Comparative genomics and epigenomics of aging

总结：衰老过程在进化过程中可以自然加速和减速，从而导致 在相关物种的寿命中存在显著的多样性。哺乳动物代表了一个特别方便的系统， 在分子水平上检查这种多样性，因为这些动物的特征是近百倍的 寿命的差异，它们的组织和培养细胞是容易获得的。无偏表征 与哺乳动物寿命的自然变化有关的基因和过程可能导致 发展针对衰老过程并可能延缓衰老的方法。我们假设哺乳动物 寿命是通过共同的和血统特定的过程相结合来调整的， 数据支持这一想法。在PPG的持续阶段，我们生成了令人兴奋的数据，支持我们的一般 控制寿命的方法。我们在哺乳动物中生成了全面的分子图谱，包括 长寿的物种。这些数据集包括RNAseq、代谢物分析和化学元素分析。 以及长寿裸鼹鼠和海狸的基因组。我们还生成了DNA甲基化 时钟的小鼠，并发现它正确地报告了长寿干预的影响。我们建议利用这些 与其他项目和核心密切合作，解决我们的关键问题 了解哺乳动物寿命的自然控制。具体而言，我们建议检查：（1）分子 哺乳动物长寿的基本特征。我们将利用我们生成的图谱来识别分子特征 以及它们的组合，重点关注与长寿有关的基因表达和代谢物， 构建长寿物种的分子特征（与核心C）。我们还将进行基因表达， 海狸化SIRT 6小鼠（具有项目1和核心B）、裸鼹鼠HAS 2 转基因小鼠和用透明质酸酶抑制剂处理的小鼠（用项目2和核心B），提供关键的 这些基因促进长寿的机制的分子见解。(2)长寿基因组学 啮齿动物我们将对新的、改进很多的裸鼹鼠组件进行全面的注释， 海狸基因组（核心C），反过来为项目1，2和3提供关键资源。我们也将关注 DNA修复和染色质重塑基因的进化，以及这些基因缺失和获得的表征， 物种(3)表观遗传时钟在小鼠长寿模型中的应用。我们最近开发了一种 小鼠DNA甲基化时钟，我们将应用于PPG中检查的动物和细胞培养模型 (with项目1、2和3，以及核心B和C）。(4)裸鼹鼠表观遗传学的发展与应用 时钟我们将利用不同年龄的裸鼹鼠（项目2和核心B），量化年龄依赖性模式 DNA甲基化，并开发和应用生物年龄的分子标记。

SUMMARY: The aging process can be naturally accelerated and decelerated during evolution leading to significant diversity in lifespan among related species. Mammals represent a particularly convenient system to examine this diversity at the molecular level, because these animals are characterized by a nearly hundred-fold difference in lifespan and their tissues and cultured cells are readily available. Unbiased characterization of genes and processes that are associated with natural changes in lifespan within mammals may lead to the development of approaches that target the aging process and possibly delay it. We hypothesize that mammalian lifespan is adjusted through a combination of common and lineage-specific processes and provide preliminary data in support of this idea. In the ongoing phase of the PPG we generated exciting data that support our general approach to lifespan control. We generated comprehensive molecular profiles across mammals, including species of exceptional longevity. These datasets include RNAseq, metabolite profiling, and chemical element profiling as well as the genomes of long-lived naked mole rat and beaver. We also generated a DNA methylation clock for mice and found that it correctly reports the effects of longevity interventions. We propose to utilize these tools and approaches to address, in close collaboration with other Projects and Cores, critical questions in our understanding of natural control of mammalian lifespan. Specifically, we propose to examine: (1) Molecular features underlying longevity in mammals. We will utilize the profiles we generated to identify molecular features and their combinations, with a focus on gene expression and metabolites, linked with longevity, ultimately building molecular signatures of long-lived species (with Core C). We will also carry out gene expression and metabolite profiling analyses of beaverized SIRT6 mice (with Project 1 and Core B), naked mole rat HAS2 transgenic mice, and mice treated with hyaluronidase inhibitors (with Project 2 and Core B), providing critical molecular insights into the mechanisms by which these genes promote longevity. (2) Genomics of long-lived rodents. We will carry out comprehensive annotation of new, much improved assemblies of naked mole rat and beaver genomes (with Core C), in turn providing critical resources for Projects, 1, 2 and 3. We will also focus on the evolution of DNA repair and chromatin remodeling genes and characterization of gene loss and gain in these species. (3) Applications of the epigenetic clock to mouse models of longevity. We have recently developed a mouse DNA methylation clock, which we will apply to the animal and cell culture models examined in the PPG (with Projects 1, 2, and 3, and Cores B and C). (4) Development and application of the naked mole rat epigenetic clock. We will utilize naked mole rats differing in age (with Project 2 and Core B), quantify age-dependent patterns of DNA methylation, and develop and apply a molecular marker of biological age.