Early studies suggest regenerative medicine could halt or even reverse the onset of age-related sensory impairment
Gradually losing the ability to experience and enjoy the world around you can be one of the most debilitating aspects of ageing.
Vision impairment, hearing loss and other sensory disabilities affecting smell, taste or touch are among the most common conditions affecting older people today. In the US, two-thirds of the population aged 70 and older suffer from two or more sensory impairments.1
These disabilities typically have a major detrimental impact on quality of life. Age-related vision loss, for example, can cause difficulties from accomplishing everyday activities like driving, reading the mail, or navigating the supermarket; to enjoying leisure activities such as movies or books; to no longer being able to see loved ones or to watch grandchildren grow up.
Hearing loss can be equally isolating, while a declining sense of taste and smell takes away some of life’s great sensory pleasures and results in compromised nutritional intake.1
As a result, age-related sensory decline has major implications for broader health. Loss of hearing or vision is associated with depression, cognitive decline and shortened lifespan. Declines in sense of smell and taste leads to a poorer quality diet, and early death. People with hearing and vision impairments at age 60 can expect three additional years of physical disability and a four-year-shorted life expectancy than unimpaired peers.2
However, age-related sensory disability is not just limited to impairment of the five senses. A diverse range of conditions that afflict people in later life, from chronic pain to erectile dysfunction (ED), are also sensory in nature and can significantly shorten health-span and lifespan.3,4,5
Current treatment options for many sensory disabilities are limited. Often, the best-case scenario is a therapy that will slow the condition’s progressive worsening. Regenerative therapies such as exosomes could offer an alternative scenario. Exosome-based therapies are beginning to show potential to activate and rejuvenate the body’s natural repair mechanisms, offering the possibility not only to halt the progression of these diseases, but even begin to reverse them.6
Vision impairment and dry AMD
Of the age-related conditions affecting the five senses, impaired vision can have the greatest impact on quality of life, health-span and lifespan. The main cause of irreversible blindness in the developed world today is age-related macular degeneration (AMD).7 The most common form, dry AMD, involves the accumulation of cellular debris (‘drusen’) beneath the light-processing cells in the central area of the retina called the macula. This debris leads to dysfunction and death of these cells and a dark, blurred patch forming in the centre of the field of vision. For dry AMD there is currently no treatment available.
Although the exact mechanism behind dry AMD onset is still a matter of research, the emerging picture is that dry AMD results when fundamental mechanisms of cellular metabolism and maintenance go awry in the cells of the eye.
Publishing in the Nature journal Scientific Reports in early 2020, a US research team showed that two critical metabolic pathways – one involving biomolecules called NAD+ and sirtuin 1, and one involving a molecule called mTOR – become dysregulated during AMD.8 These are exactly the pathways that, over the past few years, researchers have shown to be behind a whole host of age-related diseases.9
When they are functioning properly, these pathways regulate cells’ response to nutrient levels. When nutrients are plentiful, growth and division is promoted. When nutrients are scarce, the pathways activate cellular recycling processes that break down damaged cellular components. As we age, the pathways seem to get stuck in the growth cycle, recycling gets neglected and harmful junk begins to accumulate.
This dysregulation of basic cellular maintenance has implications for cells around the body. When it occurs in the brain, for example, neurodegenerative diseases such as Alzheimer’s can result. In the eye, AMD can result, the new research shows.8 “Our study provides new insights for the development of novel treatment strategies in AMD,” the researchers concluded.
Exosomes to the rescue of sight?
