IDENTIFICATION OF DRUGS THAT DELAY AGING

延缓衰老药物的鉴定

• 批准号: 8738552
• 负责人: Kerry Kornfeld
• 金额: $ 37.84万
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8738552
• 关键词: Address; Adult; Affect; Afferent Neurons; Aging; Angiotensin-Converting Enzyme Inhibitors; Animal Model; Animals; Anticonvulsants; Biological Assay; Biological Models; Biology of Aging; Caenorhabditis elegans; Candidate Disease Gene; Captopril; Cell Aging; Cell physiology; Cells; Cessation of life; Congenital Abnormality; Drug Combinations; Drug effect disorder; Elderly; Employee Strikes; Ethosuximide; FDA approved; Foundations; Genes; Genetic; Genetic Screening; Germ Cells; Germ Lines; Goals; Health; Human; Imipramine; Infertility; Laboratories; Longevity; Mammals; Mediating; Medicine; Methods; Modeling; Molecular Genetics; Mus; Mutation; Nematoda; Nicotinic Acids; Notch Signaling Pathway; Nutrient; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Play; Population; Process; Property; Reagent; Reproduction; Research; Role; S Phase; Signal Transduction; Stem cells; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; Trimethadione; Valproic Acid; Woman; Yohimbine; adult stem cell; age related; base; body system; cell age; disability; functional decline; innovation; normal aging; notch protein; novel; novel therapeutic intervention; novel therapeutics; public health relevance; reproductive; research study; stem cell population; Address; Adult; Affect; Afferent Neurons; Aging; Angiotensin-Converting Enzyme Inhibitors; Animal Model; Animals; Anticonvulsants; Biological Assay; Biological Models; Biology of Aging; Caenorhabditis elegans; Candidate Disease Gene; Captopril; Cell Aging; Cell physiology; Cells; Cessation of life; Congenital Abnormality; Drug Combinations; Drug effect disorder; Elderly; Employee Strikes; Ethosuximide; FDA approved; Foundations; Genes; Genetic; Genetic Screening; Germ Cells; Germ Lines; Goals; Health; Human; Imipramine; Infertility; Laboratories; Longevity; Mammals; Mediating; Medicine; Methods; Modeling; Molecular Genetics; Mus; Mutation; Nematoda; Nicotinic Acids; Notch Signaling Pathway; Nutrient; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Play; Population; Process; Property; Reagent; Reproduction; Research; Role; S Phase; Signal Transduction; Stem cells; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; Trimethadione; Valproic Acid; Woman; Yohimbine; adult stem cell; age related; base; body system; cell age; disability; functional decline; innovation; normal aging; notch protein; novel; novel therapeutic intervention; novel therapeutics; public health relevance; reproductive; research study; stem cell population

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.

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。生殖衰老是这些变化的早期且引人注目的例子，导致女性出生缺陷和不孕症。与年龄相关的体细胞性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，但是没有药物可以延迟与年龄相关的正常变性。开发新的治疗方法是一个很高的优先事项。该提案的长期目标是确定延迟与年龄相关变性的药物，并定义成年干细胞在生殖系衰老中的作用。结果将通过阐明控制衰老的机制并提出与年龄相关的退行性变化的新治疗策略来产生重要的影响。 我们使用功能强大的秀丽隐杆线虫模型系统来发现可以延长蠕虫寿命的FDA批准的药物和营养。我们分析了秀丽隐杆线虫中的生殖老化，并鉴定出可以扩展繁殖的药物和基因。秀丽隐杆线虫生殖系含有大量的成年干细胞，我们证明该细胞种群显示与年龄相关的下降，将秀丽隐杆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）Capteropril，Yohimbine，Nigotinic Acid和ipramine对控制寿命的内源性过程作用。卡托普利引起的寿命延长可能是由ACN-1基因介导的。 （2）通过不同机制起作用的药物的组合可能会导致添加寿命延长。 （3）与年龄相关的生殖系干细胞功能的下降有助于生殖衰老，而Notch信号通路与年龄相关的下降可能会控制这种下降。为了检验这些假设，我们提出了两个具体目标。 AIM 1：表征化合物的作用机理，这些化合物的作用机理延长了蠕虫的成人寿命，包括卡托普利，Yohimbine，烟酸和氨基胺。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建立基础。确定不同药物的组合是否产生添加寿命延长。根据作用机制对药物进行优先级，并分析高优先药物的延长小鼠寿命的能力。 AIM 2：检验与年龄相关下降的假设I生殖线干细胞有助于生殖衰老。我们将建立野生型动物中生殖系干细胞年龄相关变化的时间过程，并使用遗传学来分析Notch信号的作用。表征介导生殖衰老的基因和药物，包括在向前遗传筛选中鉴定出的新基因，以延迟生殖衰老。通过结合分子和遗传学方法，这些研究将阐明衰老的机制，推进衰老药理学领域，并在当前对生殖衰老的理解中解决重要差距。重要的是，这些研究将建立新的治疗策略来解决与年龄相关的人类变化。