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。生殖老化是导致妇女出生缺陷和不孕症的这些变化的早期和突出的例子。与癌症相关的躯体组织退化是导致残疾和死亡的主要原因。延长人类健康和寿命的治疗是可取的，但没有药物可以延迟正常的年龄相关的退化。开发新的治疗方法是一个高度优先事项。这项提案的长期目标是确定延缓年龄相关性退化的药物，并确定成体干细胞在生殖细胞系衰老中的作用。这些结果将通过阐明控制衰老的机制并为年龄相关的退行性变化提出新的治疗策略产生重要影响。 我们使用了强大的C。elegans模型系统，以发现FDA批准的药物和营养素，可以延长蠕虫的寿命。我们分析了C.并确定了可以延长生殖的药物和基因。梭线虫生殖系中含有一群成体干细胞，我们证明了这一细胞群显示出与年龄相关的衰退，建立了C.线虫作为干细胞衰老的模型。在上一个项目期间进行的研究支持三个创新的假设。(1)卡托普利、育亨宾、烟酸和丙咪嗪作用于控制寿命的内源性过程。卡托普利延长寿命可能是由acn-1基因介导的。(2)通过不同机制起作用的药物组合可导致累加寿命延长。(3)生殖系干细胞功能的年龄相关性下降有助于生殖老化，而Notch信号通路中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。目标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产生附加的寿命延长。根据作用机制对药物进行优先排序，并分析高优先级药物延长小鼠寿命的能力。目的2：检验生殖系干细胞年龄相关性下降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中年龄相关变化的时间过程，并使用遗传学分析Notch信号传导的作用。表征介导生殖老化的基因和药物，包括在延迟生殖老化的正向遗传筛查中发现的新基因。通过结合分子和遗传学方法，这些研究将阐明衰老机制，推进衰老药理学领域，并解决目前对生殖衰老认识的重要空白。重要的是，这些研究将建立新的治疗策略，以解决人类与年龄相关的退行性变化。

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.