In a groundbreaking expert consensus published in Nature Aging, a collective of over 25 internationally renowned scientists and clinicians have shed new light on the pivotal role of nicotinamide adenine dinucleotide (NAD⁺) in aging biology and metabolic health. This comprehensive review comes as the scientific community intensifies efforts to decipher how modulation of NAD⁺ metabolism could revolutionize healthcare by delaying age-associated decline and mitigating chronic diseases such as Alzheimer’s and Parkinson’s. Spearheaded by researchers from the University of Oslo and Akershus University Hospital, along with global collaborators, this article delineates both the promise and the challenges of translating NAD⁺-based interventions from bench to bedside.
NAD⁺ is a coenzyme found in every living cell and acts as a crucial metabolic regulator, often likened to a cellular “fuel gauge.” It orchestrates a diverse array of biological processes, including cellular respiration, DNA repair, and maintenance of mitochondrial function. As organisms age, NAD⁺ concentrations demonstrably wane, correlating with weakened cellular resilience, diminished energy metabolism, and increased vulnerability to neurodegenerative and cardiovascular disorders. This age-related NAD⁺ depletion is not merely a biomarker but appears to be a fundamental driver of physiological decline, making it a prime target for therapeutic intervention.
The article thoroughly examines how NAD⁺ biosynthesis pathways can be augmented pharmacologically. Compounds such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) — both vitamin B3 derivatives — have emerged as leading supplements capable of elevating systemic NAD⁺ levels. Preclinical studies in animal models have yielded promising results, demonstrating enhanced cognitive function, improved muscle performance, and better metabolic profiles. However, the authors emphasize that human clinical trials remain in their infancy and present a heterogeneous landscape requiring rigorous standardization and replication to confirm efficacy and safety.
One core focus of this review is the intricate balance required in NAD⁺ modulation. Dr. Jianying Zhang, one of the key authors, highlights that while augmenting NAD⁺ holds therapeutic potential, understanding the optimal dose-response relationship is critical. Over-supplementation might have unexpected consequences given NAD⁺’s involvement in multiple signaling pathways. Hence, long-term safety profiles coupled with personalized medicine approaches are necessary to tailor NAD⁺-enhancement strategies to individual patients.
Importantly, the article serves as a clarion call for multidisciplinary collaboration. Despite NAD⁺’s fundamental biological importance, the field is plagued by fragmented data and commercial hype that cloud scientific judgment. By consolidating the current knowledge base, this consensus aims to provide researchers and clinicians with a structured framework to navigate ongoing clinical trials and exploratory research. The authors advocate for unified protocols, larger sample sizes, and stratification strategies that acknowledge interindividual variability, such as genetic differences, lifestyle factors, and comorbidities.
The timing of this review is particularly pertinent. Globally, a surge of clinical trials are underway testing NAD⁺ precursors in various contexts — from neurodegeneration and cardiovascular disease to metabolic syndromes. The public and commercial enthusiasm for these supplements has surged in parallel, sometimes eclipsing the delicate nuances of underlying biology. The experts caution against premature conclusions and stress the necessity of empirical evidence to substantiate claims. Their balanced outlook underscores the need to discern which NAD⁺-boosting agents are most effective and to identify clinical scenarios where intervention yields meaningful outcomes.
On a mechanistic level, NAD⁺ acts as a substrate for sirtuins, PARPs (poly ADP-ribose polymerases), and other enzymes pivotal in genome stability and cellular stress responses. These enzymatic activities orchestrate processes integral to longevity and disease resistance. The depletion of NAD⁺ impairs these critical functions, accelerating senescence and deterioration. Thus, strategies that restore NAD⁺ are not merely symptom-targeting but may halt or reverse foundational processes in the aging trajectory. Nonetheless, translating molecular insights into clinically viable treatments remains an intricate endeavor.
The review does not shy away from discussing the challenges confronting the field. Variability in bioavailability, tissue-specific NAD⁺ metabolism, and potential off-target effects remain unknowns. Furthermore, the authors recognize the potential for NAD⁺ metabolism to interact with other age-related pathways and emphasize the importance of integrative research that considers the broader physiological network. Regulatory frameworks and ethical considerations around NAD⁺-based therapies add further complexity, especially as commercial interests accelerate product availability.
Norwegian contributors, including Sofie Lautrup, Hilde Loge Nilsen, Leiv Otto Watne, and others, collaborated closely with international experts from Denmark, Japan, the United States, and beyond. Their collective expertise spans clinical neurology, cardiology, molecular biology, and aging research, lending unparalleled depth to the review. This global effort not only synthesizes decades of research but sets an ambitious agenda for the years ahead.
One noteworthy aspect is the transparent disclosure of potential conflicts of interest, notably by senior author Dr. Evandro Fei Fang-Stavem, who maintains ties with commercial entities developing NAD⁺ precursor technologies. The authors assert that their expert opinion is grounded in rigorous scientific evaluation and aim to delineate clear, evidence-based guidance free from commercial bias. This candidness strengthens the credibility of their conclusions.
In conclusion, this comprehensive expert opinion elucidates how NAD⁺ modulation stands at the frontier of aging research. While the therapeutic potential is undeniably compelling, the field demands a disciplined, evidence-driven approach. By highlighting current knowledge gaps, defining methodological standards, and fostering international collaboration, the authors contribute a critical roadmap for transforming the biology of NAD⁺ into viable treatments. Future breakthroughs may ultimately redefine how we approach age-related diseases and harness the power of cellular metabolism to promote healthy longevity.
Subject of Research: People
Article Title: Emerging strategies, applications and challenges of targeting NAD+ in the clinic
News Publication Date: 9-Sep-2025
Web References: DOI: 10.1038/s43587-025-00947-6
References:
Zhang J, Wang H-L, Lautrup S, Nilsen HL, Treebak JT, Watne LO, Selbæk G, Wu LE, Omland T, Pirinen E, Cheung TC, Wang J, Ziegler M, Tysnes O-B, Zapata-Pérez R, Bruzzone S, Cantó C, Deleidi M, Janssens GE, Houtkooper RH, Scheibye-Knudsen M, Koshizaka M, Yokote K, Verdin E, Bohr VA, Tzoulis C, Sinclair DA & Fang EF. Emerging strategies, applications and challenges of targeting NAD⁺ in the clinic. Nature Aging (Published online 9 September 2025).
Keywords: NAD⁺, aging, metabolism, nicotinamide riboside, nicotinamide mononucleotide, sirtuins, DNA repair, neurodegeneration, clinical trials, mitochondrial function, longevity, metabolic health
