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Antioxid Redox Signal. 2018 May 11. doi: 10.1089/ars.2017.7269. [Epub ahead of print]

Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and Outcomes.

Author information

1
1 Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales , Sydney, Australia .
2
2 Australasian Research Institute , Sydney Adventist Hospital, Sydney, Australia .
3
3 BetterHumans, Inc. , Apple Valley, California.
4
4 Mark Wainwright Analytical Centre, University of New South Wales , Sydney, Australia .
5
5 School of Medical Sciences, University of New South Wales , Sydney, Australia .
6
6 Sydney Medical School, University of Sydney , Sydney, Australia .
7
7 Neuropsychiatric Institute, Euroa Centre, Prince of Wales Hospital , Sydney, Australia .

Abstract

SIGNIFICANCE:

Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that serves as an essential cofactor and substrate for a number of critical cellular processes involved in oxidative phosphorylation and ATP production, DNA repair, epigenetically modulated gene expression, intracellular calcium signaling, and immunological functions. NAD+ depletion may occur in response to either excessive DNA damage due to free radical or ultraviolet attack, resulting in significant poly(ADP-ribose) polymerase (PARP) activation and a high turnover and subsequent depletion of NAD+, and/or chronic immune activation and inflammatory cytokine production resulting in accelerated CD38 activity and decline in NAD+ levels. Recent studies have shown that enhancing NAD+ levels can profoundly reduce oxidative cell damage in catabolic tissue, including the brain. Therefore, promotion of intracellular NAD+ anabolism represents a promising therapeutic strategy for age-associated degenerative diseases in general, and is essential to the effective realization of multiple benefits of healthy sirtuin activity. The kynurenine pathway represents the de novo NAD+ synthesis pathway in mammalian cells. NAD+ can also be produced by the NAD+ salvage pathway. Recent Advances: In this review, we describe and discuss recent insights regarding the efficacy and benefits of the NAD+ precursors, nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN), in attenuating NAD+ decline in degenerative disease states and physiological aging.

CRITICAL ISSUES:

Results obtained in recent years have shown that NAD+ precursors can play important protective roles in several diseases. However, in some cases, these precursors may vary in their ability to enhance NAD+ synthesis via their location in the NAD+ anabolic pathway. Increased synthesis of NAD+ promotes protective cell responses, further demonstrating that NAD+ is a regulatory molecule associated with several biochemical pathways.

FUTURE DIRECTIONS:

In the next few years, the refinement of personalized therapy for the use of NAD+ precursors and improved detection methodologies allowing the administration of specific NAD+ precursors in the context of patients' NAD+ levels will lead to a better understanding of the therapeutic role of NAD+ precursors in human diseases. Antioxid. Redox Signal. 00, 000-000.

KEYWORDS:

DNA damage; NAD+; nicotinamide; oxidative stress; sirtuins

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