Effects of age and social adversity on immune status and responsiveness in a non-human primate model of human aging

项目摘要 在过去的世纪里，人类的平均寿命几乎翻了一番，这导致了 老年疾病，如心血管疾病、关节炎、认知能力下降和自身免疫性疾病。衰老是 与适应性免疫功能下降和炎症增加有关，这是许多疾病的基础。 与年龄有关的疾病。这些免疫学变化类似于暴露于社会环境中的个体所见。 比之那些没有经历过逆境的人，他们可能会更快地衰老。然而，目前还不清楚社会逆境如何改变免疫力 这些数据对于确定它如何增加与衰老有关的疾病至关重要。的 该提案的中心目标是鉴定免疫系统的特定细胞类型和分子标记物。 系统，有助于衰老过程和社会逆境如何塑造这些细胞的功能， 标记。为了验证这一点，我利用了一项对自由放养的非人类灵长类动物的纵向研究--圣地亚哥岛 恒河猴这些动物为研究衰老及其社会决定因素提供了独特的机会。第一、 恒河猴与人类有很强的系统发育相似性，并且表现出非常相似的衰老轨迹， 使它们成为人类健康的杰出典范。其次，恒河猴形成了稳定的社会结构， 支配着个体对资源和同伴的获取，类似于人类群体--这使得这个物种成为理想的 该模型用于研究社会逆境对加速老龄化的潜在影响。中央 这一建议的假设是，社会逆境导致免疫系统受损，概括了 老化的影响，从而加速老化的生物学特征，独立于 个人的实际年龄。为了验证这一假设，我将收集圣地亚哥岛恒河猴的数据 猕猴种群超过两年，共计200个个体的样本量。本提案的目标1将衡量 并通过测量不同的免疫细胞来探索年龄、社会逆境和年龄如何改变基线免疫力 类型-淋巴细胞和单核细胞亚群-使用流式细胞术。该项目的目标2将测试 年龄和社会逆境如何改变对感染的免疫反应，以及他们是否以类似的方式这样做。在这里， 我们将通过分离和免疫抑制剂来产生促炎（Th 1）和抗炎（Th 2）免疫应答。 使用活病原体和病原体分子刺激外周血单核细胞（PBMC）。近几 多年来，人们已经清楚地认识到，社会环境在发展和整体健康方面发挥着关键作用。 在不同的物种之间。通过结合生理数据和行为观察，拟议的项目将 生成必要的数据，以了解社会逆境可能在诱导与衰老有关的 免疫力的变化。最终，这个项目将揭示社会环境如何改变衰老的速度， 这将为有针对性地开发社会和生理干预措施提供信息， 与衰老有关的疾病的数量。

Project Summary The average human lifespan has almost doubled over the past century, leading to an increase in the prevalence of diseases of aging, such as cardiovascular disease, arthritis, cognitive decline and autoimmune disorders. Aging is associated with a decline in adaptive immune function and an increase in inflammation, which underlie many age-related diseases. These immunological changes are similar to those seen in individuals exposed to social adversity, who may age more rapidly than those unexposed. Yet, it is unclear how social adversity alters immunity across demographic factors - data that are essential to identify how it might increase aging-related diseases. The central objective of this proposal is to identify the specific cell types and molecular markers of the immune system that contribute to the aging process and how social adversity shapes the function of these cells and markers. To test this, I draw on a longitudinal study of free-ranging nonhuman primates – the Cayo Santiago rhesus macaques. These animals present a unique opportunity to examine aging and its social determinants. First, rhesus macaques have a strong phylogenetic proximity to humans and show very similar aging trajectories, making them an exceptional model for human health. Second, rhesus macaques form stable social structures that dictate individuals' access to resources and peers, similar to human populations- making this species an ideal model in which to study the potential effect that social adversity has on accelerating aging. The central hypothesis of this proposal is that social adversity leads to an impaired immune system, recapitulating the effects of aging, which consequently accelerates the biological signatures of aging independently of an individual’s chronological age. To test this hypothesis, I will collect data from the Cayo Santiago rhesus macaque population over two years, totaling a sample size of 200 individuals. Aim 1 of this proposal will measure and explore how both age social adversity and age alter immunity at baseline by measuring different immune cell types – both lymphocytes and monocyte subpopulations- using flow cytometry. Aim 2 of this project will test how age and social adversity alter the immune response to an infection, and if they do so in a similar way. Here, we will create a pro-inflammatory (Th1) and anti-inflammatory (Th2) immune response by isolating and stimulating peripheral blood mononuclear cells (PBMCs) using live pathogens and pathogens molecules. In recent years, it has become clear that the social environment plays a critical role in the development and overall health across different species. By combining physiological data and behavioral observations, the proposed project will generate data that is necessary to understand the role that social adversity may play in inducing aging-related changes in immunity. Ultimately, this project will reveal how the social environment alters the pace of aging, which will inform the targeted development of social and physiological interventions that could reduce the burden of aging-related disease in our aging population.