Nicotinamide Riboside (NR) is a unique form of vitamin B3, distinct in its ability to boost Nicotinamide Adenine Dinucleotide (NAD+), a critical coenzyme in cellular metabolism.
The Science Behind Nicotinamide Riboside
Nicotinamide Riboside (NR), a distinctive variant of vitamin B3, stands out for its capacity to enhance Nicotinamide Adenine Dinucleotide (NAD+), an essential coenzyme in the body’s cellular energy processes.
Exploring the Mechanisms of Nicotinamide Riboside
Recognized as a nutritional supplement, Nicotinamide Riboside (NR) is a specialized form of vitamin B3 (also known as nicotinic acid or niacin). It uniquely incorporates elements of nicotinamide adenine dinucleotide (NAD+ in its oxidized state) into its structure [1]. NR is particularly influential in energy metabolism and neuroprotective functions [2,3,4].
From a broader biological perspective, NR’s role in the NAD+ cofactor suggests its connection to the ancient “RNA world” hypothesis [5], a period in early Earth’s history when RNA was a key component in both metabolism and genetics. The widespread presence of NAD+ across various life forms supports this theory [6].
However, NR is a relatively unstable molecule due to its glycosidic bond, which connects a positively charged pyridinium ring to a sugar molecule. This bond is particularly prone to breaking, posing challenges in synthesizing, storing, and transporting NR. Consequently, developing methods to synthesize NR and its more stable derivatives is of significant importance.
Today, stable NR variants are crucial. In July 2013, NR chloride (NRCl) became available in dietary supplements. Marketed under various brand names like Tru Niagen™ and Niagen® (by ChromaDex, Los Angeles, CA, USA), NRCl is widely used as a dietary supplement.
Other NRCl-containing products have also been marketed [7,8]. Interestingly, some analyses have revealed that these products sometimes contain not only pure NR but also by-products of NR’s reactivity.
Despite this, NR supplements are believed to increase NAD+ levels in consumers [8]. Research indicates that long-term NR supplementation is safe and effective in boosting NAD+ levels in middle-aged and older adults [2,3]. Studies also show NR’s oral bioavailability in both mice and humans [9].
NR’s role as a dietary supplement has been the focus of clinical research [2,3], demonstrating its effectiveness in increasing NAD+ levels in users [8,10]. This underscores the importance of reviewing the current knowledge and applications of NR.
NR, a pyridine-nucleoside version of vitamin B3, consists of nicotinamide (NAM) and ribose. It is found in various natural sources, including milk, yeast, beer, bacteria, and mammals. However, foods specifically enriched with NR are not well-defined.
Yeast-containing products are thought to be excellent natural sources of NR [11,12], though dairy products have also been identified as NR sources [9,13]. Generally, NR content in foods is relatively low, typically at micromolar concentrations.
NR shares biological properties with other NAD+ precursors like NAM and NA, which are traditional forms of vitamin B3. However, NAM and NA have their drawbacks. NAM can cause liver toxicity, and a recent study suggests that NAM is metabolized more quickly than NR in rats.
High doses of NA can lead to side effects such as skin flushing in immediate-release formulations and liver toxicity in sustained-release forms.
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The Latest Scientific Results On Effect of NR in Alzheimer’s Disease Treatment
Presented at the 2023 Alzheimer’s Association International Conference (AAIC), held June 16-20, in Amsterdam, Netherlands, the trial featured 47 individuals who received either 1500 mg twice daily of nicotinamide or a placebo for 12 months.
Results showed no significant treatment effects on secondary biomarker outcomes of cerebrospinal fluid (CSF) phosphor-tau181, amyloid-ß (Aß)40, Aß42, and total tau (all P >.05); however, mean changes in CSF p-tau181 (0.4 [±29.8] vs 10.4 [±41.8]) and total tau (8.4 [±228.6] vs 60.5 [±237.5]) favored nicotinamide.
Previous research has shown that the decline in nicotinamide adenine dinucleotide (NAD+) concentration in the brain during aging contributes to metabolic and cellular dysfunction and is implicated in the pathogenesis of aging-associated neurological disorders.
The proof-of-concept trial, led by Joshua D. Grill, PhD, professor of neurobiology and behavior at the University of California, Irvine, included individuals aged 50 years and older with mild cognitive impairment or dementia because of AD and who had a Mini-Mental State Examination score greater than 20. Patients who entered the study on stable medications for at least 4 weeks had CSF Aß42 levels less than or equal to 600 pg/mL or a ratio of total tau to Aß42 greater than 0.39.
Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered combined metabolic activators (CMA) to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals. CMA promotes mitochondrial fatty acid uptake from the cytosol, facilitates fatty acid oxidation in the mitochondria, and alleviates oxidative stress.
Methods Here, we designed a randomized, double-blinded, placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients. One-dose CMA included 12.35 g L-serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl-L-cysteine (12.75%), and 3.73 g L-carnitine tartrate (18.65%).
AD patients received one dose of CMA or placebo daily during the frst 28 days and twice daily between day 28 and day 84. The primary endpoint was the diference in the cognitive function and daily living activity scores between the
placebo and the treatment arms. This study’s secondary aim was to evaluate CMA’s safety and tolerability.
A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients.
Results We showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P=0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline (P=0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores.
Conclusions and Perspectives
NAD+ is known classically as a metabolite that stands astride both catabolic and anabolic pathways throughout the metabolism taught in introductory biochemistry courses. However, non-classical studies starting over a decade ago found that it is also involved in higher-order functions, partly because of its involvement in the activation of SIRTs and the support of the MT unfolded protein response.
Many studies have suggested that NAD+ is involved in an extensive spectrum of pathologies, including neurodegenerative disorders, cardiomyopathy, obesity, and diabetes. Further, healthy aging and longevity appear closely related to NAD+ and its related metabolites, including NR and NMN. This system appears to have prophylactic and therapeutic value in improving age-associated neurodegenerative, CV, and metabolic diseases and conditions.
Accordingly, many are now recommending using materials in this system as dietary supplements, hoping to improve overall human health. Among NAD+ precursors, NR appears to have unique values. These include better tolerance, better uptake, and overall greater potency.
Unfortunately, NR is a reactive molecule, often unstable during its manufacturing, transport, and storage. Indeed, HPLC analyses of many commercial samples of NR show that they contain substantial amounts of material that are not, in fact, NR. Therefore, more stable derivatives of NR that are easily converted upon consumption into NR are desired.
Recently, work related to prebiotic chemistry provided the borate derivative of NR. NR borate is considerably more stable than NR itself. However, immediately upon consumption, the borate dissociates from the NR borate. It is lost in the body through dilution and binding to other species, notably carbohydrates such as fructose and glucose. The NR left behind is expected to behave pharmacologically in ways identical to NR itself.
This review provides a comprehensive, uncritical summary through Q1 of 2023 of the literature that makes the case for the consumption of NR. It then summarizes the challenges of delivering quality NR to consumers using standard synthesis, manufacture, shipping, and storage approaches. It concludes by outlining the advantages of NR borate in these processes.
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