Comparative genomics and epigenomics of aging

摘要：衰老过程可以在进化过程中自然加速和减速，从而导致 相关物种的寿命存在显著差异。哺乳动物代表着一种特别方便的系统 在分子水平上研究这种多样性，因为这些动物的特征是近百倍 寿命的不同及其组织和培养细胞的差异是很容易获得的。不偏不倚地描述 与哺乳动物寿命自然变化相关的基因和过程可能会导致 开发针对老化过程的方法，并可能延缓老化过程。我们假设哺乳动物 寿命通过共同和特定于世系的过程相结合进行调整，并提供初步的 支持这一观点的数据。在PPG正在进行的阶段，我们生成了令人兴奋的数据，支持我们的将军 控制寿命的方法。我们生成了哺乳动物的全面分子图谱，包括 特别长寿的物种。这些数据集包括RNAseq、代谢物图谱和化学元素 以及长寿裸鼠和海狸的基因组图谱。我们还产生了DNA甲基化 为小鼠提供的时钟，发现它正确地报告了长寿干预的效果。我们建议利用这些 工具和方法，与其他项目和核心密切合作，解决我们的 对哺乳动物寿命自然控制的理解。具体地说，我们建议研究：(1)分子 哺乳动物的潜在长寿特征。我们将利用我们生成的轮廓来识别分子特征 以及它们的组合，重点是基因表达和代谢物，最终与长寿有关 建立长寿物种的分子签名(核心C)。我们还将进行基因表达和 海狸SIRT6小鼠(项目1和核心B)、裸鼠HAS2的代谢物谱分析 转基因小鼠，以及用透明质酸酶抑制剂治疗的小鼠(项目2和核心B)，提供关键的 对这些基因延长寿命的机制的分子洞察力。(2)长寿的基因组学 啮齿动物。我们将对裸鼠和裸鼠的新的、大大改进的集合进行全面的注释 海狸基因组(核心C)，进而为项目1、2和3提供关键资源。我们还将专注于 DNA修复和染色质重塑基因的进化及其基因缺失和获得的特征 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，我们将把它应用于PPG中检验的动物和细胞培养模型 (包括项目1、2和3，以及核心B和C)。(4)裸鼠表观遗传学的研制与应用 钟。我们将利用不同年龄的裸鼠(项目2和核心B)，量化年龄依赖的模式 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.