Your entire body is made of cells—from your skin to your heart. These trillions of cells are the foundation of all health and wellness. When cellular damage occurs, our biological robustness begins to break down. This is most common as we get older. The hallmarks of aging are most often associated with visible effects such as skin issues, yet the underlying cause is cellular senescence and dysregulated intracellular communication. For decades scientists have studied how these changes at the cellular level negatively impact every organ and tissue throughout the body. At the core of this science is the direct correlation between aging and the decrease in systemic NAD+ biosynthesis.
Why is this important?—and what is NAD+?
NAD+ (nicotinamide adenine dinucleotide) is a coenzyme present in all living cells. Certain proteins critical to DNA expression cannot properly function in the absence of this vital molecule. Even more, NAD+ is required for energy production in every tissue in the body—its importance to cellular metabolism (i.e. your health) is immeasurable. However, aging causes NAD+ concentration levels to fall dramatically, which can hinder DNA repair capacity. Other factors contribute to this as well. Smoking, excessive alcohol consumption, drug use, poor diet, chronic stress and lack of sleep can all reduce NAD+. When NAD+ levels are depleted the result is a cascading effect of cellular injury, from fine lines and wrinkles to chronic inflammation and degenerative disease.
NR (nicotinamide riboside) is a micronutrient and powerful NAD+ precursor to restore youthful NAD+ levels, supporting DNA repair capacity for intracellular health. However, purity and bioavailability are critical to the NAD+ restoration process. nrXPRO is the cutting edge of aging science and cellular therapy, professionally formulated to mitigate the negative effects of aging with a breakthrough synthesis called RiboGEN®, which is 99%+ pure Nicotinamide Riboside Chloride. And unlike nearly all NR products, nrXPRO features delayed release vegan capsules which are clinically proven to resist stomach acids for targeted absorption in the small intestine, providing maximum bioavailability.
nrXPRO is the new standard of NAD+ cellular therapy, proudly synthesized, encapsulated, bottled and exclusively sold in the USA. Every batch is third-party tested to ensure professional-grade quality and purity. Our packaging includes BPA free ultraviolet glass for superior preservation, as well as FSC mix box material and soy-based inks to help protect forests and promote sustainable practices in the packaging industry.
The science of healthy aging and cellular therapy is clear: Cell health = Your health.
Take one (1) capsule daily, without food in the morning, or as directed by your healthcare professional. Consult your healthcare professional before taking any dietary supplement, if you are pregnant, nursing, or taking any medication. Keep out of reach of children.
Store in a cool, dry place away from direct sunlight. Do not use if tamper-evident packaging is broken or missing.
Evaluating the Clinical Benefits of Nicotinamide Riboside: Current Evidence and Future Directions*
Nicotinamide Riboside (NR) has emerged with vast potential health benefits in various physiological systems, primarily through its function as a precursor of nicotinamide adenine dinucleotide (NAD+), a critical redox cofactor in cell metabolism. (1) As a form of vitamin B3, NR is involved in NAD+ biosynthesis through two main pathways: the Nrk1 and Urh1/Pnp1/Meu1 pathways. (2) Elevation of NAD+ levels, a direct outcome of NR supplementation, plays a pivotal role in enhancing biological functions, such as supporting the improvement of gene regulation, which is fundamental to extending lifespan and enhancing cellular metabolism. (2)
The Role of NR in Physiology
NR, a precursor of NAD+, not only plays a role in cell metabolism (1), but by increasing NAD+ levels in tissues, NR supplementation may help restore functions that aging or diseases have impaired. (3, 4) After being imported into cells by equilibrated nucleoside transporters (ENT), NR is predominantly metabolized by purine nucleoside phosphorylase (PNP), resulting in nicotinamide accumulation. (3) Additionally, NR can be metabolized through two pathways: a degradative pathway producing nicotinamide, and a kinase pathway involving nicotinamide riboside kinases. (5) The kinase pathway is implicated in unique effects, such as raising tissue NAD+ concentrations, enhancing insulin sensitivity, and stimulating mitochondrial propagation. (5) These metabolic pathways highlight the complexity of NR utilization within cells, and its potential impact on cellular functions. Understanding the interplay between these pathways is immensely important. Moreover, the ability to modulate these pathways through targeted interventions offers new therapeutic opportunities for age-related metabolic disorders.
