The trade-off between stress resistance and longevity

The survival and physical condition of multicellular organisms are closely associated with their ability to renew their tissues. This is particularly important for tissues that are permanently exposed to the external environment, such as the epithelium, which lines the digestive tract, and which are stimulated by it. Researchers led by Prof. Mirka Uhlirova of CECAD, the center of excellence in aging research at the University of Cologne, collaborated with the laboratory of Dr. Tony Southall of Imperial College London to identify the Ets21c transcription factor as a vital regulator of the regeneration program. in the adult intestine of Drosophila Drosophila. In addition, their work has highlighted the existence of tradeoff mechanisms between stress resilience and longevity. The results have now been published in the journal Cell reports.

Although primarily involved in the absorption and digestion of nutrients, the intestinal epithelium also serves as a selective barrier limiting the passage of pathogens and toxic substances. The renewal of the intestine is accomplished by stem cells that proliferate and differentiate to maintain the integrity of the tissues and function throughout the life of an organism. In contrast, stem cell dysfunctions have been associated with tissue degeneration or the development of cancer. New research contributes to a better understanding of the molecular underpinnings of regeneration processes under favorable and unfavorable conditions.

Transcription factors are proteins that bind directly to DNA and regulate the expression of specific genetic information. The transcription factor Ets21c has been repeatedly upregulated in response to stress, bacterial infections and aging. Yet the biological significance of its induction remains an enigma. Dr. Juliane Mundorf and her colleagues at Uhlirova and Southall Labs have therefore decided to exploit the genetic ability of the Drosophila model to disable the function of Ets21c in the complete fly or specifically in stem or differentiated cells of the epithelium intestinal. Strikingly, flies lacking Ets21c developed normally and survived the controls when they were kept in unstressed conditions, that is, housed in a clean environment and fed regularly. "The Ets21c deficiency, however, revealed its dark side as soon as the mutant flies encountered stress," Uhlirova explains. Flies lacking Ets21c died much faster when they were fed with a herbicide, which generates harmful reactive oxygen species. "The intestine of adult flies has emerged as the tissue that requires the function of Ets21c to confer stress tolerance," she adds.

By combining genetic and genome-wide approaches, the authors show that Ets21c promotes the renewal of the intestinal epithelium by regulating a specific set of target genes that coordinate the proliferation of intestinal stem cells and the elimination of cells. mature absorbents. However, the Ets21c activity must be tightly controlled. Although its loss slows epithelial turnover, which could be beneficial for life, it makes flies vulnerable to stress because they can not regenerate damaged tissues. On the other hand, too much Ets21c accelerates tissue turnover, leading to excessive proliferation and premature aging.

It is important to note that the transcription factor Ets21c and the signaling network in which it operates are conserved during evolution, from flies to mammals. This suggests that signaling pathways in which Ets-like transcription factors are involved may regulate turnover in human epithelial tissues.

In future studies, the researchers wish to focus on the mechanisms that control the levels and activity of Ets21c and whether non-intestinal tissues need the Ets21c function for their maintenance and stress response. .