Exercise for Your Eyes: A Multi-Targeted Approach?

Exercise is synonymous with the word health. We all know how good exercise is for the body, whether it be for your heart, chronic disease management, or waistline. The fact that there seems to be a new gym opening in your neighbourhood every other week, indicates that the benefits of exercise and fitness are engrained into our society.

However, the effects of exercise don’t just stop at your muscles. The benefits can also be seen throughout the entire body, including the brain and the eye. This realisation has resulted in exercise being ‘prescribed’ as a therapeutic to slow down the progression of neurodegenerative diseases such as dementia, Alzheimer’s and Parkinson’s disease.

Given the holistic benefits of exercise, uncovering the messages that are sent throughout the body during physical activity may provide a roadmap to a comprehensive therapy that can tackle the complexities of neurodegenerative diseases.

A MULTI-TARGETED APPROACH TO A COMPLEX DISEASE

Our retina is an extension of the brain and is the tissue that lines the back of our eye. The light that enters into our eye is received by the retina which, through a series of processes, converts it into a signal that is sent to the brain to eventually form the images that we see every day. The central macular region of our retina is responsible for essentially all of our useful vision. This is also the area impacted by age-related macular degeneration (AMD), the leading cause of blindness in the developed world.

One in seven Australians and New Zealanders over the age of 50 live with AMD and, the most common form of the disease, atrophic AMD, has no cure or therapy available. A large part of this is due to the inherent complexities of neurodegenerative diseases like AMD, which are multi-factorial by nature, with many pieces to the puzzle.

So which piece do you go after? And if we have to target all the pieces, how exactly do we do that? Researchers understand now, that to be successful in treating AMD and other similar neurodegenerative diseases (think Parkinson’s or Alzheimer’s disease), a multi-targeted approach is likely to be needed.

RUN FOR YOUR EYES!

Could exercise – an activity that causes wide-scale physiological changes around the entire body – provide us with a multi-targeted therapeutic template?

Exercise has been shown to provide benefits to brain health in numerous ways. It improves blood flow to the brain and hence oxygen supply, and has been demonstrated to improve learning and memory, as well as slow down age-related cognitive impairment.^1-4 Further, exercise can help build more brain cells and promote the connection between them. The brain is filled with millions of cells connected to each other in an intricate network. These connections and their maintenance are vital for the proper functioning of the brain.

As aforementioned, the retina is an extension of the brain. Therefore, it is natural to assume that whatever effects that occur within the brain from exercise may also occur similarly in the retina. However, our knowledge of the retina is less complete than our knowledge of the brain.

Emerging evidence has demonstrated that exercise is protective against degeneration of the retina, namely in diabetic retinopathy, retinitis pigmentosa and light-induced retinal degeneration which models aspects of AMD. Some evidence suggests that regular exercise reduces the incidence rate of AMD and may provide better outcomes with regards to the severity of the disease and visual outcomes in patients.^5,6 In these studies, higher levels of vigorous exercise in middle-aged adults, and moderate exercise in people over 75, was associated with a lower incidence rate of AMD. What is quite interesting is that decreased physical activity has been correlated with an increase in precursors for AMD, meaning increased chance for developing the disease.⁷

For glaucoma, there have been two long-term studies, across 5.7 years and 7.7 years, showing a link between people who regularly exercise and reduced risk of glaucoma.^8,9 While this data is promising, studies in humans have only been epidemiological with the molecular and mechanistic underpinnings still a bit muddy.

WHAT WE KNOW

Research, largely conducted in laboratory animal studies, is increasingly delving into the mechanism of what we see in the retina following exercise. Specifically, two pathways have been intensively looked at: oxidative stress and inflammation, both key facets in the disease progression of neurodegeneration. Amelioration of retinal damage has been reported in both genetic and induced retinal degenerations in animals. In the rd¹⁰ naturally degenerating mouse model of retinitis pigmentosa, voluntary exercise with the use of running wheels was shown to inhibit vision loss and damage in the retina.^10,11 Exercised mice displayed three times as many cone photoreceptors as non-exercised mice, as well as two times greater visual acuity. Additionally, there was a decrease in retinal inflammation using the same damage model with animals that had exercised.