As a coenzyme, NAD+ helps maintain certain physiological processes, enabling cellular adaptation to environmental changes, and is essential for cellular oxidative metabolic reactions, facilitating energy generation through glycolysis and mitochondrial respiration, which supports cell growth and survival. (6, 7, 8, 9) It drives metabolic pathways by transferring hydrogen in oxidation-reduction reactions, and functions as a critical cofactor for non-redox NAD+ dependent enzymes including sirtuins, CD38, and poly(ADP-ribose) polymerases (PARPs) 9. NAD+ is involved in DNA repair, cell proliferation, differentiation, redox regulation, oxidative stress response, and protein balance. (6, 7, 10, 9) Additionally, NAD+ acts as a signaling molecule, influencing processes such as calcium signaling, circadian rhythms, metabolism, inflammation, and immune cell function. (7, 8, 11, 12) NR is a potent NAD+ precursor, effectively increasing NAD+ levels in the body, which is essential for metabolic pathways and cellular energy production. (13, 14, 15) NAD+ is critical for maintaining cellular and tissue homeostasis, influencing processes such as energy production, DNA repair, chromatin remodeling, cellular senescence, and immune cell function. (10) Its diverse roles in regulating critical physiological processes underscore its importance in health and disease, particularly in aging-associated conditions. (10, 16) The maintenance of NAD+ levels are paramount for healthy aging.
Safety and Efficacy
Several studies have demonstrated the safety of NR supplementation. Acute toxicity studies in rats showed no mortality at oral doses up to 5000 mg/kg. (17) (For an average size male human of 170 lb (77.1 kg) that is equivalent to 385,500 mg of NR.) A 90-day toxicology study established no observed adverse effect level (NOAEL) of 300 mg/kg/day. (17) Human clinical trials have further confirmed the safety profile, with doses of up to 2000 mg/day being well-tolerated. (17, 18) After establishing the foundational safety profile of NR supplementation, it is imperative to explore its physiological effects, among which mitochondrial health is the primary area of interest. This section describes how NR supplementation influences mitochondrial function following the assurance of its safe application, derived from numerous studies. This safety profile provides a solid foundation for the investigation of the physiological effects of NR supplementation. With the safety concerns addressed, researchers can now focus on further exploring the potential benefits of NR, particularly its impact on mitochondrial health, unraveling the complex mechanisms by which NR influences cellular energy production and mitochondrial function. This transition from safety to efficacy studies opens new avenues for exploring NR’s potential in various health conditions related to mitochondrial dysfunction. As we delve deeper into the physiological effects of NR supplementation, it becomes clear that its effects on mitochondrial health may have far-reaching implications for overall cellular function and longevity.
Clinical Benefits of NR
Mitochondrial Health: NR supplementation has been associated with improved mitochondrial health through increased NAD+ levels. (5, 19) This leads to enhanced mitochondrial biogenesis and reduced oxidative stress. (5, 20) In aged human participants, NR supplementation led to an elevation of the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products, while muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondrial pathways in muscle tissue without altering mitochondrial bioenergetics. (21) These findings highlight the complexity of the effects of NR supplementation on mitochondrial function, suggesting that age and tissue type may play crucial roles in determining the outcomes. The potential of NR supplementation to modulate mitochondrial function remains an intriguing area of further research in the context of aging and metabolic health.
Metabolic Health: The impact of NR on metabolic health has been a key area of research. Although preclinical studies have shown promising results on insulin sensitivity and mitochondrial biogenesis (5), human trials have yielded varying results in this regard. A 12-week randomized controlled trial in obese insulin-resistant men found that NR supplementation (2000 mg/day) did not improve insulin sensitivity, whole-body glucose metabolism, or body composition. (18) Similarly, a 6-week study in overweight adults showed no effect on brown adipose tissue activity or cold-induced thermogenesis. (22) Another study demonstrated that NR supplementation improves metabolic function, protects against high-fat diet-induced obesity, and enhances oxidative metabolism by activating sirtuin enzymes. (21, 23) These findings underscore the necessity for proper nutrition protocols, as well as the complexity of translating preclinical results into human outcomes in metabolic health research.
