Brain Waste Removal

After a meal, the digestive system uses enzymes to break down the three major macronutrients, with protein being broken down into amino acids, fats being turned into fatty acids, and carbohydrates being turned into simple sugars, such as glucose.  These compounds are absorbed into the blood stream and then carried to the cells in the body to be metabolized.

Metabolism refers to the chemical reactions taking place within each cell to provide energy for vital processes in the body.  The process of metabolism also helps to get rid of harmful waste products (“trash”) and toxic substances from the cell.  While about 90% of the waste products return through the blood vessels, about 10% ends up in the lymphatic system.  The lymphatic system drains excess fluids found in the spaces around cells in the bodily tissue, filters out foreign bodies in the lymph nodes, and transports it back into the blood stream.   The lymphatic system is a collection of vessels, nodes, and ducts that span most of the body. 

The brain, however, completely lacks conventional lymphatic vessels.  The brain and spinal cord, known as the central nervous system, are highly active and metabolic waste can build up quickly.

So how does the brain take out the trash that builds up in the spaces between brain cells?

Waste removal in the brain:

The brain, in fact, does have a dedicated waste clearance system, known as the glymphatic system, which stands for “glial-dependent lymphatic transport”.

The brain mainly consists of nerve cells called neurons as well as glial cells, which form a support structure for neurons.  Glial cells protect, nourish, and insulate neurons.  A type of glial cell, known as astroglia, plays a role in the waste clearance system in the brain.  The term “glymphatic system” is a reference to the role played by the glial cells in the brain’s waste removal process, based on its similarity to the lymphatic system.

How the glymphatic system works:

Receptors (known as aquaporin-4 channels) on astroglia cells allow a clear fluid called the cerebrospinal fluid, which is continuously produced, to move into the brain and spinal cord, resulting in a current that drives fluid through the system.   In addition, the pulsing of circulating blood contributes to the flow of the glymphatic system, which runs parallel to arteries in the brain.  The glymphatic system then collects waste products from the extracellular fluid and eventually connects to the lymphatic system in the dura, which is the thick outer layer of the membrane that covers the brain.

Fluid compartments in the brain consist of intracellular fluid within cells (60-68%), extracellular fluid outside cells (12-20%), blood (10%), and cerebrospinal fluid that fills the larger spaces within and around the central nervous system (10%).

Studies have determined that while the glymphatic system constantly filters toxins from the brain, glymphatic activity is dramatically boosted during sleep, and in particular the slow-wave cycle of sleep.  This results in an 80-90% increase in glymphatic activity relative to the waking state.

Interestingly, the sleeping position also plays a role, as intracranial pressure and cerebral blood flow are influenced by body posture.  Glymphatic transport is at its most efficient when sleeping with the head and torso on the right side, resulting in more clearance than when lying in the supine position (on the back with face pointing upwards) or in the prone (stomach-down or face-down) position. 

Implications of glymphatic system impairment:

Glymphatic system impairment is suspected to play a role in several health conditions, such as the age-old phenomenon called aging, brain trauma, and neurodegenerative diseases.

Aging: 

• Various factors could play a part in disrupting the glymphatic system due to aging, such as decreased flexibility of the arteries, affecting the pulsing of arteries, which may impact the flow of the glymphatic system.   
• Aging also results in decreased levels of cerebrospinal fluid.
• Aging can lead to changes in glial cells that contain the glymphatic vessels.
• Brain aging contributes to the development of neurological disease and is seen as the highest risk factor for neurodegenerative diseases, such as Alzheimer’s disease.
• A recent study comparing young and old mice showed a reduction of 80-90% in glymphatic function in aged mice.

Alzheimer’s disease: 

• Impaired clearance of the glymphatic system is suspected to contribute to the risk of developing Alzheimer’s.
• Reduced functioning of the glymphatic system due to aging can result in reduced clearance of aggregated proteins such as amyloid beta and tau, which are the components of the amyloid beta plaque and tau neurofibrillary tangles that form in the Alzheimer’s brain, impairing the flow and resulting in reduced clearance via the glymphatic system.

This model of glymphatic function in young, old, and Alzheimer’s brains indicates how cerebrospinal fluid travels through the brain and washes solutes and waste products into the veins.  In older people reduced glymphatic clearance is due to the loss of aquaporin-4 channels in the glial cells.  In Alzheimer’s disease the accumulation of amyloid-beta plaque decreases glymphatic clearance due to impaired fluid movement.

Traumatic brain injury:

• Some researchers are of the opinion that brain trauma through injury or blows to the head can result in disruptions to the glymphatic system, which may increase the risk of developing chronic traumatic encephalopathy (damage or disease that alters brain function or structure), for example the “punch-drunk” syndrome that occurs in boxers.
• Brain trauma can result in the relocation of aquaporin-4 channels into a position that may hinder waste clearance in the brain.

Parkinson’s disease:

• As Parkinson’s disease is also characterized by the build-up of protein in the brain, in this case alpha-synuclein (and not amyloid and tau as is the case with Alzheimer’s), researchers suspect that an impaired glymphatic system might play a role.  (Not proven by studies yet.)

Conclusions:

As existing glymphatic research mainly consists of animal studies, the findings need to be replicated in human studies.  

Scientists still know comparatively little about the glymphatic system in humans.  According to the journal Trends in Neuroscience, pioneering studies have already documented the existence of the glymphatic system and meningeal lymphatic vessels in the human brain.

Currently there are no methods to manipulate glymphatic activity in humans for health reasons.  Ways to manipulate or regulate glymphatic clearance could, for example, increase waste removal of aggregates in diseases linked to protein deposits in the brain, such as Alzheimer’s and Parkinsons.

Future studies, utilizing more effective functional imaging tools that would be able to track waste molecules, could lead to further insight into the functioning of the glymphatic waste removal system, in normal health as well as in disease states.

Research into the glymphatic system could hold the key to interesting new perspectives into brain health, as it cleanses our most sensitive and complex organ.  Future studies on the glymphatic system may well reveal functions other than waste clearance.

References:

The glymphatic system – a beginner’s guide.  Published online 7 May 2015 and in the journal Neurochem Res. 2015 Dec; 40(12): 2583-2599.  PubMed Central.   (www.ncbi.nlm.nih.gov)

How does your brain take out the trash?  Published 21 June 2019.  Medical News Today.  (www.medicalnewstoday.com)

The sleeping brain: harnessing the power of the glymphatic system through lifestyle choices.  Published November 2020 in the journal Brain Sciences.  PubMed Central.  (www.ncbi.nlm.nih.gov)

Understanding the glymphatic system.  Published 17 July 2018.  Neuronline.  Society for Neurosciences.  (www.neuroline.sfn.org)

The glymphatic system and waste clearance with brain aging: A review.  Published in Gerontology, March 2019; 65: 106-119.  (www.karger.com)

The brain’s glymphatic system: Current controversies.  Published 15 May 2020.  Trends in Neurosciences.  A Cell Press Journal.  (www.cell.com)

What does the glymphatic system do?  Published online and updated 6 January 2023.  Medical News Today.  (www.medicalnewstoday.com)

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