Nicotinamide Mononucleotide Supplementation: Understanding Metabolic Variability and Clinical Implications

Abstract

Recent years have seen a surge in research focused on NAD+ decline and potential interventions, and despite significant progress, new discoveries continue to highlight the complexity of NAD+ biology. Nicotinamide mononucleotide (NMN), a well-established NAD+ precursor, has garnered considerable interest due to its capacity to elevate NAD+ levels and induce promising health benefits in preclinical models. Clinical trials investigating NMN supplementation have yielded variable outcomes while shedding light on the intricacies of NMN metabolism and revealing the critical roles played by gut microbiota and specific cellular uptake pathways. Individual variability in factors such as lifestyle, health conditions, genetics, and gut microbiome composition likely contributes to the observed discrepancies in clinical trial results. Preliminary evidence suggests that NMN's effects may be context-dependent, varying based on a person's physiological state. Understanding these nuances is critical for definitively assessing the impact of manipulating NAD+ levels through NMN supplementation. Here, we review NMN metabolism, focusing on current knowledge, pinpointing key areas where further research is needed, and outlining future directions to advance our understanding of its potential clinical significance.

Keywords: NAD+; bioavailability; human longevity; nicotinamide mononucleotide; vitamin B3.

Figure 1

Biosynthetic pathways of NAD+ synthesis in mammalian cells. The salvage pathway is the body’s main and most efficient source of NAD+. Abbreviations: 3-HK, 3-hydroxykynurenine; 3-HAA, 3-hydroxy anthranilic acid; ACMS, 2-amino-3-carboxymuconic semialdehyde; QPRT, quinolinate phosphoribosyltransferase; NA, nicotinic acid; NAPRT, nicotinic acid phosphoribosyltransferase; NAMN, nicotinic acid mononucleotide; NMNAT, nicotinamide mononucleotide adenylyltransferase; NAAD, nicotinic acid adenine dinucleotide; NADS, NAD+ synthetase; NR, nicotinamide riboside; NMN, nicotinamide mononucleotide; NRK, nicotinamide riboside kinase; NAD+/NADH, nicotinamide adenine dinucleotide; NAM, nicotinamide; NAMPT, nicotinamide phosphoribosyltransferase; 3-HAAO, 3-Hydroxyanthranilate 3,4-Dioxygenase; NADP/NADPH, Nicotinamide adenine dinucleotide phosphate; TDO2, Tryptophan 2,3-dioxygenase; KYNU, kynureninase KFase, kynurenine formidase, KMO, Kynurenine 3-Monooxygenase.

Figure 2

Metabolic fates of orally administered NAD+ Precursors. 1. NMN can be deaminated by the bacterial enzyme pncC to form NAMN. Alternatively, NMN may be broken down by other gut enzymes to produce NR or NAM, which is then metabolized by pncA to form NA and follow the Preiss Handler pathway. This deamidated route results in increased levels of NAR and NAMN in the gut and liver, and elevated NAAD specifically in the liver. A portion of oral NMN may follow the salvage route after direct entry through SLC12a8 or indirect entry through ENTs via conversion to NR. 2. During the early phase of metabolism, oral NR can directly enter cells and undergo the canonical salvage pathway. In the later phase, NR is converted into NAM by BST1, resulting in increased NA in the gut, elevated NA and NAR in the portal blood, and an increase in both amidated (NA, NAR, NAMN, and NAAD) and deamidated (NAM and NMN) metabolites in the liver. Additionally, NR may undergo a BST-1 catalyzed base-exchange reaction using NAM and NR, converting it to NAR. 3. NAM is rapidly converted to NA by the bacterial enzyme pncA in the colon, leading to elevation of deamidated precursors (NAMN, NAR, and NAAD) as well as amidated precursors (NAM and NMN) in the gut cell, portal vein, and liver. Figure created in BioRender.

Figure 3

NMN Administration Routes and Metabolic Processing. (1) Following ingestion of either a standard or liposomal formulation of NMN, (2) the capsule undergoes breakdown in the stomach, with liposomal formulations offering enhanced protection from degradation. (3) The standard NMN formulation undergoes extensive metabolism in the intestine by gut bacteria and intestinal enzymes before absorption into the enterocyte, while liposomes fuse with the intestinal lining, facilitating the absorption of encapsulated NMN. From the enterocyte, (4) standard NMN is absorbed into the portal vein and transported to the liver, where it undergoes first-pass metabolism and further enzymatic breakdown. (5) absorbed liposomes exit the enterocytes via the lymphatic system and enter the bloodstream, bypassing first-pass hepatic metabolism. (6) Intravenous administration of NMN directly introduces NMN into the bloodstream without undergoing processing in the intestine or liver. (7) Ultimately, NMN molecules enter the bloodstream for potential uptake into target tissues, albeit the amount reaching these tissues varies depending on the route of administration and the metabolic processing experienced en route. Figure created in BioRender.