Epigenetic Mechanisms Promoting Longevity

促进长寿的表观遗传机制

基本信息

批准号：
9551744
负责人：
Virginia Kraus
金额：
$ 51.51万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9551744
关键词：
Address African American Age Aging Biochemical Biological Biological Markers Biological Models Biological Process Biology Biomedical Engineering Blood Blood specimen Caloric Restriction Chronology Clinical Trials Communication Communities Complex County Data Development Dimensions Elderly Encapsulated Energy Metabolism Enrollment Epigenetic Process Exercise Funding Gender Gene Expression Gene Expression Regulation Generations Genes Genetic Transcription Genomics Glucose Health Health Benefit Human In Vitro Individual Intervention Invertebrates Knowledge Lipids Long-Term Survivors Longevity Mammals Measurable Measures Mediating Mediator of activation protein Messenger RNA MicroRNAs Molecular Monitor Muscle North Carolina Organ Culture Techniques Participant Pathway interactions Patient Self-Report Pharmaceutical Preparations Physical Function Physical activity Plasma Population RNA Race Randomized Resource Sharing Resources Reverse Transcriptase Polymerase Chain Reaction Ribonucleases Ribonucleoproteins Risk Factors Role Sampling Serum Signal Transduction Skeletal Muscle Small Interfering RNA Standardization Survivors System Systems Biology Technology Testing Therapeutic Time Tissues Travel United States National Institutes of Health Untranslated RNA Update Validation Woman age related aged base body system cardiometabolic risk circulating microRNA cohort differential expression epidemiology study extracellular extracellular vesicles functional status improved in vivo inhibitor/antagonist instrument minimally invasive mortality muscle strength next generation sequencing response sex tool virtual

项目摘要

Abstract Circulating sRNAs are short non-coding RNAs (typically ~19-25nt in size). They mediate a broad spectrum of biological processes through regulation of gene expression. Experimental evidence indicates that the serum levels of sRNAs change considerably--the vast majority increasing—with age. The ability of circulating miRNAs to travel among tissues enables them to transmit signals and regulate a broad spectrum of biological functions. sRNAs exist in a variety of RNase-insensitive ribonucleoprotein or lipid complexes, or are encapsulated inside different types of extracellular vesicles. Consequently, in contrast to messenger RNA, sRNAs are protected from extracellular RNases and are measurable and stable in samples stored for decades. Despite numerous recent developments, we are far from understanding the role of sRNAs in aging. An understanding of their role in aging mammals, and humans in particular, is still very limited due to the increased complexity and longer life-spans of mammals compared with invertebrates. This project leverages existing human sample resources from three completed NIH-funded studies (EPESE, STRRIDE and CALERIE) to discover and validate longevity-associated sRNAs in humans. Our preliminary analysis of 175 circulating microRNA--in the NIA- funded Duke Established Populations for Epidemiologic Studies of the Elderly (Duke EPESE) community- based cohort of elders--identified 32 differentially expressed circulating miRNAs (p<0.05) associated with longevity; in all cases, their concentrations at baseline were higher in long-term survivors (10+ years) compared with age, sex and race matched but short-term survivors (<2 years); a subset of these miRNAs predicted longevity independent of age, gender, race and functional status. The Duke EPESE cohort was aged 71 and older at the time of blood sampling and now has nearly 25 years of longitudinal life-span data with which to address key questions about sRNA and longevity in humans. sRNA discoveries in Duke EPESE will be validated in samples from completed human clinical trials of relevance to longevity that investigated the health promoting effects of exercise (STRRIDE cohort) and caloric restriction (CALERIE cohort). A human three-dimensional muscle tissue organ system will be used to understand their mechanisms of action (with and without simulated exercise and calorie restriction) by testing sRNA mimics and inhibitors. Together these aims will determine if sRNAs associated with longevity are favorably modulated in humans by exercise and/or caloric restriction; and if they appear to mediate any of the observed health benefits of these interventions. The totality of the data (in vivo and in vitro generated), will be systematically examined to identify pathways of sRNA action in humans and profiles of sRNA and other factors that could serve as biomarkers to predict longevity status.

抽象的循环 sRNA 是短的非编码 RNA（大小通常约为 19-25nt），它们介导多种作用。实验证据表明，血清通过调节基因表达来实现生物过程。随着年龄的增长，sRNA 的水平发生显着变化（绝大多数会增加）。在组织之间移动使它们能够传输信号并调节广泛的生物功能。 sRNA 存在于多种 RNase 不敏感的核糖核蛋白或脂质复合物中，或封装在其中经过测试，不同类型的细胞外囊泡，与信使 RNA 不同，sRNA 受到保护。来自细胞外核糖核酸酶，尽管数量众多，但在储存数十年的样品中仍可测量且稳定。尽管最近的进展，我们还远未了解 sRNA 在衰老中的作用。由于复杂性的增加和更长的时间，在衰老的哺乳动物，特别是人类中，这种方法仍然非常有限。该项目利用现有的人类样本资源。从 NIH 资助的三项已完成的研究（EPESE、STRRIDE 和 CALERIE）中发现并验证我们对 NIA 中 175 种循环 microRNA 的初步分析。资助杜克大学老年流行病学研究人群 (Duke EPESE) 社区 - 基于老年人的队列——鉴定出 32 个差异表达的循环 miRNA（p<0.05）长寿；在所有情况下，长期幸存者（10 岁以上）的基线浓度较高与年龄、性别和种族匹配但短期幸存者（<2 年）的这些 miRNA 的子集进行比较；预测的长寿与年龄、性别、种族和功能状态无关。采血时年龄为 71 岁及以上，现在拥有近 25 年的纵向寿命数据杜克大学 EPESE 的 sRNA 发现将解决有关 sRNA 和人类寿命的关键问题。在与长寿相关的已完成人体临床试验的样本中进行验证运动（STRRIDE 队列）和热量限制（CALERIE 队列）的健康促进作用。三维肌肉组织器官系统将用于了解其作用机制（与通过测试 sRNA 模拟物和抑制剂来实现这些目标（无需模拟运动和热量限制）。将确定与长寿相关的 sRNA 是否可以通过锻炼和/或热量限制；以及它们是否能够调节这些干预措施所观察到的任何健康益处。将系统地检查全部数据（体内和体外生成的），以确定 sRNA 在人类中的作用以及 sRNA 和其他可作为预测生物标志物的因素的概况长寿状态。