Epigenetic Mechanisms Promoting Longevity

促进长寿的表观遗传机制

基本信息

批准号：
10180813
负责人：
Virginia Kraus
金额：
$ 65.91万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10180813
关键词：
3-Dimensional Address African American Age Aging Biochemical Biological Biological Markers Biological Models Biological Process Biomedical Engineering Blood Blood specimen Caloric Restriction Cessation of life Chronology Clinical Trials Communication Communities Complex County Data Development Elderly Encapsulated Enrollment Epigenetic Process Exercise Funding Gender Gene Expression Regulation Genes Genetic Transcription Genomics Health Benefit Health Promotion Human In Vitro Individual Intervention Invertebrates Knowledge Lipids Long-Term Survivors Longevity Mammals Measurable Measures Mediating Mediator of activation protein Messenger RNA MicroRNAs Molecular Muscle North Carolina Organ Culture Techniques Participant Pathway interactions Patient Self-Report Pharmaceutical Preparations Physical Function Physical activity Plasma Population Production Protein Isoforms 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 Survivors System Systems Biology Technology Testing Therapeutic Time Tissues Transfection Travel United States National Institutes of Health Untranslated RNA Validation Woman aged autocrine base body system cardiometabolic risk circulating microRNA cohort differential expression epidemiology study extracellular extracellular vesicles functional status human old age (65+)improved in vivo indexing inhibitor/antagonist instrument interest minimally invasive mortality next generation sequencing novel paracrine response sex tool virtual

项目摘要

Abstract Circulating small regulatory RNAs (sRNAs) are short non-coding RNAs (typically ~19-25nt in size). They mediate a broad spectrum of biological processes through regulation of gene expression. Our experimental evidence indicates that serum levels of miRNAs (one form of sRNA) change considerably, the vast majority increasing with age. The ability of circulating sRNAs 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 in 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 miRNAs 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 25 years of longitudinal mortality data (through 2016) with which to address key questions about sRNAs and longevity in humans. sRNA discoveries in Duke EPESE will be validated in plasma and muscle 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 caloric restriction), by testing sRNA mimics and inhibitors. Our preliminary analyses of 7 of our top longevity-related miRNA in this model system demonstrated production and secretion of all of them by muscle and statistically significantly increased secretion of two of them with simulated muscle exercise. Together our approach will permit us to determine if sRNAs associated with longevity are favorably modulated in tissue and blood 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 (generated in vivo and in vitro), will be systematically examined to identify pathways of sRNA action in humans and profiles of sRNA that could serve as biomarkers to predict longevity status.

抽象的循环小调节 RNA (sRNA) 是短非编码 RNA（大小通常约为 19-25nt）。他们调解通过调节基因表达来实现广泛的生物过程。我们的实验证据表明 miRNA（sRNA 的一种形式）的血清水平发生显着变化，绝大多数增加随着年龄的增长。循环 sRNA 在组织间传播的能力使它们能够传递信号并调节广泛的生物学功能。 sRNA 存在于多种 RNase 不敏感的核糖核蛋白或脂质中复合物，或封装在不同类型的细胞外囊泡内。因此，与信使 RNA、sRNA 受到保护，免受细胞外 RNase 的影响，并且在样品中可测量且稳定保存数十年。尽管最近取得了许多进展，但我们还远未了解 sRNA 的作用在老化中。由于对它们在衰老哺乳动物，特别是人类中的作用的了解仍然非常有限与无脊椎动物相比，哺乳动物的复杂性更高，寿命更长。这个项目利用来自 NIH 资助的三项已完成研究（EPESE、STRRIDE 和 CALERIE），发现并验证人类长寿相关的 miRNA。我们初步分析 175 循环 microRNA——NIA 资助的杜克大学建立的老年人流行病学研究人群 (Duke EPESE) 基于社区的老年人队列——鉴定出 32 个差异表达的循环 miRNA (p<0.05) 与长寿相关；在所有情况下，长期来看，它们的基线浓度都较高幸存者（> 10 年）与年龄、性别和种族匹配但短期幸存者（< 2 年）进行比较；一个子集这些 miRNA 的预测寿命与年龄、性别、种族和功能状态无关。埃佩斯公爵该队列在采血时年龄为 71 岁及以上，现在拥有 25 年的纵向死亡率数据（截至 2016 年）用于解决有关 sRNA 和人类寿命的关键问题。小RNA的发现杜克大学 EPESE 将在已完成的相关人体临床试验的血浆和肌肉样本中进行验证长寿调查了运动（STRRIDE 队列）和热量限制对健康的促进作用（CALERIE 队列）。将利用人体三维肌肉组织器官系统来了解其通过测试 sRNA 模拟物和抑制剂。我们对该模型系统中 7 个最重要的长寿相关 miRNA 的初步分析表明所有这些物质均由肌肉产生和分泌，其中两种物质的分泌量在统计上显着增加通过模拟肌肉锻炼。我们的方法将使我们能够确定 sRNA 是否与通过运动和/或热量限制，可以有利地调节人体组织和血液的寿命，并且如果它们似乎可以调节这些干预措施所观察到的任何健康益处。数据总量（在体内和体外产生），将被系统地检查以确定 sRNA 在人类中的作用途径以及可作为预测寿命状态生物标志物的 sRNA 谱。