Fight Aging!

Both exercise and the practice of calorie restriction produce benefits to health in large part via an increased or more efficient operation of cellular maintenance processes such as autophagy and the ubiquitin-proteasome system, both of which act to recycle damaged or waste proteins and cell structures, improving cell function. Many research groups are involved in investigating the details of these metabolic responses, in search of ways to mimic some fraction of the beneficial effects of exercise or calorie restriction. The work noted here is an example of the type, focused on increased levels of cAMP as an important part of the process.

It is already well known that exercise has many salutary effects, but= new findings hint at the possibility that exercise and fasting could also help reduce the risk of developing conditions associated with the accumulation of misfolded proteins, such as Alzheimer's and Parkinson's. That possibility, however, remains to be explored. In their experiments, 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.

In another round of experiments, the researchers exposed the liver cells of mice to glucagon, the hormone that stimulates production of glucose as fuel for cells and tissues during periods of food deprivation or whenever blood sugar levels drop. The researchers observed that glucagon exposure stimulated proteasome activity and enhanced the cells' capacity to destroy misfolded proteins. 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. Epinephrine exposure also boosted proteasome activity - a marker of protein degradation - in the hearts of living rats. Similarly, when researchers exposed mouse kidney cells to vasopressin - the antidiuretic hormone that helps the body retain water and prevents dehydration - they observed higher levels of protein degradation as well.

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. This response was surprisingly rapid and short-lived, the scientists noted. For example, exposure to the antidiuretic hormone triggered protein breakdown in kidney cells within five minutes and subsided to pre-exposure levels within an hour, the experiments showed. The findings show that the diverse set of hormones that stimulate cAMP appear to share a common mechanism that alters the composition of cells. These have long been known to modify gene expression, but this latest research reveals they also play a critical role in cellular housecleaning by disposing of proteins that are no longer needed.

Link: https://news.harvard.edu/gazette/story/2019/02/exercise-fasting-shown-to-help-cells-shed-defective-proteins/