Autophagy is Protective in the Progression Towards Age-Related Hearing Loss

This open access paper provides a good summary of present thought on the contributing causes of hearing loss, in which the various issues of noise, aging, and toxicity cause harm via inducing stress in hair cells of the inner ear and their axonal connections to the brain. Autophagy is a cell maintenance process, the recycling of damaged component parts. More efficient autophagy helps hair cells to resist and survive a stressful environments, but autophagy declines with age. Defects arise in many of the component parts of the autophagic system and its regulation. This is likely why the threshold for loss of hair cells in response to stresses diminishes in later life, leading to the onset of hearing loss in a large fraction of the population.

Hearing loss is not only a physical and financial burden in social life, but also causes psychological problems and psychiatric disorders, including cognitive decline and depression. Genetic alterations, noise, ototoxic drugs, and aging can all contribute to hearing loss. Although the causes vary, the most common causes of deafness are damage or loss of hair cells (HCs) and degeneration of spiral ganglion neurons (SGNs). HCs are responsible for converting external sound signals into electrical signals that are transmitted to the brainstem through SGNs. Recent studies have shown that these sensory cells cannot spontaneously regenerate in adult mammals, so damage or loss of HCs and degeneration of SGNs can result in permanent deafness.

Autophagy is responsible for normal cell survival and homeostasis. A variety of human conditions, such as neurodegenerative diseases, cancer, and inflammation, have been reported to be associated with dysregulated autophagic processes. In the inner ear, many studies have shown that autophagy played an important role in cell development, differentiation, and survival, and recently there has been renewed interest in regulating autophagy to prevent sensorineural hearing loss (SNHL).

Noise and ototoxic drugs increased the levels of oxidative stress in HCs, which contributed to cell death, and in a mouse model that was exposed to noise, the level of autophagy was increased in HCs. It is worth noting that the oxidative stress level in response to noise was dose dependent, and moderate noise induced temporary threshold shifts and increased the level of autophagy in outer hair cells, while severe noise produced excess reactive oxygen species (ROS) that induced permanent threshold shifts. Increasing autophagy with rapamycin can reduce the accumulation of ROS and prevent cell death from noise exposure. In contrast, blocking autophagy via pharmacological or genetic means can increase the accumulation of ROS and promote cell death.

Presbycusis (age-related hearing loss) is a common sensory disorder associated with aging. The level of autophagy decreases with age, and the upregulation of autophagy can promote aging HC survival and slow the degeneration of auditory cells. Though we have known that some proteins and miRNAs participate in the autophagic pathways involved in SNHL making them potential targets for treatment of SNHL, the specific signaling pathways they participate in remain unclear, let alone the known connections between these proteins and miRNAs. The application of autophagy as a treatment for deafness is still a long way off. Current research has been limited to cell lines, explants, and animals, and few clinical trials have examined the role of autophagy. Given the complexity of mechanisms and functions of autophagy, the safest and most effective strategies must be studied in future research.



When do you think we will catch the LEV?

Posted by: Josep at November 12th, 2021 12:51 PM

I've always wondered if amifostine, administered regularly, would slow hearing decline. It is a free-radical scavenger and has shown promise in attenuating ototoxicity of platinum-based chemotherapy regimens in some, though not all trials.C

Posted by: Chris at November 12th, 2021 2:09 PM

I wouldn't expect miracles there. It might be statistically significant improvement, but probably a CR/regular fasting could bring better outcome, for example. It seems to have an opposite action to senolytics ; it inhibits apoptosis. p16 and p53 pathways are related also to cell and DNA repair. So in theory it can be cycled with senolytics. In theory one set of cells can have senolytic pro-drugs and another set with different markers can have a seno-modulator to promote cell repair at the same time. However, that would be a generation III approach.

Posted by: Cuberat at November 12th, 2021 3:07 PM

here's your resident party pooper. While i am in the believer camp, I can say that at some point in the feature aging will be solved. If we master self-replicating nanobots at sub-cellular level, there are no obvious barriers to repair every single cell of the body. When we reach that technological level, for sure we would be past LEV. However, that is many decades in the future. Very likely to be achieved by the end of the XXI century.

There is a notion that by , say 2065 a general artificial intelligence more intelligent than all the humans combined will emerge. At that point we might get wiped out, empowered/merged with the machines, or brought as kinda traditional pets to the starts. This by definition is beyond our abilities to comprehend or predict, so I will skip this hypothesis. There are a few softer versions, where we upload our minds to machines, where they can be independent of the squishy meatbags with possibility of backups, clones and re-synchronization. It is a nice SciFi material, so let's put those aside too.

Let me look at my foggy crystal ball.
First I will try to see the current progress and the rate of improvement.

In 90s and early aughts we were at stage 0. Only impressive talks and aspirations. But no concrete progress. There were some calorie restriction studies but not very known
2009 - Calorie restriction shown to delay aging and prolong live in mice.

2015 - first senolytics in vivo. (there were attempts since 2005, so for about 10 years the researchers were grinding until the moment they got the idea to disrupt anti-apoptotic ScC behavior)
2016 - first published in-vivo studies to reverse some damage in mice.
then each year there are more and more interesting results.
2017 - metformin was shown to increase lifespan. And the results were statistically significant, albeit not very large. There's also rapamycin which is much stronger, but for now it is considered too dangerous for general use.
2018 - OISIN published their senolytic platform result. Very impressive, but they are basically in stealth mode since then. I was expecting human trials by now. Let's hope that we will hear from them soon.
fast forward to 2020-2021 we have a couple of human trials but no world shattering results yet.
There were some promising studies to boost thymus . Reason announced on FA their intermediate results.

2025 I would expect to have multiple human studies by 2025. for senolytic, and other therapies.

So before 2025 and the first real human results it is very hard to judge the rate of progress.
2025-2030 first recognised available human therapies. (One can argue that for dedicated individuals they are already available. I have a bag of fisetin, for example. Some people order Dasatinib and Quercetin. However, we don't know the correct protocol and the best approach)

So by the end of 2030 we should have the first therapies, recognition and funding. At first those will be increase health span and not the maximum lifespan. For the maximum lifespan to be extended, it needs a few yaers because the oldest person alive is 4 years younger than the record. And the therapies have to be approved and available for super-centenarians. Say in 2030 110 years old start taking the therapies. It will be only 2042 when you can mark a new record. And it has to be statistically significant and on wide scale, so give one decade more.

On the lower end of the life expectancy, we might get more impressive results so if the therapies become available at 2030-2035 we might see an average life expectancy increase larger than a year per calendar year.
This doesn't mean LEV quite yet. However, there will be new discoveries and improvements in the mean time.

So the answer to your question, depending how you define it, LEV will be reached no earlier than 2030 and no later than 2100. Very probable by 2050. Not so probable but still quite possible by 2040. 2030 is quite improbable. There will be a lot of media declarations but the clinical percolation takes time.

Posted by: Cuberat at November 12th, 2021 4:18 PM
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