The underlying mechanisms of aging in the inner ear


Summary for a lay audience:
Many people lose their hearing as they get older, and deafness is the most common sensory loss. Progressive hearing loss can begin at any age, even in the first few years of life. Hearing impairment can be profoundly isolating, both socially and economically, and has a major impact on the quality of life of those affected. People often first show difficulty in following conversations in a noisy background, followed by a high tone hearing loss further affecting communication. Later, the disease progresses to lower frequencies affecting the ability to detect and localize sounds. The only remedial options are hearing aids and cochlear implants, but although these may provide some benefits they do not restore normal function. We know that noise exposure can have a serious impact on hearing, and certain drugs and infections can also cause deafness, but genetics also plays a role. The variants that we carry in our DNA can make us particularly sensitive to damaging environmental factors like noise, or can lead to progressive hearing loss directly through what we presume is "poor housekeeping" of the ear. However, despite efforts to understand the underlying biological processes leading to deafness in humans, we still have very little knowledge of these processes, making it difficult to think of how to develop alternative treatments to stop or reverse the progression of hearing loss. In this project, we have turned to the mouse to get a better understanding of the causes of deafness. Mice have inner ears that are very similar both in structure and in physiology to human ears, and many of the genes we have found to be involved in deafness in mice also are involved in deafness in humans, and vice versa. The advantage of using mice is that we can control the environment to ensure they are not exposed to damaging sound levels, and we can study groups of mice that have all the same genetic variants as each other except for a single genetic variant, or mutation, that causes deafness in some of them. We have three different groups of mice each with a separate mutation in a different gene, all showing progressive hearing loss. We plan to study these in detail to understand the physiological and cellular changes of the inner ear as they lose their hearing, as well as analysing how all the genes in the genome of the mice are expressed (which means the gene is used in the first step towards making a protein) by a method called transcriptomics. We can then look for common patterns of expression of genes in the three groups of deaf mice to ask if there is a common molecular mechanism leading to hearing loss even when there are three different triggers. In addition to these analyses, we will look at multiple substances in the blood of the mice by a process called metabolomics, to discover if there are any indicators of abnormal metabolism associated with hearing loss. Both the transcriptomics and metabolomics will allow us to look for common molecular features of progressive hearing loss which may reveal points in these pathways that could be modified by drug treatment to slow down or stop the progression, which is our ultimate long-term goal.

Technical Summary

Summary for a specialist reader
Age-related progressive hearing loss is very common in the human population and yet we know very little about the underlying mechanisms. Environmental factors like noise exposure, ototoxic drugs and infections can lead to hearing loss, but there is a significant genetic contribution and estimates of heritability are as high as 0.7 or more. However, human population studies have not yet led to any confirmed causative genetic factors. We propose to use the mouse to investigate the pathological processes. From a large-scale screen, we have recently detected three new mouse lines with targeted mutations that show normal development but progressive increase in Auditory Brainstem Response (ABR) thresholds: Ocm, with late onset progressive high frequency hearing loss, Synj2, with early onset slowly progressive high frequency hearing loss, and Zfp719, with early onset rapidly progressive high frequency hearing loss. Whilst the functions of these genes are not well understood, these three lines have the common feature of progressive hearing loss primarily affecting high frequencies. We propose to use these mouse lines to investigate the molecular networks that are required for maintenance of normal hearing and result in hearing loss when disrupted. We will define the pathological mechanisms underlying the hearing loss using electrophysiological and structural/ultrastructural analyses, and use transcriptomic and metabolomic data to construct functional and regulatory networks. We will ask if these different mutations lead to a common molecular pathway to hearing loss by analysis of these networks, and also look for potential therapeutic targets in the networks. This knowledge will allow us to select potential therapeutic targets for investigation in future studies.

Planned Impact

Pathways to impact summary:
The proposed project is intended to produce scientific data of excellent quality that will be at the leading edge of efforts to understand the effects of aging on the ear and progressive hearing loss. The main route to academic impact will be through regular talks at scientific and clinical conferences aimed at a wide range of relevant audiences together with publication in widely-read journals in open access format.
The societal and economic impact will result from the application of our anticipated findings to the identification of new targets for development of therapies that will slow down or reverse the progress of hearing loss. The benefits to society will be realised by the people directly affected by the increasing isolation that accompanies hearing loss as well as their families who struggle to communicate with them. Economic benefits will come in the longer term from the development of new therapeutic areas within pharmaceutical companies and small biotechs, as well as from improved economic activity opportunities for the individuals affected by hearing loss.


