Pharmacological Research · Nov 2026
From NAD+ elevation to clinical benefit: tissue-specific regulation and translational barriers in aging and age-related disease
By Pei Z, Zhong M, Jiang Q et al.
Nicotinamide adenine dinucleotide (NAD⁺) decline has been implicated in aging and age-related disease, and precursor supplementation with nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN) has shown efficacy in preclinical models. Human trials, however, have produced inconsistent functional outcomes, and the sources of this translational gap remain poorly defined. We combined a bibliometric analysis of 3,271 aging-focused NAD⁺ publications (2004–2025) with a critical synthesis of mechanistic and clinical evidence to localize where and why preclinical findings fail to translate. The bibliometric analysis revealed three structural features of the literature: (i) original research articles dominated the corpus, whereas the document-type classification cannot distinguish preclinical experiments from human observational or interventional studies; (ii) research is siloed across disease domains with limited cross-tissue comparison; and (iii) intervention-oriented keywords (NMN, NR, supplementation, drug delivery) have outpaced empirical clinical validation. Mechanistic synthesis showed that these structural gaps correspond to biological heterogeneity: NAD⁺ biosynthesis, consumption, redox balance, and subcellular compartmentalization are tissue- and compartment-specific, such that systemic precursor elevation does not uniformly restore functional NAD⁺ in disease-relevant tissues. Four subcellular pools—nuclear, cytosolic, mitochondrial, and axonal—each possess distinct rate-limiting bottlenecks, and hepatic metabolic reserve introduces an overlooked source of inter-individual variability. Across neurodegeneration, metabolic disease, cardiovascular aging, and sarcopenia, NAD⁺ dysregulation follows disease-specific mechanisms rather than a universal decline phenotype. We propose a precision-medicine framework that shifts the core question from whether NAD⁺ can be elevated to whether a defined intervention corrects a specific NAD⁺ defect in the appropriate tissue and subcellular compartment. This framework provides a structured basis for designing next-generation NAD⁺-targeted trials with tissue-specific biomarkers and function-oriented endpoints.