Protein Aggregation as a Protective Mechanism

One of the distinguishing features of old tissues is the presence of solid protein aggregrates. In some cases these are clearly linked to the pathology of specific diseases, such as Alzheimer's or forms of amyloidosis. For others no clear association with age-related dysfunction has yet been found. It seems prudent to develop means to remove these aggregates regardless, and this is one of the pillars of the SENS approach to rejuvenation treatments. In this paper, researchers propose that not all aggregates are equal, and some are the result of protective mechanisms that sequester an excess of proteins created through age-related dysfunction, rather than being a form of damage in and of themselves:

Researchers used the tiny nematode worm Caenorhabditis elegans as a model organism to analyse the changes that occur in the proteome (the entirety of all proteins) during a lifespan. "The study is the most extensive of its kind in a whole organism quantifying more than 5,000 different proteins at multiple time points during aging." The researchers were able to show that the proteome undergoes extensive changes as the worms age. About one third of the quantified proteins significantly change in abundance. The normal relation between different proteins, which is critical for proper cell function, is lost. This shift overwhelms the machinery of protein quality control and impairs the functionality of the proteins. This is reflected in the widespread aggregation of surplus proteins ultimately contributing to the death of the animals.

Based on these findings, the researchers also analysed how genetically changed worms with a substantially longer or shorter lifespan manage these changes. "We found that proteome imbalance sets in earlier and is increased in short-lived worms. In contrast, long-lived worms coped much better and their proteome composition deviated less dramatically from that of young animals." Surprisingly, the long-lived worms increasingly deposited surplus and harmful proteins in insoluble aggregates, thus relieving pressure on the soluble, functional proteome. However, in contrast to the aggregates found in short-lived animals, these deposits were enriched with helper proteins - the so-called molecular chaperones - which apparently prevented the toxic effects normally exerted by aggregates.

"These findings demonstrate that the cells specifically accumulate chaperone-rich protein aggregates as a safety mechanism. Therefore, the aggregates seem to be an important part of healthy aging." Indeed, it is known that insoluble protein aggregates also accumulate in the brains of healthy elderly people. So far, researchers assumed that neurodegeneration and dementia appear to be mainly caused by aberrant protein species accumulating in aggregates. This assumption may now be tested again: "Clearly, aggregates are not always harmful. Finding ways to concentrate harmful proteins in insoluble deposits might be a useful strategy to avoid or postpone neurodegenerative diseases as we age."



Just because you've got a landfill doesn't mean you don't need to clean up the trash.

Posted by: Slicer at May 8th, 2015 9:37 AM

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