Chronic stress and aging have been demonstrated to independently impair cognitive flexibility in rodents and humans. Together with our data, these findings VPS34-IN1 suggest progressively increasing FKBP51 expression with age may attenuate the ability to rapidly shift strategy and retain cognitive flexibility under stressful conditions. While demethylation of FKBP5 has been identified as a potential mechanism for FKBP51 upregulation in humans, it was not known if this was contributing to the progressive increases in FKBP51 that we observed in aged mice. We demonstrated that Fkbp5 methylation decreases with age in wildtype mice, underscoring the validity of utilizing aged mouse models to study Fkbp5 gene x environment interactions. Interestingly, chronic CORT treatment decreases Fkbp5 methylation in mice similar to aging, linking the effects of stress and aging through FKBP51. Previous work has shown that functional SNPs in FKBP5 lead to demethylation of the gene in an interaction with early environmental factors. Our data suggest that aging acts similarly to the SNPs, leading to epigenetic changes in FKBP5 regulation across lifespan. Because GR stimulation leads to FKBP5 demethylation, it is possible that stress throughout life may lead to progressively decreased methylation and difficulty regulating the HPA axis and the stress response with age. Elderly depressed patients suffer from increased treatment resistance and frequency of depressive episodes. Depression is frequently comorbid with AD and may be a risk factor for development of AD. Moreover, expression of FKBP5 increases with age and is even further elevated in AD, providing a putative link between LLD and AD. Therefore, GPR120-IN-1 inhibition of FKBP51 is a desirable strategy for stress-related disorders such as depression and age-related diseases. Although the development of FKBP51 ligands has been difficult due to the similarity between FKBP51 and its homologues, it is considered a tractable, viable drug target. Our data support the need for continued research into FKBP51 biology and the advancement of its therapeutic development.