Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults

Christopher R Martens, Blair A Denman, Melissa R Mazzo, Michael L Armstrong, Nichole Reisdorph, Matthew B McQueen, Michel Chonchol, Douglas R Seals, Christopher R Martens, Blair A Denman, Melissa R Mazzo, Michael L Armstrong, Nichole Reisdorph, Matthew B McQueen, Michel Chonchol, Douglas R Seals

Abstract

Nicotinamide adenine dinucleotide (NAD+) has emerged as a critical co-substrate for enzymes involved in the beneficial effects of regular calorie restriction on healthspan. As such, the use of NAD+ precursors to augment NAD+ bioavailability has been proposed as a strategy for improving cardiovascular and other physiological functions with aging in humans. Here we provide the evidence in a 2 × 6-week randomized, double-blind, placebo-controlled, crossover clinical trial that chronic supplementation with the NAD+ precursor vitamin, nicotinamide riboside (NR), is well tolerated and effectively stimulates NAD+ metabolism in healthy middle-aged and older adults. Our results also provide initial insight into the effects of chronic NR supplementation on physiological function in humans, and suggest that, in particular, future clinical trials should further assess the potential benefits of NR for reducing blood pressure and arterial stiffness in this group.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Study flow diagram
Fig. 2
Fig. 2
NAD+ metabolome. NAD+and related metabolite concentrations in peripheral blood mononuclear cells increased after oral placebo vs. NR supplementation normalized to total protein content. Data are mean ± SD. * indicates unadjusted P < 0.05 by one-tailed paired t-test. N = 21 (Group A = 11; Group B = 10)
Fig. 3
Fig. 3
Blood pressure. Effect of 6 weeks of oral placebo vs. NR supplementation on a systolic (SBP) and b diastolic (DBP) blood pressure, and c pulse pressure (PP) in healthy middle-aged and older adults as a whole N = 24 (Group A = 12; Group B = 12), and overall change from placebo in blood pressure parameters (d−f) in subjects with normal (N = 11) vs. above normal (N = 13) baseline BP. Data are mean ± SD. P-values reported in individual bars based on a one-tailed paired t-test (panels a−c only) and an adjusted alpha level set at 0.006
Fig. 4
Fig. 4
Arterial function. Effect of 6 weeks of oral placebo vs. NR supplementation on a aortic pulse wave velocity (PWV) as a whole (N = 24; 12 per group), b subgroups of individuals with normal (N = 11) vs. above-normal (N = 13) baseline BP); c carotid artery compliance (CC) and d brachial artery flow-mediated dilation (FMD) in the overall groups (N = 24; 12 per group). Data are mean ± SD. P-values reported in individual bars based on one-tailed paired t-test (panels a, c, and d only) and an adjusted alpha level set at 0.006

References

    1. Mozaffarian D, et al. Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation. 2016;133:E38–E360. doi: 10.1161/CIR.0000000000000350.
    1. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises Part I: aging arteries: a “set up” for vascular disease. Circulation. 2003;107:139–146. doi: 10.1161/01.CIR.0000048892.83521.58.
    1. Donato AJ, et al. Life-long caloric restriction reduces oxidative stress and preserves nitric oxide bioavailability and function in arteries of old mice. Aging Cell. 2013;12:772–783. doi: 10.1111/acel.12103.
    1. Young JB, FAU - Mullen D, Mullen D, FAU - Landsberg L, Landsberg L. Caloric restriction lowers blood pressure in the spontaneously hypertensive rat. Metabolism. 1978;27:1711–1714. doi: 10.1016/0026-0495(78)90256-1.
    1. Pierce GL, et al. Weight loss alone improves conduit and resistance artery endothelial function in young and older overweight/obese adults. Hypertension. 2008;52:72–79. doi: 10.1161/HYPERTENSIONAHA.108.111427.
    1. Dengo AL, et al. Arterial destiffening with weight loss in overweight and obese middle-aged and older adults. Hypertension. 2010;55:855–861. doi: 10.1161/HYPERTENSIONAHA.109.147850.
    1. King DE, Mainous AG, III, Carnemolla M, Everett CJ. Adherence to healthy lifestyle habits in US adults, 1988−2006. Am. J. Med. 2009;122:528–534. doi: 10.1016/j.amjmed.2008.11.013.
    1. Villareal DT, et al. Effect of two-year caloric restriction on bone metabolism and bone mineral density in non-obese younger adults: a randomized clinical trial. J. Bone Miner. Res. 2016;31:40–51. doi: 10.1002/jbmr.2701.
    1. Miller SL, Wolfe RR. The danger of weight loss in the elderly. J. Nutr. Health Aging. 2008;12:487–491. doi: 10.1007/BF02982710.
