Identification of drugs that delay aging

延缓衰老药物的鉴定

• 批准号: 7144719
• 负责人: Kerry Kornfeld
• 金额: $ 30.19万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7144719
• 关键词: Caenorhabditis elegans; aging; amidohydrolases; animal population study; anticonvulsants; biological models; body movement; dosage; drug discovery /isolation; drug screening /evaluation; enzyme activity; enzyme inhibitors; laboratory mouse; longevity; macular degeneration; mutant; neuromuscular function; nonhuman therapy evaluation; protein structure function; pyrrolidinediones; valproate

DESCRIPTION (provided by applicant): Aging is characterized by progressive, degenerative changes in many organ systems. These changes result in significant functional declines in elderly people and often contribute to death. Treatments that delay age- related degeneration would be desirable, but few are available. The long-term objective of this proposal is to identify drugs that can delay age-related degeneration. This proposal exploits nematode worms and mice as model systems to analyze aging. Nematodes are a powerful experimental system that is convenient for genetic, molecular, and pharmacologic studies, whereas mice are highly relevant to humans. The preliminary studies describe the identification of FDA-approved drugs that can extend the adult lifespan of worms including ethosuximide, trimethadione and valproic acid. Specific aim 1 proposes to characterize the mechanism of action of valproic acid by testing the hypothesis that valproic acid functions as an inhibitor of histone deacetylases. In addition, the hypothesis that ethosuximide and trimethadione function by modulating neural activity will be tested by analyzing mutants that are resistant to these drugs. A detailed, mechanistic understanding of the action of these drugs is important because it will elucidate endogenous pathways that influence aging, and establish a foundation for considering the therapeutic use of these drugs. Specific aim 2 proposes to identify FDA-approved drugs that can extend worm lifespan and characterize the mechanism of action of these drugs. The identification of drugs that delay aging is significant for two reasons. First, it might lead to the identification of new mechanisms that influence aging. Second, because these drugs are approved for human use, these studies might lead to therapies that can delay age-related degenerative changes in humans. Specific aim 3 proposes to determine if trimethadione and valproic acid can extend the lifespan of mice or delay age-related changes. The demonstration that these FDA-approved drugs delay aging in a vertebrate would be significant.

描述（由申请人提供）：衰老的特征是许多器官系统的进行性，退化性变化。这些变化导致老年人的功能下降，并且经常导致死亡。延迟与年龄相关的变性的治疗是可取的，但很少有可用。该提案的长期目标是确定可以延迟与年龄相关的变性的药物。该建议利用线虫蠕虫和小鼠作为分析衰老的模型系统。线虫是一个强大的实验系统，可方便地用于遗传，分子和药理学研究，而小鼠与人类高度相关。初步研究描述了FDA批准的药物的鉴定，这些药物可以延长蠕虫的成年寿命，包括乙糖胺，三甲二亚二硫代和丙丙酸。特定目的1提出，通过检验丙戊酸作为组蛋白脱乙酰基酶抑制剂的假设来表征丙戊酸的作用机理。此外，通过分析对这些药物有抗性的突变体来测试通过调节神经活性来调节神经活性的假设。对这些药物的作用的详细机械理解很重要，因为它将阐明影响衰老的内源性途径，并为考虑使用这些药物的治疗使用而建立基础。具体目标2提出，识别FDA批准的药物可以延长蠕虫寿命并表征这些药物的作用机理。鉴定延迟衰老的药物有两个原因。首先，它可能导致鉴定影响衰老的新机制。其次，由于这些药物被批准用于人类使用，因此这些研究可能导致疗法可能延迟与年龄相关的人类变化。具体目标3提出，确定三甲二二二酮和丙戊酸是否可以延长小鼠的寿命或延迟与年龄相关的变化。这些经FDA批准的药物在脊椎动物中延迟衰老的证明是显着的。