A reduced form of nicotinamide riboside defines a new path for NAD(+) biosynthesis and acts as an orally bioavailable NAD(+) precursor

OBJECTIVE: A decay in intracellular NAD(+) levels is one of the hallmarks of physiological decline in normal tissue functions. Accordingly, dietary supplementation with NAD(+) precursors can prevent, alleviate, or even reverse multiple metabolic complications and age-related disorders in diverse model organisms. Within the constellation of NAD(+) precursors, nicotinamide riboside (NR) has gained attention due to its potent NAD(+) biosynthetic effects in vivo while lacking adverse clinical effects. Nevertheless, NR is not stable in circulation, and its utilization is rate-limited by the expression of nicotinamide riboside kinases (NRKs). Therefore, there is a strong interest in identifying new effective NAD(+) precursors that can overcome these limitations. METHODS: Through a combination of metabolomics and pharmacological approaches, we describe how NRH, a reduced form of NR, serves as a potent NAD(+) precursor in mammalian cells and mice. RESULTS: NRH acts as a more potent and faster NAD(+) precursor than NR in mammalian cells and tissues. Despite the minor structural difference, we found that NRH uses different steps and enzymes to synthesize NAD(+), thus revealing a new NRK1-independent pathway for NAD(+) synthesis. Finally, we provide evidence that NRH is orally bioavailable in mice and prevents cisplatin-induced acute kidney injury. CONCLUSIONS: Our data identify a new pathway for NAD(+) synthesis and classify NRH as a promising new therapeutic strategy to enhance NAD(+) levels.