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Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are poorly understood. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress exposure along the lifespan could confer disease risk by epigenetically deregulating molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with mechanistic in vitro investigations, we found that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n=3,131), aging and stress-related phenotypes were synergistically associated with epigenetic derepression of FKBP5. These age/stress-related epigenetic effects were recapitulated in an in vitro model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-kB-related gene networks. Accordingly, experiments in immune cells showed that FKBP5 overexpression promotes inflammation by strengthening the interactions of NF-kB regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-kB. Further, the age/stress-related epigenetic signature enhanced FKBP5 responsivity to NF-kB through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that FKBP5-NF-kB signaling mediates inflammation associated with aging and stress, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.

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