Skip to main content
Journal cover image

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

Publication ,  Journal Article
Zannas, AS; Jia, M; Hafner, K; Baumert, J; Wiechmann, T; Pape, JC; Arloth, J; Ködel, M; Martinelli, S; Roitman, M; Röh, S; Haehle, A; Wahl, S ...
Published in: Proceedings of the National Academy of Sciences of the United States of America
June 2019

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-κB-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 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 enhanced FKBP5 response 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 aging/stress-driven FKBP5-NF-κB signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.

Altmetric Attention Stats
Dimensions Citation Stats

Published In

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

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

June 2019

Volume

116

Issue

23

Start / End Page

11370 / 11379

Related Subject Headings

  • Up-Regulation
  • Tacrolimus Binding Proteins
  • Stress, Psychological
  • Signal Transduction
  • Risk Factors
  • NF-kappa B
  • Male
  • Inflammation
  • Humans
  • Genome-Wide Association Study
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Zannas, A. S., Jia, M., Hafner, K., Baumert, J., Wiechmann, T., Pape, J. C., … Binder, E. B. (2019). Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-κB-driven inflammation and cardiovascular risk. Proceedings of the National Academy of Sciences of the United States of America, 116(23), 11370–11379. https://doi.org/10.1073/pnas.1816847116
Zannas, Anthony S., Meiwen Jia, Kathrin Hafner, Jens Baumert, Tobias Wiechmann, Julius C. Pape, Janine Arloth, et al. “Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-κB-driven inflammation and cardiovascular risk.Proceedings of the National Academy of Sciences of the United States of America 116, no. 23 (June 2019): 11370–79. https://doi.org/10.1073/pnas.1816847116.
Zannas AS, Jia M, Hafner K, Baumert J, Wiechmann T, Pape JC, et al. Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-κB-driven inflammation and cardiovascular risk. Proceedings of the National Academy of Sciences of the United States of America. 2019 Jun;116(23):11370–9.
Zannas, Anthony S., et al. “Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-κB-driven inflammation and cardiovascular risk.Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 23, June 2019, pp. 11370–79. Epmc, doi:10.1073/pnas.1816847116.
Zannas AS, Jia M, Hafner K, Baumert J, Wiechmann T, Pape JC, Arloth J, Ködel M, Martinelli S, Roitman M, Röh S, Haehle A, Emeny RT, Iurato S, Carrillo-Roa T, Lahti J, Räikkönen K, Eriksson JG, Drake AJ, Waldenberger M, Wahl S, Kunze S, Lucae S, Bradley B, Gieger C, Hausch F, Smith AK, Ressler KJ, Müller-Myhsok B, Ladwig K-H, Rein T, Gassen NC, Binder EB. Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-κB-driven inflammation and cardiovascular risk. Proceedings of the National Academy of Sciences of the United States of America. 2019 Jun;116(23):11370–11379.
Journal cover image

Published In

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

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

June 2019

Volume

116

Issue

23

Start / End Page

11370 / 11379

Related Subject Headings

  • Up-Regulation
  • Tacrolimus Binding Proteins
  • Stress, Psychological
  • Signal Transduction
  • Risk Factors
  • NF-kappa B
  • Male
  • Inflammation
  • Humans
  • Genome-Wide Association Study