Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations

Abstract Alterations in cellular nicotinamide adenine dinucleotide (NAD + ) levels have been observed in multiple lifestyle and age-related medical conditions. This has led to the hypothesis that dietary supplementation with NAD + precursors, or vitamin B3s, could exert health benefits. Among the different molecules that can act as NAD + precursors, Nicotinamide Riboside (NR) has gained most attention due to its success in alleviating and treating disease conditions at the pre-clinical level. However, the clinical outcomes for NR supplementation strategies have not yet met the expectations generated in mouse models. In this review we aim to provide a comprehensive view on NAD + biology, what causes NAD + deficits and the journey of NR from its discovery to its clinical development. We also discuss what are the current limitations in NR-based therapies and potential ways to overcome them. Overall, this review will not only provide tools to understand NAD + biology and assess its changes in disease situations, but also to decide which NAD + precursor could have the best therapeutic potential.