How fasting and exercise can supercharge the body's cellular vacuum cleaner

Nick Lavars   February 28, 2019

Scientists have discovered that hormonal changes brought on by exercise and fasting can increase the body's capacity to shed defected proteins(Credit: Daxiao_Productions/Depositphotos)

One of the many useful things our bodies do on their own is rid themselves of proteins that are no longer of use. Whether the proteins are defective, toxic or simply surplus to requirements, our cellular machinery can act swiftly and decisively when shedding this dead weight. But by figuring out new ways to control this process, scientists hope to uncover new treatments for a host of degenerative diseases such as Alzheimer's and Parkinson's, and they've just discovered some new levers in the form of fluctuating hormone levels triggered by exercise and fasting.

The body's natural protein-disposal mechanisms are necessary for the overall health of the organisms and the best understood of them is known as the ubiquitin-proteasome pathway. It works by tagging defective proteins with an ubiquitin molecule, with the protein-disposal unit then taking this "kiss of death" as a green light to embark on its destruction.

But sometimes the protein-disposal unit doesn't work properly, creating a backlog of misfolded proteins that are left to clog up the cell and impact the way it functions. So much so that scientists, including those at Harvard Medical School behind the new study, believe they act as precursors for neurodegenerative conditions such as Alzheimer's.

"We know that misfolded proteins accumulate in neurons in some neurodegenerative diseases, such as Alzheimer's, ALS, Parkinson's, and that this accumulation is associated with defects in protein destruction by the ubiquitin proteasome system," study lead author Jordan VerPlank explains to New Atlas. "In collaborative studies, we found in brains of a mouse models of Alzheimer's disease and early-onset dementia that the expression of the mutant tau reduced protein destruction by the proteasome and caused a further accumulation of misfolded proteins."

Thankfully, there are ways to swing things back in the protein-disposal unit's favor when it fails to do the job on its own. Previous research conducted by VerPlank and his fellow cell biologists has uncovered drugs that target a chemical trigger for protein destruction called cAMP and give the process a boost. But in doing so, the team began to wonder if they were overlooking a key, and potentially useful step, in the process. 

"Because many hormones cause an intracellular rise in cAMP, we wondered if hormones would also stimulate protein degradation, or if the effect documented in the previous study was exclusive to the drugs used to raise cAMP," VerPlank tells us. "It turns out hormones do, in addition to their already known actions, indeed trigger protein destruction."

The scientists landed at this conclusion after a carefully designed round of experiments put their hypothesis to the test. They focused on the hormonal changes brought about through exercise and fasting and set out to observe changes in cells before and after. 

"This is truly a new way of looking at whether we can turn up the cellular vacuum cleaner," says Alfred Goldberg, senior author on the study.

One experiment involved the thigh muscles of four human volunteers put through a tough cycling exercise, with the cAMP levels and signs of protein degradation heightened thereafter. Another involving the hind leg muscles of anesthetized rats brought similar results. As did tests on mouse liver cells exposed to a fasting-related hormone called glucago, as well as the hormone behind adrenaline, epinephrine.

"Thus, stimulating protein degradation by raising cAMP is not just a phenomenon seen with drugs, it also happens with many hormones and therefore is likely happening in our bodies all the time," says VerPlank.

With a new way to promote junk protein destruction, the scientists may have a new way to intervene in the development of diseases such as Alzheimer's, Parkinson's and ALS. Harnessing existing drugs or developing new ones that trigger this process as early forms of treatment will be subject to to further study. But if nothing else, the scientists have discovered yet another health benefit of regular exercise and added further weight to the argument that fasting can lead to a longer and healthier life.

"We know that misfolded proteins accumulate in neurons in some neurodegenerative diseases, such as Alzheimer's, ALS, Parkinson's, and that this accumulation is associated with defects in protein destruction by the ubiquitin proteasome system," study lead author Jordan VerPlank explains to New Atlas. "In collaborative studies, we found in brains of a mouse models of Alzheimer's disease and early-onset dementia that the expression of the mutant tau reduced protein destruction by the proteasome and caused a further accumulation of misfolded proteins."

Thankfully, there are ways to swing things back in the protein-disposal unit's favor when it fails to do the job on its own. Previous research conducted by VerPlank and his fellow cell biologists has uncovered drugs that target a chemical trigger for protein destruction called cAMP and give the process a boost. But in doing so, the team began to wonder if they were overlooking a key, and potentially useful step, in the process. 

"Because many hormones cause an intracellular rise in cAMP, we wondered if hormones would also stimulate protein degradation, or if the effect documented in the previous study was exclusive to the drugs used to raise cAMP," VerPlank tells us. "It turns out hormones do, in addition to their already known actions, indeed trigger protein destruction."

The scientists landed at this conclusion after a carefully designed round of experiments put their hypothesis to the test. They focused on the hormonal changes brought about through exercise and fasting and set out to observe changes in cells before and after. 

"This is truly a new way of looking at whether we can turn up the cellular vacuum cleaner," says Alfred Goldberg, senior author on the study.

One experiment involved the thigh muscles of four human volunteers put through a tough cycling exercise, with the cAMP levels and signs of protein degradation heightened thereafter. Another involving the hind leg muscles of anesthetized rats brought similar results. As did tests on mouse liver cells exposed to a fasting-related hormone called glucago, as well as the hormone behind adrenaline, epinephrine.

"Thus, stimulating protein degradation by raising cAMP is not just a phenomenon seen with drugs, it also happens with many hormones and therefore is likely happening in our bodies all the time," says VerPlank.

With a new way to promote junk protein destruction, the scientists may have a new way to intervene in the development of diseases such as Alzheimer's, Parkinson's and ALS. Harnessing existing drugs or developing new ones that trigger this process as early forms of treatment will be subject to to further study. But if nothing else, the scientists have discovered yet another health benefit of regular exercise and added further weight to the argument that fasting can lead to a longer and healthier life.

https://newatlas.com/fasting-exercise-/58661/