Studies on the roundworm species C. elegans have shown that disruptions in RNA transfer between cells in various tissues can lead to shortened lifespan. Cells in different tissues interact using common RNA molecules. A study by scientists from the State University of Campinas (UNICAMP) in Brazil using the roundworm Caenorhabditis elegans found that disruptions in this form of communication can lead to a shortened lifespan of the organism. The research was recently published in the journal Gene. The data obtained contributes to a better understanding of the aging process and related diseases.

“Previous studies have shown that some types of RNA can be transferred from one cell to another by mediating intertissue communication, such as in proteins and metabolites. It is considered a mechanism for signal transduction between organs or neighboring cells. This part [фізіопатології] Marcelo Mori, corresponding author of the article and professor at the Institute of Biology (IB-UNICAMP), “various diseases and the normal functioning of the body.” said. “What was unclear, and what we can now prove, is that changes in the pattern of this ‘talk’ between RNA molecules can affect aging.”

The study was conducted at UNICAMP’s Obesity and Related Diseases Research Center (OCRC), one of the Research, Innovation and Dissemination Centers (RIDC) funded by FAPESP. It was also funded through a project on which Mori was the principal investigator.

“This communication mechanism must be fine-tuned to provide the organism with a sufficient lifespan. In our study, we found that if any tissue increases its ability to take up certain types of RNA from the extracellular environment, this ultimately affects the lifespan of the organism.” said Morey.

The researchers added that the reduction in lifespan is not only due to the disruption of RNA-based communication between tissues in the same organism, but also due to an increased ability to absorb RNA (bacteria in the microbiota) from the environment. , For example. As they explain in the paper: “Our data support the idea that systemic RNA signaling must be tightly regulated and that an imbalance in this process results in reduced lifespan. We termed this phenomenon intercellular/extracellular systemic RNA imbalance (InExS).”

Breach

Mori explained that his decision to investigate the mechanism of intercellular transport of RNA was inspired by the discovery of RNA interference, for which American scientists Andrew Fire and Craig Mello received the 2006 Nobel Prize in Physiology or Medicine. They introduced double-stranded RNA C. elegans “silencing” genes with high precision. “They found that the silencing mechanism affects genes in other tissues as well as the relevant tissues, and this is passed on to the next generation,” he said.

The discovery of RNA interference elucidated the mechanisms underlying the transfer of RNA between body cells and between the body and the environment. It also relativized the central dogma of molecular biology. Until then, it was thought that the information contained in the genetic code flowed only from DNA to RNA to proteins, but Fire and Craig’s work revealed that double-stranded RNA could block this flow. The disruption of messenger RNA by RNA interference that silences specific genes without changing the DNA sequence suggests that RNA may also have a regulatory function in the genome. Although the human genome contains approximately 30,000 genes, only a few of them are used in protein synthesis in each cell. A significant number of them play a regulatory role, affecting the expression of other genes.

Balance is everything

“We wanted to understand how this process might affect important physiological functions associated with aging. IN C. elegans Transfer of RNA between cells involves genes known as systemic RNA interference defects (SIDs). [відповідальні за різні етапи поглинання та експорту РНК]. We observed that the gene expression pattern associated with this pathway in certain tissues changes during aging. Matrix RNA encoding SID-1 protein [фундаментальний для клітинного поглинання РНК]for example, there was an increase in some tissues and a decrease in others,” Morey said.

To learn more about the role of RNA in interstitial signaling, the researchers conducted experiments in which they manipulated the expression of the SID-1 protein in specific tissues. C. elegansTo change the functions of neurons, gut and muscle cells.

“We found that while SID-1 loss-of-function mutants were as healthy as wild-type worms, overexpression of SID-1 in the intestine, muscle, or neurons shortened the lifespan of the relevant worms. We also found that the reduced lifespan was associated with overexpression of other proteins in the RNA transport pathway, such as SID-2 and SID-5.” “We also found that it is associated with its expression,” he said.

There may be irregularity in the distribution of RNA in the tissue. “We increased SID-1 expression in specific tissues to disrupt regulation of RNA distribution in worms [кишковій системі, м’язах і нейронах] and found that directing it to a specific organ led to a reduction in life expectancy,” he said.

“We also showed that this imbalance in transfer RNA leads to loss of function in the pathway that produces miRNAs. [невеликі шматочки некодуючої РНК з регуляторною функцією]. The increased amount of RNA transported to these tissues appears to create a form of competition that results in loss of miRNA production. Previous studies have already shown that loss of miRNA production function leads to reduced lifespan.”

The UNICAMP group also investigated exogenous transfer of RNA (between the external environment and the organism). As in previous experiments, reduced lifespan was associated with overexpression of SID-2, which mediates RNA uptake from the gut, and overproduction of RNA by bacteria on which the worms feed and enter the gut microbiota.

“We believe that worms can use exogenous RNA to monitor microorganisms in the environment, but when it ingests tissues in excess, negative consequences can occur,” Morey said. “When we forced bacteria in the laboratory to express more double-stranded RNA, the lifespan of the worms was shortened. Excessive RNA transfer interferes with homeostasis and endogenous RNA production, accelerating the aging process.”