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.