NAD(+) metabolism: Bioenergetics, signaling and manipulation for therapy.
Review
Overview
abstract
We survey the historical development of scientific knowledge surrounding Vitamin B3, and describe the active metabolite forms of Vitamin B3, the pyridine dinucleotides NAD+ and NADP+ which are essential to cellular processes of energy metabolism, cell protection and biosynthesis. The study of NAD+ has become reinvigorated by new understandings that dynamics within NAD+ metabolism trigger major signaling processes coupled to effectors (sirtuins, PARPs, and CD38) that reprogram cellular metabolism using NAD+ as an effector substrate. Cellular adaptations include stimulation of mitochondrial biogenesis, a process fundamental to adjusting cellular and tissue physiology to reduced nutrient availability and/or increased energy demand. Several mammalian metabolic pathways converge to NAD+, including tryptophan-derived de novo pathways, nicotinamide salvage pathways, nicotinic acid salvage and nucleoside salvage pathways incorporating nicotinamide riboside and nicotinic acid riboside. Key discoveries highlight a therapeutic potential for targeting NAD+ biosynthetic pathways for treatment of human diseases. A recent emergence of understanding that NAD+ homeostasis is vulnerable to aging and disease processes has stimulated testing to determine if replenishment or augmentation of cellular or tissue NAD+ can have ameliorative effects on aging or disease phenotypes. This experimental approach has provided several proofs of concept successes demonstrating that replenishment or augmentation of NAD+ concentrations can provide ameliorative or curative benefits. Thus NAD+ metabolic pathways can provide key biomarkers and parameters for assessing and modulating organism health.
