Lifespan extension is undeniably interesting, delving into the fundamental questions of what determines the expiration date of our cells (and our bodies). Research has found various genetic manipulations and treatments that can achieve lifespan extension. For example, caloric restriction, the disruption of insulin/IGF1 signaling, or a decrease in mitochondrial respiration. The one factor that seems common to these known mechanisms is increased resistance to various stresses like heat, oxidative stress, or radiation.

Most manipulations that extend lifespan also increase resistance to various stress factors and environmental cues in a range of animals from yeast to mammals. However, the underlying molecular mechanisms regulating stress resistance during aging are still largely unknown.

The upregulation of genes involved in xenobiotic detoxification (the metabolic breakdown of drugs that are not naturally made by the organism) is a transcriptional signature of many long-lived mutants. Now, a team from the Center for Molecular Medicine Cologne (CMMC), in Cologne, Germany, suggests that increased resistance to oxidative stress in long-lived animals stems from the activation of a complex xenobiotic detoxification pathway shown to be upregulated in by all major longevity models.

Now, a new study uncovers some of the poorly understood mechanisms that underlie stress resistance during aging. Researchers identified the Caenorhabditis elegans gene Krüppel-like factor 1 (KLF-1) as a major regulator of drug detoxification and show that is it vital for a response to oxidative stress.

The work is published in the paper “KLF-1 orchestrates a xenobiotic detoxification program essential for longevity of mitochondrial mutants,” which was recently published in Nature Communications.

In this work, the researchers identify KLF-1 as a mediator of a cytoprotective response that dictates longevity induced by reduced mitochondrial function. A redox-regulated KLF-1 activation and transfer to the nucleus coincides with the peak of somatic mitochondrial biogenesis that occurs around a transition from larval stage L3 to D1.

The team showed that upon mild mitochondrial dysfunction and/or oxidative stress, KLF-1 translocates to the nucleus and activates cyp genes that in different organisms often encode enzymes involved in the xenobiotic detoxification process.

They further identified cytochrome P450 oxidases, the KLF-1 main effectors, as longevity-assurance factors of mitochondrial mutants. Collectively, these findings underline the importance of the xenobiotic detoxification in the mitohormetic, longevity assurance pathway and identify KLF-1 as a central factor in orchestrating this response.

A mutant worm with a change in one 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 type. Aleksandra Trifunovic, PhD, professor at the University of Cologne showed for the first time that this longevity is driven by a detoxification pathway, directly regulated by the level of ROS. What makes these results more compelling is that this pathway, which is necessary for the cells to get rid of unwanted unnatural substances, is conserved throughout the animal kingdom and important, for example, in the liver for the drug metabolism.

Mitochondria produce energy using oxygen during a process called respiration. The side effect of this process is the occurrence of ROS, which are always a by-product of respiration. During aging, mitochondria reduce their capability to keep ROS production under control. Some scientists even believe that aging is a consequence of damage inflicted by ROS. Indeed, as we age, more ROS and other toxic metabolites are produced. 

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

Marija Herholz, PhD, author on the study, showed that one transcription factor plays an important role: “When we deleted KLF-1, the mutant lost its longevity and returned to a normal lifespan, while at the same time the detox pathway was shut off. This shows that KLF-1 keeps the pathway working and is important for the longevity of the organism.”

“But,” Herholz added, “the longer life of the mutants has some downsides too. We could see that the mutants move slower and develop slower, since they make less energy and have to support the complex detox machinery running.”

So far, ROS were mostly seen as something bad, disturbing the cells. Newer research shows that ROS play an important role as a signaling molecule. Within the study, the researchers could show that higher levels of antioxidants given to the worms lead to a decreased lifespan by removing ROS and therefore blocking the signaling pathway. “The public perception of ROS in a solely negative way is therefore not backed by scientific findings,” said Herholz. “Indeed, if the levels of antioxidants are too high, this might be harmful, as our study shows.”

In following studies, the researchers want to have a closer look at what exactly happens on the molecular level before and after activation of the signaling pathway.