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Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-?B-driven inflammation and cardiovascular risk.

ABSTRACT: Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/stress-related epigenetic effects were recapitulated in a cellular 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-?B-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-?B regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-?B. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-?B 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 aging/stress-driven FKBP5-NF-?B signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.

SUBMITTER: Zannas AS

PROVIDER: S-EPMC6561294 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-κB-driven inflammation and cardiovascular risk.

Zannas Anthony S AS Jia Meiwen M Hafner Kathrin K Baumert Jens J Wiechmann Tobias T Pape Julius C JC Arloth Janine J Ködel Maik M Martinelli Silvia S Roitman Maria M Röh Simone S Haehle Andreas A Emeny Rebecca T RT Iurato Stella S Carrillo-Roa Tania T Lahti Jari J Räikkönen Katri K Eriksson Johan G JG Drake Amanda J AJ Waldenberger Melanie M Wahl Simone S Kunze Sonja S Lucae Susanne S Bradley Bekh B Gieger Christian C Hausch Felix F Smith Alicia K AK Ressler Kerry J KJ Müller-Myhsok Bertram B Ladwig Karl-Heinz KH Rein Theo T Gassen Nils C NC Binder Elisabeth B EB

Proceedings of the National Academy of Sciences of the United States of America 20190521 23

Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protei ...[more]

PMID: 31113877

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Dataset Information

Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-?B-driven inflammation and cardiovascular risk.

Publications

Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-κB-driven inflammation and cardiovascular risk.

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