, C. et al. NAD+ metabolite levels as a function of vitamins and calorie restriction: evidence for different mechanisms of longevity. BMC Chem. Biol. 10, 2 (2010). 10.1186/1472-6769-10-2

[9]

Trammell, S. A. & Brenner, C. Targeted, LCMS-based metabolomics for quantitative measurement of NAD metabolites. Comput. Struct. Biotechnol. J. 4, e201301012 (2013). 10.5936/csbj.201301012

[10]

Gazzaniga, F., Stebbins, R., Chang, S. Z., McPeek, M. A. & Brenner, C. Microbial NAD metabolism: lessons from comparative genomics. Microbiol. Mol. Biol. Rev. 73, 529–541 (2009). 10.1128/mmbr.00042-08

[11]

Elvehjem, C. A., Madden, R. J., Strong, F. M. & Woolley, D. W. The isolation and identification of the anti-black tongue factor. J. Biol. Chem. 123, 137–149 (1938). 10.1016/s0021-9258(18)74164-1

[12]

Koehn, C. J. & Elvehjem, C. A. Further studies on the concentration of the antipellagra factor. J. Biol. Chem. 118, 693–699 (1937). 10.1016/s0021-9258(18)74475-x

[13]

Conze, D. B., Crespo-Barreto, J. & Kruger, C. L. Safety assessment of nicotinamide riboside, a form of vitamin B3. Hum. Exp. Toxicol. doi:10.1177/0960327115626254 (2016). 10.1177/0960327115626254

[14]

Zamporlini, F. et al. Novel assay for simultaneous measurement of pyridine mononucleotides synthesizing activities allows dissection of the NAD(+) biosynthetic machinery in mammalian cells. FEBS J. 281, 5104–5119 (2014). 10.1111/febs.13050

[15]

Mori, V. et al. Metabolic profiling of alternative NAD biosynthetic routes in mouse tissues. PLoS ONE 9, e113939 (2014). 10.1371/journal.pone.0113939

[16]

Brenner, C. Metabolism: targeting a fat-accumulation gene. Nature 508, 194–195 (2014). 10.1038/508194a

[17]

Ramsey, K. M. et al. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science 324, 651–654 (2009). 10.1126/science.1171641

[18]

Nakahata, Y., Sahar, S., Astarita, G., Kaluzova, M. & Sassone-Corsi, P. Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science 324, 654–657 (2009). 10.1126/science.1170803

[19]

Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in Mice

Jun Yoshino, Kathryn F. Mills, Myeong Jin Yoon et al.

Cell Metabolism 2011 10.1016/j.cmet.2011.08.014

[20]

Gomes, A. P. et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624–1638 (2013). 10.1016/j.cell.2013.11.037

[21]

Braidy, N. et al. Mapping NAD(+) metabolism in the brain of ageing Wistar rats: potential targets for influencing brain senescence. Biogerontology 15, 177–198 (2014). 10.1007/s10522-013-9489-5

[22]

Verdin, E. NAD+ in aging, metabolism, and neurodegeneration. Science 350, 1208–1213 (2105). 10.1126/science.aac4854

[23]

DiPalma, J. R. & Thayer, W. S. Use of niacin as a drug. Annu. Rev. Nutr. 11, 169–187 (1991). 10.1146/annurev.nu.11.070191.001125

[24]

Kuvin, J. T. et al. Effects of extended-release niacin on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease. Am. J. Cardiol. 98, 743–745 (2006). 10.1016/j.amjcard.2006.04.011

[25]

Bitterman, K. J., Anderson, R. M., Cohen, H. Y., Latorre-Esteves, M. & Sinclair, D. A. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast Sir2 and human SIRT1. J. Biol. Chem. 277, 45099–45107 (2002). 10.1074/jbc.m205670200

[26]

Belenky, P. et al. Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD(+). Cell 129, 473–484 (2007). 10.1016/j.cell.2007.03.024

[27]

The NAD+ Precursor Nicotinamide Riboside Enhances Oxidative Metabolism and Protects against High-Fat Diet-Induced Obesity

Carles Cantó, Riekelt H. Houtkooper, Eija Pirinen et al.

Cell Metabolism 2012 10.1016/j.cmet.2012.04.022

[28]

Brown, K. D. et al. Activation of SIRT3 by the NAD+ precursor nicotinamide riboside protects from noise-induced hearing loss. Cell Metab. 20, 1059–1068 (2014). 10.1016/j.cmet.2014.11.003

[29]

Zhang, H. et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352, 1436–1443 (2016). 10.1126/science.aaf2693

[30]

Trammell, S. A. J. et al. Nicotinamide riboside opposes Type 2 diabetes and neuropathy in mice. Sci. Rep. 6, 26933 (2016). 10.1038/srep26933

[31]

Pathways and Subcellular Compartmentation of NAD Biosynthesis in Human Cells

Andrey Nikiforov, Christian Dölle, Marc Niere et al.

