Nicotinamide Adenine Dinucleotide (NAD+) is a coenzyme in all living cells, central to energy production and repair processes. Its levels naturally decline with age, contributing to cellular dysfunction. This decline has spurred interest in compounds that boost NAD+ levels, such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). Both are precursors, meaning the body converts them into NAD+. This article explores the scientific understanding of NR and NMN, comparing their pathways, efficacy in raising NAD+ levels, human health outcomes, and regulatory statuses.
The Cellular Conversion Pathway
Both nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are precursors in NAD+ biosynthesis, converted into NAD+ within the body. NR’s journey is well-established: inside the cell, NR is phosphorylated by nicotinamide riboside kinase (NRK) to become NMN. This NMN then converts to NAD+ via NMN adenylyltransferase (NMNAT). The pathway for NMN has been investigated in more detail. It was once believed NMN molecules were too large to directly enter cells, requiring dephosphorylation into NR outside the cell before entry. This NR would then convert back to NMN and then to NAD+ inside the cell. However, this view has been refined. Research identified a dedicated NMN transporter, Slc12a8, facilitating direct uptake of NMN into some cells and tissues, especially in the gut. This suggests NMN does not always need conversion to NR to enter cells. The transporter’s presence and activity vary across tissues, influencing NMN’s effectiveness in reaching intracellular targets for NAD+ conversion.
Comparing Bioavailability and Efficacy
Comparing NR and NMN’s bioavailability and efficacy in raising human NAD+ levels involves examining how much reaches circulation and how effectively it converts. Both can increase NAD+ levels in various tissues, though extent and speed differ. For example, a single 1000 mg oral dose of NR significantly increased whole blood NAD+ levels by 2.7-fold at 6 hours in healthy middle-aged and older adults. Another NMN study showed 250 mg daily for 8 weeks increased NAD+ levels in peripheral blood mononuclear cells. Bioavailability is the proportion of a substance entering circulation and having an active effect. NR shows high oral bioavailability in human studies, with 100 mg to 1000 mg daily doses increasing NAD+ metabolites in blood dose-dependently. NR’s stability in the digestive tract allows for efficient absorption. NMN’s bioavailability is also researched, particularly its direct absorption. While the Slc12a8 transporter allows some direct uptake, other research suggests NMN can convert to NR in the gut before absorption, then back to NMN intracellularly. Oral NMN doses up to 1250 mg daily increase NAD+ levels in human blood. Both compounds appear promising for elevating NAD+ in humans, though direct head-to-head comparisons in identical populations are still emerging.
Human Research on Health Outcomes
Human research on nicotinamide riboside (NR) explores its potential benefits across physiological systems. NR supplementation can improve metabolic health markers; some trials observed improved insulin sensitivity in obese men, suggesting a role in glucose metabolism. However, these effects are not consistently observed across all populations, with some studies in healthy individuals showing no significant metabolic changes. NR has also been investigated for muscle function. While animal studies indicate benefits for muscle endurance and regeneration, human trials show mixed results, with some finding no significant improvements in muscle strength or physical performance in older adults. Cardiovascular health is another focus, with research suggesting NR could help lower blood pressure and improve arterial stiffness in older adults, possibly by enhancing NAD+-dependent processes. Human studies on nicotinamide mononucleotide (NMN) are more recent. Preliminary findings suggest NMN may influence metabolic health, with one study indicating improved muscle insulin sensitivity in postmenopausal women with prediabetes. Research into NMN’s effects on muscle function shows promise, with a study on older adults demonstrating improved muscle strength, including grip strength and walking speed. Evidence for both compounds is still accumulating, with many studies being relatively small or short-term. More extensive, long-duration trials are needed to fully understand their long-term effects and confirm consistent benefits across diverse populations.
Safety and Regulatory Differences
Both nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are considered safe for human consumption at typical supplemental doses. Clinical trials report mild, infrequent side effects like minor gastrointestinal discomfort, nausea, diarrhea, headaches, or fatigue. These instances are rare and usually resolve quickly. The safety profiles suggest a low risk of adverse events when used appropriately. A significant difference between NR and NMN is their regulatory status, particularly in the United States. Nicotinamide riboside has achieved New Dietary Ingredient (NDI) status with the U.S. Food and Drug Administration (FDA), indicating it is safe for dietary supplements. Certain NR forms also have Generally Recognized As Safe (GRAS) status, meaning experts agree it is safe for food products. These designations allow NR to be marketed as a dietary supplement. In contrast, NMN’s regulatory landscape changed in 2022. The FDA determined NMN can no longer be marketed as a dietary supplement because it is being investigated as a new drug. Under U.S. law, a substance authorized for investigation as a new drug with publicly available clinical investigations cannot be marketed as a dietary supplement. This shift means NMN is now primarily considered a drug candidate by the FDA, impacting its availability and marketing as a consumer product.
References
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