A high-throughput anti-aging drug screen was developed that simultaneously measures senescence-associated β-galactosidase activity and proliferation. Applied to replicatively pre-aged fibroblasts, this screen yielded violuric acid (VA) and 1-naphthoquinone-2-monoxime (N2N1) as its top two hits. These lead compounds extended the replicative life spans of normal and progeroid human cells in a dose-dependent manner and also extended the chronological life spans of mice and C. elegans. They are further shown here to function as redox catalysts in oxidations of NAD(P)H. They thus slow age-related declines in NAD(P)⁺/NAD(P)H ratios. VA participates in non-enzymatic electron transfers from NAD(P)H to oxidized glutathione or peroxides. N2N1 transfers electrons from NAD(P)H to cytochrome c or CoQ₁₀ via NAD(P)H dehydrogenase (quinone) 1 (NQO1). Our results indicate that pharmacologic manipulation of NQO1 activity via redox catalysts may reveal mechanisms of senescence and aging.

开发了一种高通量抗衰老药物筛选剂，可同时测量与衰老相关的β-半乳糖苷酶活性和增殖。应用于可复制的预老化成纤维细胞，该筛选产生了紫尿酸（VA）和1-萘醌-2-一肟（N2N1）作为其前两大热门。这些先导化合物以剂量依赖的方式延长了正常和早衰人类细胞的复制寿命，并且还延长了小鼠和秀丽隐杆线虫的按时间顺序的寿命。它们在此处进一步显示在NAD（P）H的氧化中起氧化还原催化剂的作用。因此，它们减缓了与年龄相关的NAD（P）⁺ / NAD（P）H比值的下降。VA参与从NAD（P）H到氧化型谷胱甘肽或过氧化物的非酶电子转移。N2N1将电子从NAD（P）H转移到细胞色素c或CoQ ₁₀通过NAD（P）H脱氢酶（醌）1（NQO1）。我们的结果表明，通过氧化还原催化剂对NQO1活性进行药理处理可能揭示了衰老和衰老的机制。