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.