by Benjamin Andreone
figures by Nick Lue

An apple a day keeps the doctor away, right?

From packing in nutrients with a veggie-rich diet, to keeping off body fat through daily exercise, we have been taught our whole lives that healthy lifestyle choices are good for our bodies.  What has been more mysterious, however, is how these same choices affect our minds.

Researchers from the Nedergaard group at the University of Rochester Medical Center have spent the last several years uncovering how healthy lifestyle choices translate into better brain function.  Most recently, in a study published in January 2018 in Neuroscience Letters, Nedergaard’s team demonstrated that exercise helps clear away harmful debris in the brain.

The brain’s trash dilemma

The brain is a very expensive organ.  Although it takes up only 2 percent of the body’s mass, it uses about 20 percent of the body’s total energy in order to work efficiently.  While this high energy demand allows us to sense our world, communicate with one another, and remember how to get to work each morning, it unfortunately comes at a cost.

When brain cells called neurons consume high amounts of energy, they spit out a lot of debris that floats around the brain and prevents it from functioning normally.  This debris consists mostly of leftover proteins, which when left alone, can form clumps that are toxic to the brain.  In particular, clumping of the protein amyloid beta has been linked to decreases in cognition, memory, and overall brain function in people with Alzheimer’s disease.

In most organs of the body, the lymphatic system acts as a waste disposal factory to clear away harmful debris.  The lymphatic system—comprised primarily of an extensive series of vessels that traverse the body—produces a fluid called lymph. Lymph flows through each organ, mops up debris, and washes it into a network of ducts that eventually drain into blood vessels.  Once in the blood, the debris travels on to the kidneys and liver, where it is eliminated from the body.

It makes sense that the brain would also have a waste disposal system to prevent the buildup of toxic debris. For decades, though, scientists had not been able to observe the lymphatic system acting in the brain. This mystery prompted some to speculate that perhaps the brain possesses an alternative way of flushing out its waste.

A waste disposal system in our brains

The big break came several years ago when Nedergaard and colleagues discovered that cerebrospinal fluid—a body fluid that normally surrounds the brain and serves as a cushion in the skull—also acts as the lymph of the brain.  By performing imaging experiments in the brains of mice, they visualized cerebrospinal fluid entering and flowing throughout the brain, eventually draining into the same ducts used by the lymphatic system in the rest of the body.  Best of all, the cerebrospinal fluid took harmful amyloid beta along for the ride, clearing it from the brain.  While the researchers chose to focus on the clearance of amyloid beta in their study, other leftover proteins were likely cleared from the brain at the same time.

Nedergaard’s initial work also described key details of how cerebrospinal fluid flow through the brain occurs (Figure 1).  Cerebrospinal fluid surrounding the brain flows into ring-shaped spaces that encircle blood vessels within the brain.  These spaces act as portals for the entry of cerebrospinal fluid into the rest of the brain, and a class of brain cells called glia serves as gatekeepers for these portals.  Glia wrap around blood vessels and have cellular machinery that takes up cerebrospinal fluid from the ring-shaped spaces and gives it access to neurons and other brain cells. As it flows through the brain, the cerebrospinal fluid collects proteins and other debris and carries it to lymphatic ducts, thereby clearing the brain of waste. Given these observations, Nedergaard coined the newfound brain waste disposal system the “glymphatic system”—a combination of glia and lymphatic.

It’s all in a good night’s sleep

It is easy to imagine the feeling of mental rejuvenation after a good night’s rest, or how the mind seems clearer after a hard workout. As it turns out, the cognitive benefits of these lifestyle choices can be explained by the glymphatic system. Work from Nedergaard’s group has established a connection between behaviors considered to be healthy lifestyle choices and an increase in glymphatic brain clearance.

The first behavior the group analyzed was sleep.  Using imaging experiments in mice once again, the researchers showed that glymphatic flow significantly increased when mice entered sleep. This increase correlated with a twofold faster clearance of amyloid beta in sleeping mice, compared with awake mice.

While sleep is known to be important for functions such as memory formation and consolidation, these data suggest that sleep is also critical for clearance of harmful debris from the brain, allowing it to work as well as possible while we are awake.  A 2017 study from the Beldlin group at the University of Wisconsin-Madison strengthened this idea by showing a link between poor sleep and the build up of biological markers for Alzheimer’s disease in humans.

Exercise: the newest player in glymphatic system function

Regular exercise has been shown to promote memory, improve mood, and decrease anxiety in humans.  A new study published earlier this year from Nedergaard’s group showed that exercise can also positively affect the function of the glymphatic system.  In the study, they gave one group of mice access to a running wheel, while another group of mice had no access to exercise.   After five weeks, the exercising mice showed a more than two-fold increase in glymphatic flow, compared to the sedentary group.

These data provide an explanation for the brain-boosting effects of exercise.  The increased glymphatic flow following exercise may be just what the brain needs to clear away debris and function at its best (Figure 2).

Surprisingly, Nedergaard’s group observed the post-exercise increase in glymphatic flow in mice that were awake.  Prior to this study, such increases were only ever seen in mice that were either asleep or anesthetized.  This observation suggests that exercise and sleep are both independent and powerful drivers of brain waste disposal.

The brain is arguably the body’s most complex organ, so it is only fitting that the brain has evolved a unique method of clearing out its waste to make way for new thoughts and ideas.  Scientists are beginning to understand that making healthy lifestyle choices—be it getting adequate sleep or going for that early morning run—may be a simple yet effective way to tweak the brain’s waste disposal system in our favor.

Benjamin Andreone is a postdoctoral fellow and alumnus of the Program in Neuroscience at Harvard Medical School.

For more information:

• How sleep promotes memory formation and brain function has been discussed in other SITN articles, here and here.
• For more information about how the glymphatic system works, check out the Nedergaard lab webpage.