In a model of glaucoma, swimming was demonstrated to protect retinal ganglion cells against elevated intraocular pressure, a glaucoma hallmark.¹² Several laboratory studies have also investigated the effect of physical activity in protecting against diabetic retinopathy, where it was demonstrated that regular treadmill exercise preserved visual function, inhibited apoptotic neuronal cell death, and suppressed VEGF expression in the retina.^13-15 In a study on obese mice, physical exercise was shown to reduce the inflammatory profile of the retina.¹⁶ The implemented exercise here consisted of a combination of climbing movements and treadmill aerobic exercise, and showed that key pro-inflammatory proteins (TNF-α and IL-1β) in the serum and retina were reduced following exercise.

Exercise has also been shown to preserve both retinal morphology and function in a light-induced model of retinal degeneration.^17,18 This model has been considered to mimic facets of AMD, with an increase in central retinal oxidative stress and inflammation, photoreceptor degeneration and retinal pigment epithelium instability.¹⁹ Using this model, animals that had performed treadmill exercise exhibited a 20% increase in brain-derived neurotrophic factor (BDNF) levels, which is the molecule largely suspected to be the main player in mediating the neural benefits seen with exercise.

Our lab (Clear Vision Research Lab), at The Australian National University, has also generated preliminary, unpublished data using the photo-oxidative damage of AMD that suggests aerobic exercise protects against damage to the retina and preserves visual function. We’ve demonstrated a consistent decrease in photoreceptor cell death as well as reduced inflammation within the retina of animals that have exercised for a period of time.

THE MESSAGE OF EXERCISE

Landmark studies have discovered that when we exercise, our muscles release messages that get delivered to the rest of the body – much like an endocrine organ.^20,21 

The endocrine system is a collection of organs that releases signals to mediate and control a multitude of mechanisms throughout our body. Examples are your thyroid gland, which helps with growth and energy expenditure; your pancreas, which releases insulin to help control blood sugar; and your adrenal gland, which controls sex drive and stress. The discovery of our muscles behaving in the same manner has provided a big clue to how exercise can benefit the entire body.

These exercise-mediated messages are packaged in lipid particles known as extracellular vesicles. These particles transport the messages to other organs of the body, through our circulation, to influence how those organs behave. In other words, exercise triggers conversations between different tissues all over the body, including the brain and very likely, the eye and retina.

WHERE TO NEXT?

Much remains to be discovered in the field of exercise physiology within the retina. There are many questions that remain unanswered, in terms of whether the significant health improvements from exercise are translated to retinal tissue. But more importantly, we need to understand the molecular mechanisms underpinning the correlations studied thus far. For example, what level of exercise intensity and time, analogous to the dosage of a drug, is required to exert a therapeutic effect?

Further, the issue of differences between ‘forced’ and ‘voluntary’ exercise must also be consolidated. It has been demonstrated that significant differences exist in brain behaviour under forced and voluntary exercise animal paradigms, with, for example, forced exercise animals demonstrating much higher anxiety-like behaviours than voluntary exercise animals.²² These facets would significantly confound the physiological response to exercise, making it difficult to decipher the true effect of physical activity. With highly variable exercise regimes implemented in the current literature, it is important to determine a standardised and optimal approach to be able to effectively study the molecular underpinnings of exercise with consistency.

The important take-away is that it is the messages within the carrier molecules that researchers believe may hold the key to what makes exercise so good for the entire body. Uncovering these messages that are sent throughout the body during physical activity, along with their carriers, may provide a roadmap to a comprehensive, multi-targeted therapy that is vital to tackle the complexities of neurodegenerative diseases.

For a comprehensive review on exercise in the retina and CNS, please read the review by Chu-Tan et al (pubmed.ncbi.nlm.nih.gov/34741489/).

Dr Joshua Chu-Tan completed a Bachelor of Medical Science with First Class Honours in 2014 and a PhD in Neuroscience in 2019 from The Australian National University (ANU). He is a Research Fellow at the John Curtin School of Medical Research and the Business Development Manager for the College of Health and Medicine at the ANU.

References 

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