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Quantifying the genomic consequences of chronic social stress for accelerated aging

量化慢性社会压力对加速衰老的基因组影响

基本信息

批准号：
10063842
负责人：
Noah Simons
金额：
$ 1.56万
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：
2018-12-01 至 2021-02-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063842
关键词：
Address Adult Age Aging Aleurites Animal Model Animals Area Biological Biological Aging Cell Aging Cells Characteristics Chronic Complex Data Disease Environment Environmental Risk Factor Exhibits Exposure to Female Gene Expression Gene Expression Profile Gene Expression Regulation Genetic Transcription Genomic approach Genomics Goals Health Helper-Inducer T-Lymphocyte Human Immune Immune system Immunization In Vitro Individual Inflammation Inflammatory Interleukin-6 Intervention Intervention Studies Lead Leukocytes Light Link Longevity Macaca Macaca mulatta Mediating Mentors Modeling Molecular Pathway interactions Pattern Peripheral Blood Mononuclear Cell Phenotype Physiological Population Postdoctoral Fellow Primates Process Regulator Genes Reporting Research Research Design Risk Sampling Social isolation Social status Statistical Models Stimulus Stress Study Subject Study models System Testing Time Training Variant Work aged experience experimental study genome-wide genomic data healthspan healthy aging inflammatory marker insight low socioeconomic status mortality nonhuman primate novel resilience response single-cell RNA sequencing social social group social stress study population telomere translational model

项目摘要

PROJECT SUMMARY People that experience chronic exposure to unresolved social stress, including that induced by low socioeconomic status or social isolation, exhibit increased risk of immune dysregulation, major diseases of aging, and mortality itself. These observations have led to the hypothesis that social stress accelerates the process of aging by altering some of same biological pathways that are also changed with age. Support for this idea has come from a small number of well-characterized markers of inflammation and cellular senescence (e.g., IL-6 levels, CRP levels, and shortened leukocyte telomeres). However, we know much less about how changes in gene regulation link experienced social stress to biological aging, in part because identifying the causal effects of social stress on gene regulation remains a major challenge. Recent work in nonhuman primate animal models has helped overcome this challenge by showing a direct causal relationship between chronic social stress and gene expression in immune cells. The goal of the proposed research is to build on these models to address three outstanding questions about the relationship between social stress and aging. First, does chronic, social subordination-induced social stress cause accelerated aging in immune gene expression patterns, such that low status animals exhibit expression patterns typical of older individuals? Second, is the relationship between the gene regulatory signature of social stress and the gene regulatory signature of aging exacerbated by environmental challenge with aging-relevant environmental stimuli? Third, does social stress induce increased cell-to-cell variance in gene expression levels, either at baseline or in an immune challenged state, consistent with recently reported increased variance during aging? To address these questions, the proposed study will take advantage of a powerful model for studying the causal effects of social status: experimental manipulation of dominance rank in adult female rhesus macaques, where earlier introduction into newly formed social groups predicts higher social status. It will draw on both cross- sectional and longitudinal samples from 50 animals in 10 social groups, allowing us to ask whether the alleviation of social stress also alters gene expression signatures of aging. Together, the proposed analysis will provide valuable insight into whether, when, and to what degree social stress recapitulates, and potentially accelerates, aging at the gene regulatory level. Notably, rhesus macaques are not only excellent translational models for human social stress, but also the most intensively studied primate model for environmental effects on human aging. The results of this project will therefore have direct translational value for understanding the risks that chronic social stress pose to healthy aging, including environmental factors that exacerbate or ameliorate these risks.

项目摘要长期暴露在未解决的社会压力下的人，包括由低社会经济地位或社会孤立，表现出免疫失调，重大衰老疾病，死亡本身。这些观察结果导致了一个假设，即社会压力加速了通过改变一些同样的生物学途径，这些途径也会随着年龄的增长而改变。支持这一想法的有来自少量充分表征的炎症和细胞衰老的标志物（例如，IL-6 水平、CRP水平和缩短的白细胞端粒）。然而，我们对地球的变化知之甚少。基因调控将经历的社会压力与生物衰老联系起来，部分原因是确定了因果关系基因调控的社会压力仍然是一个重大挑战。最近在非人类灵长类动物模型中的研究通过显示出一种新的基因，慢性社会压力与免疫细胞基因表达之间的直接因果关系。的目标建议的研究是建立在这些模型，以解决三个悬而未决的问题的关系社会压力和衰老之间的联系首先，长期的、社会从属关系引起的社会压力是否会导致免疫基因表达模式的加速老化，使得低地位动物表现出表达模式，典型的老年人？第二，是基因调控信号与社会压力的关系以及衰老的基因调控特征，由于环境挑战而加剧，环境刺激？第三，社会压力是否会导致基因表达水平的细胞间差异增加，无论是在基线还是在免疫激发状态，与最近报告的增加的方差一致，老化？为了解决这些问题，拟议的研究将利用一个强大的模型来研究社会地位的因果效应：成年雌性恒河猴支配地位的实验操作，较早进入新形成的社会群体预示着较高的社会地位。它将吸引双方的交叉- 来自10个社会群体的50只动物的横断面和纵向样本，使我们能够询问是否可以缓解社会压力也改变了衰老的基因表达特征。总之，拟议的分析将提供有价值的见解，是否，何时，以及在何种程度上，社会压力在基因调节水平上重演并潜在地加速衰老。值得注意的是，猕猴不仅是人类社会压力的优秀翻译模型，研究环境对人类衰老影响的灵长类动物模型。因此，该项目的结果将具有理解慢性社会压力对健康老龄化造成的风险的直接转化价值，包括加剧或减轻这些风险的环境因素。