    1. Martens CR, Deals DR. Practical alternatives to chronic caloric restriction for optimizing vascular function with aging. J. Physiol. 2016;594:7177–7195. doi: 10.1113/JP272348.
    1. Chung KW, et al. Recent advances in calorie restriction research on aging. Exp. Gerontol. 2013;48:1049–1053. doi: 10.1016/j.exger.2012.11.007.
    1. Ingram DK, et al. Calorie restriction mimetics: an emerging research field. Aging Cell. 2006;5:97–108. doi: 10.1111/j.1474-9726.2006.00202.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. Lin S, Defossez P, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. 2000;289:2126–2128. doi: 10.1126/science.289.5487.2126.
    1. Donato AJ, et al. SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans. J. Physiol. 2011;589:4545–4554. doi: 10.1113/jphysiol.2011.211219.
    1. Chen D, et al. Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev. 2008;22:1753–1757. doi: 10.1101/gad.1650608.
    1. Canto C, et al. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab. 2010;11:213–219. doi: 10.1016/j.cmet.2010.02.006.
    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. 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. 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. Zhu X, Lu M, Lee B, 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. Bogan KL, Brenner C. Nicotinic acid nicotinamide and nicotinamide riboside: a molecular evaluation of NAD(+) precursor vitamins in human nutrition. Annu. Rev. Nutr. 2008;28:115–130. doi: 10.1146/annurev.nutr.28.061807.155443.
    1. MacKay D, Hathcock J, Guarneri E. Niacin: chemical forms, bioavailability, and health effects. Nutr. Rev. 2012;70:357–366. doi: 10.1111/j.1753-4887.2012.00479.x.
    1. Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, Sinclair DA. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast Sir2 and human SIRT1. J. Biol. Chem. 2002;277:45099–45107. doi: 10.1074/jbc.M205670200.
    1. Guan, X., Lin, P., Chakrabarti, R. & Knoll, E. Mechanism of inhibition of the human sirtuin enzyme SIRT3 by nicotinamide: computational and experimental studies. PLoS One.9, e107729 (2014).
    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. Mills KF, et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 2016;24:795–806. doi: 10.1016/j.cmet.2016.09.013.
    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. de Picciotto NE, et al. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell. 2016;15:522–530. doi: 10.1111/acel.12461.
    1. Sato S, et al. Circadian reprogramming in the liver identifies metabolic pathways of aging. Cell. 2017;170:664–66. doi: 10.1016/j.cell.2017.07.042.
    1. Chi Y, Sauve AA. Nicotinamide riboside, a trace nutrient in foods, is a Vitamin B3 with effects on energy metabolism and neuroprotection. Curr. Opin. Clin. Nutr. Metab. Care. 2013;16:657–661. doi: 10.1097/MCO.0b013e32836510c0.
    1. Imai S. A possibility of nutriceuticals as an anti-aging intervention: Activation of sirtuins by promoting mammalian NAD biosynthesis. Pharmacol. Res. 2010;62:42–47. doi: 10.1016/j.phrs.2010.01.006.
    1. Ratajczak J, et al. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat. Commun. 2016;7:13103. doi: 10.1038/ncomms13103.
    1. Trammell SA, Brenner C. Targeted, LCMS-based metabolomics for quantitative measurement of NAD+ metabolites. Comput. Struct. Biotechnol. J. 2013;4:e201301012. doi: 10.5936/csbj.201301012.
    1. Houtkooper RH, Canto C, Wanders RJ, Auwerx J. The secret life of NAD(+): an old metabolite controlling new metabolic signaling pathways. Endocr. Rev. 2010;31:194–223. doi: 10.1210/er.2009-0026.
    1. Chobanian A, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure—the JNC 7 report. JAMA—J. Am. Med. Assoc. 2003;289:2560–2572. doi: 10.1001/jama.289.19.2560.
    1. Whelton, P. K. et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Am. Coll. Cardiol.10.1016/j.jacc.2017.11.005 (2017).
    1. Laurent S, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur. Heart J. 2006;27:2588–2605. doi: 10.1093/eurheartj/ehl254.
    1. Tunaru S, Lattig J, Kero J, Krause G, Offermanns S. Characterization of determinants of ligand binding to the nicotinic acid receptor GPR109A (HM74A/PUMA-G) Mol. Pharmacol. 2005;68:1271–1280. doi: 10.1124/mol.105.015750.
    1. Benyo Z, Gille A, Bennett CL, Clausen BE, Offermanns S. Nicotinic acid-induced flushing is mediated by activation of epidermal langerhans cells. Mol. Pharmacol. 2006;70:1844–1849. doi: 10.1124/mol.106.030833.
