Genetic and Pharmacological Regulation of Epigenetic Aging

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Biomedical Genetics, 2018.Organisms rely on dynamic signaling networks in order to sense and respond to environmental perturbations and to maintain homeostasis. The robustness of such networks declines with age, leading to increased vulnerability to various types of stress and challenges. Previous data generated in our laboratory suggested an age-associated functional decline of antioxidant defense in Drosophila melanogaster resulting from the deregulation of Nrf2 signaling, one of the key regulators of cellular antioxidant response. I found that one cause for this decline is an erosion of functional chromatin organization. Accordingly, promoter-binding and the subsequent transcription activation of multiple antioxidant genes by Nrf2 is blocked in old fruit flies. Interestingly, we were able to delay the epigenetic decline by long-term overexpression of MafS, the dimerization partner and transcription co-factor of Nrf2, or by a chronic oral treatment of adult flies with Oltipraz, a well-tolerated therapeutic Nrf2 activator. However, no beneficial effect was achieved when flies were exposed to MafS overexpression or oltipraz later in life, indicating an irreversible loss of functional chromatin organization and transcriptional responses in old flies. In addition, we found that dSirt6 overexpression can also maintain effective Nrf2 signaling through the aging process. Taken together, my work suggests that epigenetic degeneration can contribute to the loss of transcriptional competence and stress responsiveness in aged organisms. One may speculate that the genetic and pharmacological interventions found here to delay epigenetic degeneration could be developed into feasible anti-aging strategies