Mouse study reveals how running can prevent a downside of aging

As people age, millions experience vision loss due to macular degeneration (AMD). Vision blurs, straight lines bend, and eventually, it becomes impossible to see objects in sharp clarity. This decline can make it hard to drive, read, and cook.

In a new study, researchers identify one activity that may slow or even stop this life-altering progression: endurance exercise.

In mice, voluntary running reduced harmful overgrowth of blood vessels in eyes by up to 45 percent. This overgrowth drives macular degeneration and contributes to other eye disorders that jeopardize vision.

"Exercise is an inexpensive and patient-centric intervention that gives patients and eye doctors another arrow in their quills to help improve the vision of those suffering from or at risk of developing macular degeneration," study co-author Bradley Gelfand, a researcher at the University of Virginia Center for Advanced Vision Science, tells Inverse. The team's findings were published in the May issue of the journal Investigative Ophthalmology & Visual Science.

Scientists have known for decades that people who are more active have a lower risk of developing advanced macular degeneration. However, much of this research is based on surveys from participants, which can be "notoriously inaccurate," Gelfand explains. People aren't necessarily great at self-reporting when or how much they work out.

These studies also have trouble detangling confounding effects that retinal disease has on the amount of exercise someone undertakes, Gelfand adds. When someone cannot see clearly, they are less likely to exercise. In turn, exactly how much exercise is influencing disease progression has been a mystery.

This study provides the first direct, experimental evidence that exercise plays a role in this disease process, Gelfand says.

To gather this evidence and understand how exercise affects vision loss from macular degeneration, Gelfand and his team rounded up a group of male and female mice and housed them in cages. Half of the mice's homes had running wheels.

For four weeks, the researchers recorded the mice's daily activity on the wheel or in the cages without wheels. Then, one month into the observation period, the team used lasers to injure all the mice's eyes and induce a condition called choroidal neovascularization (CNV). CNV occurs when abnormal "leaky" blood vessels grow into the retina and allow fluid from blood, including red blood cells, to enter the retina. This can distort vision, create a blister in the retina, and ultimately, damage the ability to see.

After the mice recovered from the laser injury, the researchers placed them back in their respective cages and observed their activity for one week. Then, the animals were euthanized and the team analyzed how many blood vessels had grown and if there were resulting CNV lesions in their eyes.

An initial test comparing active to sedentary mice found that exercise reduced the blood vessel overgrowth by 45 percent. A second experiment, which included male mice in group cages, found a reduction of 32 percent.

Eye exercise — Crucially, the study doesn't reveal a magic workout or daily activity goal to preserve vision in humans. Gelfand stresses that people with or at risk of macular degeneration consult their doctor before mixing up their activity routines.

The research does hint that more exercise isn't necessarily better. In the study, as long as mice had access to a wheel and ran, researchers saw a positive effect on the volume of abnormal blood vessel growth.

This finding suggests that relatively small amounts of exercise could be beneficial to people, Gelfand says.

Importantly, timing matters. When mice exercised only after the disease process started, there was no measurable benefit.

"If extrapolated to people, this implies that exercising before the disease begins would be important to achieve a maximal benefit," Gelfand says.

Currently, the team hasn't pinned down exactly how exercise can positively disrupt this potentially harmful process.

"Exercise has complex effects on the body — among these are changes in blood flow, skeletal muscle biology, and immunity," Gelfand says. "We don't have a great handle on which of these is responsible, though we hope to answer this question in future studies using this experimental platform, as well as looking at human patient data."

Ultimately, staving off vision loss is just one of a wide array of reasons to work out. And for people who can't break a sweat due to physical limitations, Gelfand hopes to create an alternative treatment that could boost vision.

"The next step is to look at how and why this happens, and to see if we can develop a pill or method that will give you the benefits of exercise without having to exercise," Gelfand says. "Many older people have obstacles to exercising. We hope to one day develop a medicine that can mimic the beneficial effects of exercise."

Abstract:

PURPOSE. To determine the effect of voluntary exercise on choroidal neovascularization (CNV) in mice.

METHODS. Age-matched wild-type C57BL/6J mice were housed in cages equipped with or without running wheels. After four weeks of voluntary running or sedentariness, mice were subjected to laser injury to induce CNV. After surgical recovery, mice were placed back in cages with or without exercise wheels for seven days. CNV lesion volumes were measured by confocal microscopy. The effect of wheel running only in the seven days after injury was also evaluated. Macrophage abundance and cytokine expression were quantified.

RESULTS. In the first study, exercise-trained mice exhibited a 45% reduction in CNV volume compared to sedentary mice. In the replication study, a 32% reduction in CNV volume in exercise-trained mice was observed (P = 0.029). Combining these two studies, voluntary exercise was found to reduce CNV by 41% (P = 0.0005). Exercise-trained male and female mice had similar CNV volumes (P = 0.99). The daily running distance did not correlate with CNV lesion size. Exercise only after the laser injury without a preconditioning period did not reduce CNV size (P = 0.41). CNV lesions of exercise-trained mice also exhibited significantly lower F4/80+ macrophage staining and Vegfa and Ccl2 mRNA expression.

CONCLUSIONS. These findings provide the first experimental evidence that voluntary exer- cise improves CNV outcomes. These studies indicate that exercise before laser treatment is required to improve CNV outcomes.