Epigenetic Aging: The Impact of Social and Environmental Realism - Correlational studies in human populations strongly indicate that the environment in which we live has a large impact on our health and well-being, including influencing lifespan and relative rates of aging. Increasingly, it is clear that both the physical and social environments in which we are embedded can shape our health. Establishing causality requires animal experimentation, though experimental manipulation of natural social environments, including social structures or demography is often impossible or challenging. As the model mammal mice have been instrumental in studies of age-related patterns of epigenetic change. There has been a recent push to examine how lab environments may skew or limit understanding of biology, especially of complex processes known to be socio-environmentally sensitive, like age-related methylation. We have established an experimental paradigm that allows us to study mice in replicable, experimentally tractable free- living populations in large outdoor enclosures. By ‘rewilding’ mice we can bridge the gap between ecological and biomedical approaches by using the tools available in biomedicine while studying animals in semi-natural abiotic, biotic, and social environments. We propose to use this paradigm to study how natural complexity in the physical and social environment shapes patterns of aging, as measured by epigenetic changes and behavioral performance. Our preliminary data indicate that rewilded lab mice show faster rates of epigenetic aging in their liver, though whether similar patterns of seemingly accelerated patterns of aging translate to other tissues, behavioral senescence, and lifespan is unknown. We propose to study epigenetic aging in an ongoing population of inbred lab mice that we maintain in a field enclosure. We will compare patterns of genome-wide methylation and behavioral performance in age-matched samples of mice reared in traditional lab environment versus rewilded mice living in an enclosure. In Aim 1, we will assess the impact of living in semi-natural versus lab environments on methylation across multiple tissues. These results will reveal whether differences in epigenetic processes between lab and rewilded mice vary depending on the tissue examined. Using the methylation data, we will generate tissue-specific and multi-tissue clocks in Aim 2 to test how natural environments shape the pace of aging relative to the lab. In addition to methylation, we will also document age- related changes in behavior to document overall patterns of senescence in performance. Deciphering the processes that contribute to the broad-scale shifts in epigenetic regulation across lab and field environments is critical for relating studies of lab mouse models to the biology of free-living mammals, including humans. Once we have firmly established the patterns of age-related changes in methylation and performance in free-living mice through this R21, we will manipulate mouse populations and genetics to experimentally test ecological, social, and genetic factors shaping epigenetic changes in a free-living mammalian population in subsequent grants.
