The therapeutic perspective of NAD⁺ precursors in age-related diseases

Nicotinamide adenine dinucleotide (NAD⁺) is the fundamental molecule that performs numerous biological reactions and is crucial for maintaining cellular homeostasis. Studies have found that NAD⁺ decreases with age in certain tissues, and age-related NAD⁺ depletion affects physiological functions and contributes to various aging-related diseases. Supplementation of NAD⁺ precursor significantly elevates NAD⁺ levels in murine tissues, effectively mitigates metabolic syndrome, enhances cardiovascular health, protects against neurodegeneration, and boosts muscular strength. Despite the versatile therapeutic functions of NAD⁺ in animal studies, the efficacy of NAD⁺ precursors in clinical studies have been limited compared with that in the pre-clinical study. Clinical studies have demonstrated that NAD⁺ precursor treatment efficiently increases NAD⁺ levels in various tissues, though their clinical proficiency is insufficient to ameliorate the diseases. However, the latest studies regarding NAD⁺ precursors and their metabolism highlight the significant role of gut microbiota. The studies found that orally administered NAD⁺ intermediates interact with the gut microbiome. These findings provide compelling evidence for future trials to further explore the involvement of gut microbiota in NAD⁺ metabolism. Also, the reduced form of NAD⁺ precursor shows their potential to raise NAD⁺, though preclinical studies have yet to discover their efficacy. This review sheds light on NAD⁺ therapeutic efficiency in preclinical and clinical studies and the effect of the gut microbiota on NAD⁺ metabolism.