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进行性退行性变化。这些变化导致老年人的功能显著下降，并常常导致死亡。延缓与年龄有关的变性的治疗是可取的，但很少可用。这项提议的长期目标是确定可以延缓年龄相关变性的药物。该方案利用线虫和小鼠作为模型系统来分析衰老。线虫是一种强大的实验系统，可以方便地进行遗传、分子和药理学研究，而小鼠则与人类高度相关。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，包括乙砜胺、甲美二酮和丙戊酸。具体目标1提出通过验证丙戊酸作为组蛋白去乙酰化酶抑制剂的假设来表征丙戊酸的作用机制。此外，乙氧亚胺和甲美二酮通过调节神经活动起作用的假设将通过分析对这些药物具有耐药性的突变体来验证。对这些药物作用的详细、机制的了解是很重要的，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用途奠定基础。具体目标2提出确定fda批准的延长蠕虫寿命的药物，并描述这些药物的作用机制。发现延缓衰老的药物意义重大，原因有二。首先，它可能导致发现影响衰老的新机制。其次，由于这些药物已被批准用于人类，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治疗方法。具体目标3提出确定甲美二酮和丙戊酸是否可以延长小鼠寿命或延缓与年龄相关的变化。这些fda批准的药物延缓脊椎动物衰老的证明意义重大。

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.