Shoji Mayumi, Kato Hisaya, Koshizaka Masaya, Kaneko Hiyori, Baba Yusuke, Ishikawa Takahiro, Teramoto Naoya, Kinoshita Daisuke, Yamaguchi Ayano, Maeda Yukari, Inaba Yosuke, Shiko Yuki, Ozawa Yoshihito, Bohr Vilhelm A, Maezawa Yoshiro, Yokote Koutaro
Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.
Division of Diabetes, Department of Medicine, Metabolism and Endocrinology, Chiba University Hospital, Chiba, Japan.
Aging Cell. 2025 Aug;24(8):e70093. doi: 10.1111/acel.70093. Epub 2025 Jun 3.
Werner syndrome (WS) is a rare hereditary progeroid syndrome caused by mutations in the WRN gene. Patients frequently develop various age-associated diseases prematurely, often leading to early mortality (≤ 60 years of age). Depletion of nicotinamide adenine dinucleotide (NAD) has been reported in patients with WS, suggesting a key role in the pathogenesis of WS. NAD supplementation may improve the condition of WS and other accelerated aging diseases. Therefore, we conducted a double-blind, randomized, crossover, placebo-controlled trial in patients with WS to evaluate the safety and efficacy of the NAD precursor, nicotinamide riboside (NR). NR (1000 mg) or placebo capsules were self-administered once daily for 26 weeks, followed by a crossover to the opposite arm for another 26 weeks. The primary endpoint was the safety of NR. Secondary endpoints included NAD levels in plasma, number, and size of skin ulcers, blood examinations, sarcopenia, heel pad thickness, cardio-ankle vascular index (CAVI), and ankle-brachial index. The exploratory endpoints involved metabolome profiles of plasma. No serious adverse events were observed during NR treatment. Importantly, CAVI improved, the skin ulcer area decreased, and heel pad thinning showed a declining trend. Metabolomic analysis revealed a significant decrease in blood creatinine. NR treatment significantly improved arterial stiffness, as indicated by CAVI, and likely suppressed renal functional decline in patients with WS. Therefore, NR may be beneficial for preventing atherosclerosis, skin ulcers, and kidney dysfunction in patients with WS.
沃纳综合征（WS）是一种由WRN基因突变引起的罕见遗传性早老综合征。患者经常过早出现各种与年龄相关的疾病，常导致过早死亡（≤60岁）。据报道，WS患者体内烟酰胺腺嘌呤二核苷酸（NAD）水平降低，提示其在WS发病机制中起关键作用。补充NAD可能改善WS及其他加速衰老疾病的病情。因此，我们对WS患者进行了一项双盲、随机、交叉、安慰剂对照试验，以评估NAD前体烟酰胺核糖苷（NR）的安全性和有效性。NR（1000毫克）或安慰剂胶囊每天自行服用一次，持续26周，然后交叉至另一组再进行26周。主要终点是NR的安全性。次要终点包括血浆中NAD水平、皮肤溃疡的数量和大小、血液检查、肌肉减少症、足跟垫厚度、心踝血管指数（CAVI）和踝臂指数。探索性终点涉及血浆代谢组谱。在NR治疗期间未观察到严重不良事件。重要的是，CAVI改善，皮肤溃疡面积减小，足跟垫变薄呈下降趋势。代谢组学分析显示血肌酐显著降低。如CAVI所示，NR治疗显著改善了动脉僵硬度，并可能抑制了WS患者的肾功能下降。因此，NR可能对预防WS患者的动脉粥样硬化、皮肤溃疡和肾功能障碍有益。
