Identification of drugs that delay aging

描述(由申请人提供)：衰老的特征是许多器官系统的渐进性、退行性变化。这些变化导致老年人的功能显著下降，并经常导致死亡。延缓与年龄相关的退化的治疗方法是可取的，但几乎没有可用的方法。这项提案的长期目标是确定可以延缓年龄相关性退化的药物。这项提议利用线虫和老鼠作为模型系统来分析衰老。线虫是一个强大的实验系统，便于进行遗传学、分子和药理学研究，而老鼠与人类高度相关。初步研究描述了FDA批准的可以延长蠕虫成虫寿命的药物的鉴定，包括乙硫胺、三甲二酮和丙戊酸。具体目标1建议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制。此外，乙硫胺和三甲二酮通过调节神经活动发挥作用的假设将通过分析对这些药物具有抗药性的突变来检验。对这些药物作用机制的详细了解很重要，因为它将阐明影响衰老的内源性途径，并为考虑这些药物的治疗使用奠定基础。特定目标2建议识别FDA批准的可以延长蠕虫寿命的药物，并表征这些药物的作用机制。确定延缓衰老的药物具有重要意义，原因有两个。首先，它可能导致发现影响衰老的新机制。其次，由于这些药物被批准用于人类，这些研究可能会导致延缓人类与年龄相关的退行性变化的疗法。具体目标3建议确定三甲二酮和丙戊酸是否可以延长小鼠的寿命或延缓与年龄相关的变化。FDA批准的这些药物延缓脊椎动物衰老的证据将是重要的。

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.