Werner syndrome (WS) represents a profoundly rare genetic disorder characterized by an accelerated aging phenotype, afflicting individuals with premature onset of conditions typically observed in elderly populations. Manifesting usually in individuals’ twenties, this syndrome rapidly progresses to cause hallmark symptoms such as graying hair, alopecia, cataracts, diabetes mellitus, and an array of degenerative changes across multiple organ systems. Beyond mere cosmetic concerns, patients commonly suffer from chronic and debilitating skin ulcers, which frequently resist conventional therapies and often necessitate limb amputation. This systemic affliction culminates tragically, with cardiovascular disease and malignancies constituting the primary causes of early mortality among sufferers. Despite being exceedingly scarce—affecting approximately nine per million in Japan—WS remains largely untreatable, rendering it a devastating diagnosis with profound impacts on patient quality of life.
At the molecular core of WS lies a deficiency in the Werner protein, a DNA helicase integral to genomic stability, DNA repair, and telomere maintenance. Disruptions in these crucial cellular processes precipitate accelerated cellular senescence and dysfunction. Recent advances in understanding WS pathogenesis highlight a significant depletion of nicotinamide adenine dinucleotide (NAD⁺), a central coenzyme involved in redox reactions, energy metabolism, and DNA repair pathways. This finding emerged from pioneering research conducted by the Bohr laboratory, which revealed that both WS patient-derived cells and model systems exhibited markedly reduced NAD⁺ levels. NAD⁺’s multifaceted role in cellular bioenergetics and genomic maintenance suggested its depletion could be a driving force behind the systemic manifestations of WS.
Direct NAD⁺ supplementation presents substantial challenges in mammalian systems, primarily due to its poor bioavailability and rapid degradation. Consequently, attention has shifted toward administering NAD⁺ precursors capable of enhancing intracellular NAD⁺ pools more effectively. Nicotinamide riboside (NR), an NAD⁺ precursor produced and patented by Niagen Bioscience, has demonstrated remarkable efficacy in preclinical models by boosting NAD⁺ levels, extending lifespan, and ameliorating age-associated functional decline. Human clinical trials have corroborated NR’s potential, revealing favorable outcomes in reducing chronic inflammation, improving metabolic parameters, and enhancing muscle strength across diverse demographics. However, the therapeutic potential of NR in the context of WS remained unexplored until the groundbreaking endeavor led by Associate Professor Masaya Koshizaka at Chiba University, Japan.
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In an unprecedented rigorously designed clinical trial, Koshizaka and colleagues orchestrated the world’s first randomized, double-blind, placebo-controlled crossover study assessing the safety and efficacy of NR supplementation in individuals diagnosed with WS. The trial incorporated a sophisticated crossover model in which participants received either 250 mg NR capsules or placebo daily for 26 weeks before swapping treatments for a subsequent 26-week period. This meticulous protocol maximized statistical power despite the rarity of the disease and allowed each patient to serve as their own control. The study meticulously evaluated several biomarkers inclusive of blood NAD⁺ concentration, skin ulcer dimensions, arterial stiffness via pulse wave velocity measurements, and renal function indices.
The results from this landmark trial illuminated substantial elevations in NAD⁺ levels within patient bloodstreams during NR administration phases compared to the placebo periods. This biochemical restoration correlated strongly with clinically meaningful improvements: arterial stiffness showed marked reduction, indicating amelioration of vascular health and reduced cardiovascular risk. Concurrently, skin ulcer areas diminished significantly, suggesting enhanced tissue repair and mitigation of one of WS’s most debilitating clinical features. Furthermore, renal function parameters indicated a deceleration in the progression of kidney impairment—a common and severe complication in WS—signaling NR’s protective effects extend beyond vascular and integumentary systems.
Comprehensive metabolomic analyses unveiled that NR supplementation effectively decreased circulating levels of creatinine and other metabolites typically elevated during renal dysfunction, underscoring NR’s multifactorial role in systemic health preservation. Critically, no serious adverse events or toxicity signals emerged, underscoring the intervention’s safety profile for this vulnerable patient cohort. These findings collectively position NR supplementation as a promising therapeutic avenue targeting fundamental pathophysiological mechanisms underlying WS, namely NAD⁺ depletion and its downstream deleterious effects.
