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

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渐进性、退行性变化。生殖老龄化是导致女性出生缺陷和不孕不育的这些变化的早期和显著的例子。与年龄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方法是可取的，但目前还没有延缓正常年龄相关退化的药物。开发新的治疗方法是当务之急。这项提案的长期目标是确定延缓年龄相关退化的药物，并确定成人干细胞在生殖系老化中的作用。这一结果将对阐明控制衰老的机制并为与年龄相关的退行性变化提出新的治疗策略产生重要影响。我们使用了功能强大的线虫模型系统来发现FDA批准的可以延长蠕虫寿命的药物和营养物质。我们分析了线虫的生殖衰老，并确定了可以延长生殖的药物和基因。线虫生殖系包含成体干细胞群，我们证明了这一细胞群表现出与年龄相关的下降，建立了线虫作为干细胞老化的模型。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、烟酸和丙咪嗪作用于控制长寿的内源性过程。卡托普利的延寿作用可能与acn-1基因有关。(2)不同作用机制的药物组合可导致额外的寿命延长。(3)生殖系干细胞功能的年龄相关性下降有助于生殖衰老，而Notch信号通路的年龄相关性下降可能控制这一下降。为了检验这些假设，我们提出了两个具体目标。目的1：研究卡托普利、育亨宾、烟酸和丙咪嗪等延长成虫寿命的化合物的作用机制。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会产生额外的寿命延长。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：验证生殖系干细胞与年龄相关的衰退导致生殖衰老的假说。我们将建立野生型动物生殖系干细胞随年龄变化的时间进程，并利用遗传学分析Notch信号的作用。描述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查中发现的新基因。通过结合分子和遗传学的方法，这些研究将阐明衰老的机制，推动衰老药理学领域的发展，并解决目前对生殖衰老的理解中的重要空白。重要的是，这些研究将建立新的治疗策略，以应对人类与年龄相关的退行性变化。