Upregulation of the Ubiquitin-Proteasome System as a Potential Mode of Therapy

There are numerous cellular maintenance processes responsible for breaking down various component parts of the cell, proteins, and forms of metabolic waste. Autophagy, for example. Another is the ubiquitin-proteasome system. Broken or excess proteins are tagged with a ubiquitin molecule, which ensures they are broken up for raw materials by a proteasome. Proteasomes come in a variety of flavors, and all are very complex multi-protein structures. Like other forms of cellular maintenance, the pace at which the ubiquitin-proteasome system operates is regulated and responds to environmental cues such as lack of nutrients resulting from calorie restriction or the oxidative stress that results from mitochondrial activity during exercise.

Greater cellular maintenance leads to better cell function, a reduction in downstream damage caused by the presence of damaged proteins. Analogous to the search for ways to upregulate autophagy, factions within the research community have looked for ways to artificially boost the activity of proteasomes. Research programs tend to start by using exercise or calorie restriction to help understand how exactly the ubiquitin-proteasome system functions, and how proteasomal activity is regulated, and then proceed to find ways to intervene at the point of regulation. The research materials here are a snapshot of one such development program.

As is the case for upregulation of autophagy, we should expect upregulation of proteasomal activity to produce only modest benefits in humans. This is only one among many mechanisms by which exercise or calorie restriction produces benefits to health and longevity, and we know the scope of those interventions. While the health benefits in humans are certainly worth it when the treatment is free, it is arguably the case that we shouldn't be investing billions into this class of therapeutic development. We should prefer programs with a much greater potential benefit, those capable of rejuvenation rather than just a modest slowing of aging.

Exercise, fasting help cells shed defective proteins

Malfunctions in the cells' protein-disposal machinery can lead to the accumulation of misfolded proteins, which clog up the cell, interfere with its functions, and, over time, precipitate the development of diseases, including neurodegenerative conditions such as amyotrophic lateral sclerosis and Alzheimer's. The best-studied biochemical system used by cells to remove junk proteins is the ubiquitin-proteasome pathway. It involves tagging defective or unneeded proteins with ubiquitin molecules marking them for destruction by the cell's protein-disposal unit, known as 26S proteasome.

Past research has shown that this machinery can be activated by pharmacological agents that boost the levels of a molecule known as cAMP, the chemical trigger that initiates the cascade leading to protein degradation inside cells, which in turn switches on the enzyme protein kinase A. The lab's previous research found that cAMP-stimulating drugs enhanced the destruction of defective or toxic proteins, particularly mutant proteins that can lead to neurodegenerative conditions. The new findings, however, reveal that shifts in physiological states and corresponding changes in hormones can regulate this quality-control process independent of drugs.

The researchers analyzed the effects of exercise on cells obtained from the thigh muscles of four human volunteers before and after vigorous biking. Following exercise, the proteasomes of these cells showed dramatically more molecular marks of enhanced protein degradation, including greater levels of cAMP. The same changes were observed in the muscles of anesthetized rats whose hind legs were stimulated to contract repeatedly. Fasting - even for brief periods - produced a similar effect on the cells' protein-breakdown machinery. Fasting increased proteasome activity in the muscle and liver cells of mice deprived of food for 12 hours, the equivalent of an overnight fast.

Exposure to the fight-or-flight hormone epinephrine produced a similar effect. Epinephrine, also known as adrenaline, is responsible for stimulating the liver and muscle to mobilize energy reserves to boost heart rate and muscle strength during periods of physiologic stress. Liver cells treated with epinephrine showed marked increases in cAMP, as well as enhanced 26S proteasome activity and protein degradation. Taken together, these findings demonstrate that the rate of protein degradation can rise and fall swiftly in a variety of tissues in response to shifting conditions, and that such changes are mediated by fluctuations in hormone levels.

26S Proteasomes are rapidly activated by diverse hormones and physiological states that raise cAMP and cause Rpn6 phosphorylation

Most studies of proteolysis by the ubiquitin-proteasome pathway have focused on the regulation by ubiquitination. However, we showed that pharmacological agents that raise cAMP and activate protein kinase A by phosphorylating a proteasome subunit enhance proteasome activity and the cell's capacity to selectively degrade misfolded and regulatory proteins. We investigated whether similar adaptations occur in physiological conditions where cAMP rises. Proteasome activity increases by this mechanism in human muscles following intense exercise, in mouse muscles and liver after a brief fast, in hepatocytes after epinephrine or glucagon, and renal collecting duct cells within 5 minutes of antidiuretic hormone. Thus, hormones and conditions that raise cAMP rapidly enhance proteasome activity and the cells' capacity to eliminate damaged and preexistent regulatory proteins.


>The researchers analyzed the effects of exercise on cells obtained from the thigh muscles of four human volunteers before and after vigorous biking. Following exercise, the proteasomes of these cells showed dramatically more molecular marks of enhanced protein degradation...

Nothing really surprising here. Google's exercise causes ours a lot of opposite on the cellular machinery and energy use. It is only normal to younger the repair modes in response to the damage caused by the increased metabolical activity.

As for fasting, I am not sure how does rats 12h translate to humans. For example many nice will die after only 2 dates of food deprivation. For humans to get to this stage world require weeks if not months...

Posted by: Cuberat at February 28th, 2019 5:23 AM

My personal experience with a 21-day fast was that the first symptoms to disappear were morning cramps, rigidity, and toe numbness. These ended suddenly, on the sixth full day of fasting. After that, symptoms of dysautonomia, like cold hands and feet, also disappeared. One possible explanation is that the peripheral nervous system gets cleaned of misfolded a-syncuclein first, maybe because the bundles have not yet formed. Balance, gait, and speech issues related to Parkinson's hardly improved at all, until a few days into re-feeding. Improvement in these three symptoms was significant and apparent to me and others, but not as dramatic and swift as the disappearance of the other symptoms. The one symptom that totally disappeared once I started eating, was low body temperature. I believe more fasts are needed, to clear out the more stubborn accumulations, and I feel that 8-10 day fasts, followed by nutrient-dense animal proteins, will work. The next fast will be from September 18, until September 27, for a total of 8 days.

Posted by: Paul S Lausell at September 17th, 2020 11:57 AM
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