Dr. Yasmeen Nkrumah-Elie, who oversees the External Research Program at Niagen Bioscience, eloquently underscored the significance of this work, describing it as a pivotal advancement in elucidating how NAD⁺ restoration may intervene in WS’s complex biology. By evidencing tangible benefits to cardiovascular, dermatologic, and renal systems, NR supplementation opens a novel therapeutic frontier for enhancing life quality and potentially extending life expectancy in WS patients. Niagen Bioscience’s role, though restricted to provision of investigational materials, highlights an evolving partnership between academia and industry driving forward NAD⁺ science in the realm of rare and neglected diseases.
Beyond immediate clinical implications, Koshizaka’s study advances fundamental aging research by substantiating NAD⁺ depletion as a key mechanistic link connecting genomic instability with systemic tissue dysfunction. The research provides a compelling exemplar of precision medicine approaches that leverage molecular insights to counteract debilitating premature aging syndromes. Dr. Koshizaka emphasized that NR’s dual capacity to combat arteriosclerosis and chronic skin ulcer formation—both profoundly impactful symptoms in WS—heralds a critical step toward mitigating early mortality and enhancing patient mobility and autonomy.
The broader scope of this research offers implications for geroscience at large. WS serves as a human model for accelerated aging, and therapeutic successes in this population may inform interventions for common age-related diseases afflicting millions globally. Researchers anticipate that augmenting NAD⁺ levels through precursor supplementation could emerge as a cornerstone in strategies aimed at prolonging healthspan and counteracting physiological decline rooted in metabolic insufficiency and impaired DNA maintenance.
Although the study’s sample size was inherently limited due to WS’s rarity, the robust crossover design and comprehensive biomarker assessment provide compelling preliminary evidence warranting expanded clinical investigations. Ongoing and future studies are anticipated to delve into NR’s mechanistic actions more deeply, optimize dosing strategies, and explore combinatorial regimens that may synergize NR’s effects with other emergent therapies targeting senescence and inflammation.
Dr. Koshizaka concluded with an optimistic vision that the findings will catalyze accelerated research not only within the domain of WS but also across diverse premature aging disorders and broader age-related pathologies. This integrative approach aims to ultimately extend healthspan and enhance quality of life across populations, embodying a paradigm shift in precision aging therapeutics shaped by molecular medicine.
In conclusion, this pioneering clinical trial marks a transformative moment in the treatment landscape of Werner syndrome by elucidating the therapeutic potential of nicotinamide riboside supplementation. By restoring NAD⁺ homeostasis, the intervention counters multiple facets of WS pathology—including vascular dysfunction, chronic ulceration, and renal decline—without compromising safety. This advancement fosters renewed hope for an underserved patient population and enriches the scientific understanding of aging biology with tangible translational ramifications.
Subject of Research: People
Article Title: Nicotinamide riboside supplementation benefits in patients with Werner syndrome: A double-blind randomized crossover placebo-controlled trial
News Publication Date: 3-Jun-2025
Web References:
https://doi.org/10.1111/acel.70093
References:
Koshizaka M, et al. Nicotinamide riboside supplementation benefits in patients with Werner syndrome: A double-blind randomized crossover placebo-controlled trial. Aging Cell. 2025 Jun 3;10(1):5284.
Image Credits:
Department of Pathology at the University of Washington, USA.
Keywords: Werner syndrome, nicotinamide riboside, NAD⁺, accelerated aging, double-blind clinical trial, vascular health, skin ulcers, kidney function, metabolic disorders, DNA repair, age-related disease, therapeutic intervention
Tags: accelerated aging syndromescardiovascular disease in WS patientschronic skin ulcers in Werner syndromeearly mortality in rare diseasesgenetic disorders and agingNAD+ role in DNA repairquality of life for WS patientsrare genetic disorders prevalencerecent research on Werner syndromesystemic effects of Werner syndromeWerner protein deficiencyWerner syndrome treatment breakthroughs
