Nicotinamide Riboside: From Discovery to Human Translation
Molecules related to nicotinamide adenine dinucleotide (NAD) are the central mediators of essentially all metabolic processes including converting fuels to energy, generating and repairing DNA, producing lipids and steroid hormones, and regulating the expression and activity of genes and proteins. Despite our body’s best attempts to maintain homeostasis of NAD and related co-enzymes, these molecules are under attack in conditions of metabolic stress including diabesity, alcoholism, DNA damage, free radical stress, time zone disruption, heart failure and neurodegeneration. The most extreme form of NAD deficiency, pellagra, can be prevented by 15 mg/day of either of two B3 vitamins discovered in 1938. In 2004, we discovered nicotinamide riboside (NR) as an unanticipated vitamin precursor of NAD in the course of testing the wiring diagram of NAD synthesis in yeast. We went on to identify and characterize several new genes, enzymes, metabolites and transporters involved in NAD homeostasis and developed quantitative targeted NAD metabolomics to characterize regulation and dysregulation of the NAD system in health and disease. We and our collaborators have used these two orthogonal tools: targeted NAD metabolomics and targeted NAD transcriptomics to discover that genes and metabolites in the NAD system are dysregulated in obesity, diabetic and chemotherapeutic neuropathy, heart failure and central brain injury. In addition, we have shown that provision of oral NR is protective in rodent models each of these conditions by virtue of sustained and stress-induced expression of the NR kinase genes. In parallel, we have served as the adviser for NR commercialization, which required intellectual property protection, a clean scalable synthesis, toxicology, review by the US Food & Drug Administration and its international equivalents, and early stage clinical testing. These trans-disciplinary activities collectively enabled further clinical testing, development and investment in discovery science.
Our current research interests in NAD involve a genotype-specific cancer strategy, the mechanism and development of NR-based neuroprotection, and characterization of the maternal and neonatal effects of NR. Our main developmental interest is in miniaturizing targeted NAD metabolome diagnostics for more widespread applications to human health.
P. Bieganowski & C. Brenner, "Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD+ in Fungi and Humans," Cell, v. 117, pp. 495-502 (2004). Download pdf reprint.
P. Belenky, F.G. Racette, K.L. Bogan, J.M. McClure, J.S. Smith & C. Brenner, "Nicotinamide Riboside Promotes Sir2 Silencing and Extends Lifespan via Nrk and Urh1/Pnp1/Meu1 Pathways to NAD+," Cell, v. 129, pp. 473-484 (2007). Download pdf reprint and supplementary data. Read Leading Edge Preview in Cell, Research Highlights in Nature and Spotlight in ACS Chemical Biology.
F. Syeda, R.L. Fagan, M. Wean, G.V. Awakumov, J.R. Walker, S. Xue, S. Dhe-Paganon & C. Brenner, "The RFTS Domain is a DNA-Competitive Ingibitor of Dnmt1," JBC, v. 286, pp. 15344-15351 ( 2011). Download pdf reprint
S.A.J. Trammell & C. Brenner, "Targeted, LCMC-Based Metabolomics for Quantitative Measurement of NAD+ Metabolites," Computational and Structural Biotechnology Journal, v. 4, e201301012 (2013). DOI: 10.5936/csbj.201301012. Download pdf reprint
B.-K. Wu & C. Brenner, “Suppression of TET1-Dependent DNA Demethylation is Essential for KRAS-Mediated Transformation,” Cell Reports, v. 9, pp. 1827-1840 (2014). DOI:10.1016/j.celrep.2014.10.063. Download pdf reprint
S.A.J. Trammell, B.J.Weidemann, A.Chadda, M.S. Yorek, A. Holmes, L.J.Coppey, A. Obrosov, R.H. Kardon, M.A. Yorek & C. Brenner, “Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice,” Scientific Reports, v. 6, 26933 (2016). DOI: 10.1038/srep26933. Download pdf reprint
S.A.J Trammell, M.S. Schmidt, B.J. Weidemann, P. Redpath, F. Jaksch, R.W. Dellinger, Z. Li, E.D. Abel, M.E. Migaud & C. Brenner, "Nicotinamide riboside is uniquely and orally bioavailable in mice and humans." Nat Commun. v. 7, pp. 12948 (2016). DOI: 10.1038/ncomms12948. Download pdf reprint
J. Ratajczak, M. Joffraud, S.A.J. Trammell, R. Ras, N. Canela, M. Boutant, S.S. Kulkarni, M. Rodrigues, P. Redpath, M.E. Migaud, J. Auwerx, O. Yanes, C. Brenner & C. Canto, "NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells." Nat Commun. v. 7, pp. 13103 (2016). DOI: 10.1038/ncomms13103. Download pdf reprint.
M.V. Hamity, S.R. White, R.Y. Walder, M.S. Schmidt, C. Brenner & D.L. Hammond, “Nicotinamide Riboside, a Form of Vitamin B3 and NAD+ Precursor, Relieves the Nociceptive and Aversive Dimensions of Paclitaxel-induced Peripheral Neuropathy in Female Rats,” Pain, v. 158, pp. 962–972 (2017). DOI:10.1097/j.pain.0000000000000862. Download PDF reprint.
N. Diguet, S.A.J. Trammell, C. Tannous, R. Deloux, J. Piquereau, N. Mougenot, A. Gouge, M. Gressette, B. Manoury, J. Blanc, M. Breton, J.F. Decaux, G. Lavery, I. Baczkó, J. Zoll, A. Garnier, Z. Li, C. Brenner, M. Mericskay, "Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy," Circulation, v. 137 (6), in press (2018). DOI: 10.1161/CIRCULATIONAHA.116.026099. Download PDF reprint
H.W. Liu, C.B. Smith, M.S. Schmidt, X.A. Cambronne, M.S. Cohen, M.E. Migaud, C. Brenner & R.H. Goodman, "Pharmacological bypass of NAD+ salvage pathway protects neurons from chemotherapy-induced degeneration," Proc Natl Acad Sci U S A. v.115 (42), pp.10654-10659 (2018). DOI: 10.1073/pnas.1809392115. Download PDF reprint
P. H. Ear, A. Chadda, S. B. Gumusoglu, M. S. Schmidt, S. Vogeler, J. Malicoat, J. Kadel, M. M. Moore, M. E. Migaud, H. E. Stevens & C. Brenner, "Maternal Nicotinamide Riboside Enhances Postpartum Weight Loss, Juvenile Offspring Development, and Neurogenesis of Adult Offspring," Cell Reports. v. 26 (4), pp. 969-983 (2019). DOI: 10.1016/j.celrep.2019.01.007. Download PDFreprint
Conze, D., Brenner, C. & Kruger, C.L, "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," Scientific Reports, v. 9, 9772 in press, 2019. Download PDF reprint