Exercise staves off Alzheimer’s by affecting iron in the brain

• Lack of physical activity is known to increase a person’s risk of Alzheimer’s disease.
• A new study in mice suggests that exercise may protect against Alzheimer’s by improving the regulation of iron metabolism in the brain.
• Regular exercise reduces circulating levels of a protein called interleukin-6 that promotes inflammation.
• The protein may also change the way in which the brain stores iron.

Regular physical activity has a wide range of health benefits. These include a reduced risk of cardiovascular disease, type 2 diabetes, various mental health conditions, and dementia.

Keeping physically active helps maintain the brain’s flexibility and improve memory. It also minimizes the decline that can occur in nerve cell growth and connectivity as people age.

Previous research in a mouse model of Alzheimer’s disease showed that exercise might even reverse some of the cognitive impairments that characterize this form of dementia.

The same scientists have now discovered that exercise may delay the progress of Alzheimer’s by changing the way the brain stores iron.

The study, which researchers at the University of Eastern Finland in Kuopio led, appears in the International Journal of Molecular Sciences.

Lifestyle risk factors

Alzheimer’s disease, the most common form of dementia, causes the degeneration of parts of the brain that play a role in thinking, memory, and language.

In 2020, up to 5.8 million people in the United States were living with Alzheimer’s.

Most cases are associated with age-related disease and genetic risk factors, but lifestyle factors — such as physical inactivity and a nonnutritious diet — play important roles.

Exactly how physical activity protects the brain against the effects of Alzheimer’s has been unclear, however.

One clue is that both the normal aging process and Alzheimer’s are associated with changes in the way the brain handles iron.

Research has linked the accumulation of iron in the brain and changes in iron metabolism to the formation of plaques of a toxic protein called beta-amyloid that characterize the disease.

Regular exercise can improve iron metabolism and prevent the buildup of this mineral in the brain, but the mechanisms behind this effect are uncertain.

The new study helps resolve the mystery.

Exercise wheels

In the new study, the scientists compared mice genetically predisposed to develop Alzheimer’s with ordinary, or “wild-type,” mice.

Half of the mice had free access to an exercise wheel in their cages, whereas the other animals led a more sedentary life.

After 6 months, the scientists measured the levels of iron and the proteins essential for regulating it in the brains and muscles of the mice.

They discovered that running altered iron metabolism and transport in the brain and increased the iron content of muscle.

Exercise reduced the levels of the proteins ferritin and hepcidin, which promote iron storage in the cortex of the brain.

It also decreased the amount of beta-amyloid in the brains of the mice that were predisposed to develop Alzheimer’s.

At the same time, concentrations of the signaling molecule interleukin-6 (IL-6), which promotes inflammation, were lower in the cortex and blood plasma of the animals that exercised.

In humans, regular exercise is known to suppress the amount of IL-6 circulating in the blood, whereas inactivity increases these levels.

IL-6, which can cross the blood-brain barrier, promotes iron storage through its effects on hepcidin during inflammation.

Tentative conclusions

The researchers, therefore, speculate that by suppressing IL-6, regular exercise helps shield the brain from the disruption of iron homeostasis, which is a feature of both aging and Alzheimer’s.

They conclude:

“This study highlights the importance of iron dysregulation in [Alzheimer’s] and demonstrates that long-term voluntary running exercise modulates iron homeostasis in the brain and skeletal muscles of both [wild type mice and mice with Alzheimer’s]. Our study is the first to link brain alterations of iron homeostasis with decreases in hepcidin and IL-6 in response to regular physical exercise.”

The main limitation of the study was that it involved an animal model of the disease, which may differ in important ways from the presentation of the disease in humans.

In addition, exercise may have different effects on the metabolism of iron in mice and people.

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