Social and dietary modifiers of neuroinflammation and aging

项目总结 社会经历塑造了人类和其他社会哺乳动物的健康和长寿。社会逆境 在人类和社会性的非人类灵长类动物中，与更高的死亡率和更差的健康有关。一 普遍的解释是，慢性压力失调了对压力的生理反应，导致 慢性炎症性表型加速衰老并与慢性神经退行性变相关 阿尔茨海默氏症等疾病。这些炎症结果与饮食影响的结果重叠。在……里面 西方和地中海两种营养成分不同的流行饮食的比较 饮食--西方饮食不仅与较差的健康和增加阿尔茨海默病的风险有关 等痴呆症，也是一种慢性炎症性表型。这些特点提出了一个问题： 饮食和社会经历如何相互作用影响衰老和健康。 这项拟议的研究的目标是确定将社会逆境和 饮食对压力和炎症的反应。如果社会逆境和饮食的炎症结果是相同的 一些常见的分子机制，我假设饮食可以缓解衰老加速的表型在 通过调节对社会逆境的神经炎性反应来影响大脑。为了检验这一假设，我将利用 研究雌性猕猴的优势，这是人类社会中公认的动物模型 行为、衰老和慢性病。我提出了一种双管齐下的方法，将自由放养的研究结合起来 中年猕猴整个成年寿命(目标1)与饮食的实验操作 猕猴队列(目标2和3)，从而深入了解压力、 在一个综合模型中，神经炎症和衰老。在这两种情况下，我将结合全基因组基因 表达测量，以表征与社会逆境和饮食相关的基因组途径。 从自由活动的人群中收集的见解(目标1)将被用来描述社会逆境和 饮食相互作用影响神经退行性变和脑老化(目标2-3)，并了解关键细胞的作用 类型，包括小胶质细胞(目标3)。 在其结论中，这个项目将对社会逆境和饮食如何影响基因产生详细的理解 衰老大脑中的调节和神经炎症，以及饮食干预如何缓解健康 慢性社会压力的后果。综上所述，这些结果将促进我们对 饮食或社会逆境影响老年人认知和神经复原力的机制 人口。此外，拟议的导师培训活动计划将使我发展出强大的， 在老龄化方面的独立研究生涯，专注于老龄化、社会行为、神经科学和 基因组学。

PROJECT SUMMARY Social experiences shape the health and longevity of humans and other social mammals. Social adversity in humans and in social nonhuman primates is associated with higher mortality and poorer health. One prevailing explanation is that chronic stress dysregulates the physiological response to stress, resulting in a chronic inflammatory phenotype that accelerates aging and is associated with chronic neurodegenerative diseases such as Alzheimer's disease. These inflammatory outcomes overlap with those influenced by diet. In comparisons of two prevailing diets that differ in nutritional composition—the Western and Mediterranean diets—Western diets are associated with not only poorer health and an increased risk of Alzheimer's disease and other dementias, but also a chronic inflammatory phenotype. These characteristics raise the question of how diet and social experiences interact to influence aging and health. The objective of the proposed study is to identify the molecular mechanisms that link social adversity and diet to the stress response and inflammation. If the inflammatory outcomes of social adversity and diet share some common molecular mechanisms, I hypothesize that the diet can mitigate age-accelerating phenotypes in the brain by modulating neuroinflammatory responses to social adversity. To test this hypothesis, I will leverage the advantages of studying female macaques, which are well-established animal models of human social behavior, aging, and chronic disease. I propose a two-pronged approach that combines studies of free-ranging macaques spanning the entire adult lifespan (Aim 1) with experimental manipulations of diet in a middle-aged macaque cohort (Aims 2 and 3), thus yielding insights into the relationships between stress, neuroinflammation, and aging in an integrated model. In both contexts, I will combine genome-wide gene expression measurements to characterize the genomic pathways associated with social adversity and diet. Insights gleaned from the free-ranging population (Aim 1) will be used to characterize how social adversity and diet interact to influence neurodegeneration and brain aging (Aims 2-3), and to understand the role of key cell types, including microglia (Aim 3). At its conclusion, this project will yield a detailed understanding of how social adversity and diet affect gene regulation and neuroinflammation in the aging brain, and how diet interventions can buffer against the health consequences of chronic social stress. Together, these results will advance our understanding of the mechanisms through which diet or social adversity impact cognitive and neurological resilience in the aging population. In addition, the proposed program of mentored training activities will allow me to develop a strong, independent research career in aging, focused on the nexus of aging, social behavior, neuroscience, and genomics.