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，衰老过程可以自然地加速和减速，从而导致 相关物种的寿命存在显着差异。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 寿命差异及其组织和培养细胞很容易获得。公正的描述 与哺乳动物寿命自然变化相关的基因和过程可能会导致 开发针对衰老过程并可能延缓衰老的方法。我们假设哺乳动物 通过共同和谱系特定过程的结合来调整寿命，并提供初步的 数据支持这个想法。在 PPG 的持续阶段，我们生成了令人兴奋的数据来支持我们的总体目标 寿命控制方法。我们生成了哺乳动物的全面分子谱，包括 非常长寿的物种。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 老鼠的时钟，发现它正确地报告了长寿干预措施的效果。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的工具和方法 了解哺乳动物寿命的自然控制。具体来说，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配置文件来识别分子特征 及其组合，重点关注基因表达和代谢物，最终与长寿相关 构建长寿物种的分子特征（使用核心 C）。我们还将进行基因表达和 海狸化 SIRT6 小鼠（使用项目 1 和核心 B）、裸鼹鼠 HAS2 的代谢物分析 转基因小鼠和用透明质酸酶抑制剂治疗的小鼠（项目 2 和核心 B），提供了关键的 对这些基因促进长寿的机制的分子洞察。 (2) 长寿基因组学 啮齿动物。我们将对裸鼹鼠和裸鼹鼠的新的、改进的组件进行全面注释 海狸基因组（带有核心 C），进而为项目 1、2 和 3 提供关键资源。我们还将重点关注 DNA 修复和染色质重塑基因的进化以及这些基因丢失和获得的特征 物种。 (3)表观遗传时钟在小鼠长寿模型中的应用。我们最近开发了一个 小鼠 DNA 甲基化时钟，我们将其应用于 PPG 中检查的动物和细胞培养模型 （包含项目 1、2 和 3，以及核心 B 和 C）。 (4)裸鼹鼠表观遗传学的开发与应用 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。