Epigenetic Mechanisms Promoting Longevity

促进长寿的表观遗传机制

• 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
• 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

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.

摘要 循环小调节RNA（sRNA）是短的非编码RNA（通常大小为~19- 25 nt）。它们介导 通过调控基因表达的广泛的生物过程。我们的实验证据 表明血清中miRNAs（sRNA的一种形式）的水平变化很大，绝大多数增加 随年龄循环sRNAs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RNA酶不敏感的核糖核蛋白或脂质中 复合物，或被封装在不同类型的细胞外囊泡内。因此，与 信使RNA，sRNA受到细胞外RNA酶的保护，在样品中可测量且稳定 储存了几十年。尽管最近取得了许多进展，但我们还远未了解sRNA的作用。 在衰老。对它们在衰老的哺乳动物，特别是人类中的作用的理解仍然非常有限， 与无脊椎动物相比，哺乳动物的复杂性增加，寿命延长。这个项目 利用现有的人类样本资源，从三个完成的NIH资助的研究（EPESE，STRRIDE和 CALERIE），以发现和验证人类长寿相关的miRNA。初步分析175 循环microRNA--在美国国立卫生研究院资助的杜克大学老年人流行病学研究的既定人群中 (Duke EPESE）基于社区的老年人队列-确定了32个差异表达的循环miRNA （p<0.05）与寿命相关;在所有情况下，其基线浓度高于长期 存活者（>10年）与年龄、性别和种族匹配但短期存活者（<2年）相比;一个子集 这些miRNAs的预测寿命独立于年龄，性别，种族和功能状态。杜克·伊普斯 队列在采血时年龄为71岁及以上，现在有25年的纵向死亡率数据 （到2016年），以解决有关sRNA和人类寿命的关键问题。sRNA发现 在杜克，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 研究了运动（STRRIDE队列）和热量限制对健康的促进作用 （CALERIE队列）。一个人体三维肌肉组织器官系统将被用来了解他们的 作用机制（有和没有模拟运动和热量限制），通过测试sRNA模拟物和 抑制剂的我们在该模型系统中对7种与长寿相关的顶级miRNA的初步分析表明， 所有这些物质都由肌肉产生和分泌，其中两种物质的分泌量在统计学上显着增加 模拟肌肉锻炼。总之，我们的方法将使我们能够确定是否sRNAs与 通过锻炼和/或热量限制，长寿在人体组织和血液中得到有利的调节， 它们似乎介导了这些干预措施所观察到的任何健康益处。总体数据 （在体内和体外产生），将系统地检查，以确定sRNA在人类中的作用途径 以及sRNA的图谱，可以作为预测长寿状态的生物标志物。