L-Ergothioneine slows the progression of age-related hearing loss in CBA/CaJ mice.

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, to be utilized by cells as an antioxidant and anti-inflammatory. 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 - Auditory Brainstem Responses (ABRs) and Distortion Product Otoacoustic Emissions (DPOAEs). Males exhibited lower threshold declines in both low dose (LD) and high dose (HD) test groups throughout the testing period and did not display some of the characteristic aging declines in hearing seen in Control animals. In contrast, female mice did not show any therapeutic effects 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. Males and females exhibited significant differences in biomarkers related to apoptosis (Cas-3), inflammation (TNF-a), oxidative stress (SOD2), and mitochondrial health (PGC1a).These changes were more prominent in males as compared to females, especially in stria vascularis tissue. Taken together, these findings suggest that EGT has the potential to be a naturally derived therapeutic for slowing down the progression of ARHL, and possibly other neurodegenerative diseases. EGT, while effective in the treatment of some features 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 to see if therapeutic conditions can be developed where aging females show better responsiveness to EGT.

Post-translational modifications and age-related hearing loss.

Post-translational modifications (PTMs) affect nearly all systems of the human body due to their role in protein synthesis and functionality. These reversible and irreversible modifications control the structure, localization, activity, and properties of proteins. For this reason, PTMs are essential in regulating cellular processes and maintaining homeostasis. Diseases such as Alzheimer's, cardiovascular disease, diabetes, cancer, and many others have been linked to dysfunctions of PTMs. Recent research has also shown that irregularities in PTMs can be linked to hearing loss, including age-related hearing loss (ARHL) - the number one communication disorder and one of the top neurodegenerative diseases in our aging population. So far, there has been no FDA approved treatment for ARHL; however, translational studies investigating PTMs involvement in ARHL show promising results. In this review, we summarize key findings for PTMs within the auditory system, the involvement of PTMs with aging and ARHL, and lastly discuss potential treatment options focusing on utilizing PTMs as biomarkers and therapeutic pathway components.

Cochlear Inflammaging in Relation to Ion Channels and Mitochondrial Functions.

The slow accumulation of inflammatory biomarker levels in the body-also known as inflammaging-has been linked to a myriad of age-related diseases. Some of these include neurodegenerative conditions such as Parkinson's disease, obesity, type II diabetes, cardiovascular disease, and many others. Though a direct correlation has not been established, research connecting age-related hearing loss (ARHL)-the number one communication disorder and one of the most prevalent neurodegenerative diseases of our aged population-and inflammaging has gained interest. Research, thus far, has found that inflammatory markers, such as IL-6 and white blood cells, are associated with ARHL in humans and animals. Moreover, studies investigating ion channels and mitochondrial involvement have shown promising relationships between their functions and inflammaging in the cochlea. In this review, we summarize key findings in inflammaging within the auditory system, the involvement of ion channels and mitochondrial functions, and lastly discuss potential treatment options focusing on controlling inflammation as we age.

Roles of Key Ion Channels and Transport Proteins in Age-Related Hearing Loss.

The auditory system is a fascinating sensory organ that overall, converts sound signals to electrical signals of the nervous system. Initially, sound energy is converted to mechanical energy via amplification processes in the middle ear, followed by transduction of mechanical movements of the oval window into electrochemical signals in the cochlear hair cells, and finally, neural signals travel to the central auditory system, via the auditory division of the 8th cranial nerve. The majority of people above 60 years have some form of age-related hearing loss, also known as presbycusis. However, the biological mechanisms of presbycusis are complex and not yet fully delineated. In the present article, we highlight ion channels and transport proteins, which are integral for the proper functioning of the auditory system, facilitating the diffusion of various ions across auditory structures for signal transduction and processing. Like most other physiological systems, hearing abilities decline with age, hence, it is imperative to fully understand inner ear aging changes, so ion channel functions should be further investigated in the aging cochlea. In this review article, we discuss key various ion channels in the auditory system and how their functions change with age. Understanding the roles of ion channels in auditory processing could enhance the development of potential biotherapies for age-related hearing loss.