Epigenetic Mechanisms Promoting Longevity

摘要 循环sRNA是短的非编码RNA（通常大小为约19- 25 nt）。它们介导了广泛的 通过调控基因表达的生物过程。实验证据表明血清 sRNA的水平变化很大--绝大多数随着年龄的增长而增加。循环中的miRNAs 在组织之间的移动使它们能够传递信号并调节广泛的生物功能。 sRNA存在于各种RNA酶不敏感的核糖核蛋白或脂质复合物中，或被封装在 不同类型的细胞外囊泡。因此，与信使RNA相反，sRNA受到保护， 从细胞外RNA酶，是可测量的和稳定的样品储存了几十年。尽管多次 尽管最近的发展，我们还远未了解sRNA在衰老中的作用。了解他们的作用 在衰老的哺乳动物，特别是人类，仍然非常有限，由于增加的复杂性和更长的 哺乳动物的寿命与无脊椎动物相比。该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）中发现和验证 长寿相关的sRNAs。我们对NIA中175种循环microRNA的初步分析， 由杜克大学资助的老年人流行病学研究人群（杜克大学EPESE）社区- 基于老年人的队列--鉴定了32种差异表达的循环miRNA（p<0.05）， 长寿;在所有情况下，长期存活者（10年以上）的基线浓度较高 与年龄、性别和种族匹配但短期存活者（<2年）相比， 预测寿命独立于年龄、性别、种族和功能状态。杜克大学EPESE队列年龄 71岁及以上，现在有近25年的纵向寿命数据， 来解决sRNA和人类寿命的关键问题。在杜克EPESE中发现的sRNA将 在已完成的与寿命相关的人体临床试验样本中进行验证， 运动（STRRIDE队列）和热量限制（CALERIE队列）的健康促进作用。人类 三维肌肉组织器官系统将用于了解其作用机制（与和 没有模拟运动和卡路里限制）。这些目标一起 将确定与长寿相关的sRNAs是否在人类中通过运动和/或 热量限制;以及它们是否似乎介导了这些干预措施的任何观察到的健康益处。 将系统检查全部数据（体内和体外生成），以确定 sRNA在人类中的作用以及sRNA和其他可作为生物标志物预测 长寿状况。

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.