Epigenetic Mechanisms Promoting Longevity

摘要 循环中的sRNA是短小的非编码RNA(通常大小约为19-25nt)。他们调解了广泛的 通过基因表达调控的生物过程。实验证据表明，血清 随着年龄的增长，sRNA的水平会发生很大的变化--绝大多数会增加。MiRNAs的循环能力 在组织之间旅行使它们能够传递信号并调节广泛的生物功能。 SRNA存在于各种对核糖核蛋白或脂质不敏感的核糖核蛋白或脂类复合体中，或者被包裹在 不同类型的胞外小泡。因此，与信使rna相比，sRNA受到保护。 来自细胞外核糖核酸酶，在储存数十年的样品中是可测量和稳定的。尽管有许多 尽管最近的发展，我们还远远不了解sRNA在衰老中的作用。对他们角色的理解 在衰老的哺乳动物中，尤其是人类中，由于复杂性的增加和更长的时间，仍然非常有限 哺乳动物的寿命与无脊椎动物相比。该项目利用了现有的人力样本资源 从NIH资助的三项已完成研究(EPESE、STRRIDE和CALERIE)中发现和验证 人类中与长寿相关的sRNA。我们对NIA中175个循环microRNA的初步分析 资助的杜克大学建立了老年人流行病学研究(Duke EPESE)社区- 基于老年人的队列--鉴定出32个差异表达的循环miRNAs(p&lt；0.05)与 长寿；在所有病例中，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(&lt；2年)相比；这些miRNAs的子集 预测寿命不受年龄、性别、种族和功能状态的影响。埃佩斯公爵的队伍已经上了年纪 71岁及以上，现在有近25年的纵向寿命数据 以解决有关sRNA和人类寿命的关键问题。在Duke EPESE发现的SRNA将 在已完成的与长寿相关的人类临床试验的样本中得到验证，这些试验调查了 运动(STRRIDE队列)和热量限制(CALERIE队列)的健康促进作用。一个人类 将使用三维肌肉组织器官系统来了解它们的作用机制(与和 在没有模拟运动和卡路里限制的情况下)，通过测试sRNA模拟和抑制剂。把这些目标放在一起 将确定与长寿相关的sRNA是否在人类中通过锻炼和/或有利地调节 卡路里限制；以及它们是否似乎调解了这些干预措施所观察到的任何健康益处。 将对(体内和体外产生的)全部数据进行系统检查，以确定 SRNA在人体中的作用以及sRNA和其他可作为生物标志物进行预测的因素的分布 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.