Graduation Year

2022

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Biomedical Engineering

Major Professor

Robert D. Frisina, Ph.D.

Committee Member

Joseph Walton, Ph.D.

Committee Member

Mark Jaroszeski, Ph.D.

Committee Member

Bo Ding, M.D.

Committee Member

Victoria Sanchez, Ph.D.

Keywords

Anti-Oxidant, Correlation, Sex Selectivity, Thresholds, Tissue Analysis

Abstract

The naturally occurring amino acid, L-Ergothioneine (EGT), has immense potential as a therapeutic, having shown promise in the treatment of other disease models, including neurological disorders. EGT is naturally uptaken into cells via its specific receptor, OCTN1, suggesting that it is highly conserved, to be utilized by cells as an antioxidant and anti-inflammatory, particularly under stressed conditions. In our current study, EGT was administered over a period of 6 months to 25-26 month old CBA/CaJ mice as a possible treatment for age-related hearing loss (ARHL), since presbycusis has been linked to higher levels of cochlear oxidative stress, apoptosis and chronic inflammation. Results from the current study indicate that EGT can prevent aging declines of some key features of ARHL. However, we found a distinct sex difference for the response to the treatments, for hearing measurements – Auditory Brainstem Responses (ABRs) and Distortion Product Otoacoustic Emissions (DPOAEs). Males exhibited improvements in both low dose (LD) and high dose (HD) test groups throughout the entire testing period for both DPOAEs and ABRs and did not display the characteristic aging declines in hearing seen in Control animals. In contrast, female mice did not show any improvements with either treatment dose. Further confirming this sex difference, EGT levels in whole blood sampling throughout the testing period showed greater uptake of EGT in males compared to females. Additionally, RT-PCR results from three tissue types of the inner ear confirmed EGT activity in the cochlea in both males and females. Here, both males and females exhibited significant differences in biomarkers related to apoptosis, inflammation, oxidative stress, and mitochondrial health: Cas-3, TNF-α, SOD2, and PGC1α, respectively. Taken together, these findings suggest that EGT has a future as a naturally derived therapeutic for slowing down the progression of ARHL, and possibly other neurodegenerative diseases. EGT, while seemingly effective in the treatment of presbycusis in aging males, could also be modified into a general prophylaxis for other age-related disorders where treatment protocols would include eating a larger proportion of EGT-rich foods or supplements. Lastly, the sex difference discovered here, needs further investigation [1] to see if therapeutic conditions can be developed where females show responsiveness to EGT, similar to the dramatic effects seen here in the aging males.

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