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

Abstract

<p><strong><em>Significance:</em></strong> 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 <em>de novo</em> NAD⁺ synthesis pathway in mammalian cells. NAD⁺ can also be produced by the NAD⁺ salvage pathway.</p> <p><strong><em>Recent Advances:</em></strong> 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.</p> <p><strong><em>Critical Issues:</em></strong> 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 <em>via</em> 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.</p> <p><strong><em>Future Directions:</em></strong> 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.</p>