    1. Carlson L. Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review. J. Intern. Med. 2005;258:94–114. doi: 10.1111/j.1365-2796.2005.01528.x.
    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 SAJ, Yu L, Redpath P, Migaud ME, Brenner C. Nicotinamide riboside is a major NAD(+) precursor vitamin in cow milk. J. Nutr. 2016;146:957–963. doi: 10.3945/jn.116.230078.
    1. Wright JT, Jr., et al. A randomized trial of intensive versus standard blood-pressure control. N. Engl. J. Med. 2015;373:2103–2116. doi: 10.1056/NEJMoa1511939.
    1. Centers for Disease Control and Prevention (CDC). National Center for Health Statistics (NCHS). National Health and Nutrition Examination Survey Data. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. (2011−2016).
    1. Hardy ST, et al. Reducing the blood pressure-related burden of cardiovascular disease: impact of achievable improvements in blood pressure prevention and control. J. Am. Heart Assoc. 2015;4:e002276. doi: 10.1161/JAHA.115.002276.
    1. Materson BJ, Garcia-Estrada M, Degraff SB, Preston RA. Prehypertension is real and can be associated with target organ damage. J. Am. Soc. Hypertens. 2017;11:704–708. doi: 10.1016/j.jash.2017.09.005.
    1. Pase MP, et al. Aortic stiffness and the risk of incident mild cognitive impairment and dementia. Stroke. 2016;47:2256–2261. doi: 10.1161/STROKEAHA.116.013508.
    1. Chue CD, Townend JN, Steeds RP, Ferro CJ. Arterial stiffness in chronic kidney disease: causes and consequences. Heart. 2010;96:817–823. doi: 10.1136/hrt.2009.184879.
    1. Ochi M, et al. Arterial stiffness is associated with low thigh muscle mass in middle-aged to elderly men. Atherosclerosis. 2010;212:327–332. doi: 10.1016/j.atherosclerosis.2010.05.026.
    1. Abbatecola AM, et al. Pulse wave velocity is associated with muscle mass decline: Health ABC study. Age. 2012;34:469–478. doi: 10.1007/s11357-011-9238-0.
    1. Mitchell GF. Arterial stiffness and hypertension chicken or egg? Hypertension. 2014;64:210–214. doi: 10.1161/HYPERTENSIONAHA.114.03449.
    1. Dernellis J, Panaretou M. Aortic stiffness is an independent predictor of progression to hypertension in nonhypertensive subjects. Hypertension. 2005;45:426–431. doi: 10.1161/01.HYP.0000157818.58878.93.
    1. Kaess BM, et al. Aortic stiffness, blood pressure progression, and incident hypertension. JAMA—J. Am. Med. Assoc. 2012;308:875–881. doi: 10.1001/2012.jama.10503.
    1. Mattagajasingh I, et al. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. USA. 2007;104:14855–14860. doi: 10.1073/pnas.0704329104.
    1. Gao D, et al. Activation of SIRT1 attenuates Klotho deficiency-induced arterial stiffness and hypertension by enhancing AMP-activated protein kinase activity. Hypertension. 2016;68:1191–1199. doi: 10.1161/HYPERTENSIONAHA.116.07709.
    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. Trammell SAJ, et al. Nicotinamide riboside opposes type 2 diabetes and neuropathy in mice. Sci. Rep. 2016;6:26933. doi: 10.1038/srep26933.
    1. Evans C, et al. NAD+metabolite levels as a function of vitamins and calorie restriction: evidence for different mechanisms of longevity. BMC Chem. Biol. 2010;10:2. doi: 10.1186/1472-6769-10-2.
    1. Tanaka H, DeSouza C, Seals D. Arterial stiffness and hormone replacement use in healthy postmenopausal women. J. Gerontol. A Biol. Sci. Med. Sci. 1998;53:M344–M346. doi: 10.1093/gerona/53A.5.M344.
    1. Tanaka H, DeSouza CA, Seals DR. Absence of age-related increase in central arterial stiffness in physically active women. Arterioscler. Thromb. Vasc. Biol. 1998;18:127–132. doi: 10.1161/01.ATV.18.1.127.
    1. Eskurza I, et al. Ascorbic acid does not affect large elastic artery compliance or central blood pressure in young and older men. Am. J. Physiol. Heart Circ. Physiol. 2004;286:H1528–H1534. doi: 10.1152/ajpheart.00879.2003.
    1. Moreau KL, Donato AJ, Seals DR, DeSouza CA, Tanaka H. Regular exercise, hormone replacement therapy and the age-related decline in carotid arterial compliance in healthy women. Cardiovasc. Res. 2003;57:861–868. doi: 10.1016/S0008-6363(02)00777-0.
