Long-lived mice and species as test beds for drug and pathway discovery

实验计划集中在两个中心主题：(A)长期和长期培养的细胞系的特性比较。 寿命短的物种可以提出关于调节衰老速度的途径的假说，以及(B) 多个小鼠延缓衰老模型的可用性可以测试关于指示因素的想法，以及 在某些情况下，与衰老和晚年疾病的生物学有因果关系。目标1将评估 来自不同种类的啮齿动物、鸟类和灵长类动物细胞系的代谢和多肽特征(“分析物”)。 寿命从4年到70年，看看哪些分析物特征在进化分支中是共享的，以及 因此很可能是长寿进化所必需的。目标2将开发来自血浆和 六种缓慢衰老小鼠的内部组织(三种药物，一种饮食，两种突变)。我们预测我们 将在这些长寿的小鼠身上发现重叠的签名，这表明与 健康长寿，不分长寿方式。我们预测其中一些生物标记物将 在异常健康、长寿的人的血浆中也可以看到这种情况。我们还预测分析物和 在AIM 1的跨物种比较中发现的特征也可以在缓慢衰老的小鼠中检测到。目标 3专注于与化学信息学核心的合作，在细胞系和小鼠身上测试药物集。这个 假设核心提名的药物将使小鼠和人类细胞对多种压力产生抗药性， 并将修改小鼠的分析物图谱，使其类似于衰老缓慢的小鼠和长寿的人类。 药物治疗方案的终点，在细胞和小鼠中，也将包括我们之前展示的那些 作为长寿物种的细胞和长寿小鼠器官的特征，包括PSMB8，干扰素R2- 响应性mRNAs和线粒体TXNRD2。我们将广泛利用与 该联盟的代谢组学和蛋白质组学项目以及化学信息学核心，我们的数据将是 为Schork项目和系统生物学核心提供了丰富的信息来源。我们希望证明这一点 分析特定物种的细胞特征，以及来自缓慢衰老小鼠的材料，可以极大地丰富搜索内容 对于保护人们免受衰老和衰老影响的特别感兴趣的途径、基因和药物- 依附性疾病。

The experimental plans focus on two central themes: (a) that comparison of properties of cell lines from long- and short-lived species can suggest hypotheses about pathways that modulate the pace of aging, and (b) that availability of multiple mouse models for delayed aging can test ideas about factors that are indicative of, and in some cases causally connected to, the biology of aging and late-life disease. Aim 1 will evaluate metabolomic and peptide signatures ("analytes") from cell lines of rodents, birds, and primates varying in lifespan from 4 to 70 years, to see which analyte signatures are shared among evolutionary clades and are thus likely to be required for evolution of longevity. Aim 2 will develop analyte signatures from plasma and internal tissues of six varieties of slow-aging mice (three drugs, one diet, and two mutations). We predict we will find overlapping signatures in these long-lived mice, suggesting "common pathways" associated with healthy longevity regardless of the mode of lifespan extension. We predict that some of these biomarkers will also be seen in plasma from exceptionally healthy, long-lived people. We also predict that analytes and signatures found in the cross-species comparisons of Aim 1 will be detectable in slow-aging mice as well. Aim 3 focuses on a collaboration with the Cheminformatics Core, to test sets of drugs in cell lines and in mice. The hypothesis is that the Core-nominated drugs will render mouse and human cells resistant to multiple stresses, and will modify analyte profiles in mice to resemble those of slow-aging mice and long-lived humans. Endpoints for the drug treatment protocols, in cells and mice, will also include those we have previously shown to be characteristic of cells from long-lived species and organs of long-lived mice, including PSMB8, IFN R2- responsive mRNAs, and mitochondrial TXNRD2. We will make extensive use of collaborations with the Consortium's projects on metabolomics and proteomics, and the Cheminformatics Core, and our data will be a rich source of information for the Schork project and the systems biology core as well. We hope to show that analyses of species-specific cellular traits, and materials from slow-aging mice, can greatly enrich the search for pathways, genes, and drugs of special interest for protection of people from the effects of aging and age- dependent diseases.