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

Show full item record



Permalink

http://hdl.handle.net/10138/304027

Citation

Zannas , A S , Jia , M , Hafner , K , Baumert , J , Wiechmann , T , Pape , J C , Arloth , J , Ködel , M , Martinelli , S , Roitman , M , Roeh , S , Haehle , A , Emeny , R T , Iurato , S , Carrillo-Roa , T , Lahti , J , Räikkönen , K , Eriksson , J G , Drake , A J , Waldenberger , M , Wahl , S , Kunze , S , Lucae , S , Bradley , B , Gieger , C , Hausch , F , Smith , A K , Ressler , K J , Mueller-Myhsok , B , Ladwig , K-H , Rein , T , Gassen , N C & Binder , E B 2019 , ' Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-kappa B-driven inflammation and cardiovascular risk ' , Proceedings of the National Academy of Sciences of the United States of America , vol. 116 , no. 23 , pp. 11370-11379 . https://doi.org/10.1073/pnas.1816847116

Title: Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-kappa B-driven inflammation and cardiovascular risk
Author: Zannas, Anthony S.; Jia, Meiwen; Hafner, Kathrin; Baumert, Jens; Wiechmann, Tobias; Pape, Julius C.; Arloth, Janine; Ködel, Maik; Martinelli, Silvia; Roitman, Maria; Roeh, 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.; Mueller-Myhsok, Bertram; Ladwig, Karl-Heinz; Rein, Theo; Gassen, Nils C.; Binder, Elisabeth B.
Contributor: University of Helsinki, Doctoral Programme in Psychology, Learning and Communication
University of Helsinki, Department of Psychology and Logopedics
University of Helsinki, Research Programs Unit
Date: 2019-06-04
Language: eng
Number of pages: 10
Belongs to series: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
URI: http://hdl.handle.net/10138/304027
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-kappa B-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-kappa B regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-kappa B. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-kappa 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-kappa B signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.
Subject: aging
epigenetics
FKBP5
inflammation
psychosocial stress
ADVERSE CHILDHOOD EXPERIENCES
ALL-CAUSE MORTALITY
C-REACTIVE PROTEIN
DNA METHYLATION
DEPRESSIVE SYMPTOMS
LYMPHOCYTE RATIO
HEALTHY-MEN
DISEASE
HEART
IL-8
515 Psychology
3121 General medicine, internal medicine and other clinical medicine
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
11370.full.pdf 1.261Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record