Researchers have found that rapamycin supplementation attenuates but not reverses age-related hearing loss in mice, even if the treatment starts later in life [1].
Hear ye, aging is coming
Gradual hearing loss might not be as physically harmful as cancer, Alzheimer’s or many other age-related pathologies, but even with the newest hearing aid technology, it can be detrimental to our emotional health and to the quality of our contacts with the outside world. In multiple studies, age-related hearing loss has been linked to depression [2] and dementia [3]. It is also one of the most widespread age-related pathologies: approximately one in three people between the ages of 65 and 74 has hearing loss, and nearly half of people older than 75 have difficulty hearing.
Age-related hearing loss has been associated with the decline in the number of healthy hair cells. Despite their name, these have nothing to do with human hair; instead, hair cells reside in our cochlear and transform the vibration of the cochlear-filling liquid into electrical impulses using bunches of hair-like filaments. The impulses then enter the nervous system to be registered as sound. Unlike birds and fish, humans and other mammals are generally incapable of regrowing hair cells.
Rapamycin: a not-so-new hope
Rapamycin is probably the most promising compound currently studied by longevity researchers. Discovered decades ago, rapamycin has repeatedly demonstrated its ability to drastically prolong life in various model organisms and to attenuate many age-related pathologies. Rapamycin targets mTOR (mechanistical target of rapamycin), a protein that plays an important role in nutrient sensing. The dysregulation of nutrient sensing pathways – that is, the growing inability of a cell to correctly detect the amount of nutrients available and to adjust its activity accordingly – is a hallmark of aging. Rapamycin is also one of the few potential age-reversing agents currently in human trials.
Rapamycin has been shown to have a major effect on the prevalence of cancer, cardiac diseases, cognitive decline, macular degeneration, and other age-related conditions. So, it was only a matter of time before age-related hearing loss gets caught in researchers’ crosshairs.
Effective even later in life
In their previous research, the same researchers found that age-related hearing loss was alleviated in mice who had been receiving rapamycin since they were young. In this new study, the scientists wanted to see whether these results could be replicated in mice that only began to receive rapamycin-laced food later in life. It is worth noting that one of the most hope-inspiring aspects of rapamycin is its ability to offset aging in model organisms even when the treatment starts relatively late.
Hearing loss is measured by the so-called TS (threshold shift). It gauges how much air pressure at a certain frequency is enough for the animal to hear the sound, relative to a baseline, which, in this study, was measured at the age of 5 months. As mice age, they need sound to be louder (more air pressure) for their brains to register it.
In this study, healthy mice were divided into a study group and a control group at the age of 14 months, which roughly corresponds to 50 human years. The study group then began receiving food enriched with rapamycin.
The researchers found that rapamycin significantly rescues hearing over the remaining lifespan of the mice. Interestingly, this effect seemed to wane for the lowest measured frequency (4Hz) in the oldest mice. The reason is probably that hair cells at the top part of the cochlear, where low frequency sounds are registered, are known to begin to atrophy earlier. This led the researchers to conclude that rapamycin does not reverse but rather attenuates age-related hearing loss.
Generally, research shows that rapamycin has a slightly stronger life-prolonging effect on female mice compared to males. In this particular study, though, the researchers did not detect any sex-related differences in its effects.
Quantity or quality?
In a seeming paradox, the researchers also did not detect less hair cell loss in the rapamycin-fed animals. In the absence of an obvious reason for that, the authors hypothesize that, rather than promoting the survivability of hair cells, rapamycin helps to maintain the function of the cells that remain.
The researchers did not analyze the molecular underpinnings of the rapamycin-induced hearing loss attenuation, though they suggest several possible pathways. One of them is based on rapamycin’s ability to positively affect the endoplasmic reticulum (ER) [4], the ribosome-hosting organelle in charge of protein production. ER stress has been linked to age-related hearing loss [5].
Conclusion
The ability of rapamycin to attenuate age-related hearing loss reinforces the emerging understanding that rapamycin works on a fundamental level, affecting common cellular pathways that induce various aging-related pathologies across an organism. On the other hand, the failure to reverse hearing loss tells us that rapamycin is far from being the miracle cure that we need to defeat aging. To do this, science will probably need to develop a much more complex and integrated approach.
Literature
[1] Altschuler, R. A., Kabara, L., Martin, C., Kanicki, A., Stewart, C. E., Kohrman, D. C., & Dolan, D. F. (2021). Rapamycin Added to Diet in Late Mid-Life Delays Age-Related Hearing Loss in UMHET4 Mice. Frontiers in Cellular Neuroscience, 15, 100.
[2] Brewster, K. K., Ciarleglio, A., Brown, P. J., Chen, C., Kim, H. O., Roose, S. P., … & Rutherford, B. R. (2018). Age-related hearing loss and its association with depression in later life. The American Journal of Geriatric Psychiatry, 26(7), 788-796.
[3] Liu, C. M., & Lee, C. T. C. (2019). Association of hearing loss with dementia. JAMA network open, 2(7), e198112-e198112.
[4] Cho, B. J., Hwang, J. S., Shin, Y. J., Kim, J. W., Chung, T. Y., & Hyon, J. Y. (2019). Rapamycin rescues endoplasmic reticulum stress–induced dry eye syndrome in mice. Investigative ophthalmology & visual science, 60(4), 1254-1264.
[5] Hu, J., Li, B., Apisa, L., Yu, H., Entenman, S., Xu, M., … & Zheng, Q. Y. (2016). ER stress inhibitor attenuates hearing loss and hair cell death in Cdh23 erl/erl mutant mice. Cell death & disease, 7(11), e2485-e2485.
