NAD+ metabolism as a target for metabolic health: have we found the silver bullet?

Abstract

NAD⁺ has gone in and out of fashion within the scientific community a number of times since its discovery in the early 1900s. Over the last decade, NAD⁺ has emerged as a potential target for combatting metabolic disturbances and the mitochondrial dysfunction that is mediated through sirtuin (SIRT) enzymes. The beneficial metabolic effects of the NAD⁺/SIRT axis have triggered an increased interest in NAD⁺ as an enhancer of energy metabolism. As a result, a myriad of publications have focused on NAD⁺ metabolism, with the majority of the work having been performed using in vitro models, and in vivo work largely consisting of interventions in Caenorhabditis elegans and rodents. Human intervention trials, on the other hand, are scarce. The aim of this review is to provide an overview of the state-of-the-art on influencing NAD⁺ metabolism in humans and to set the stage for what the future of this exciting field may hold.

Keywords: Diabetes; Energy metabolism; Human; Metabolic disease; NAD+; Review.

Fig. 1

Summary of NAD⁺ metabolism. NAD⁺ can be synthesised from Trp through the de novo biosynthesis pathway in the liver and kidneys. Nicotinic acid (more commonly known as vitamin B₃) enters the NAD⁺ pool through the Preiss–Handler pathway, whereas nicotinamide, nicotinamide riboside and NMN (re-)enter the NAD⁺ pool through the salvage pathway. NAD⁺ is consumed by SIRTs, CD38, and PARP enzymes, producing nicotinamide, which enters the pool of NAD⁺ precursors for resynthesis into NAD⁺. Dashed arrow, movement of NAD⁺ within the NAD⁺ pool. NA, nicotinic acid; NAAD, nicotinic acid adenine dinucleotide; NAM, nicotinamide; NR, nicotinamide riboside. This figure is available as part of a downloadable slideset

Fig. 2

Effect of activating the NAD⁺/SIRT axis by increasing NAD⁺ bioavailability. Several approaches may be used to increase NAD⁺ bioavailability, including exercise, caloric restriction, dietary supplementation and inhibition of NAD⁺ consumption. These changes positively affect SIRT activation and subsequent PGC-1α and FOXO1 expression, resulting in mitochondrial changes and, as a consequence, metabolic adaptations. CD38i, CD38 inhibitor; FOXO1, forkhead box protein O1; NAM, nicotinamide; PARPi, PARP inhibitor. This figure is available as part of a downloadable slideset