by Ryan Camire
figures by Shreya Mantri

Many of us exercise and push ourselves to new limits without a specific goal; we lace up our sneakers and don our neon running shorts for the purest of intentions – to ‘stay healthy’. But what exactly does this mean? Most of us think only of the physical benefits reaped by our hardworking muscles. Exercise can help improve heart health, promote weight management, and reduce overall disease incidence. We may not, however, consider how exercise may benefit us outside of that. For example, can we harness physical exercise to also improve our brain functioning?

Studies have shown that exercise can in fact help prevent the development of neurocognitive and neurodegenerative diseases, like Alzheimer’s Disease, which continue to be a major healthcare burden for an aging population. Exercise has also been shown to promote neuroplasticity, defined as our brains’ ability to change or adapt over time. Neuroplasticity can be achieved by growing new neurons or reshaping current connections to improve neural pathways. Moreover, exercise can help prevent the negative consequences of neuroinflammation – an immune reaction in the brain associated with infections or injuries. But how exactly exercise is able to exert all these benefits on the brain has mostly remained a mystery. Findings from a recent study now shed insight into this question and may even help motivate us to get up and move.

From the blood to the brain – a pathway of communication 

When one typically considers the ways in which exercise may influence brain health, there’s a potential major roadblock – the brain is physically separated from the body parts that are usually engaged in exercise, such as your leg muscles. Due to this physical separation, there needs to be a pathway through which the exercising muscles can communicate with the brain itself. Since the brain is an extremely vascularized organ, meaning it receives a tremendous volume of blood, one possibility is that blood itself serves as a ‘superhighway,’ connecting the brain to peripheral organs. With this in mind, a group of researchers at Stanford University hypothesized that exercise might induce molecules called ‘exercise factors’ to travel in the circulating blood, like cars on the superhighway, and then enter the brain and offer protective features.

In order to study this hypothesis, the researchers designed an experiment where one group of mice ran on a running wheel daily for 28 consecutive days. They then obtained their blood plasma – the liquid portion of blood that was suspected to contain possible ‘exercise factors’, and injected it into a second group of mice that did not exercise. Interestingly, this study found that non-active mice injected with active mice’s plasma experienced many of the same beneficial brain-related outcomes, such as improved cognition, as the active mice. This was the first sign that something in the blood plasma was responsible for the observed benefits. 

Exercise dampens brain inflammation 

In addition to improved cognition, the researchers also observed a decrease in activity related to many inflammatory genes within the hippocampus, a brain region involved in memory and learning that is susceptible to inflammatory damage. Intrigued by this observation, the group next wanted to determine if exercise can actually prevent negative effects of neuroinflammation. Since neuroinflammation is an immune reaction, to investigate this question, mice were injected with a component of bacteria known to elicit a strong immune response. The hippocampus showed signs of damage and uncontrolled inflammation, but when mice were exposed to plasma from the active mice, many of these effects were reversed. This finding demonstrated that not only are there neuroprotective factors in the blood that are induced by exercise, but that they may also be anti-inflammatory in nature, meaning they can limit or reverse inflammation. 

The researchers next sought to determine the specific molecule that is responsible for these effects. In order to do this, they identified 568 individual proteins that are induced by exercise and narrowed it down to the top four. Only one of these proteins, called clusterin, was shown to be important because the neuroprotective effects were lost when plasma was depleted of clusterin prior to exposing the mice. Clusterin can be produced by cells of the liver and heart during exercise, and the cells that make up blood vessel walls in the brain – known as brain endothelial cells – contain a receptor that can detect clusterin. Therefore, it’s entirely possible that clusterin uses the blood as a superhighway to connect muscles with the brain during exercise. (Figure 1)

Figure 1: Exercise factors can be produced by the liver and muscles during exercise. These soluble factors can then enter the systemic circulation and reach the brain through the dense blood vessel network. In the brain, endothelial cells that make up the blood vessel walls have receptors that can detect circulating molecules, thus potentially mediating neuroprotective effects to the brain.

Running to the future

The recent findings described above are both interesting and exciting, but they also introduce new questions and avenues for future research. How brain endothelial cells communicate the message of sensing clusterin across the blood vessels to other important brain cells remains unclear. Are there other intermediate steps that need to be carried out or other cell types that play distinct roles in this communication process? (Figure 2) It is also not yet known whether these findings translate to humans. The study did find that exercised human subjects also have clusterin in their blood, but whether it can mediate the same effects as in mice and help prevent neuroinflammation and degenerative diseases remains to be studied. It would also be important to determine whether other forms of exercise, such as yoga or strength-training, can induce similar effects. 

Figure 2: There are many cell types that make up the brain. It is currently unclear how endothelial cells that separate the blood from the brain communicate the message of clusterin to these various cell types.

Identifying specific factors like clusterin that may be induced in the blood by exercise has potential applications as a therapeutic, too. One avenue for future research is exploring whether blood donations or purified protective exercise factors could be given to individuals who cannot exercise. Until then, the next time we head out with laces tied and headphones on, we can thank clusterin for acting as a potentially helpful hand to protect our brain for the long-term – all the more reason to start exercising. 

Ryan Camire is a graduate student in the Immunology Ph.D. program at Harvard Medical School. He studies immune regulation of the blood-brain barrier. 

Shreya Mantri is a G2 in the Biomedical & Biological Sciences Ph.D. program. You can find her art on Instagram @phudding_away 

For more information: 

  • Check out this review to learn more about the regulation and structure of the blood-brain barrier – the endothelial barrier that separates the blood from the brain. 
  • Clusterin is only one example of the potential exercise factors that may ultimately shape brain health. Learn more about other molecules and pathways that may shape brain health by reading this review or this article
  • SITN has recently covered the biology of one brain cell, microglia, in depth. It is interesting to speculate whether messages from endothelial cells reach microglia to mediate some of the neuroprotective features of clusterin.

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