10 25 50
Description We have carried out electrophysiological measurements of hearing at different stages in the progression of hearing loss in three different mutant mouse lines, and have defined the rate of progression. We have found that all three mutant lines show normal endocochlear potentials, but have evidence from scanning electron microscopy that sensory hair cells progressively degenerate. In one of the lines, the Ocm mutation, we have found that the increase in Auditory Brainstem Response (ABR) thresholds is matched by the increase in Distortion Product Otoacoustic Emmissions (DPOAEs), that the gene is expressed predominantly in outer hair cells, and that only outer hair cells show signs of degeneration, all of which suggests that the hearing impairment can be explained by an outer hair cell defect. The Zfp719 mutant has more widespread abnormalities evident in the organ of Corti. Finally, the Synj2 mutant line has outer hair cell loss in the very high-frequency sensitive regions of the cochlea but no apparent inner hair cell defects, normal innervation and synapse numbers below inner hair cells, and single hair cell recordings indicate normal capacitance, K+ current and Ca2+ current of inner hair cells. We are currently working on the final drafts of two papers describing some of these results.
Exploitation Route We have presented two talks to groups of professionals involved in auditory services: firstly to the British Society of Audiology meeting, attended by many audiologists and health care professionals, and secondly to the Association for Research in Otolaryngology, also attended by many clinicians. We have also discussed this research during three visits by 20+ supporters of Action on Hearing Loss at three open days we organised for them.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

Description Election to Royal Society Council
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Description Royal Society Grants Committee
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Title Developing the protocol for lipidomics analysis of mouse inner ear 
Description We developed a protocol to assay lipid composition in a very small sample, the mouse inner ear. 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? No  
Impact We succeeded in getting useful information about lipid changes during hearing deterioration in a mouse mutant inner ear. 
Title Development of advanced protocols for ABR analysis of auditory function 
Description We have developed a new battery of tests that we use to ask if mouse mutants show any defects in frequency selectivity or temporal processing. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Main research is in progress. 
Description Analysis of Synaptojanin2 mutant mouse 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution We generated the derived tm1b allele from the original tm1a mutation, carried out ABRs, DPOAEs, expression studies, scanning electron microscopy, confocal imaging of innervation of hair cells, and characterisation of the effects of the allele on expression levels.
Collaborator Contribution Single hair cell recordings.
Impact So far a chapter in the student's thesis which is being adapted to form the basis of a publication.
Start Year 2014
Description Caprin1 in hearing 
Organisation University College London
Department Ear Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution We have produced a derived allele of the Caprin1 conditional mouse mutant and measured their hearing function during development and ageing using Auditory Brainstem Response recordings.
Collaborator Contribution Our collaborators have been working on the role of Caprin1 in cochlear responses to stress for some time, so proposed the hypothesis that the hearing of mutants would be affected. The knockout turned out to be lethal, so we made the conditional knockout using Sox10-Cre to delete in the inner ear. Now our collaborators are picking up the analysis in their own laboratory.
Impact We have discovered that the conditional mutants do have progressive hearing loss.
Start Year 2011
Description Lipidomics analysis of multiple classes of lipids in mutant mouse samples 
Organisation Babraham Institute
Country United Kingdom 
Sector Private 
PI Contribution We have collected samples for a pilot study to check the feasibility of carrying out lipidomics analysis on very small samples. We have discussed and agreed the overall experimental design. We continue to collect samples ready for the full study.
Collaborator Contribution The Babraham group have tested the small samples as a pilot and found that the analysis is possible. They bring their expertise in mass spec and lipid analysis to the collaboration, and contributed to the agreed experimental design.
Impact This collaboration is in its early stages so nothing to report yet.
Start Year 2018
Description AoHL supporters laboratory visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Supporters
Results and Impact We hosted a visit of around 30 active supporters of the charity Action on Hearing Loss plus 6 charity staff, who visited the labs, watched demonstrations of research methods, listened to talks and posters, and discussed our research.
Year(s) Of Engagement Activity 2018
Description AoHL supporters laboratory visit, carried out twice 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Supporters
Results and Impact The visits resulted in at least 6 offers of legacies to the charity Action on Hearing Loss.
There was considerable interest and many questions from the group of supporters during the events.

The visits resulted in at least 6 offers of legacies to the charity Action on Hearing Loss
Year(s) Of Engagement Activity 2015
Description Interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Interview and article with The Scientist magazine
Year(s) Of Engagement Activity 2015
Description Women in Science event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Around 40 people attended an evening event on "Women in Science" organised by Action on Hearing Loss. Many were scientists supported by the charity, others were active or potential supporters. There were 4 talks and Karen Steel gave one of these. There was lively discussion afterwards, and the supporters expressed appreciation of the work done.
Year(s) Of Engagement Activity 2018