Nicotinamide adenine dinucleotide (NAD⁺) stands at the forefront of cellular metabolism, serving as a pivotal coenzyme in redox reactions, DNA repair, and signaling pathways essential for maintaining cellular homeostasis. Over recent decades, the scientific community has increasingly focused on the role of NAD⁺ in ageing and age-associated disorders, driven by compelling evidence from preclinical animal studies suggesting a decline in NAD⁺ levels as organisms age. This decline is hypothesized to contribute to metabolic dysfunction, genome instability, and impaired cellular resilience, collectively exacerbating the ageing process and the onset of chronic diseases. Despite this, the translation of these findings to humans has yielded inconsistent and often contradictory results, prompting a re-examination of NAD⁺’s role in human ageing and the therapeutic potential of NAD⁺ precursor supplementation.
The allure of NAD⁺ precursors as anti-ageing interventions originates from their capacity to replenish cellular NAD⁺ pools, thereby ostensibly restoring metabolic balance and enhancing cellular repair mechanisms. In rodent models, supplementation with compounds such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) has been associated with improvements in mitochondrial function, cognitive performance, and lifespan extension. However, human clinical trials investigating the efficacy of NAD⁺ precursor supplements have largely produced modest or equivocal outcomes. These discrepancies underscore the complexity of NAD⁺ metabolism in humans and hint at nuanced, tissue-specific dynamics that diverge from those observed in animal models.
Critically, the quantification of NAD⁺ levels in human tissues remains a formidable challenge, constrained by the invasiveness of sampling techniques and the paucity of longitudinal data. Unlike rodents, where tissue biopsies can be systematically obtained and analyzed, human studies often rely on peripheral blood or limited tissue biopsies, which may not fully capture the systemic and local variations of NAD⁺ status. Moreover, the heterogeneity of human populations, influenced by genetics, lifestyle, diet, and comorbidities, adds layers of variability challenging the interpretation of NAD⁺ dynamics with ageing.
Emerging evidence tentatively confirms an age-associated decline in NAD⁺ in select human tissues such as skeletal muscle and brain, yet this decline is neither universal nor consistent across all studies. The complexity deepens when considering NAD⁺ precursor supplementation, which has shown variable efficacy across different tissues. For instance, some studies report increased NAD⁺ concentrations in skeletal muscle or blood following NR or NMN administration, while others detect minimal or transient changes. This variability raises pivotal questions about the bioavailability, tissue targeting, and metabolic fate of supplemented precursors in humans.
At the molecular level, NAD⁺ functions both as a substrate for enzymes like sirtuins and poly(ADP-ribose) polymerases (PARPs) and as a redox carrier shuttling electrons during metabolic reactions. The balance between NAD⁺ synthesis, consumption, and recycling governs cellular energetic and stress responses. Ageing disrupts this balance by elevating NAD⁺ consumption through DNA damage and chronic inflammation, simultaneously impairing biosynthetic pathways. Understanding how these opposing forces influence NAD⁺ pools in distinct tissues remains fundamental for devising effective therapeutic strategies.
In addition to systemic factors, intracellular compartmentalization of NAD⁺ adds complexity. NAD⁺ pools exist in cytosolic, nuclear, and mitochondrial compartments, each fulfilling unique roles. The crosstalk between these pools and their regulation may vary with age and disease states, potentially explaining the differential responses observed upon supplementation. Current analytical methods often measure total NAD⁺ without resolving compartment-specific dynamics, limiting mechanistic insights.
Clinical trials to date have predominantly focused on relatively healthy older adults, often employing short-duration supplementation and limited dosing regimens. Such parameters may be insufficient to elicit measurable biological effects, especially considering age-related declines in NAD⁺ biosynthetic efficiency and possible alterations in precursor uptake or metabolism. Future studies will need to explore optimized dosing, duration, and combination therapies, as well as stratify participants based on metabolic and molecular biomarkers to identify responders versus non-responders.
Beyond ageing, NAD⁺ metabolism intersects intimately with various pathological conditions, including metabolic syndrome, neurodegenerative diseases, and cardiovascular disorders. The interplay between disease processes and NAD⁺ homeostasis may complicate interpretation of supplementation outcomes. For example, chronic diseases may impose heightened NAD⁺ consumption or impair salvage pathways, necessitating tailored therapeutic approaches. Personalized medicine frameworks incorporating NAD⁺ metabolism profiling could enhance intervention efficacy.
Furthermore, the safety profile of long-term NAD⁺ precursor supplementation warrants thorough investigation. While generally well-tolerated in short-term trials, potential off-target effects, metabolic imbalances, or perturbations of cellular signaling pathways must be carefully scrutinized in larger and extended studies. Regulatory oversight and standardized protocols will be crucial as these compounds gain popularity as nutraceuticals.
Technological advancements in mass spectrometry, imaging, and omics methodologies promise to shed light on the intricate landscape of NAD⁺ metabolism across tissues and disease states. These tools enable quantification of NAD⁺ and related metabolites with high spatial and temporal resolution, providing unprecedented opportunities to elucidate mechanisms underlying NAD⁺ dynamics and to refine supplementation strategies.
In sum, the enthusiasm for NAD⁺ precursor supplementation as a panacea for ageing-related decline is tempered by a nascent and fragmented clinical evidence base. Bridging the translational gap from rodent models to humans demands a concerted effort to conduct comprehensive, multisystem clinical studies integrating molecular, cellular, and physiological endpoints. Such endeavors will clarify the true potential and limitations of NAD⁺-targeted therapies in promoting healthy human ageing.
Ultimately, advancing this field hinges on embracing the biological complexity of NAD⁺ metabolism and recognizing the multifactorial nature of ageing. Integrative research initiatives that factor in genetics, lifestyle, metabolic health, and environmental exposures are essential to devise precision interventions. As the scientific community accelerates towards these goals, NAD⁺ precursor supplementation remains a compelling yet evolving frontier in the quest to decipher and modulate the ageing process.
Subject of Research:
Nicotinamide adenine dinucleotide (NAD⁺) metabolism and its modulation through precursor supplementation in the context of human ageing.
Article Title:
NAD⁺ precursor supplementation in human ageing: clinical evidence and challenges.
Article References:
Vinten, K.T., Trętowicz, M.M., Coskun, E. et al. NAD⁺ precursor supplementation in human ageing: clinical evidence and challenges. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01387-7
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