NAD⁺, the essential metabolite involved in multiple reactions such as the regulation of cellular metabolism, energy production, DNA repair, mitophagy and autophagy, inflamma-tion, and neuronal function, has been the subject of intense research in the field of aging and disease over the last decade. NAD⁺ levels decline with aging and in some age-related dis-eases, and reduction in NAD⁺ affects all the hallmarks of aging. Here, we present an overview of the discovery of NAD⁺, the cellular pathways of producing and consuming NAD⁺, and discuss how imbalances in the production rate and cellular request of NAD⁺ likely contribute to aging and age-related diseases including neurodegeneration. Preclinical studies have revealed great potential for NAD⁺ precursors in promotion of healthy aging and improvement of neurodegeneration. This has led to the initiation of several clinical trials with NAD⁺ precursors to treat accelerated aging, age-associated dysfunctions, and diseases including Alzheimer’s and Parkinson’s. NAD supplementation has great future potential clinically, and these studies will also provide insight into the mechanisms of aging.