Journal of Biological Chemistry 2011 10.1074/jbc.m110.213298

[32]

Brenner, C. Boosting NAD to spare hearing. Cell Metab. 20, 926–927 (2014). 10.1016/j.cmet.2014.11.015

[33]

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). 10.1016/j.cmet.2015.05.023

[34]

Belenky, P., Christensen, K. C., Gazzaniga, F. S., Pletnev, 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). 10.1074/jbc.m807976200

[35]

Bieganowski, P., Pace, H. C. & Brenner, C. Eukaryotic NAD+ synthetase Qns1 contains an essential, obligate intramolecular thiol glutamine amidotransferase domain related to nitrilase. J. Biol. Chem. 278, 33049–33055 (2003). 10.1074/jbc.m302257200

[36]

Wojcik, M., Seidle, H. F., Bieganowski, P. & Brenner, C. Glutamine-dependent NAD+ synthetase: how a two-domain, three-substrate enzyme avoids waste. J. Biol. Chem. 281, 33395–33402 (2006). 10.1074/jbc.m607111200

[37]

Langan, T. A. Jr, Kaplan, N. O. & Shuster, L. Formation of the nicotinic acid analogue of diphosphopyridine nucleotide after nicotinamide administration. J. Biol. Chem. 234, 2161–2168 (1959). 10.1016/s0021-9258(18)69885-0

[38]

Collins, P. B. & Chaykin, S. The management of nicotinamide and nicotinic acid in the mouse. J. Biol. Chem. 247, 778–783 (1972). 10.1016/s0021-9258(19)45675-5

[39]

Grunicke, H., Keller, H. J., Liersch, M. & Benaguid, A. New aspects of the mechanism and regulation of pyridine nucleotide metabolism. Adv. Enzyme. Regul. 12, 397–418 (1974). 10.1016/0065-2571(74)90024-7

[40]

Dose translation from animal to human studies revisited

Shannon Reagan‐Shaw, Minakshi Nihal, Nihal Ahmad

The FASEB Journal 2008 10.1096/fj.07-9574lsf

[41]

Tempel, W. et al. Nicotinamide riboside kinase structures reveal new pathways to NAD+. PLoS Biol. 5, e263 (2007). 10.1371/journal.pbio.0050263

[42]

Hong, S. et al. Nicotinamide N-methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization. Nat. Med. 21, 887–894 (2015). 10.1038/nm.3882

[43]

Trammell, S. A. & Brenner, C. NNMT: a bad actor in fat makes good in liver. Cell Metab. 22, 200–201 (2015). 10.1016/j.cmet.2015.07.017

[44]

Altschul, R., Hoffer, A. & Stephen, J. D. Influence of nicotinic acid on cholesterol in man. Arch. Biochem. Biophys. 54, 558–559 (1955). 10.1016/0003-9861(55)90070-9

[45]

Imai, S. & Guarente, L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 24, 464–471 (2014). 10.1016/j.tcb.2014.04.002

[46]

Mills, E. et al. The safety of over-the-counter niacin. A randomized placebo-controlled trial [ISRCTN18054903]. BMC Clin. Pharmacol. 3, 4 (2003). 10.1186/1472-6904-3-4

[47]

Norquist, J. M. et al. Validation of a questionnaire to assess niacin-induced cutaneous flushing. Curr. Med. Res. Opin. 23, 1549–1560 (2007). 10.1185/030079907x199637

[48]

Ratajczak, J. et al. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat. Commun. 7, 13103 doi: 10.1038/ncomms13103 (2016). 10.1038/ncomms13103

[49]

Preiss, J. & Handler, P. Biosynthesis of diphosphopyridine nucleotide II. Enzymatic aspects. J. Biol. Chem. 233, 493–500 (1958). 10.1016/s0021-9258(18)64790-8

[50]

Guse, A. H. Calcium mobilizing second messengers derived from NAD. Biochim. Biophys. Acta. 1854, 1132–1137 (2015). 10.1016/j.bbapap.2014.12.015

Showing 50 of 57 references

Cited By

651

Effect of nicotinamide riboside on airway inflammation in COPD: a randomized, placebo-controlled trial

Kristoffer L. Norheim, Michael Ben Ezra · 2024

Nature Aging

Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men

Masaki Igarashi, Yoshiko Nakagawa-Nagahama · 2022

npj Aging

The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease

Brage Brakedal, Christian Dölle · 2022

Cell Metabolism

Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans

Carlijn ME Remie, Kay HM Roumans · 2020

The American Journal of Clinical Nu...

Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults

Dietrich Conze, Charles Brenner · 2019

Scientific Reports

A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects

Ole L Dollerup, Britt Christensen · 2018

The American Journal of Clinical Nu...

NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR

Jun Yoshino, Joseph A. Baur · 2018

Cell Metabolism

Metrics

651

Citations

57

References

Details

Published: Oct 10, 2016
Vol/Issue: 7(1)
License: View

Authors

S

Samuel A. J. Trammell

M

Mark S. Schmidt

B

Benjamin J. Weidemann

Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Ave, Mobile 36604, AL, U.S.A.

C

Charles Brenner

Cite This Article

Samuel A. J. Trammell, Mark S. Schmidt, Benjamin J. Weidemann, et al. (2016). Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nature Communications, 7(1). https://doi.org/10.1038/ncomms12948

Nicotinamide riboside is uniquely and orally bioavailable in mice and humans

You May Also Like