Discovery of an important molecular pathway for the control of aging

One way that cells in different tissue types communicate is by exchanging RNA molecules. In experiments with roundworms of the species Caenorhabditis elegans, researchers from the State University of Campinas (UNICAMP) in Brazil discovered that when this communication pathway is dysregulated, the organism’s lifespan is shortened.

An article on the study is published in the journal Embarrassed. The results contribute to a better understanding of the aging process and associated diseases.

“Previous research has shown that certain types of RNA can be transferred from one cell to another, thus providing communication between tissues, such as that which occurs with proteins and metabolites, for example. This is considered a signaling mechanism between organs or neighboring cells. It is part (of the pathophysiology) of several diseases and of the normal functioning of the organism,” 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 managed to prove it, is that changes in the pattern of this ‘conversation’ between RNA molecules can affect aging.”

“This communication mechanism must be well adjusted to give the organism an adequate lifespan. In the study, we found that if a tissue increases its ability to absorb certain types of RNA from the extracellular medium, it eventually impact the lifespan of the organism,” Mori said.

The researchers demonstrated that the reduction in lifespan was due not only to the disruption of RNA-based communication between tissues within the same organism, he added, but also to an increase in ability to absorb RNA from the environment – ​​bacteria in the microbiota, for example. example.

As they explain in the paper: “Our data support the idea that systemic RNA signaling must be tightly regulated and imbalance in this process causes a reduction in lifespan. We called this phenomenon systemic intercellular/extracellular RNA imbalance (InExS). »

Break the rules

Mori explained that the decision to research the mechanism of intercellular RNA transport was inspired by the discovery of RNA interference, for which American scientists Andrew Fire and Craig Mello won the Nobel Prize in Physiology and of Medicine in 2006. They injected double-stranded RNA into C. elegans to “silence” genes with great precision.

“They found that the silencing mechanism affected genes in other tissues as well as the involved tissues and was passed on to subsequent generations,” he said.

The discovery of RNA interference has elucidated the mechanisms underlying the transfer of RNA between the cells of an organism and between the organism and the environment. It also put into perspective a central dogma of molecular biology. Until then, it was thought that the information contained in the genetic code flowed only from DNA to RNA and from there to proteins, but the work of Fire and Craig revealed that double-stranded RNA could block this flow.

Messenger RNA is destroyed by RNA interference, which silences specific genes without altering the DNA sequence, showing that RNA can also serve a regulatory function in the genome. Although the human genome includes some 30,000 genes, only a few are used in each cell to synthesize proteins. Much of it plays a regulatory role, influencing the expression of other genes.

Balance is everything

“We wanted to understand how this process might interfere with important physiological functions linked to aging. In C. elegans, RNA transfer between cells involves so-called systemic RNA interference defective (SID) genes (responsible for of different stages of RNA absorption and export).

“We observed that a pattern of gene expression associated with this pathway in specific tissues changed during aging. The messenger RNA that encodes the SID-1 protein (fundamental to cellular uptake of RNA) , for example, increased in some tissues and decreased in others,” Mori says.

To learn more about the role of RNA in intertissue signaling, the researchers conducted experiments in which they manipulated SID-1 protein expression in specific C. elegans tissues, such as neuronal cells, intestinal and muscular, in order to change its function.

“We found that mutants lacking SID-1 function were as healthy as wild-type worms, while overexpression of SID-1 in the gut, muscle, or neurons shortened the lifespan of affected worms. We also found that a reduction in lifespan correlated with overexpression of other proteins in the RNA transport pathway, such as SID-2 and SID-5. “, did he declare.

The dysregulation may reside in the distribution of RNA in tissues. “To deregulate RNA distribution in worms, we increased the expression of SID-1 in specific tissues (intestines, muscles and neurons) and found that channeling it to a specific organ led to a reduction in the duration of life,” he said.

“We also showed that this imbalance in RNA transfer led to a loss of function in the microRNA production pathway (small pieces of non-coding RNA with a regulatory function). It is as if the greatest number of RNA transported to these tissues created a sort of competition in which microRNA production was a loser. Previous research had already shown that loss of function in microRNA production led to a reduction in lifespan.

The UNICAMP group also studied the transfer of exogenous RNA (between the external environment and the organism). As in previous experiments, a reduction in lifespan is correlated with the overexpression of SID-2, which is involved in the absorption of RNA by the intestine, and with excessive production of RNA by bacteria including the worms feed on and which are found in its intestinal microbiota.

“We believe that worms can use exogenous RNA to monitor microorganisms in the environment, but negative effects can occur when excessive amounts are taken up by their tissues,” Mori said. “When we forced bacteria in the laboratory to express more double-stranded RNA, the lifespan of the worms decreased. Excessive RNA transfer interferes with homeostasis and endogenous RNA production, thereby speeding up the process of aging.”