A systematic analysis of 113 studies reveals that while NAD⁺ precursors like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) consistently increase NAD-related metabolites in humans, their effects on functional health outcomes remain largely unproven. The review examined 33 human studies and 80 rodent studies, finding that oral NR and NMN supplements reliably demonstrate 'biochemical target engagement' in plasma and cells over weeks to months of use. This represents a crucial disconnect in the longevity field. The consistent ability of these compounds to boost NAD⁺ levels creates compelling biological rationale, given NAD⁺'s central role in cellular energy production, DNA repair, and sirtuin activation. Yet the translation to meaningful health benefits appears far more complex than the direct supplementation model suggests. The findings underscore a broader challenge in aging research: biological activity doesn't automatically translate to clinical benefit. This is particularly relevant given the rapid commercialization of NAD⁺ supplements, often marketed with claims that outpace the evidence. The review's call for longer, larger trials with clinically meaningful endpoints reflects the field's maturation from proof-of-concept to rigorous clinical validation.