Aging and Longevity: NR has emerged as a potential promoter of longevity and healthy aging owing to its ability to increase NAD+ levels in humans. Clinical trials have demonstrated that NR supplementation can lead to significant increases in whole blood NAD+ levels, with one study reporting a dose-dependent increase of up to 142% after two weeks of consumption. (24) This finding is particularly relevant, given the consistent decline in NAD+ levels observed across multiple organisms, including humans, as they age. (25, 26)
Age-related decrease in NAD+ levels, which occurs in various tissues, is now considered a hallmark of aging. (27) A large-scale study involving 1,518 participants revealed a declining trend in whole blood NAD+ content with aging, particularly before 50 years of age. (28) The decline in NAD+ levels has been linked to various age-associated diseases, including metabolic disorders, cancer, neurodegenerative diseases, and cognitive decline. (25, 10, 29) This decrease impairs tissue function and cellular processes, such as DNA repair, chromatin remodeling, and immune cell function. (10) Restoring NAD+ levels through supplementation with precursors like NR has shown promise in ameliorating age-related disorders and potentially extending the lifespan of model organisms. (29, 30)
NAD+ plays a crucial role in longevity and transcriptional regulation through NAD-dependent deacetylases such as the Sir2p family. (10, 31, 32) The correlation between NAD+ concentration and longevity is strong. Current evidence primarily highlights NR’s potential to counteract biochemical markers of aging, such as the decline in NAD+ levels. NR supplementation has shown promising results in elevating NAD+ levels and potentially mitigating age-related decline. Preclinical studies on the effects of NR on human longevity are still ongoing (4, 33) and more comprehensive investigations are required to fully understand its profound implications and direct effects (other than a precursor of NAD+) as an anti-aging intervention.
Neurodegenerative disease*: NAD+ levels are crucial for neuronal health and function. (13, 14) While promising in preclinical studies for neurodegenerative conditions, the translation of NR’s effects to clinical applications requires further validation through human trials. In animal models of Alzheimer’s disease, NR administration reduced senescence, attenuated DNA damage, and decreased neuroinflammation. (34) A clinical trial in patients with Parkinson’s disease found that short-term high-dose NR therapy led to increased cerebral NAD+ levels, altered cerebral metabolism, and mild clinical improvements in some patients. (35)
Liver Health: NR plays a significant role in liver health as a precursor of NAD+. Studies have shown that NR supplementation can protect against various liver injuries and metabolic disorders. NR exerts protective effects against ethanol-induced liver injury by activating SirT1, reducing oxidative stress, and improving mitochondrial function through the SirT1/PGC-1α/mitochondrial biosynthesis pathway. (36) It can also prevent and reverse liver fibrosis by suppressing the activation of hepatic stellate cells through Sirt1-mediated deacetylation of the SMAD signaling pathway. (37) In alcohol-related liver diseases, NAD+ and its precursors (including NR) are significantly reduced, which correlates with disease severity. (38) Interestingly, while NR supplementation shows promise for liver health, its metabolism is regulated by purine nucleoside phosphorylase (PNP). Inhibition of PNP can enhance the efficacy of NR supplementation by maintaining higher levels of NR in the blood, kidneys, and liver. (3) Despite its potential to treat various liver disorders, NR’s efficacy may depend on factors, such as the underlying condition, dosage, and individual metabolism, warranting further research to fully understand its liver health potential.
Stem Cells: NR has demonstrated significant potential in promoting stem cell health and tissue regeneration in various cell types. In hematopoietic stem cells (HSCs), NR supports regeneration by reducing mitochondrial stress and enhancing mitochondrial clearance, which are crucial for blood recovery and immune function. (19) NR treatment has been shown to rejuvenate muscle stem cells (MuSCs) in aged mice by inducing the mitochondrial unfolded protein response and synthesis of prohibitin proteins, while also preventing MuSC senescence in a muscular dystrophy mouse model and delaying senescence of neural and melanocyte stem cells. (39) In HSCs, NR reduces mitochondrial activity through increased mitochondrial clearance, leading to a more asymmetric HSC division and an enlarged pool of progenitors without HSC exhaustion. (19) Furthermore, NR supplementation improved survival and accelerated blood recovery after irradiation and HSC transplantation. (19) In aged HSCs, NR restores youthful metabolic capacity by modifying mitochondrial function, resulting in a more youthful bone marrow composition and improved regenerative capacity. (40)
Conclusion
NR supplementation has demonstrated safety and the ability to increase NAD+ levels in humans. As promising as this is, however, the full spectrum of its clinical benefits have yet to be uncovered due to the complexity of translating NR’s biochemical benefits. Future studies require more clinically relevant endpoints than those to date, to better establish the benefits of NR supplementation in humans across various health domains.
*This literature review has not been evaluated by the Food and Drug Administration, and therefore the information contained herein is not intended to diagnose, treat, cure, or prevent any disease. According to the FDA, only drugs can make those claims.
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