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病的最大风险因素，因此造成了巨大的社会和经济负担。生物医学界必须优先考虑制定旨在减少或延缓与年龄有关的疾病的治疗或预防措施。然而，当涉及到老年人的主要慢性病时，传统的药物发现模式正在失败。也许直接瞄准衰老会提高我们增加健康寿命的机会。根据无脊椎动物寿命决定的累积遗传数据，可能有数百个潜在的目标来减缓或以其他方式改变衰老过程。可能有一组更有限的代谢或生理改变，赋予长寿，如增强的稳态机制，最佳的生物能量学，改善干细胞功能等，可以作为目标。尽管有大量的靶点，但我们手头没有大量的减缓哺乳动物衰老的化合物来测试靶向衰老可能导致改善年龄相关疾病临床试验结果的想法。可以说非常成功的NIA资助的干预性测试计划（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。本提案是对RFA-AG-13-010的回应，RFA-AG-13-010旨在在易处理的短寿命生物体（小杆线虫菌株）中建立一个检测项目，以提供一组高质量的耐用化合物，用于检测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学的发病，延长寿命。这些化合物在合成化合物和天然产物的集中化学筛选和高通量筛选中鉴定。这些化合物中的一些现在被用于小鼠衰老研究。在这里，我们建议利用这一经验，以及一些创新的方法来研究化合物的作用，以测试新的，作为CITP的一部分，建议的化合物结构。

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.