Social and dietary modifiers of neuroinflammation and aging

项目摘要 社会经验塑造了人类和其他社会性哺乳动物的健康和长寿。社会逆境 在人类和社会性非人类灵长类动物中，与更高的死亡率和更差的健康状况有关。一 流行的解释是，慢性压力使对压力的生理反应失调，导致 慢性炎症表型，加速老化，并与慢性神经退行性疾病相关 老年痴呆症等疾病。这些炎症结果与饮食影响的结果重叠。在 比较两种营养成分不同的流行饮食-西方和地中海饮食 西方饮食不仅与更差的健康和阿尔茨海默病的风险增加有关 和其他痴呆症，而且还有慢性炎症表型。这些特征提出了一个问题， 饮食和社会经验如何相互作用影响衰老和健康。 这项研究的目的是确定联系社会逆境的分子机制， 饮食对应激反应和炎症的影响。如果社会逆境和饮食的炎症结果 一些常见的分子机制，我假设饮食可以减轻年龄加速表型， 通过调节对社会逆境的神经炎症反应来改变大脑。为了验证这个假设，我将利用 研究雌性猕猴的优势，它们是人类社会的公认动物模型， 行为、衰老和慢性疾病。我提出了一个双管齐下的方法，结合研究自由放养 猕猴跨越整个成年寿命（目的1）与实验操作的饮食在中年 猕猴队列（目标2和3），从而深入了解压力， 神经炎症和衰老的综合模型。在这两种情况下，我将联合收割机结合全基因组基因 表达测量来表征与社会逆境和饮食相关的基因组途径。 从自由放养人口（目标1）中收集的见解将用于描述社会逆境和 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，这个项目将产生一个详细的了解如何社会逆境和饮食影响基因 调节和神经炎症在老龄化的大脑，以及如何饮食干预可以缓冲对健康的影响， 慢性社会压力的后果。总之，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恢复力的机制 人口此外，建议的指导培训活动计划将使我能够发展一个强大的， 独立的研究生涯在老龄化，专注于老龄化，社会行为，神经科学， 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.