The cellular molecular basis of cochlear aging

As one of the five major sensory organs, the cochlea can sense the vibration of sound waves from the outside world, convert sound signals into electrical signals and transmit them to the temporal lobe of the brain to form hearing
.
With age, the physiological functions of the cochlea gradually deteriorate, which leads to the occurrence of presbycusis and seriously affects the quality of life
of the elderly.
Understanding the mechanism of cochlear aging is an important basis
for understanding and intervening in presbycusis.
However, the structure of the cochlea is delicate and complex, consisting of different anatomical areas such as cochlear curtis, basement membrane, cochlear axis, vascular striae, spiral ligaments, etc.
, including dozens of cell types, and traditional methods are difficult to accurately reveal the aging laws and molecular regulatory networks
of different cell types in the aging process of cochlea.

On November 12, 2022, Liu Guanghui Research Group of the Institute of Zoology, Chinese Academy of Sciences, Chai Renjie Research Group of Southeast University, Wang Si Research Group of Xuanwu Hospital of Capital Medical University, and Qu Jing Research Group of Institute of Zoology, Chinese Academy of Sciences published a research paper
entitled "Single-cell Transcriptomic Atlas of Mouse Cochlear Aging" online in the journal Protein & Cell 。 This study systematically plotted the high-resolution cross-temporal single-cell transcriptome map of cochlear aging in mice for the first time, revealed the key time nodes and cellular molecular regulation mechanisms of cochlear function decline accompanied by aging, and provided a theoretical basis
for exploring the early warning signs and potential intervention targets of cochlear aging and related degeneration.

In this study, the researchers obtained the cochlear tissues of C57BL/6J mice aged 1, 2, 5, 12 and 15 months, and found through hearing function testing that C57BL/6J mice showed high-frequency hearing loss with increasing age, which is similar
to the characteristics of human presbycusis.
Further histological analysis showed that cochlear aging was characterized by different degrees of loss of important cell types such as inner hair cells, outer hair cells, spiral neurons and fibroblasts in the spiral ligament region, as well as aging-related vascular atrophy
。 In order to clarify the cellular and molecular changes in the aging process of mouse cochlea, the researchers used high-throughput single-cell transcriptome sequencing technology to systematically reveal the cochlear curtis, basement membrane, cochlear axis, vascular striae, spiral ligaments and other regions, including hair cells (HC), spiral ganglion neurons (SGN), and intermediate cells (IC) Gene expression characteristics
associated with aging in 27 cochlear cell types.

The study found that transcriptional noise in cochlear cells increased with aging, indicating that aging led to increased
instability in cochlear cell RNA expression.
Among them, the transcription noise of the middle layer cells of the vascular stria was particularly significant
.
In order to determine the temporal pattern of cochlear aging, the researchers identified the difference genes (PDEGs) between specific time points through pairwise comparative analysis between different time points, and found that mouse cochlea at 5 months of age had exhibited transcriptional profile characteristics of cellular aging
.
By analyzing the number of PDEGs, it was found that the cells in the middle layer of the vascular stria showed more differences
in gene expression during aging.
Different from the pairwise comparison between time points, multiple time nodes can identify dynamic differentially expressed genes (DDEGs), and study the continuous change of gene expression over time in a high-resolution form, which can theoretically reveal the cross-temporal change
law of cochlear aging 。 Therefore, the researchers further constructed the corresponding algorithm and identified the set of DDEGs gene in six expression modes, including continuous upregulation and continuous downregulation, among which the vascular stria middle layer cells had more differential expression genes
with continuous upregulation and continuous downregulation.
The genes that continue to be upregulated are mainly related to unfolded protein reaction (UPR), apoptosis, and immunoinflammatory response, while the genes that continue to be downregulated are mainly related to ion transport and cell matrix adhesion, suggesting that the aging process of cochlea is accompanied by the accumulation of cell damage and the decline
of function.

The researchers further focused on the middle layer cells of the vascular striae, and through a detailed analysis of the UPR pathway, they found that the expression of genes related to the three main branches of UPR (including ATF6, IRE1 and PERK signaling pathway) was upregulated
with aging.
On the one hand, the stress compensation pathways downstream of UPR, including endoplasmic reticulum chaperones, endoplasmic reticulum associated protein degradation, NRF2 and other pathway-related genes are expressed with
aging.
On the other hand, the expression of apoptosis-related genes also showed an upregulation
accompanied by increasing age.
These results suggest that the UPR compensatory pathway is insufficient to counteract the ongoing endoplasmic reticulum stress associated with aging to prevent aging-related damage in the cochlea, leading to apoptosis
of mesocells.
In addition, the upregulation of the UPR-related gene Hsp90aa1 in the middle layer cells of the vascular stria was found to be the most obvious, suggesting that it may play a role
in mesocyte aging as a potential regulator of cochlear aging-related damage.
Experiments have shown that knocking down Hsp90aa1 in mouse angiostriated cells can aggravate the degree of UPR and apoptosis of cells, while activating Hsp90aa1 can reduce intracellular protein aggregation and antagonize apoptosis
under stress.
The above research results suggest that targeting the Hsp90aa1-UPR pathway may provide new ideas and strategies
for the intervention of cochlear aging.

This study reported for the first time the high-resolution single-cell transcriptome landscape map of mouse cochlear aging across multiple time points, systematically analyzed the law of the change of multiple cell types in cochlear tissues with aging, and revealed new molecular characteristics
of cochlear aging.
This study not only deepens people's understanding of the structural and functional age-related degeneration of cochlea, elucidates the key susceptible cell types and susceptibility molecules in the aging process of cochlea, but also provides potential diagnostic biomarkers for assessing the aging degree of cochlear aging and warning presbysbysis, laying a theoretical foundation
for the development of new intervention strategies targeting cochlear aging.

Liu Guanghui, researcher at the Institute of Zoology, Chinese Academy of Sciences, Professor Chai Renjie from Southeast University, Wang Si, researcher at Xuanwu Hospital of Capital Medical University, and Qu Jing, researcher at the Institute of Zoology, Chinese Academy of Sciences, are the co-corresponding authors
of the paper.
Sun Guoqiang and Zheng Yandong, doctoral students of the Institute of Zoology, Chinese Academy of Sciences, Fu Xiaolong, associate professor of Southeast University, and Zhang Weiqi and Ren Jie, Beijing Institute of Genomics, Chinese Academy of Sciences, are the co-first authors
of the paper.
The research has been funded
by the Ministry of Science and Technology of the People's Republic of China, the National Natural Science Foundation of China, the Chinese Academy of Sciences and other projects.

The data were uploaded to the aging multiomics database Aging Atlas (https://ngdc.
cncb.
ac.
cn/aging/landscape?project=Mouse_Cochlea).

Original link: https://academic.
oup.
com/proteincell/advance-article/doi/10.
1093/procel/pwac058/6823876

Figure: Cellular molecular mechanisms of cochlear aging in mice