Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study

Ryan W Dellinger, Santiago Roel Santos, Mark Morris, Mal Evans, Dan Alminana, Leonard Guarente, Eric Marcotulli, Ryan W Dellinger, Santiago Roel Santos, Mark Morris, Mal Evans, Dan Alminana, Leonard Guarente, Eric Marcotulli

Abstract

NRPT is a combination of nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD+) precursor vitamin found in milk, and pterostilbene (PT), a polyphenol found in blueberries. Here, we report this first-in-humans clinical trial designed to assess the safety and efficacy of a repeat dose of NRPT (commercially known as Basis). NRPT was evaluated in a randomized, double-blind, and placebo-controlled study in a population of 120 healthy adults between the ages of 60 and 80 years. The study consisted of three treatment arms: placebo, recommended dose of NRPT (NRPT 1X), and double dose of NRPT (NRPT 2X). All subjects took their blinded supplement daily for eight weeks. Analysis of NAD+ in whole blood demonstrated that NRPT significantly increases the concentration of NAD+ in a dose-dependent manner. NAD+ levels increased by approximately 40% in the NRPT 1X group and approximately 90% in the NRPT 2X group after 4 weeks as compared to placebo and baseline. Furthermore, this significant increase in NAD+ levels was sustained throughout the entire 8-week trial. NAD+ levels did not increase for the placebo group during the trial. No serious adverse events were reported in this study. This study shows that a repeat dose of NRPT is a safe and effective way to increase NAD+ levels sustainably.

Conflict of interest statement

NRPT (commercially known as Basis) is a supplement marketed by Elysium Health, which funded the trial. To avoid any bias in the collection of the trial data, the trial itself was conducted independently by KGK Synergize, a CRO based in London, Ontario. R.W.D., S.R.S., M.M., D.A., L.G., and E.M. are all employees of Elysium Health and all own shares in the company.

Figures

Fig. 1
Fig. 1
Clinical trial diagrams. a Clinical Trial Design diagram. Schematic depicting the randomized, double-blind, placebo controlled, three-arm parallel group study. The study consisted of a single eight-week study period. Clinic visits occurred at day 0 (baseline), day 30, and day 60. Subjects were asked to fast 12 h prior to each clinic visit. Each clinic visit consisted of a physical exam including as well as blood draws to evaluate safety and efficacy endpoints of the trial. b Clinical Trial Flow Diagram. Schematic depicting recruitment and disposition of study participants. A total of 159 potential subjects were screened to successfully enroll 120 eligible subjects and randomize them 1:1:1 to the three arms. One-hundred fifteen subjects completed the 60-day study
Fig. 2
Fig. 2
NRPT increases NAD+ levels. Total NAD+ levels were measured in whole blood from all subjects at day 0 (baseline), day 30, and day 60. Graph depicts change from baseline NAD+ concentration (μg/ml) for Placebo (blue diamonds), NRPT 1X (red squares) and NRPT 2X (green triangles). Data shown is the mean ± standard deviation of the mean for each time point

