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

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 NAD synthesis pathway in mammalian cells. NAD can also be produced by the NAD salvage pathway. 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. 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 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. 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.