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Review
. 2023 Feb 3;12(3):500.
doi: 10.3390/cells12030500.

Beyond Pellagra-Research Models and Strategies Addressing the Enduring Clinical Relevance of NAD Deficiency in Aging and Disease

Morgan B Feuz  1 , Mirella L Meyer-Ficca  1   2 , Ralph G Meyer  1   2
Affiliations
Review

Beyond Pellagra-Research Models and Strategies Addressing the Enduring Clinical Relevance of NAD Deficiency in Aging and Disease

Morgan B Feuz et al. Cells. .

Abstract

Research into the functions of nicotinamide adenine dinucleotide (NAD) has intensified in recent years due to the insight that abnormally low levels of NAD are involved in many human pathologies including metabolic disorders, neurodegeneration, reproductive dysfunction, cancer, and aging. Consequently, the development and validation of novel NAD-boosting strategies has been of central interest, along with the development of models that accurately represent the complexity of human NAD dynamics and deficiency levels. In this review, we discuss pioneering research and show how modern researchers have long since moved past believing that pellagra is the overt and most dramatic clinical presentation of NAD deficiency. The current research is centered on common human health conditions associated with moderate, but clinically relevant, NAD deficiency. In vitro and in vivo research models that have been developed specifically to study NAD deficiency are reviewed here, along with emerging strategies to increase the intracellular NAD concentrations.

Keywords: CD38; NAD; NAD animal models; aging; niacin; niacin deficiency; nicotinamide; nicotinic acid; poly(ADP-ribose); sirtuin.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the writing of the manuscript.

Figures

Figure 2
Figure 2
Genetically modified mouse models of altered NAD biosynthetic pathways. Tryptophan can be converted into nicotinamide adenine dinucleotide (NAD) by enzymes of the kynurenine pathway. (1) Tryptophan is an essential amino acid and, among other things, it is required for serotonin and melatonin synthesis; (2) the enzymes tryptophan dioxygenase (TDO) and indoleamine dioxygenase (IDO) convert tryptophan into formyl-kynurenine; (3–5) the enzymes kynurenine hydroxylase, kynureninase and 3-hydroxyanthraniate 3,4, dioxygenase convert kynurenine into the intermediate 2-amino-3-carboxymuconate semialdehyde (ACMS) in successive steps; (6) ACMSD can be converted to 2-aminomuconate semialdehyde (AMS) by the enzyme 2-amino-3-carboxymuconate semialdehyde decarboxylase (ACMSD) or rearranges non-enzymatically to become quinolinic acid (QA); (7) QA serves as substrate for quinolinate phophoribosyl transferase (QPRT) and it undergoes successive reactions that lead to NAD production. In order to prevent effective tryptophan-to-NAD conversion and to generate animal models of NAD deficiency, the following genetically modified mice were produced: one with a gene knock-out of Tdo to prevent step 2 [141,142,143], one with a gene knock-out of Qprt to prevent step 7 [140,141], and one with enhanced ACMSD activity that depleted ACMS in step 6 through an inducible ACMSD transgene [122]. In the salvage pathway (left), the enzyme nicotinamide phosphoribosyltransferase (NAMPT) uses nicotinamide (Nam) to generate nicotinamide mononucleotide (NMN) (step 8), which is further processed until it becomes NAD by nicotinamide nucleotide adenylyltransferase enzymes 1-3 (NMNATs 1-3) (step 9). Gene knock-out of the Nampt gene prevents NAD synthesis in the salvage pathway. While the complete body-wide loss of the Nampt gene is embryonically lethal, tissue-specific gene ablations are used to study the effects of local NAD depletion [145,146,147,148,149]. The chemical structures were retrieved from PubChem (https://pubchem.ncbi.nlm.nih.gov/, accessed on 18 January 2023).
Figure 1
Figure 1
Precursor molecules used for boosting NAD metabolism. Orally administered compounds (top row, red font) are metabolized by the gut microbiome to four main bioavailable metabolites: nicotinamide riboside (NR), nicotinamide (NAM), nicotinic acid (NA), and nicotinic acid riboside (NAR), which enter cells either by passive diffusion or with the help of cellular transporters, as indicated (* symbol designates microbiome conversion reactions). Extracellular nicotinamide adenine dinucleotide (NAD) and nicotinamide mononucleotide (NMN) are metabolized by extracellular NAD hydrolases CD38/CD157 and ecto-nucleotidase CD73, respectively, to NR, which crosses hepatic cell membranes with the help of equilibrative nucleoside transporters (ENTs). Once they are inside the (hepatic) cell, NR and NAM are converted into NMN by nicotinamide riboside kinases NRK1-2 and nicotinamide phosphoribosyltransferase (NAMPT), respectively, and enter the salvage pathway. In the cell, NA and NAR are metabolized into nicotinic acid mononucleotide (NAMN) by the enzymes nicotinic acid ribosyltransferase (NAPRT) and NRK1-2, respectively, to enter the Preiss-Handler pathway. Dietary tryptophan (Trp) is transported into the cell by several transporters, including SLC7A5 and SLC36A4, where it is metabolized by TDO and IDO to enter the kynurenine (de novo) NAD synthesis pathway (see Figure 2) to form NAMN, which enters the Preiss-Handler pathway to form NAD. The uptake and metabolism of NADH are poorly understood, but they likely include extracellular conversion steps. The different fates of NAD in the cell include phosphorylation by NAD kinase (NADK) to NADP+/NADPH and cleavage by NAD consuming enzymes into ADP-ribosyl moieties transferred to target molecules or to cyclo-ADP-ribose (not shown here) and NAM. NAM is then recycled in the salvage pathway, where it is converted into NMN by NAMPT. The clearance of NAM is achieved by S-adenosyl methionine-dependent methylation, which changes it into N-methylnicotinamide (mNAM), a reaction mediated by nicotinamide N-methyltransferase (NNMT).
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