Ageing inherently involves a gradual misalignment of diurnal cycles, which are tightly regulated physiological processes synchronized with the day-night cycle. These rhythms underpin critical biological functions, including metabolism, hormone secretion, and cellular repair. As organisms age, a noticeable decline in the coherence and amplitude of these cycles occurs, resulting in global reductions in physiological fitness. However, the molecular underpinnings governing this diurnal misalignment and its causal relationship with ageing phenotypes have long eluded scientists.

Addressing this knowledge gap, the investigative team employed comprehensive transcriptomic analyses across eight peripheral tissues in aged murine models, capturing high-resolution diurnal gene expression profiles. Their analyses revealed pervasive alterations in redox oscillations, characterized by attenuated rhythmicity and amplitude reduction in several tissues, particularly the liver and skeletal muscle. These findings suggest that disrupted redox homeostasis is a conserved hallmark of organismal ageing, implicating it as a potential driver of systemic physiological decline.

Crucially, the study did not stop at correlation but ventured into causative explorations. By implementing time-restricted interventions involving antioxidants and pro-oxidants, the researchers successfully restored redox oscillatory dynamics in aged mice. This temporal modulation of redox states yielded striking improvements in glucose metabolism and motor functions, two critical markers of physiological fitness. Moreover, the interventions alleviated classical ageing phenotypes in the liver and skeletal muscle, establishing a direct link between redox rhythm restoration and functional rejuvenation.

Beyond mere physiological observations, the study delved into multi-omics integrations, combining transcriptomics and epigenetics to uncover the molecular architecture altered by redox rhythm modulation. Notably, restoration efforts partially rejuvenated the hepatic transcriptome and chromatin accessibility patterns, specifically within ageing-associated signaling and metabolic pathways. This chromatin remodeling underscores the epigenetic plasticity retained in aged tissues and highlights redox oscillations as epigenetic modulators orchestrating gene expression landscapes during ageing.

At the molecular level, the circadian transcription factor CLOCK emerged as a pivotal mediator connecting redox rhythms with ageing biology. Through meticulous biochemical assays, the researchers demonstrated that redox modifications on specific cysteine residues of the CLOCK protein modulate its activity and, consequently, downstream gene regulatory networks. Importantly, perturbations to a redox-sensitive cysteine at position 195 induced premature ageing phenotypes and hepatic gene reprogramming in vivo, underscoring the functional significance of this post-translational modification in maintaining tissue homeostasis.

The cross-talk between redox biochemistry and circadian regulation exposed in this study challenges previous paradigms that have often treated these systems in isolation. By integrating redox chemistry into the circadian framework, the findings reveal a complex, bidirectional regulatory axis that controls metabolic and transcriptional fidelity with ageing. This insight opens new conceptual vistas for developing interventions that target temporal redox dynamics to sustain organismal fitness.

From a translational perspective, the use of time-restricted antioxidant and pro-oxidant delivery represents an intriguing and practical strategy. Unlike continuous dosing regimens, temporal modulation leverages intrinsic biological rhythms to maximize efficacy and minimize adverse effects. This approach aligns with emerging chronotherapy principles, which advocate synchronizing treatments with circadian phases to optimize outcomes, especially in age-related diseases such as diabetes and sarcopenia.

Furthermore, the improvements seen in glucose homeostasis indicate potential applications extending to metabolic syndromes prevalent in aged populations. By restoring redox rhythms, it might be possible to counteract insulin resistance and energy metabolism dysregulation, which are central to the pathogenesis of type 2 diabetes and other chronic conditions. Such clinical relevance underscores the importance of redox biology as a therapeutic target with wide-reaching implications.

Motor performance enhancements following redox rhythm reinstatement also highlight the impact on neuromuscular function and physical endurance. These findings suggest that oxidative timing influences muscle regeneration and neural coordination, which deteriorate with age, leading to frailty and loss of independence. Interventions capitalizing on redox oscillation restoration could thereby enhance quality of life and reduce healthcare burdens associated with ageing populations.

On a broader scale, this research underscores the interconnectedness of circadian biology, redox homeostasis, and ageing, motivating a systemic rather than reductionist approach to studying organismal decline. It invites a multidisciplinary integration of chronobiology, redox chemistry, epigenetics, and gerontology, propelling ageing research towards holistic models that better reflect biological complexity.

The revelation that redox rhythms influence chromatin accessibility also incites further investigation into the epigenetic landscapes governing longevity. Understanding how temporal redox states interface with histone modifications and DNA methylation patterns could unravel additional layers of gene regulation that sustain youthful functions or precipitate ageing. Such knowledge might catalyze development of novel epigenetic therapies sensitive to diurnal timing cues.

Moreover, the identification of CLOCK cysteine 195 as a redox-sensitive switch molecule paves the way for targeted molecular engineering. Future efforts could design small molecules or peptides that selectively modulate this site, harnessing redox modifications to fine-tune circadian output and delay ageing onset. This precision medicine approach exemplifies the promise of molecular chronobiology in extending healthspan.

Conclusively, this compelling body of work expedites a paradigm shift in ageing biology by placing redox rhythms at the nexus of physiological fitness and diurnal gene regulation. It substantiates the concept that aging is not merely a cumulative damage phenomenon but also a dynamic process amenable to temporal reprogramming. As the global demographic tilt towards older populations intensifies, such insights hold immense promise for devising longevity strategies that promote vibrant, healthy ageing.

The integration of multi-tissue transcriptomics with functional assays and epigenomic analyses delivers a comprehensive view of the ageing organism, bridging molecular events to systemic outcomes. This holistic methodology sets a new benchmark for ageing research, advocating for intricate temporal mapping of physiological states to decode the complexities underlying health decline.

Looking ahead, expanding investigations into human tissues and clinical trials will be critical to translate these findings. The conservation of redox and circadian mechanisms across species suggests strong translational potential, yet human heterogeneity and lifestyle factors must be accounted for in therapeutic design. Nonetheless, time-sensitive redox modulation emerges as a highly promising frontier in the quest to combat age-related diseases and enhance longevity.

Ultimately, this study exemplifies an elegant convergence of biochemistry, genetics, and physiology, illustrating how nuanced control of temporal biochemical oscillations can reshape the ageing trajectory. It advocates for a future where interventions are not only molecularly precise but temporally optimized, fostering a new era in ageing science and medicine centered on the synchrony of internal clocks and redox chemistry.

Subject of Research: Ageing biology; redox rhythms; circadian regulation; multi-omics; liver and skeletal muscle physiology; epigenetic reprogramming; metabolic and motor function in aged mice.

Article Title: Redox rhythms promote fitness by modulating ageing-dependent reprogramming.

Article References:
Wang, X., Cui, SS., Li, XK. et al. Redox rhythms promote fitness by modulating ageing-dependent reprogramming. Nat Metab (2026). https://doi.org/10.1038/s42255-026-01515-x

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s42255-026-01515-x

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