Rejuvenation Of The Epigenetic Landscape Of The Aged Brain Through Manipulation Of Circulating Factors

Author

Edward Koellhoffer, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical SciencesFollow

Author ORCID Identifier

0000-0002-7260-9507

Date of Graduation

5-2019

Document Type

Dissertation (PhD)

Program Affiliation

Neuroscience

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Louise D. McCullough, M.D., Ph.D.

Committee Member

Jaroslaw Aronowski, M.D., Ph.D.

Committee Member

Robert M. Bryan, Jr., Ph.D.

Committee Member

Andrew J. Bean, Ph.D.

Committee Member

Edgar T. Walters, Ph.D.

Abstract

The aging population of the United States is expanding at an alarming rate. The Center for Disease Control and Prevention estimates that the population of those age 65 years and older will reach over 50 million by 2020 and will double to 100 million by 2060. This will not only put a massive strain on national healthcare resources, but will also increase the number of those who are not able to live and function independently. It is becoming increasingly vital to understand how the brain changes with age and mechanisms to possibly protect and rejuvenate the aged brain to a younger, healthier phenotype to promote healthy aging.

In this work, we found that there is an increase in the number and amount of pro-inflammatory cytokines in the brain with age, demonstrating that the brain becomes progressively pro-inflammatory with age. Notably, we observed an increase in IFNγ and GM-CSF which are two cytokines implicated in the detrimental priming phenotype of the aged brain. Additionally, we found that the aged brain becomes epigenetically dysregulated, with an increase in Ezh2 function and simultaneous loss of the opposing function of Jmjd3, thereby leading to a respective increase in H3K27me3 and decrease in H3K27me1 in the brain with age. Furthermore, when we examined the role of Ezh2 in primary microglia cultures in vitro, we found that inhibition of Ezh2 could simultaneously abrogate pro-inflammatory polarization and enhance anti-inflammatory polarization. Together, this data suggests that increasing function of Ezh2 may directly contribute to the pro-inflammatory phenotype of the brain with age.

We also found that culturing primary microglia with plasma from healthy aged mice resulted in up-regulation of pro-inflammatory cytokines Il1b and Il6 in vitro, suggesting that circulating peripheral factors may directly influence the transition of the brain to a pro-inflammatory phenotype with age. We tested if the age-associated epigenetic dysregulation and pro-inflammatory phenotype could be reversed by utilizing the surgical model of heterochronic parabiosis. In this model, a young and aged animal are surgically attached so that the two come to share a common blood supply. Using young-young and aged-aged isochronic surgical controls, we found that young blood rejuvenates the levels of H3K27me3 to those of a younger animal. Additionally, when we induced a neuroinflammatory response in the heterochronic and aged isochronic parabionts, we found that the neuroinflammatory response of aged heterochronic animals was rejuvenated and reduced compared to aged isochronic controls.

This work is the first to investigate the role of epigenetic dysregulation of Ezh2 and Jmjd3 in the brain with age. Additionally, this is the first work to examine the ability of the circulating peripheral immune system to rejuvenate the epigenetic landscape of the aged brain and functional response to a pro-inflammatory stimulus. Future identification of the specific circulating peripheral factor(s) responsible for brain aging and rejuvenation may allow for therapeutic intervention to promote healthy brain aging in older individuals.

Keywords

microglia, epigenetics, Ezh2, Jmjd3, parabiosis, aging