Longevity Briefs: New Targets For Reversing Age-Related Hearing Loss?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

We all expect to suffer from at least a partial loss of hearing as we age, but some might not appreciate the fact that hearing loss is more than just an annoying consequence of the ageing process. Hearing loss can lead to feelings of social isolation and loneliness. More alarmingly, there is some evidence to suggest that untreated hearing loss accelerates cognitive decline and increases dementia risk, possibly due to reduced auditory stimulation. Improving our ability to treat age-related hearing loss would not only improve quality of life in old age, but may also help to improve mental health and prevent cognitive decline.

Hearing loss is caused by the death of hair cells in the inner ear – the cells responsible for sensing sound waves and converting them into an electrical signal. As a result, many strategies for reversing hearing loss have focused on regenerating hair cells. However, a growing amount of evidence suggests that degeneration of the auditory nerve (the bundle of nerve fibres that transmits information from the inner ear to the brain) also plays a major role. Specifically, the auditory nerve’s myelin (the insulating sheath around nerve fibres that helps electrical signals travel quickly) degenerates with age, due to myelin-producing Schwann cells losing some of their ability to move and repair myelin. In this study, researchers investigate the molecular mechanisms behind this loss of function and find a way to reverse it, at least in mice.

The discovery:

Researchers first compared cochleae (inner ear tissue) and Schwann cells from young (2 month old) and aged (12 month old) mice to find genes and pathways that change with age. Using single-cell transcriptomics (a technique that allows researchers to identify which genes are most active in a given cell) they found that a gene called BST2 (bone marrow stromal antigen 2) was strongly upregulated in cochlear Schwann cells in aged mice, and its expression appeared to correlate with worse hearing and with loss of myelin.

To test weather BST2 was actually causing hearing loss or was merely correlated with it, they created an adeno-associated virus (AAV) to deliver RNA that would silence the BST2 gene, thereby significantly reducing its expression. This AAV was then administered to groups of 6-10 young (2 month-old) and older (6 month-old) mice. They found that two months after AAV injection, treated older mice had improved Schwann cell migration and preserved myelin structure around inner ear nerve fibres. They also showed improvements in auditory brainstem response thresholds indicating better nerve conduction and hearing compared to mice treated with a control AAV.

So, what is BST2 and what is it actually doing? The main role of BST2 is in immune cells, where it modulates the immune response. It is also involved in regulating cell growth and inflammation. Researchers found that in Schwann cells, BST2 acts through a major inflammatory pathway in order to suppress a transcription factor (a protein that regulates gene expression) called POU6F1. This transcription factor is known to promote myelin production and nerve repair, so by suppressing BST2, researchers were able to lift the suppression of POU6F1 and restore Schwann cell function. They confirmed this in further experiments by showing that boosting POU6F1 activity produced similar effects to BST2 suppression, while suppressing POU6F1 blocked the benefits of BST2 suppression.

The implications:

This study suggests that an age related increase in BST2 in Schwann cells may contribute to myelin loss in the inner ear, meaning that both BST2 and POU6F1 could be potential targets for reversing age-related hearing loss. It’s also entirely possible that these targets could play a role in demyelination outside of the inner ear as well. In addition to specific diseases like multiple sclerosis (MS), loss of myelin is thought to contribute to general cognitive decline and even loss of muscle function due to reduced nerve conduction speed. BST2 expression appears to increase with age as part of the general age-related increase in inflammation, so it is possible that lifestyle practices that lower inflammation may prevent increases in BST2.

While the results of this study are interesting, it’s important to remember that this study was in mice, not humans. Not only that, but the mice used in this study were of a specific, highly inbred strain that rapidly develops hearing loss due to a genetic mutation that causes their hair cells and inner ear nerves to degenerate. Human hearing loss, on the other hand, usually occurs over several decades through some combination of environmental noise exposure and gradual age-related changes. These experiments will therefore need to be repeated in other animal models and human cells.