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

项目总结 对酵母复制老化的研究有助于确定衰老的机制方面，在 识别保守的真核衰老基因，并导致了一些最好的抗衰老药物候选 目前正在开发中。然而，传统的显微解剖寿命测定方法费时费力。 消耗，这使得它不可能执行数千个分子的大型文库屏幕。在这里，我们建议 开发一种新的高通量方法来系统地识别延缓衰老的小分子，并 在蠕虫和人类细胞中测试有前途的候选者。在目标1中，我们将开发一种高吞吐量 基于新的遗传系统和深度测序的方法来测量对数千人寿命的影响 小分子，包括FDA批准的药物和天然产品库。我们也会放映 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中被确定为延长酵母寿命的目标将被输送到目标2，其中描述了确定(1)的努力。 这些药物是否对线虫的衰老有保护作用，以及(2)药物是否可以 在衰老的人类细胞培养模型中改善与年龄相关的特征。这两个目标加在一起将 产生一系列药物，为在哺乳动物身上进行试验奠定了基础。扩充剧目的重要性 延长寿命和延缓衰老的药物的重要性不能被强调。每个新的小分子不仅 作为一个探测器来定义导致衰老的机制，但也代表了一种新的潜在药物类别 这可能会延长人类的健康寿命。

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.