Discovering compounds with robust pro-longevity activities

发现具有强大的长寿活性的化合物

• 批准号: 9117934
• 负责人: Gordon J Lithgow
• 金额: $ 8.82万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-04-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9117934
• 关键词: Address; Age; Aging; Alzheimer' s Disease; Animal Model; Biochemical; Bioenergetics; Biological Assay; Biological Factors; Caenorhabditis; Caenorhabditis elegans; Cell physiology; Chemicals; Chronic Disease; Clinical Trials; Communities; Data; Developed Countries; Development; Disease; Dose; Economic Burden; Elderly; Failure; Funding; Future; Genes; Genetic; Hand; Homeostasis; Individual; Institutes; Invertebrates; Laboratories; Lead; Life; Longevity; Mammals; Measures; Metabolic; Modeling; Mus; Nematoda; Organism; Outcome; Parkinson Disease; Pathology; Phase III Clinical Trials; Phenotype; Physiological; Play; Preventive; Probability; Protocols documentation; Publishing; Risk Factors; Series; Sirolimus; Site; Specialist; Stem cells; Structure; Testing; age related; base; drug development; drug discovery; efficacy testing; experience; high throughput screening; improved; innovation; mouse model; novel; programs; public health relevance; research facility; research study; response; sex; social; therapy development

DESCRIPTION (provided by applicant): Aging is the single largest risk factor for chronic disease in developed countries and is consequently responsible for an enormous social and economic burden. The development of therapies or preventive measures aimed at reducing or delaying age-related disease must be a priority for the biomedical community. However, the traditional models of drug discovery are failing when it comes to the major chronic diseases of the elderly. Perhaps targeting aging directly would improve our chances of increasing healthspan. Based on the accumulated genetic data on lifespan determination in invertebrates there may be hundreds of potential targets to pharmacologically slow or otherwise alter the course of aging. There may be a more limited set of metabolic or physiological alterations that confer longevity such as enhanced homeostatic mechanisms, optimal bioenergetics, improved stem cell function etc. that could be targeted. Despite the wealth of targets, we do not have a large range of chemical compounds that slow aging in mammals at hand to test the idea that targeting aging could lead to improved clinical trial outcomes for age-related disease. The arguably very successful NIA-funded Interventional Testing Program (ITP) addresses this issue by testing compounds for effects principally on longevity in the lab mouse following a standardized protocol at multiple research facilities. This has led to the important discovery that rapamycin reproducibly extends lifespan. This proposal is a response to RFA-AG-13-010 which sets out to build a testing program in a tractable, short-lived organism (Caenorhabditis strains) to provide a set of high quality robust compounds for testing mouse models of aging and age-related disease. We have discovered a series of chemical compounds that delay the onset of age-related pathology and extend lifespan. These compounds were identified in focused chemical screens and high throughput screens of both synthetic compounds and natural products. Some of these compounds are now being utilized in mouse aging studies. Here we propose to leverage this experience, together with some innovative approaches to studying compounds action to test new, sponsor-suggested compound structures as part of the CITP.

描述（由申请人提供）：老龄化是发达国家慢性病的最大单一危险因素，因此造成巨大的社会和经济负担。开发旨在减少或延缓与年龄相关的疾病的疗法或预防措施必须成为生物医学界的首要任务。然而，传统的药物发现模式在治疗老年人的主要慢性疾病时却失败了。也许直接针对衰老可以提高我们延长健康寿命的机会。根据积累的关于无脊椎动物寿命决定的遗传数据，可能有数百个潜在靶标可以在药理学上减缓或以其他方式改变衰老过程。可能存在一组更有限的代谢或生理改变可以赋予长寿，例如增强的稳态机制、最佳的生物能学、改善的干细胞功能等。尽管有丰富的靶点，但我们手头没有大量可以减缓哺乳动物衰老的化合物来测试靶向衰老可能会改善与年龄相关疾病的临床试验结果的想法。可以说非常成功的 NIA 资助的介入测试计划 (ITP) 通过在多个研究机构按照标准化方案测试化合物主要对实验室小鼠寿命的影响来解决这个问题。这导致了一个重要的发现： 雷帕霉素可重复地延长寿命。该提案是对 RFA-AG-13-010 的回应，RFA-AG-13-010 旨在在一种易处理的短命生物体（秀丽隐杆线虫菌株）中建立一个测试程序，以提供一套高质量的稳健化合物来测试衰老和年龄相关疾病的小鼠模型。我们发现了一系列化合物，可以延缓与年龄相关的病理的发生并延长寿命。这些化合物是在合成化合物和天然产物的重点化学筛选和高通量筛选中鉴定的。其中一些化合物现在被用于小鼠衰老研究。在这里，我们建议利用这一经验以及一些创新方法来研究化合物的作用，以测试赞助商建议的新化合物结构，作为 CITP 的一部分。