Social and dietary modifiers of neuroinflammation and aging

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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.