Breaking the rules – discovering an important molecular pathway for controlling aging

Research on the roundworm species C. elegans has shown that disturbances in the transfer of RNA between cells across different tissues can lead to shortened lifespan.

Cells in different tissues interact by sharing RNA Molecules. A study conducted by scientists from the State University of Campinas (UNICAMP) in Brazil, using roundworms Classify Caenorhabditis elegans discovered that disruptions in this method of communication can lead to a reduced lifespan of the organism. The study was recently published in the journal The gene. The results contribute to a better understanding of the aging process and associated diseases.

“Previous research has shown that some types of RNA can be transferred from cell to cell, through communication between tissues, of the kind that occurs with proteins and metabolites, for example. This is a signaling mechanism between organs or neighboring cells. It is part [of the physiopathology] said Marcelo Mori, corresponding author of the article and professor at the Institute of Biology (IB-UNICAMP). “What was not clear and we have now succeeded in proving is that changes in the pattern of this ‘conversation’ between RNA molecules can influence aging.”

The study was conducted at the Obesity and Comorbidities Research Center (OCRC) of UNICAMP, one of the Research, Innovation and Dissemination Centers (RIDCs) funded by FAPESP. It was also funded by a project in which Mori is the principal investigator.

“This communication mechanism must be well adjusted to give the organism a suitable lifespan. In the study, we found that if any tissue increases its ability to absorb certain types of RNA from the extracellular milieu, it ends up “It affects the lifespan of the organism.”

He added that researchers have proven that decreased lifespan is due not only to the interruption of RNA-based communication between tissues in the same organism, but also to an increased ability to absorb RNA from the environment – bacteria found in microorganisms. , Example. As they explain in the article, “Our data support the idea that systemic RNA signaling must be tightly regulated, and imbalance of this process leads to a reduction in lifespan. We have termed this phenomenon systemic intracellular/extracellular RNA dysregulation.” Cell(InExS).”

breaking the rules

Murray explained that the decision to investigate the mechanism of transferring RNA between cells was inspired by the discovery of RNA interference, for which the American scientists Andrew Fire and Craig Mello won the 2006 Nobel Prize in Physiology and Medicine. They injected the acid Double-stranded RNA C. elegans To “silence” genes with great precision. “They found that the silencing mechanism affected genes in other tissues as well as the tissues in question, and that it was passed on to subsequent generations,” he said.

The discovery of RNA interference has clarified the mechanisms behind RNA transfer between cells in an organism and between the organism and the environment. It also attributed a central doctrine to molecular biology. Until then, it was thought that information embodied in the genetic code only flowed from… DNA To RNA, and from there to proteins, but Fire and Craig's work revealed that double-stranded RNA could block this flow. Messenger RNA is destroyed by RNA interference, which silences specific genes without changing the DNA sequence, showing that RNA can also perform a regulatory function in the genome. Although the human genome contains about 30,000 genes, only a few are used in each cell to synthesize proteins. A large proportion 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 associated with aging. In C. elegansThe transfer of RNA between cells involves what are known as RNA interference defective (SID) genes. [responsible for different stages in RNA absorption and export]. We observed that the pattern of gene expression associated with this pathway in specific tissues changed during aging. Messenger RNA that encodes the SID-1 protein [fundamental to cellular uptake of RNA]“For example, it increased in some tissues and decreased in others,” Morey said.

To learn more about the role of RNA in tissue signaling, the researchers conducted experiments in which they manipulated the expression of the SID-1 protein in specific tissue lines. C. elegansSuch as nerve cells, intestines, and muscles, in order to change their function.

“We found that mutants with no-function SID-1 were as healthy as wild-type worms, while overexpression of SID-1 in the intestine, muscle, or neurons shortened the lifespan of the respective worms. We also found that reduced lifespan was associated with “By overexpressing other proteins in the RNA transfer pathway, such as SID-2 and SID-5.”

Dysregulation may underlie the distribution of RNA to tissues. “To dysregulate RNA distribution in worms, we increased SID-1 expression in specific tissues [gut, muscles, and neurons] It was found that directing it to a specific organ led to a decrease in lifespan.

“We also showed that this defect in transfer RNA led to a loss of function in the pathway that produces microRNAs.” [small pieces of non-coding RNA with a regulatory function]. It is as if the greater number of RNAs transferred to these tissues created a kind of competition in which the production of microRNAs was the loser. Previous research had already shown that loss of function in microRNA production led to decreased lifespan.

The UNICAMP group has also investigated the transfer of exogenous RNA (between the external environment and the organism). As in previous experiments, decreased lifespan is associated with overexpression of SID-2, which mediates RNA uptake from the intestine, and with overproduction of RNA by the bacteria that the worms feed on and that end up In intestinal microorganisms.

“We think worms may use exogenous RNA to monitor microorganisms in the environment, but negative effects may occur when their tissues absorb excessive amounts,” Morey said. “When we forced bacteria in the laboratory to express more dsRNA, the lifespan of the worms decreased. Excess RNA transfer interferes with homeostasis and endogenous RNA production, which accelerates the aging process.”

Reference: “Tissue-specific overexpression of systemic RNA interference components limits lifespan in C. elegans” by Henrique Camara, Mehmet Dinçer Inan, Karls A. Vergani-Junior, Silas Pinto, Thiago L. Knittel, Willian G. Salgueiro, Guilherme Tonon-da Silva, Juliana Ramírez, Diogo de Moraes, Dessie L. Braga, Evandro A. D'Souza and Marcelo A. Mori, November 18, 2023, The gene.
doi: 10.1016/j.gene.2023.148014

The study was funded by the Sao Paulo Research Foundation.