Identifying small molecules that delay aging using a high-throughput method for measuring yeast replicative lifespan

项目摘要 酵母复制老化的研究有助于确定老化的机制方面， 确定了保守的真核衰老基因，并导致了一些抗衰老药物的最佳候选人 目前正在开发中。然而，传统的显微切割寿命测定是费力和费时的， 消耗，使得不可能执行数千个分子的大型文库筛选。在这里我们建议 开发一种新的高通量方法来系统地鉴定延缓衰老的小分子， 在蠕虫和人类细胞中测试有希望的候选物。在目标1中，我们将开发高通量 一种基于新型遗传系统和深度测序的方法，可以测量对数千人寿命的影响 包括FDA批准的药物和天然产物库。我们还将筛选 针对已知酵母长寿基因的人类同源物的小分子药物。小分子 在目标1中确定延长酵母寿命的方法将被纳入目标2，目标2描述了确定（1） 是否药物对衰老有保守的作用，使用C.（2）药物是否可以 改善人细胞培养衰老模型中与年龄相关的特征。这两个目标将 产生一系列药物，为在哺乳动物中进行测试奠定基础。扩大剧目的重要性 延长寿命和延缓衰老的药物的数量不能被强调。每个新的小分子不仅 作为一种探针来定义驱动衰老的机制，但也代表了一类新的潜在药物 that may可能extend延长human人的healthspan健康.

PROJECT SUMMARY The study of yeast replicative aging has been instrumental in defining mechanistic aspects of aging, in identifying conserved eukaryotic aging genes, and has led to some of the best candidates for anti-aging drugs currently under development. However, the traditional micro-dissection lifespan assay is laborious and time consuming, making it impossible to perform large library screens of thousands of molecules. Here we propose to develop a novel high throughput method to systematically identify small molecules that delay aging, and to test the promising candidates in worms and in human cells. In Aim 1, we will develop a high-throughput method based on a novel genetic system and deep sequencing to measure the effect on lifespan of thousands of small molecules, including FDA approved drugs and the library of natural products. We will also screen small molecule drugs that target the human homologs of known yeast longevity genes. Small molecules identified to extend yeast lifespan in Aim 1 will be funneled into Aim 2, which describes efforts to determine (1) whether the drugs have conserved effects on aging using C. elegans, and (2) whether the drugs can ameliorate age-associated hallmarks in a human cell culture model of aging. Together these two aims will generate a set of drugs that set the stage for testing in mammals. The importance of expanding the repertoire of drugs that extend lifespan and delay aging cannot be underscored. Each new small molecule not only serves as a probe to define the mechanisms driving aging but also represents a new potential class of drugs that may extend human healthspan.