title: Age-associated epigenetic upregulation of the FKBP5 gene selectively impairs stress resiliency.
abstract: Single nucleotide polymorphisms (SNPs) in the FK506 binding protein 5 (FKBP5) gene combine with traumatic events to increase risk for post-traumatic stress and major depressive disorders (PTSD and MDD). These SNPs increase FKBP51 protein expression through a mechanism involving demethylation of the gene and altered glucocorticoid signaling. Aged animals also display elevated FKBP51 levels, which contribute to impaired resiliency to depressive-like behaviors through impaired glucocorticoid signaling, a phenotype that is abrogated in FKBP5-/- mice. But the age of onset and progressive stability of these phenotypes remain unknown. Moreover, it is unclear how FKBP5 deletion affects other glucocorticoid-dependent processes or if age-associated increases in FKBP51 expression are mediated through a similar epigenetic process caused by SNPs in the FKBP5 gene. Here, we show that FKBP51-mediated impairment in stress resiliency and glucocorticoid signaling occurs by 10 months of age and this increased over their lifespan. Surprisingly, despite these progressive changes in glucocorticoid responsiveness, FKBP5-/- mice displayed normal longevity, glucose tolerance, blood composition and cytokine profiles across lifespan, phenotypes normally associated with glucocorticoid signaling. We also found that methylation of Fkbp5 decreased with age in mice, a process that likely explains the age-associated increases in FKBP51 levels. Thus, epigenetic upregulation of FKBP51 with age can selectively impair psychological stress-resiliency, but does not affect other glucocorticoid-mediated physiological processes. This makes FKBP51 a unique and attractive therapeutic target to treat PTSD and MDD. In addition, aged wild-type mice may be a useful model for investigating the mechanisms of FKBP5 SNPs associated with these disorders.
authors.affiliation: Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida, Tampa, Florida, United States of America.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Sabbagh
authors.affiliation: Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida, Tampa, Florida, United States of America.
authors.forename: John C
authors.initials: JC
authors.lastname: O'Leary
authors.affiliation: Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida, Tampa, Florida, United States of America.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Blair
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, Unites States of America; Department of Translational Research, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Klengel
authors.affiliation: Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida, Tampa, Florida, United States of America.
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Nordhues
authors.affiliation: Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida, Tampa, Florida, United States of America.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Fontaine
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, Unites States of America; Department of Translational Research, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
authors.affiliation: Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida, Tampa, Florida, United States of America.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
mesh_terms: D000375:Aging / Q000097:blood / Q000235:genetics*; D000818:Animals; D019175:DNA Methylation; D003865:Major Depressive Disorder / Q000235:genetics; D044127:Epigenesis, Genetic / Q000502:physiology*; D006854:Hydrocortisone / Q000097:blood; D008136:Longevity / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D055500:Resilience, Psychological; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics; D013315:Stress, Psychological / Q000097:blood / Q000235:genetics*; D022021:Tacrolimus Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D000099159:Tacrolimus Binding Protein 5
chemical_list: D006854:Hydrocortisone; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5