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

摘要

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.