A molecular pathway important for controlling aging has been revealed

Maria Fernanda Ziegler | FAPESP Agency One way cells from different tissues communicate is through the exchange of ribonucleic acid (RNA) molecules. In experiments on worms of this type Certain types are elegantResearchers from the State University of Campinas (Unicamp) note that when this communication pathway is deregulated, the longevity of an organism decreases. finding, Released In the magazine The geneBrings a new understanding of the aging process and associated diseases.

“Previous studies have already demonstrated that some types of RNA can be transferred from one cell to another, through communication between tissues – just as happens with proteins and metabolites, for example. This is a signaling mechanism between organs or between neighboring cells.” It is involved in many disease processes. [fisiopatologia] And the normal functioning of the body. “What was not yet clear and we were able to prove is that changes in the pattern of this 'conversation' that occurs through RNA molecules can influence aging,” says the professor at the Institute of Biology at Unicamp. Marcelo Morico-author of the article.

The work was performed within scope Center for Obesity and Comorbidities Research (OCRC) – FAPESP Center for Research, Innovation and Dissemination (CEPID) based at Unicamp. The investigation also received funding through A project In coordination with Mori.

“This communication mechanism needs to be fine-tuned to give the organism a proper lifespan. We observed in the study that if any tissue increases its ability to absorb certain types of RNA from the extracellular environment, [de fora da célula]“It ends up affecting the longevity of the organism,” he says.

According to Mori, it was possible to prove that the decrease in average lifespan occurred not only due to the disruption of communication via RNA between tissues of the same organism, but also due to an increased ability to capture RNA from the environment – coming From bacteria to microorganisms, for example. The researchers coined the moniker InExS (an English acronym meaning intercellular/extracellular RNA imbalance) to refer to the deregulation of RNA transfer between tissues and also with the external environment.

breaking the rules

The researcher says that research into the mechanism of transferring ribonucleic acid (RNA) between cells was inspired by the discovery of the phenomenon of RNA interference (RNAi), which won the Nobel Prize in Physiology and Medicine for North American scientists Andrew Fire and Craig Mello in 2006. In their experiments, they were able to, Using RNA interference, genes are precisely “turned off.”

By injecting double-stranded RNA into C. elegansNobel Prize winners have managed to silence genes. “They observed that the silencing mechanism affected genes in other tissues, not just where the application occurred, and was passed on to subsequent generations,” says Mori.

In addition to enabling elucidation of the mechanisms by which RNAs are transferred between cells of an organism and between the organism and the environment, the discovery of RNAi has given relativity to the central dogma of molecular biology. Until then, it was thought that the flow of information from the genetic code would be a one-way street, starting with DNA, passing through RNA, and ending with proteins.

In the Nobel Prize-winning study, it was discovered that double-stranded RNA molecules can block this process that moves from DNA to protein. RNAi destroys messenger RNA, silencing specific genes without having to change the DNA sequence. It then became clear that RNA could also have a regulatory function on the genome. It is worth noting that the human genome consists of about 30 thousand genes. However, only a small portion of it is used in each cell to synthesize proteins. Many of them play a regulatory role (affecting the expression of other genes).

Balance is everything

“We wanted to understand how this process might interfere with important physiological functions related to aging. In C. elegansThe transfer of RNA between cells is characterized by a pathway involving proteins called SID [responsáveis por diferentes estágios de absorção e exportação de RNAs]. We have observed that there is a pattern of gene expression for this pathway in specific tissues, which changes with age. Messenger RNA that encodes the SID-1 protein [fundamental para fazer a internalização do RNA para dentro das células]“For example, it increases in some tissues, while it decreases in others,” says Mori.

To better understand the role of RNA as signaling molecules between tissues, researchers conducted experiments in which the function of the SID-1 protein was modified in specific tissues. C. elegansSuch as nerve cells, intestines, and muscles. To do this, they manipulated the expression of the protein in these tissues.

“We observed that SID-1 loss-of-function mutants were as healthy as wild-type worms. However, overexpressing SID-1 in the intestine, muscle, or neurons made the worms' lives shorter. Reduced lifespan was also observed by overexpressing the proteins Others are in the RNA transfer pathway, such as SID-2 and SID-5.

The researcher explains that the deregulation may be specifically in the distribution of RNA in tissues. “To deregulate the distribution of RNA in the worm body, we overexpressed SID-1 in specific tissues. [intestino, músculo ou neurônios]. “In this way, we noticed that targeting a specific organ leads to reduced longevity.”

“We also showed that this defect in transfer RNAs leads to loss of function of the microRNA production pathway [pequenas moléculas de RNA com função regulatória]. It is as if the fact that more RNAs are transported to these tissues generates a kind of competition and the production of microRNAs ends up losing the contest. It has already been shown that loss of function in the production of microRNAs leads to a decrease in lifespan.

The Unicamp group also investigated the relationship between the transfer of exogenous RNAs, that is, between the environment and the organism. As in previous experiments, overexpression of SID-2, which captures RNA from the environment via the intestines, and excess RNA produced by bacteria that serve as a food source and the worms' vital microbiota, resulted in shortened lifespan.

“We believe that worms can use exogenous RNAs to monitor microorganisms in the environment, but when they are in excess and absorbed by tissues, they can lead to a harmful effect. When we force bacteria, in the laboratory, to express more,” he adds, “there was a reduction in Lifespan of worms. “This process, which involves excessive transfer of RNA, interferes with homeostasis and production of endogenous RNA, which accelerates aging.”

the study Tissue-specific overexpression of systemic RNA interference components limits lifespan in C. elegans. It can be read on: www.sciencedirect.com/science/article/abs/pii/S0378111923008557.