References

    1. Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000;403:795–800. doi: 10.1038/35001622.
    1. Bonkowski MS, Sinclair DA. Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat. Rev. Mol. Cell. Biol. 2016;17:679–690. doi: 10.1038/nrm.2016.93.
    1. Guarente L. Calorie restriction and sirtuins revisited. Genes Dev. 2013;27:2072–2085. doi: 10.1101/gad.227439.113.
    1. Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trend. Cell Biol. 2014;24:464–471. doi: 10.1016/j.tcb.2014.04.002.
    1. Chang HC, Guarente L. SIRT1 and other sirtuins in metabolism. Trend. Endocrinol. Metab. 2014;25:138–145. doi: 10.1016/j.tem.2013.12.001.
    1. 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. 2004;117:495–502. doi: 10.1016/S0092-8674(04)00416-7.
    1. Trammell SA, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat. Commun. 2016;7:12948. doi: 10.1038/ncomms12948.
    1. Ramsey KM, Mills KF, Satoh A, Imai S. Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cell-specific Sirt1-overexpressing (BESTO) mice. Aging Cell. 2008;7:78–88. doi: 10.1111/j.1474-9726.2007.00355.x.
    1. Mouchiroud L, Houtkooper RH, Auwerx J. NAD(+) metabolism: a therapeutic target for age-related metabolic disease. Crit. Rev. Biochem. Mol. Biol. 2013;48:397–408. doi: 10.3109/10409238.2013.789479.
    1. Massudi H, et al. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS ONE. 2012;7:e42357. doi: 10.1371/journal.pone.0042357.
    1. Zhu XH, Lu M, Lee BY, Ugurbil K, Chen W. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proc. Natl Acad. Sci. USA. 2015;112:2876–2881. doi: 10.1073/pnas.1417921112.
    1. Canto C, Menzies KJ, Auwerx J. NAD(+) Metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab. 2015;22:31–53. doi: 10.1016/j.cmet.2015.05.023.
    1. Gomes AP, et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013;155:1624–1638. doi: 10.1016/j.cell.2013.11.037.
    1. Zhang H, et al. NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016;352:1436–1443. doi: 10.1126/science.aaf2693.
    1. Fang EF, et al. NAD+ replenishment improves lifespan and healthspan in Ataxia Telangiectasia models via mitophagy and DNA repair. Cell Metab. 2016;24:566–581. doi: 10.1016/j.cmet.2016.09.004.
    1. Scheibye-Knudsen M, et al. A high-fat diet and NAD(+) activate Sirt1 to rescue premature aging in cockayne syndrome. Cell Metab. 2014;20:840–855. doi: 10.1016/j.cmet.2014.10.005.
    1. Canto C, et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012;15:838–847. doi: 10.1016/j.cmet.2012.04.022.
    1. Yoshino J, Mills KF, Yoon MJ, Imai S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011;14:528–536. doi: 10.1016/j.cmet.2011.08.014.
    1. Frederick DW, et al. Loss of NAD homeostasis leads to progressive and reversible degeneration of skeletal muscle. Cell Metab. 2016;24:269–282. doi: 10.1016/j.cmet.2016.07.005.
    1. Cheng, Y. et al. SIRT1 activation by pterostilbene attenuates the skeletal muscle oxidative stress injury and mitochondrial dysfunction induced by ischemia reperfusion injury. Apoptosis 21, 905–916 (2016).
    1. Neves AR, Lucio M, Lima JL, Reis S. Resveratrol in medicinal chemistry: a critical review of its pharmacokinetics, drug-delivery, and membrane interactions. Curr. Med. Chem. 2012;19:1663–1681. doi: 10.2174/092986712799945085.
    1. McCormack D, McFadden D. A review of pterostilbene antioxidant activity and disease modification. Oxid. Med. Cell Longev. 2013;2013:575482. doi: 10.1155/2013/575482.
    1. Kapetanovic IM, Muzzio M, Huang Z, Thompson TN, McCormick DL. Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemother. Pharmacol. 2011;68:593–601. doi: 10.1007/s00280-010-1525-4.
    1. Dellinger RW, Garcia AM, Meyskens FL., Jr. Differences in the glucuronidation of resveratrol and pterostilbene: altered enzyme specificity and potential gender differences. Drug Metab. Pharmacokinet. 2014;29:112–119. doi: 10.2133/dmpk.DMPK-13-RG-012.
    1. Riche DM, et al. Analysis of safety from a human clinical trial with pterostilbene. J. Toxicol. 2013;2013:463595. doi: 10.1155/2013/463595.
    1. Guarente L. Sir2 links chromatin silencing, metabolism, and aging. Genes Dev. 2000;14:1021–1026.
    1. Guarente L, Franklin H. Epstein lecture: sirtuins, aging, and medicine. N. Engl. J. Med. 2011;364:2235–2244. doi: 10.1056/NEJMra1100831.
    1. Conze, D.B., Crespo-Barreto, J. & Kruger, C.L. Safety assessment of nicotinamide riboside, a form of vitamin B3. Hum. Exp. Toxicol.35, 1149–1160 (2016).
    1. Riche DM, et al. Pterostilbene on metabolic parameters: a randomized, double-blind, and placebo-controlled trial. Evid. Based Complement Alternat. Med. 2014;2014:459165. doi: 10.1155/2014/459165.
    1. Marcovina SM, Gaur VP, Albers JJ. Biological variability of cholesterol, triglyceride, low- and high-density lipoprotein cholesterol, lipoprotein(a), and apolipoproteins A-I and B. Clin. Chem. 1994;40:574–578.
    1. Raatz SK, Johnson LK, Rosenberger TA, Picklo MJ. Twice weekly intake of farmed Atlantic salmon (Salmo salar) positively influences lipoprotein concentration and particle size in overweight men and women. Nutr. Res. 2016;36:899–906. doi: 10.1016/j.nutres.2016.06.011.
    1. Backes J, Anzalone D, Hilleman D, Catini J. The clinical relevance of omega-3 fatty acids in the management of hypertriglyceridemia. Lipids Health Dis. 2016;15:118. doi: 10.1186/s12944-016-0286-4.
    1. Mukherjee S, et al. Nicotinamide adenine dinucleotide biosynthesis promotes liver regeneration. Hepatology. 2016;65:616–630. doi: 10.1002/hep.28912.
    1. Gariani K, et al. Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology. 2016;63:1190–1204. doi: 10.1002/hep.28245.

Source: PubMed

3
Abonneren