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.