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Patients frequently develop various age\u2010associated diseases prematurely, often leading to early mortality (\u2264\u200960\u2009years of age). Depletion of nicotinamide adenine dinucleotide (NAD)<jats:sup>+<\/jats:sup> has been reported in patients with WS, suggesting a key role in the pathogenesis of WS. NAD<jats:sup>+<\/jats:sup> supplementation may improve the condition of WS and other accelerated aging diseases. Therefore, we conducted a double\u2010blind, randomized, crossover, placebo\u2010controlled trial in patients with WS to evaluate the safety and efficacy of the NAD<jats:sup>+<\/jats:sup> precursor, nicotinamide riboside (NR). NR (1000\u2009mg) or placebo capsules were self\u2010administered once daily for 26\u2009weeks, followed by a crossover to the opposite arm for another 26\u2009weeks. The primary endpoint was the safety of NR. Secondary endpoints included NAD<jats:sup>+<\/jats:sup> levels in plasma, number, and size of skin ulcers, blood examinations, sarcopenia, heel pad thickness, cardio\u2013ankle vascular index (CAVI), and ankle\u2013brachial 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. 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