Enter the exosomes. These packages of proteins and genetic material are released by virtually every cell type, and play a central role in communication between cells near and far in the body. Exosomes released by reparative cells called stem cells can have a powerful rejuvenating effect on the cells that take them up. Exosomes from stem cells have shown the ability to restore healthy mTOR and NAD+ function in animal studies, which suggests they have great potential for treating dry AMD – and many other age-related diseases, sensory or otherwise.10,11
Previous research in animals has already shown that regenerative therapies can actually reverse damage to the retina and help restore sight. A research team showed that, in mice with retinal damage, first bringing inflammation under control, and then using a stem cell therapy to initiate regeneration of the retina, led to recovery of sight.12
However, as the US Food and Drug Administration has highlighted, implanting live cells into the eye has significant risks.13 In 2015, three patients in the US suffered severe vision loss when an unapproved injection of stem cells into the eye – intended to treat their AMD – went wrong, seemingly because the stem cells transformed into fibroblasts in the eye.14
It is now well accepted that exosomes released from stem cells are the main source of stem cells’ regenerative properties, and are inherently safer than injections of live cells.15 A recent study showed that exosomes from stem cells were just as effective as the cells themselves at curbing inflammation and reducing retinal damage when injected into the eye.16 Exosomes’ natural role travelling around the body ensures they can readily reach sites of damage within the deeper layers of the eye. In animal studies of eye injury, exosomes could deliver their cargo to inner retinal areas.17
Exosomes also have proven potential in other common age-related disabilities affecting vision, such as glaucoma. This condition occurs when pressure builds in the eye and the neurons that conduct visual information to the brain start to self-destruct, in a form of cell death called apoptosis. Exosomes can prevent apoptosis and instead initiate repair mechanisms in a range of cell types – including the neurons afflicted by glaucoma in the eye, a late 2019 animal study showed.18
Exosomes and ED
Another sensory disability very common in older men is ED, which affects more than half of men over 50 and around 70% of men by the age of 70.19 Although Viagra and other phosphodiesterase type 5 inhibitor (PDE5-i) drugs can be effective, these drugs require generally intact healthy penile nerves, muscles and blood vessels. However, the nerve that triggers erection, the cavernous nerve, is very vulnerable to damage during pelvic surgery for prostate or colorectal cancer. ED affects up to 85% of men following radical prostatectomy, and PDE5-i drugs typically have little effect in these cases.20
The challenge is that even though the nerve can eventually recover some function post-surgery, the corpus cavernosum smooth muscle cells in the penis that control blood flow to achieve erection rapidly degrade and die due to the interim lack of nerve signalling. As a result, recovery of the nerve does not lead to erectile function recovery. However, in a rat model of cavernous nerve injury, exosomes were able to alleviate smooth muscle cell death and avoid the onset of ED.21
Exopharm has also recently released initial results showing that its exosomes can significantly improve the response of corpus cavernosum smooth muscle cells, and so potentially restore erectile function.22 Further non-clinical testing, followed by human clinical trials, are the next steps, the company says.
Combined with the proven ability of stem cell-derived exosomes to promote nerve repair following damage, as well as their general pro-regenerative capabilities, complex multifactorial sensory conditions such as ED could prove to be the ideal target for exosome therapies.23,24
Ageing is a process of increasing dysregulation of basic cellular function, that leaves the body vulnerable to numerous progressive disabilities. Sensory impairment, from vision loss to ED, is a clear outward sign of the damage taking place, and a major source of poor health in later years of life.
Although modern medicine has extended lifespan, it has not been able to halt these progressive disabilities, so the final decade or more of life is now typically characterised by increasing infirmity and ill health.25 Regenerative therapies such as exosomes have the potential to reverse the underlying damage that is now being shown to be a major contributing factor to age-related disease. Sensory disabilities appear to be an area where exosomes could have a major beneficial impact.
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9. Campisi, J. et al. From discoveries in ageing research to therapeutics for healthy ageing. Nature 571, 183 (2019) https://doi.org/10.1038/s41586-019-1365-2
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14. Kuriyan, A. E., et al. Vision Loss after Intravitreal Injection of Autologous “Stem Cells” for AMD. New England Journal of Medicine 376, 1047 (2017) https://doi.org/10.1056/NEJMoa1609583
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