New drugs for pharmacological extension of replicative life span in normal and progeroid cells.
New drugs for pharmacological extension of replicative life span in normal and progeroid cells.
复制标题
用于药理学延长正常细胞和早衰细胞复制寿命的新药。
DOI：
10.1038/s41514-018-0032-4
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发表时间：
2019
影响因子：
5
通讯作者：
Maciejewski,JaroslawP
中科院分区：
文献类型：
--
作者：
Vatolin,Sergei;Radivoyevitch,Tomas;Maciejewski,JaroslawP
开发了高通量抗衰老药物筛选，其同时测量衰老相关的β-半乳糖苷酶活性和增殖。应用于复制性预老化的成纤维细胞，该筛选产生紫尿酸（VA）和1-萘醌-2-单肟（N2 N1）作为其前两个命中。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，也延长了小鼠和C。优雅本文进一步显示它们在NAD（P）H的氧化中作为氧化还原催化剂起作用。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促电子转移。N2 N1通过NAD（P）H脱氢酶（醌）1（NQO 1）将电子从NAD（P）H转移到细胞色素c或辅酶Q10。我们的研究结果表明，通过氧化还原催化剂的NQO 1活性的药理学操纵可能揭示衰老和老化的机制。
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 CoQ10via 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.