Epigenetic Mechanisms Promoting Longevity

促进长寿的表观遗传机制

• 批准号: 10434680
• 负责人: Virginia Kraus
• 金额: $ 65.76万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434680
• 关键词: 3-Dimensional; Address; African American population; 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; 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.

抽象的 循环的小调节RNA（SRNA）是短的非编码RNA（通常大小约为19-25nt）。他们调解 通过调节基因表达来进行广泛的生物学过程。我们的实验证据 表明血清miRNA水平（一种形式的SRNA）发生了很大变化，绝大多数都在增加 随着年龄的增长。循环SRNA之间传播组织的能力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中。因此，与 Messenger RNA，SRNA受到保护免受细胞外RNass的保护，在样品中可测量且稳定 存储了数十年。尽管最近有许多发展，但我们远没有理解SRNA的作用 在衰老中。了解它们在衰老哺乳动物中的作用，尤其是在人类中，仍然非常有限 与无脊椎动物相比，哺乳动物的复杂性增加和寿命更长。这个项目 从三项完成的NIH资助研究中利用现有的人类样本资源（Epese，Strride和 卡利亚），发现并验证人类中与寿命相关的miRNA。我们对175的初步分析 循环microRNA-在NIA资助 （杜克·埃斯皮斯）基于社区的长老队员 - 已确定的32个差异表达的循环miRNA （p <0.05）与寿命相关；在所有情况下，它们的基线浓度长期较高 与年龄，性别和种族相比，幸存者（> 10岁）匹配，但短期幸存者（<2岁）；子集 在这些miRNA中，预测寿命独立于年龄，性别，种族和功能状况。杜克·埃普斯 同时在血液采样时年龄71岁及以上，现在有25年的纵向死亡率数据 （直到2016年），以解决有关人类SRNA和长寿的关键问题。 SRNA发现 在杜克（Duke）中，Epese将在血浆和肌肉样本中进行验证 研究锻炼（Strride队列）和热量限制的健康促进作用的长寿 （Calerie COHORT）。人类的三维肌肉组织器官系统将用于了解其 通过测试SRNA模拟和 抑制剂。我们对该模型系统中最高长寿相关的7个最高寿命相关的miRNA的初步分析证明了 肌肉的生产和分泌，从肌肉和统计学上显着增加了其中两个的分泌物 进行模拟肌肉运动。我们的方法共同确定SRNA是否与 通过运动和/或热量限制，寿命在人类的组织和血液中受到调节，如果 他们似乎调解了这些干预措施的任何观察到的健康益处。数据的总数 （在体内和体外产生）将被系统地检查以识别人类的sRNA作用途径 以及可以作为预测寿命状态的生物标志物的SRNA的概况。

项目成果

Tissue-Engineered Skeletal Muscle Models to Study Muscle Function, Plasticity, and Disease.

• DOI: 10.3389/fphys.2021.619710
• 发表时间: 2021
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Khodabukus A

Proteasome- and Calpain-Mediated Proteolysis, but Not Autophagy, Is Required for Leucine-Induced Protein Synthesis in C2C12 Myotubes.

• DOI: 10.3390/physiologia1010005
• 发表时间: 2021-12
• 期刊: Physiologia
• 作者: Osburn SC;Vann CG;Church DD;Ferrando AA;Roberts MD
• 通讯作者: Roberts MD

Calorie restriction improves lipid-related emerging cardiometabolic risk factors in healthy adults without obesity: Distinct influences of BMI and sex from CALERIE™ a multicentre, phase 2, randomised controlled trial.

• DOI: 10.1016/j.eclinm.2021.101261
• 发表时间: 2022-01
• 期刊: EClinicalMedicine
• 影响因子: 15.1
• 作者: Huffman KM;Parker DC;Bhapkar M;Racette SB;Martin CK;Redman LM;Das SK;Connelly MA;Pieper CF;Orenduff M;Ross LM;Ramaker ME;Dorling JL;Rosen CJ;Shalaurova I;Otvos JD;Kraus VB;Kraus WE;CALERIE™ Investigators
• 通讯作者: CALERIE™ Investigators