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Chronic nicotinamide riboside NR supplementation: well-tolerated and elevates NAD+ in healthy middle-aged + older adult

nicotinamide adenine dinucleotide nad+ nad+ precursors nicotinamide riboside cvd longevity

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#1 Engadin

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Posted 26 April 2019 - 04:16 PM



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.





Advancing age is the primary risk factor for the development of cardiovascular disease (CVD), which remains the leading cause of morbidity and mortality in industrial and post-industrial societies1. The increase in CVD risk with aging is driven largely by adverse changes to arteries, including stiffening of the aorta, and by increases in systolic blood pressure2. As such, interventions designed to lower blood pressure and/or improve arterial function hold promise for preventing age-related CVD.


Chronic calorie restriction (CR) prevents the development of arterial dysfunction and increases in blood pressure with aging in rodents3,4, and lowers arterial stiffness and blood pressure in overweight-obese middle-aged and older adults5,6. Despite numerous health benefits, adherence to chronic CR remains poor and possibly even unsafe in normal weight older adults7,8,9. As such, there is a critical need to establish safe, practical alternatives to regular CR for enhancing cardiovascular function and health with aging in humans10.


The recent identification of several key molecular mechanisms responsible for CR-mediated longevity in model organisms has led to an exciting search for “CR-mimetic” interventions to improve cardiovascular and other physiological functions with aging11,12. In this regard, nicotinamide adenine dinucleotide (NAD+) has emerged as a critical signaling molecule and essential substrate for sirtuins, a class of enzymes that mediate several of the beneficial effects of CR in model organisms13,14, including the maintenance of cardiovascular function15. Moreover, CR has been shown to increase NAD+ levels in pre-clinical models16,17. The cellular bioavailability of NAD+ and related metabolites declines in animals and in humans during normal aging13,18,19,20,21 and may contribute to physiological aging by reducing sirtuin activity. Although NAD+ can be synthesized de novo from the amino acid tryptophan, this process does not occur in all tissues, requiring most cells to rely on a salvage pathway for regenerating NAD+ from other intracellular intermediates, which are primarily made available through dietary sources22. Vitamin B3 (niacin: i.e., nicotinic acid and nicotinamide) enters this salvage pathway and acts as a NAD+ precursor; however, nicotinic acid is associated with undesirable flushing at therapeutic doses23 and nicotinamide does not reliably activate (and may even inhibit) sirtuins despite raising concentrations of NAD+24,25,26. Therefore, administration of nicotinic acid or nicotinamide is unlikely to be widely adopted for maintaining health and function with aging.


In contrast to these compounds, oral supplementation with either of the NAD+ metabolites, nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), increases levels of NAD+ and improves multiple physiological functions in animal models18,27,28. Indeed, we recently demonstrated that supplementation of NMN in the drinking water improved cardiovascular function in old mice29. Moreover, CR increases concentrations of NR and NAD+ and restores normal circadian gene transcription in the liver, further suggesting that NR may act as a CR mimetic30. Thus, NMN and NR are NAD+ boosting compounds that hold promise for enhancing cardiovascular health and physiological function with aging31,32.


Despite these encouraging results from preclinical studies, the tolerability and effectiveness of chronic supplementation with NMN or NR have not been established in humans. Because NR is readily taken up by cells and acts as a direct vitamin precursor for NAD+ synthesis33, its recent development as a dietary ingredient (NIAGEN®, ChromaDex Inc., Irvine, CA) has provided the first opportunity to translate the potential benefits of NAD+ boosting molecules to people. In this regard, a recent study showed that single doses of NR stimulated blood cellular NAD+metabolism in healthy humans in a dose-dependent manner26. However, the tolerability of chronic NR supplementation and its efficacy for increasing NAD+ bioavailability have not been established in humans, and we lack even initial insight into the potential of NR for improving cardiovascular and other physiological functions with human aging.


To address these important research gaps, we conducted a small randomized, placebo-controlled, crossover clinical trial of NR supplementation (500 mg, 2×/day) to assess its overall tolerability and efficacy vs. placebo for raising levels of NAD+-related metabolites in healthy middle-aged and older men and women. We also took the opportunity to gain preliminary insight into the effects of chronic NR supplementation for improving cardiovascular and other physiological functions associated with risk of clinical diseases and/or disability with aging. Our results demonstrate that 6 weeks of NR supplementation at this dose is well-tolerated in humans and effectively increases blood cellular NAD+ concentrations. Exploratory analyses of the effects of chronic NR supplementation on physiological function in this cohort of healthy middle-aged and older adults suggest that the potential for reducing systolic blood pressure and arterial stiffness may be the most promising hypotheses to investigate in future larger-scale clinical trials, particularly in individuals with elevated baseline blood pressure.


The rest at source: https://www.nature.c...467-018-03421-7


Also tagged with one or more of these keywords: nicotinamide adenine dinucleotide, nad+, nad+ precursors, nicotinamide riboside, cvd, longevity

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