The Unfolded Protein Response in Mitochondria

The unfolded protein response is a housekeeping mechanism that repairs disarrayed protein machinery in cells or guides those cells to self-destruction if there is too much damage. Like many cellular repair and quality control mechanisms, it appears to be associated with longevity via its effects on mitochondria - but in this case only in early life, which raises a number of as yet unanswered questions:

[Researchers] analyzed mice genomes as a function of longevity and found a group of three genes situated on chromosome number two that, up to this point, had not been suspected of playing any role in aging. But the numbers didn't lie: a 50 percent reduction in the expression of these genes - and therefore a reduction in the proteins they code for - increased mouse life span by about 250 days [in a lineage that normally lives between 400 to 900 days]. Next, the team reproduced the protein variations in a species of nematode, Caenorhabditis elegans. "By reducing the production of these proteins during the worms' growth phase, we significantly increased their longevity." The average life span of a worm manipulated in this way went from 19 to more than 30 days, an increase of 60 percent. The scientists then conducted tests to isolate the common property and determined that the presence of mitochondrial ribosomal proteins (MRPs) is inversely proportional to longevity.

The researchers concluded that a lack of MRP at certain key moments in development created a specific stress reaction known as an "unfolded protein response" within the mitochondria. "The strength of this response was found to be directly proportional to the life span. However, we noted that it was more pronounced if the protein imbalance - the reduction in MRP - occurred at a young age. A similar stimulation in an adult did not affect the worms' longevity." What's more, the effect can be induced without genetically manipulating the worms. "Exposure to certain readily available drugs inhibits ribosomal function and thus causes the desired reaction." In other words, mitochondria are sensitive to certain antibiotics, and the drugs can be used to prolong life.

The process examined in worms exists in mice (and humans for that matter), so it looks like the next step is to explore these specific antibiotics in mice to see whether they also exhibit longevity effects and dependence on age at treatment.

Link: http://www.sciencedaily.com/releases/2013/05/130522131120.htm

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