    1. Pierce GL, et al. Tetrahydrobiopterin supplementation enhances carotid artery compliance in healthy older men: a pilot study. Am. J. Hypertens. 2012;25:1050–1054. doi: 10.1038/ajh.2012.70.
    1. Moreau KL, Gavin KM, Plum AE, Seals DR. Ascorbic acid selectively improves large elastic artery compliance in postmenopausal women. Hypertension. 2005;45:1107–1112. doi: 10.1161/01.HYP.0000165678.63373.8c.
    1. Eskurza I, Monahan KD, Robinson JA, Seals DR. Effect of acute and chronic ascorbic acid on flow-mediated dilatation with sedentary and physically active human ageing. J. Physiol. 2004;556:315–324. doi: 10.1113/jphysiol.2003.057042.
    1. Jablonski KL, et al. Dietary sodium restriction reverses vascular endothelial dysfunction in middle-aged/older adults with moderately elevated systolic blood pressure. J. Am. Coll. Cardiol. 2013;61:335–343. doi: 10.1016/j.jacc.2012.09.010.
    1. Walker AE, Kaplon RE, Pierce GL, Nowlan MJ, Seals DR. Prevention of age-related endothelial dysfunction by habitual aerobic exercise in healthy humans: possible role of nuclear factor kappa B. Clin. Sci. 2014;127:645–654. doi: 10.1042/CS20140030.
    1. Kaplon RE, Gano LB, Seals DR. Vascular endothelial function and oxidative stress are related to dietary niacin intake among healthy middle-aged and older adults. J. Appl. Physiol. 2014;116:156–163. doi: 10.1152/japplphysiol.00969.2013.
    1. Bell C, Jones PP, Seals DR. Oxidative stress does not modulate metabolic rate or skeletal muscle sympathetic activity with primary aging in adult humans. J. Clin. Endocrinol. Metab. 2003;88:4950–4954. doi: 10.1210/jc.2003-030454.
    1. Bell C, Stob N, Seals D. Thermogenic responsiveness to beta-adrenergic stimulation is augmented in exercising versus sedentary adults: role of oxidative stress. J. Physiol.-Lond. 2006;570:629–635. doi: 10.1113/jphysiol.2005.098756.
    1. Bergman RN, Prager R, Volund A, Olefsky JM. Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp. J. Clin. Invest. 1987;79:790–800. doi: 10.1172/JCI112886.
    1. DeVan AE, et al. Regular aerobic exercise protects against impaired fasting plasma glucose-associated vascular endothelial dysfunction with aging. Clin. Sci. 2013;124:325–331. doi: 10.1042/CS20120291.
    1. DeSouza CA, et al. Regular aerobic exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy men. Circulation. 2000;102:1351–1357. doi: 10.1161/01.CIR.102.12.1351.
    1. Reuben DB, et al. Motor assessment using the NIH Toolbox. Neurology. 2013;80:S65–S75. doi: 10.1212/WNL.0b013e3182872e01.
    1. Justice JN, et al. Improved motor and cognitive performance with sodium nitrite supplementation is related to small metabolite signatures: a pilot trial in middle-aged and older adults. Aging-Us. 2015;7:1004–1021. doi: 10.18632/aging.100842.
    1. Lunsford BR, Perry J. The standing heel-rise test for ankle plantar flexion—criterion for normal. Phys. Ther. 1995;75:694–698. doi: 10.1093/ptj/75.8.694.
    1. Vestergaard S, et al. Stopping to rest during a 400-meter walk and incident mobility disability in older persons with functional limitations. J. Am. Geriatr. Soc. 2009;57:260–265. doi: 10.1111/j.1532-5415.2008.02097.x.
    1. Cho B, Scarpace D, Alexander N. Tests of stepping as indicators of mobility, balance, and fall risk in balance-impaired older adults. J. Am. Geriatr. Soc. 2004;52:1168–1173. doi: 10.1111/j.1532-5415.2004.52317.x.
    1. Eriksrud O, Bohannon RW. Relationship of knee extension force to independence in sit-to-stand performance in patients receiving acute rehabilitation. Phys. Ther. 2003;83:544–551.
    1. DeVan AE, et al. Effects of sodium nitrite supplementation on vascular function and related small metabolite signatures in middle-aged and older adults. J. Appl. Physiol. 2016;120:416–425. doi: 10.1152/japplphysiol.00879.2015.
    1. Kaplon RE, et al. Oral trehalose supplementation improves resistance artery endothelial function in healthy middle-aged and older adults. Aging. 2016;8:1167–1183. doi: 10.18632/aging.100962.
    1. Peace KE. One-sided or two-sided p values: which most appropriately address the question of drug efficacy? J. Biopharm. Stat. 1991;1:133–138. doi: 10.1080/10543409108835010.

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