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

项目摘要 在过去的一个世纪里，人类的平均寿命几乎翻了一番，导致糖尿病患病率上升 老年性疾病，如心血管疾病、关节炎、认知功能减退和自身免疫性疾病。老龄化是 与适应性免疫功能下降和炎症增加有关，这是许多 与年龄有关的疾病。这些免疫学变化与暴露在社会环境中的个人相似 逆境，他们可能比那些没有暴露的人衰老得更快。然而，目前尚不清楚社会逆境如何改变免疫力。 跨人口因素--这些数据对于确定衰老可能如何增加与衰老相关的疾病至关重要。这个 这项建议的中心目标是确定免疫的特定细胞类型和分子标记 有助于衰老过程的系统，以及社会逆境如何塑造这些细胞和 记号笔。为了验证这一点，我对自由活动的非人类灵长类动物--圣地亚哥卡尤进行了纵向研究 恒河猴。这些动物为研究衰老及其社会决定因素提供了一个独特的机会。第一, 恒河猴与人类有很强的亲缘关系，并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。第二，恒河猴形成稳定的社会结构， 规定个人获得资源和同伴的机会，类似于人类群体--使这个物种成为理想物种 研究社会逆境对加速老龄化的潜在影响的模型。中环 这一建议的假设是，社会逆境导致免疫系统受损，概括地说 衰老的影响，从而加速了衰老的生物特征，而不依赖于 个人的时间顺序年龄。为了验证这一假设，我将收集圣地亚哥恒河猴的数据 猕猴种群数量超过两年，样本总数为200只。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在基线上改变免疫力 用流式细胞术检测淋巴细胞和单核细胞亚群的类型。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，以及它们是否以类似的方式做到这一点。这里, 我们将通过分离和分离出促炎症(Th1)和抗炎(Th2)的免疫反应 使用活病原体和病原体分子刺激外周血单核细胞(PBMC)。在最近 多年来，人们已经清楚地看到，社会环境对发展和整体健康起着至关重要的作用 跨越不同的物种。通过将生理数据和行为观察相结合，拟议的项目将 产生必要的数据，以了解社会逆境可能在导致老龄化相关因素中所起的作用 豁免权的变化。最终，这个项目将揭示社会环境如何改变老龄化的速度， 这将为有针对性地开展可减轻负担的社会和生理干预措施提供信息 在我们老龄化的人口中，与老龄化相关的疾病。

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.