Abstract
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.