NAD homeostasis in human health and disease.

Depletion of nicotinamide adenine dinucleotide (NAD ), a central redox cofactor and the substrate of key metabolic enzymes, is the causative factor of a number of inherited and acquired diseases in humans. Primary deficiencies of NAD homeostasis are the result of impaired biosynthesis, while secondary deficiencies can arise due to other factors affecting NAD homeostasis, such as increased NAD consumption or dietary deficiency of its vitamin B3 precursors. NAD depletion can manifest in a wide variety of pathological phenotypes, ranging from rare inherited defects, characterized by congenital malformations, retinal degeneration, and/or encephalopathy, to more common multifactorial, often age-related, diseases. Here, we discuss NAD biochemistry and metabolism and provide an overview of the etiology and pathological consequences of alterations of the NAD metabolism in humans. Finally, we discuss the state of the art of the potential therapeutic implications of NAD repletion for boosting health as well as treating rare and common diseases, and the possibilities to achieve this by means of the different NAD -enhancing agents.