Impacts of Social Resilience on Immunometabolic Hallmarks of Aging in Prairie Voles - PROJECT ABSTRACT Social isolation is a significant risk factor for numerous diseases of aging, including cardiometabolic disease. Conversely, multiple studies of age-related health outcomes find that sustained relationships and social bonds can protect against these effects. Our preliminary data suggests that, in prairie voles, a rodent species that forms long term pair bonds, the effects of adult social isolation differ from those in non-pair- bonding species. We have also shown that social isolation leads to altered metabolic health span, and that with age, individual variation contributes to diversity in social behavior. We propose to use the vole as a valuable model to examine how such variation in response to a chronic adult stressor may contribute to differences in social resilience and modify the physiological response to stress with age, reflected in the hallmarks of aging. In the R61 phase, we will test the impact of chronic social isolation on immunometabolic hallmarks of aging and will correlate these changes with social resilience phenotypes identified in isolated populations. In Aim 1, we will use unbiased metabolomics and targeted analysis of inflammatory markers pre- and post- isolation from plasma of chronically isolated prairie voles compared to animals that are socially housed. These studies will identify changes in global metabolic state and specific hallmarks of aging, including mitochondrial dysfunction, inflammatory and senescence profiles. Following isolation, we will use a battery of behavioral assessments in different social conditions to identify populations of animals that are resilient or vulnerable to the effects of isolation stress. These measures will be used to develop a social resilience index, then correlated with metabolic phenotypes in order to associate social function with physiological markers of health and aging. The R33 phase will be undertaken only if well-defined milestones are achieved. In Aim 3, we will perform tissue specific assessments of metabolic status using targeted LCMS metabolomic analyses, which will be integrated with gene expression data from vole brain, liver, and adipose tissue. Importantly, we will also test the hypothesis that Oxtr signaling in these individual tissues mediates the changes in metabolic and inflammatory hallmarks that have been identified using tissue from genetically modified Oxtr knock out prairie voles. We will assess the outcome of these effects on overall health span in isolated animals. In aim 4, we will determine whether pair bonding as an intervention following isolation rescues effects on metabolic function and health span. The outcome of this phase will provide novel insights into behavioral modifiers of aging. Our goal is to validate a chronic stressor in adults for a critical model system. This model incorporates individual social resilience and attachment biology into our understanding of social stress and aging, providing novel strategies for interventions in age-related disease.
