Quantifying the genomic consequences of chronic social stress for accelerated aging

项目总结 长期暴露在未解决的社会压力下的人，包括由低血压引起的压力 社会经济地位或社会孤立，表现出免疫失调、主要老年病、 以及死亡本身。这些观察结果导致了一种假设，即社会压力会加速 衰老是通过改变一些同样的生物途径来实现的，这些途径也会随着年龄的增长而改变。对这一想法的支持 来自少量具有良好特征的炎症和细胞衰老标志物(例如，IL-6 水平、C反应蛋白水平和白细胞端粒缩短)。然而，我们知道的要少得多， 基因调控与生物衰老的社会压力有关，部分原因是确定了因果关系。 消除社会压力对基因调控的影响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展示一种 慢性社会压力与免疫细胞基因表达之间的直接因果关系。的目标是 建议的研究是建立在这些模型的基础上，以解决关于这种关系的三个突出问题 在社会压力和老龄化之间。首先，长期的社会从属导致的社会压力是否会导致 免疫基因表达模式的加速老化，使得低状态动物表现出表达模式 老年人的典型特征是什么？二是基因调控特征与社会压力的关系 与衰老相关的环境挑战加剧了衰老的基因调控特征 环境刺激？第三，社会压力是否会导致细胞间基因表达水平的差异增加， 要么处于基线状态，要么处于免疫挑战状态，与最近报告的 变老？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：成年雌性恒河猴优势等级的实验操作， 较早进入新成立的社会群体预示着较高的社会地位。它将在两个十字架上画出- 来自10个社会群体的50只动物的横断面和纵向样本，让我们可以问一问，缓解 社会压力也会改变衰老的基因表达特征。 总之，建议的分析将提供宝贵的洞察力，以了解是否、何时以及在多大程度上 社会压力在基因调控水平上概括并潜在地加速衰老。值得注意的是，恒河猴 猕猴不仅是人类社会压力的优秀翻译模型，而且也是最强烈的 研究了环境对人类衰老影响的灵长类模型。因此，这个项目的结果将会有 对了解慢性社会压力对健康老龄化构成的风险的直接翻译价值，包括 加剧或改善这些风险的环境因素。

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.