Dr. Ron’s Research Review – November 9, 2011

This week’s research review: NAD

Because the cellular redox status depends on both the absolute concentration of pyridine dinucleotides and their respective ratios of oxidized and reduced forms (i.e., NAD/NADH and NADP/NADPH), it is conceivable that an altered regulation of the synthesis and degradation of NAD impairs the cell redox state and likely contributes to the mechanisms underlying the pathogenesis of diabetes, inflammatory syndromes, neurodegeneration and cancer. (Magni, Orsomando et al. 2008)

Metabolism of Vitamin B3 and the nicotinamide adenine dinucleotides and their derivatives occupies a central place in the aging processes of mammals. (Xu and Sauve 2010)

NAD is of importance in multiple sclerosis. (Penberthy and Tsunoda 2009)

Among the best sources of aging-related cell-surface NADH oxidase inhibitors are certain culinary seasonings, all of which are ingredients used extensively in the French kitchen. Their regular use may contribute to an understanding of the nutritional basis for the French Paradox. (Morre, Morre et al. 2010)

Dr. Ron


Articles

NADH monograph

         Kelley 2006 Download

Enzymology of mammalian NAD metabolism in health and disease

            (Magni, Orsomando et al. 2008) Download

Mounting evidence attests to the paramount importance of the non-redox NAD functions. Indeed, NAD homeostasis is related to the free radicals-mediated production of reactive oxygen species responsible for irreversible cellular damage in infectious disease, diabetes, inflammatory syndromes, neurodegeneration and cancer. Because the cellular redox status depends on both the absolute concentration of pyridine dinucleotides and their respective ratios of oxidized and reduced forms (i.e., NAD/NADH and NADP/NADPH), it is conceivable that an altered regulation of the synthesis and degradation of NAD impairs the cell redox state and likely contributes to the mechanisms underlying the pathogenesis of the above mentioned diseases. Taking into account the recent appearance in the literature of comprehensive reviews covering different aspects of the significance of NAD metabolism, with particular attention to the enzymes involved in NAD cleavage, this monograph includes the most recent results on NAD biosynthesis in mammals and humans. Due to recent findings on nicotinamide riboside as a nutrient, its inclusion under "niacins" is proposed. Here, the enzymes involved in the de novo and reutilization pathways are overviewed.

Aging-related nicotinamide adenine dinucleotide oxidase response to dietary supplementation: the French paradox revisited

            (Morre, Morre et al. 2010) Download

Aging-related cell-surface NADH oxidase (arNOX)-specific activities increase with age between age 30 and ages 50-65. The protein is shed and circulates. Activity correlates with a number of aging-related disorders including low-density lipoprotein (LDL) oxidation as a precondition to atherosclerosis as well as oxidation of collagen and elastin as a major contributor to skin aging. arNOX inhibitors formulated for sustained release are capable of maintaining circulating arNOX at low levels with regular use as food supplements formulated with natural compounds. Among the best sources are certain culinary seasonings, all of which are ingredients used extensively in the French kitchen. Their regular use may contribute to an understanding of the nutritional basis for the French Paradox.


The importance of NAD in multiple sclerosis

            (Penberthy and Tsunoda 2009) Download

The etiology of multiple sclerosis (MS) is unknown but it manifests as a chronic inflammatory demyelinating disease in the central nervous system (CNS). During chronic CNS inflammation, nicotinamide adenine dinucleotide (NAD) concentrations are altered by (T helper) Th1-derived cytokines through the coordinated induction of both indoleamine 2,3-dioxygenase (IDO) and the ADP cyclase CD38 in pathogenic microglia and lymphocytes. While IDO activation may keep auto-reactive T cells in check, hyper-activation of IDO can leave neuronal CNS cells starving for extracellular sources of NAD. Existing data indicate that glia may serve critical functions as an essential supplier of NAD to neurons during times of stress. Administration of pharmacological doses of non-tryptophan NAD precursors ameliorates pathogenesis in animal models of MS. Animal models of MS involve artificially stimulated autoimmune attack of myelin by experimental autoimmune encephalomyelitis (EAE) or by viral-mediated demyelination using Thieler's murine encephalomyelitis virus (TMEV). The Wld(S) mouse dramatically resists razor axotomy mediated axonal degeneration. This resistance is due to increased efficiency of NAD biosynthesis that delays stress-induced depletion of axonal NAD and ATP. Although the Wld(S) genotype protects against EAE pathogenesis, TMEV-mediated pathogenesis is exacerbated. In this review, we contrast the role of NAD in EAE versus TMEV demyelinating pathogenesis to increase our understanding of the pharmacotherapeutic potential of NAD signal transduction pathways. We speculate on the importance of increased SIRT1 activity in both PARP-1 inhibition and the potentially integral role of neuronal CD200 interactions through glial CD200R with induction of IDO in MS pathogenesis. A comprehensive review of immunomodulatory control of NAD biosynthesis and degradation in MS pathogenesis is presented. Distinctive pharmacological approaches designed for NAD-complementation or targeting NAD-centric proteins (SIRT1, SIRT2, PARP-1, GPR109a, and CD38) are outlined towards determining which approach may work best in the context of clinical application.

Vitamin B3, the nicotinamide adenine dinucleotides and aging

            (Xu and Sauve 2010) Download

Organism aging is a process of time and maturation culminating in senescence and death. The molecular details that define and determine aging have been intensely investigated. It has become appreciated that the process is partly an accumulation of random yet inevitable changes, but it can be strongly affected by genes that alter lifespan. In this review, we consider how NAD(+) metabolism plays important roles in the random patterns of aging, and also in the more programmatic aspects. The derivatives of NAD(+), such as reduced and oxidized forms of NAD(P)(+), play important roles in maintaining and regulating cellular redox state, Ca(2+) stores, DNA damage and repair, stress responses, cell cycle timing and lipid and energy metabolism. NAD(+) is also a substrate for signaling enzymes like the sirtuins and poly-ADP-ribosylpolymerases, members of a broad family of protein deacetylases and ADP-ribosyltransferases that regulate fundamental cellular processes such as transcription, recombination, cell division, proliferation, genome maintenance, apoptosis, stress resistance and senescence. NAD(+)-dependent enzymes are increasingly appreciated to regulate the timing of changes that lead to aging phenotypes. We consider how metabolism, specifically connected with Vitamin B3 and the nicotinamide adenine dinucleotides and their derivatives, occupies a central place in the aging processes of mammals.


References

Magni, G., G. Orsomando, et al. (2008). "Enzymology of mammalian NAD metabolism in health and disease." Front Biosci 13: 6135-54.

Morre, D. J., D. M. Morre, et al. (2010). "Aging-related nicotinamide adenine dinucleotide oxidase response to dietary supplementation: the French paradox revisited." Rejuvenation Res 13(2-3): 159-61.

Penberthy, W. T. and I. Tsunoda (2009). "The importance of NAD in multiple sclerosis." Curr Pharm Des 15(1): 64-99.

Xu, P. and A. A. Sauve (2010). "Vitamin B3, the nicotinamide adenine dinucleotides and aging." Mech Ageing Dev 131(4): 287-98.