Epigenetic derepression of FKBP5 by aging and stress contributes to NF-ĸB-driven inflammation and cardiovascular risk
Authors: Zannas Anthony S. , Jia Meiwen , Hafner Kathrin , Baumert Jens , Wiechmann Tobias , Pape Julius C. , Arloth Janine , Ködel Maik , Martinelli Silvia , Roitman Maria , Röh Simone , Haehle Andreas , Emeny Rebecca T. , Iurato Stella , Carrillo-Roa Tania , Lahti Jari , Räikkönen Katri , Eriksson Johan G. , Drake Amanda J. , Waldenberger Melanie , Wahl Simone , Kunze Sonja , Lucae Susanne , Bradley Bekh , Gieger Christian , Hausch Felix , Smith Alicia K. , Ressler Kerry J. , Müller-Myhsok Bertram , Ladwig Karl-Heinz , Rein Theo , Gassen Nils C. , Binder Elisabeth B. 
Published: December 2018

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 mechanisticin vitroinvestigations, 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 ofFKBP5. These age/stress-related epigenetic effects were recapitulated in anin vitromodel of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higherFKBP5mRNA with a proinflammatory profile and altered NF-κB-related gene networks. Accordingly, experiments in immune cells showed thatFKBP5overexpression promotes inflammation by strengthening the interactions of NF-κB regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-κB. Further, the age/stress-related epigenetic signature enhancedFKBP5responsivity to NF-κB 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-κB signaling mediates inflammation associated with aging and stress, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.

Significance

Diseases of the aging are the leading cause of morbidity and mortality. Elucidating the molecular mechanisms through which modifiable factors, such as psychosocial stress, confer risk for aging-related disease can have profound implications. Here, by combining studies in humans with experiments in cells, we find that aging and stress synergize to epigenetically derepress FKBP5, a protein implicated in stress physiology. Higher FKBP5 promotes inflammation by activating the master immune regulator NF-κB, whereas opposing FKBP5 – either genetically or pharmacologically– prevents the effects on NF-κB. Further, the age/stress-related epigenetic signature ofFKBP5is associated with history of myocardial infarction, a disease state linked to inflammation. These findings provide molecular insights into stress-related disease and may point to novel biomarker and treatment possibilities.