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。生殖老化是这些变化的早期和显著的例子，导致妇女出生缺陷和不孕。与年龄相关的躯体组织变性是导致残疾和死亡的主要原因。延长人类健康跨度和寿命的治疗是可取的，但没有药物可以延缓正常的与年龄有关的退化。开发新的治疗方法是当务之急。这项提议的长期目标是确定延缓年龄相关变性的药物，并确定成体干细胞在生殖系衰老中的作用。该结果将通过阐明控制衰老的机制和提出与年龄相关的退行性变化的新治疗策略产生重要影响。我们使用强大的秀丽隐杆线虫模型系统来发现fda批准的可以延长线虫寿命的药物和营养物质。我们分析了秀丽隐杆线虫的生殖衰老，并确定了可以延长生殖的药物和基因。秀丽隐杆线虫的生殖系包含一个成体干细胞群体，我们证明了这个细胞群体表现出与年龄相关的衰退，建立秀丽隐杆线虫作为干细胞衰老的模型。在前一个项目期间进行的研究支持三个创新假设。(1)卡托普利、育亨宾、烟酸和丙咪嗪对控制寿命的内源性过程起作用。卡托普利的延寿作用可能与acn-1基因有关。(2)通过不同机制作用的药物组合可以延长寿命。(3)生殖系干细胞功能的年龄相关性下降有助于生殖衰老，而Notch信号通路的年龄相关性下降可能控制这种下降。为了验证这些假设，我们提出了两个具体目标。目的1：描述延长蠕虫成虫寿命的化合物的作用机制，包括卡托普利、育亨宾、烟酸和丙咪嗪。这可以确定调节寿命的内源性途径，并为评估这些化合物的治疗用途奠定基础。确定不同药物的组合是否能延长寿命。根据作用机制对药物进行排序，分析高优先级药物对小鼠寿命的延长能力。目的2：验证生殖系干细胞与年龄相关的衰退导致生殖衰老的假设。我们将建立野生型动物生殖系干细胞年龄相关变化的时间过程，并利用遗传学分析Notch信号的作用。表征介导生殖衰老的基因和药物，包括在延迟生殖衰老的正向遗传筛选中发现的新基因。这些研究将通过分子和遗传方法的结合，阐明衰老的机制，推动衰老药理学领域的发展，填补目前对生殖衰老认识的重要空白。重要的是，这些研究将为解决人类年龄相关的退行性变化建立新的治疗策略。

DESCRIPTION (provided by applicant): Aging is characterized by progressive, degenerative changes in many organ systems. Reproductive aging is an early and striking example of these changes that results in birth defects and infertility in women. Age-related degeneration of somatic tissues is a major contributor to disability and death. Treatments that extend human health span and life span are desirable, but no drugs that delay normal age-related degeneration are available. It is a high priority to develop new therapeutic approaches. The long-term objectives of this proposal are to identify drugs that delay age-related degeneration and define the role of adult stem cells in germ line aging. The results will have an important impact by elucidating mechanisms that control aging and suggesting new therapeutic strategies for age-related degenerative changes. We used the powerful C. elegans model system to discover FDA-approved drugs and nutrients that can extend the life span of worms. We analyzed reproductive aging in C. elegans and identified drugs and genes that can extend reproduction. The C. elegans germ line contains a population of adult stem cells, and we demonstrated that this cell population displays age-related decline, establishing C. elegans as a model of stem cell aging. Studies conducted during the previous project period support three innovative hypotheses. (1) Captopril, yohimbine, nicotinic acid, and imipramine act on endogenous processes that control longevity. The life span extension caused by captopril may be mediated by the acn-1 gene. (2) A combination of drugs that act by different mechanisms can cause an additive life span extension. (3) An age-related decline of germ line stem cell function contributes to reproductive aging, and an age-related decline in the Notch signaling pathway may control this decline. To test these hypotheses, we propose two specific aims. Aim 1: Characterize the mechanism of action of compounds that extend the adult life span of worms, including captopril, yohimbine, nicotinic acid and imipramine. This can identify endogenous pathways that modulate longevity and establish the foundation for evaluating therapeutic uses of these compounds. Determine if combinations of different drugs produce an additive life span extension. Prioritize drugs based on mechanism of action, and analyze high priority drugs for the ability to extend the life span of mice. Aim 2: Test the hypothesis that age-related declines i germ line stem cells contribute to reproductive aging. We will establish the time course of age- related changes in germ line stem cells in wild-type animals and use genetics to analyze the role of Notch signaling. Characterize genes and drugs that mediate reproductive aging, including new genes identified in a forward genetic screen for delayed reproductive aging. By combining molecular and genetic approaches, these studies will elucidate mechanisms of aging, advance the field of aging pharmacology and address important gaps in the current understanding of reproductive aging. Importantly, these studies will establish new therapeutic strategies for addressing age-related degenerative changes in humans.