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

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

展开

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（通常大小约为19-25nt）。他们介导了一系列通过调节基因表达的生物过程。实验证据表明串行随着年龄的增长，SRNA的水平谨慎地变化 - 绝大多数人都在增加。循环miRNA的能力在组织之间旅行，使它们能够传输信号并调节广泛的生物学功能。 SRNA存在于多种RNase不敏感的色带核蛋白或脂质复合物中，或者被封装在内部不同类型的细胞外蔬菜。因此，与Messenger RNA相反，SRNA受到保护从细胞外RNass中，可测量且稳定，在存储数十年的样品中。尽管有很多最近的发展，我们远没有理解SRNA在衰老中的作用。对他们角色的理解由于复杂性的增加和更长的与无脊椎动物相比，哺乳动物的寿命。该项目利用现有的人类样本资源从三项完成的NIH资助研究（Epese，Strride和Calerie）中发现和验证人类与长寿相关的SRNA。我们对175个循环microRNA的初步分析 - 在Nia-中资助的杜克大学成立了老年人（杜克·埃皮斯）社区流行病学研究的人口基于长老的队列 - 已确定的32个不同表达的循环miRNA（p <0.05）长寿;在所有情况下，它们的基线浓度在长期生存中均高（10多年）与年龄相比，性别和种族匹配，但短期生存（<2岁）；这些miRNA的子集预测寿命独立于年龄，性别，种族和功能状况。杜克大学杜克大学队列年龄 71岁及以上的血液采样时，现在拥有将近25年的纵向生命数据这要解决有关人类SRNA和长寿的关键问题。斯里纳在杜克杜克·埃斯特的发现通过完成的人类与寿命相关性的临床试验的样本进行验证，该试验研究了健康促进运动的影响（Strride队列）和热量限制（Calerie COHORT）。人类三维肌肉组织器官系统将用于了解其作用机理（使用和通过测试SRNA模拟和抑制剂，无需模拟运动和卡路里限制）。这些目标在一起将确定与寿命相关的SRNA是否经常通过锻炼和/或在人类中调节热量限制；如果它们似乎调解了这些干预措施的任何健康益处。将系统检查数据的总数（体内和体外生成），以识别 SRNA在人类中的作用以及SRNA的曲线以及其他可以作为生物标志物预测的因素寿命状态。