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

Abstract

<p id="d4516686e325"> <b> <i>Significance:</i> </b> 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 <i>de novo</i> NAD ⁺ synthesis pathway in mammalian cells. NAD ⁺ can also be produced by the NAD ⁺ salvage pathway. </p><p id="d4516686e364"> <b> <i>Recent Advances:</i> </b> 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 id="d4516686e378"> <b> <i>Critical Issues:</i> </b> 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 <i>via</i> 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 id="d4516686e405"> <b> <i>Future Directions:</i> </b> 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>