Detox pathway extends lifespan of the worm C. elegans

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Detox pathway extends lifespan of the worm C. elegans

A mutant worm with a change in a mitochondrial gene produces more reactive oxygen species (ROS), which can be harmful to cells by causing oxidative stress. However, this mutant worm is able to live twice as long as the wild worm. Professor Aleksandra Trifunovic and her team from the CECAD Cluster of Excellence in Aging Research at the University of Cologne have shown for the first time that this longevity is determined by a detoxification pathway, directly regulated by the level of ROS.

What makes these results more convincing is that this pathway, which is necessary for cells to get rid of undesirable unnatural substances, is stored throughout the animal kingdom and is important, for example, in the liver for the metabolism of the drug. The study "KLF-1 orchestrates a xenobiotic detoxification program essential for the longevity of mitochondrial mutants" is now published in the journal Nature Communications.

Mitochondria are the motors of cells. They produce energy by using oxygen during a process called breathing. The side effect of this process is the presence of reactive oxygen species or ROS, which are always a by-product of respiration. As they age, the mitochondria wear out, reducing their ability to control the production of ROS. Some scientists even believe that aging is a consequence of the damage inflicted by EROs. As we age, we produce more ROS and other toxic metabolites.

Detoxification pathways remove toxic metabolites in three steps. In the first phase, metabolites are recognized and modified, so that they can be neutralized in the second phase, and eliminated from the cell in the third phase. All machinery to maintain degradation is extremely energy-intensive and is maintained under tight transcriptional control. Usually, it is only turned on when needed.

Dr. Marija Herholz, lead investigator in the recent study, showed that a transcription factor plays an important role: "When we removed KLF-1, the mutant lost its longevity and returned to a normal life span, while the detoxification pathway was closed. This shows that KLF-1 maintains track operation and is important for the longevity of the body." But the longer life of mutants also has its disadvantages: "We have seen that mutants move more slowly and develop more slowly, because they produce less energy and have to support the complex detoxification machines that work," adds Herholz.

Until now, ROS was mainly considered as something bad, disrupting cells. More recent research shows that ROS plays an important role as a signalling molecule. In the study, researchers were able to show that higher levels of antioxidants given to worms reduce life span by eliminating SARs and blocking the signalling pathway. "The public's perception of ROS in a purely negative way is therefore not supported by scientific results," said Marija Herholz. "Indeed, if antioxidant levels are too high, it could be harmful, as our study shows."

In subsequent studies, researchers want to take a closer look at what exactly happens at the molecular level before and after the activation of the signalling pathway.