Discovering compounds with robust pro-longevity activities

描述（由申请人提供）：老龄化是发达国家慢性疾病的最大单一风险因素，因此造成了巨大的社会和经济负担。开发旨在减少或延缓与年龄有关的疾病的疗法或预防措施必须成为生物医学界的优先事项。然而，当涉及到老年人的主要慢性疾病时，传统的药物发现模式正在失败。也许直接针对老龄化会增加我们延长健康寿命的机会。根据积累的无脊椎动物寿命决定的遗传数据，可能有数百种潜在的靶点可以从药理学上延缓或改变衰老过程。可能有一组更有限的代谢或生理改变赋予长寿，如增强的体内平衡机制，最佳的生物能量学，改善的干细胞功能等，可以作为目标。尽管有丰富的靶点，但我们手头上还没有大量能延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有关的疾病的临床试验结果。nia资助的介入测试项目（interonal Testing Program， ITP）可以说是非常成功的，它通过在实验室老鼠身上测试化合物对长寿的影响，遵循多个研究机构的标准化方案，解决了这个问题。这导致了一个重要的发现

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.