Author ORCID Identifier

Defense Date


Document Type


Degree Name

Doctor of Philosophy


Pharmaceutical Sciences

First Advisor

Dr. Joseph McClay

Second Advisor

Dr. Mary Peace McRae

Third Advisor

Dr. Elvin Price

Fourth Advisor

Dr. Mikhail Dozmorov

Fifth Advisor

Dr. Dana Lapato


Aging is considered a major risk factor for most diseases and is associated with multimorbidity and polypharmacy. Older adults aged 65 or older are considered more vulnerable to adverse drug reactions (ADRs), which may be partly due to changes in how the body processes drugs with age. Aging causes many epigenetic alterations affecting how certain genes are expressed. We reviewed the literature and found that epigenetic mechanisms can affect genes encoding phase I, II, III reactions, indicating its importance in absorption, distribution, metabolism, and excretion (ADME) processes. This dissertation is comprised of multiple projects. First, we identified genome-wide age associated differentially methylated regions (a-DMRs) in mouse livers (4- and 24-months) and showed how specific drug metabolizing enzymes are affected by epigenetic regulations. In the second project, we focused on super-agers by expanding our age range to include a super aged mice group (32-months) to represent human centenarians and an 18-months group as an intermediate group. The data revealed a marked change in DNA methylation between young (4-months) and old (18, 24 and 32-months), while the majority of xenobiotic pathways were affected in both aging pathways. In the final project, we investigated the transcription factor the aryl hydrocarbon receptor (AhR). Through data integration, we found that AhR regulates many ADME genes in liver that undergo epigenetic aging, so we hypothesized that epigenetic aging may affect AhR binding. We found that the activation of AhR by the potent ligand 2,3,7,8 -Tetrachlorodibenzo-p-dioxin (TCDD) reduces DNA methylation levels at the AhR target gene Cyp1a1, indicating the involvement of AhR in modulating DNA methylation through epigenetic dynamics. We found that DNA methylation change with age in the DMSO control group and that the DNA methylation levels were associated with the Cyp1a1 gene expression data. These findings offer valuable insights into how age-related epigenetic changes and transcription factors can affect drug metabolism molecular pathways with age.


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Available for download on Monday, September 18, 2028