延长正常细胞和类早衰细胞复制寿命的新药。

IF 5.4 Q1 GERIATRICS & GERONTOLOGY NPJ Aging and Mechanisms of Disease Pub Date : 2019-01-16 eCollection Date: 2019-01-01 DOI:10.1038/s41514-018-0032-4
Sergei Vatolin, Tomas Radivoyevitch, Jaroslaw P Maciejewski
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引用次数: 9

摘要

开发了一种高通量抗衰老药物筛选,同时测量衰老相关β-半乳糖苷酶活性和增殖。应用于复制性预衰老成纤维细胞,该筛选结果显示,紫尿酸(VA)和1-萘醌-2-单肟(N2N1)是其前两大热门。这些先导化合物以剂量依赖的方式延长了正常和类早衰人类细胞的复制寿命,也延长了小鼠和秀丽隐杆线虫的按时间顺序的寿命。它们在NAD(P)H的氧化过程中起到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比率的下降。VA参与从NAD(P)H到氧化谷胱甘肽或过氧化物的非酶电子转移。N2N1通过NAD(P)H脱氢酶(醌)1 (NQO1)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对NQO1活性的药理学操作可能揭示衰老和衰老的机制。
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New drugs for pharmacological extension of replicative life span in normal and progeroid cells.

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.

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来源期刊
NPJ Aging and Mechanisms of Disease
NPJ Aging and Mechanisms of Disease Medicine-Geriatrics and Gerontology
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审稿时长
8 weeks
期刊介绍: npj Aging and Mechanisms of Disease is an online open access journal that provides a forum for the world’s most important research in the fields of aging and aging-related disease. The journal publishes papers from all relevant disciplines, encouraging those that shed light on the mechanisms behind aging and the associated diseases. The journal’s scope includes, but is not restricted to, the following areas (not listed in order of preference): • cellular and molecular mechanisms of aging and aging-related diseases • interventions to affect the process of aging and longevity • homeostatic regulation and aging • age-associated complications • translational research into prevention and treatment of aging-related diseases • mechanistic bases for epidemiological aspects of aging-related disease.
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