Nicotinamide Riboside and Dihydronicotinic Acid Riboside Synergistically Increase Intracellular NAD⁺ by Generating Dihydronicotinamide Riboside

Through evolution, eukaryote organisms have developed the ability to use different molecules as independent precursors to generate nicotinamide adenine dinucleotide (NAD⁺), an essential molecule for life. However, whether these different precursors act in an additive or complementary manner is not truly well understood. Here, we have evaluated how combinations of different NAD⁺ precursors influence intracellular NAD⁺ levels. We identified dihydronicotinic acid riboside (NARH) as a new NAD⁺ precursor in hepatic cells. Second, we demonstrate how NARH, but not any other NAD+ precursor, can act synergistically with nicotinamide riboside (NR) to increase NAD⁺ levels in cultured cells and in mice. Finally, we demonstrate that the large increase in NAD⁺ prompted by the combination of these two precursors is due to their chemical interaction and conversion to dihydronicotinamide riboside (NRH). Altogether, this work demonstrates for the first time that NARH can act as a NAD⁺ precursor in mammalian cells and how different NAD⁺ precursors can interact and influence each other when co‐administered.