Comparative genomics and epigenomics of aging

衰老的比较基因组学和表观基因组学

• 批准号: 10399524
• 负责人: Vadim N. Gladyshev
• 金额: $ 41.89万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399524
• 关键词: Address; Age; Aging; Animals; Balaena; Beavers; Biological; Biological Markers; Blood; Cell Culture Techniques; Cells; Chemicals; Collaborations; Cultured Cells; DNA Damage; DNA Methylation; DNA Repair; Data; Data Analyses; Data Set; Development; Elements; Epigenetic Process; Evolution; Gamma Rays; Gene Expression; Genes; Genome; Genomics; Goals; HAS2 gene; Hyaluronidase; Intervention; Lead; Life; Link; Longevity; Maintenance; Mammals; Modeling; Mole Rats; Molecular; Molecular Profiling; Mus; Nature; Pattern; Phase; Process; Reporting; Resources; Rodent; Sampling; Sequence Analysis; Shrews; System; Testing; Tissues; Transgenic Mice; age related; base; chromatin remodeling; comparative; comparative genomics; data framework; data visualization; epigenomics; genome analysis; genome annotation; genome-wide; healthspan; improved; inhibitor; insight; molecular marker; mouse model; overexpression; social; tool; trait; transcriptome; transcriptome sequencing; whole genome

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.

摘要：在进化过程中，衰老过程可以自然加速和减速，导致 相关物种之间的寿命多样性。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一百倍 寿命及其组织和培养细胞的差异很容易获得。公正的表征 与哺乳动物内寿命自然变化相关的基因和过程可能导致 开发针对衰老过程并可能延迟它的方法。我们假设哺乳动物 寿命通过共同和谱系特异性过程的组合进行调整，并提供初步 支持这个想法的数据。在PPG的持续阶段，我们生成了支持我们一般的令人兴奋的数据 寿命控制的方法。我们在包括 特殊寿命的物种。这些数据集包括RNASEQ，代谢物分析和化学元素 分析以及长寿命的裸痣大鼠和海狸的基因组。我们还产生了DNA甲基化 小鼠时钟，发现它正确地报告了寿命干预的影响。我们建议利用这些 与其他项目和核心密切合作的工具和方法在我们的关键问题中密切合作 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 哺乳动物的寿命基础。我们将利用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，与寿命有关 建立长寿命物种（核心C）的分子特征。我们还将执行基因表达和 Beaverized Sirt6小鼠的代谢物分析分析（带有项目1和核心B），裸mole鼠HAS2 转基因小鼠和用透明质酸酶抑制剂（带有项目2和核心B）处理的小鼠，提供关键 分子洞察这些基因促进寿命的机制。 （2）长寿的基因组学 啮齿动物。我们将对新的，大量改进的裸mole鼠的组合进行全面注释 海狸基因组（与核心C）又为项目提供关键资源，1、2和3。我们还将重点关注 DNA修复和染色质重塑基因的演变以及基因丧失和增益的表征 物种。 （3）表观遗传时钟应用于寿命的小鼠模型。我们最近开发了 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 （带有项目1、2和3，以及核心B和C）。 （4）裸痣大鼠表观遗传学的开发和应用 钟。我们将利用年龄不同（项目2和核心B）的裸痣大鼠，量化与年龄有关的模式 DNA甲基化，并开发和应用生物年龄的分子标记。