Healthcare

Mild stress on mitochondria increases longevity in worms

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Mitochondria are vital organelles for the body, as they produce most of the energy used by cells from food. Although it seems counter-intuitive, there is evidence that mild impairment of mitochondrial function is associated with increased longevity.

In a study recently published in The Embo Journal, an international group of researchers discovered how this happens. According to the authors, the work is the first to show the involvement of the innate immune system (the first line of defense against pathogens) in this process.

“When mitochondria work below what is considered optimal, it generates stress for the cell, which triggers a series of responses that protect this organism against pathogens, making it live longer. But there is a threshold: if the reduction of mitochondrial function is too intense, the system can collapse”, explains Juliane Campos, first author of the work, who is currently doing a postdoctoral internship at Harvard Medical School (United States) with a grant from Fapesp.

“Today we know that, in the face of mild mitochondrial stress, [como o induzido pelo exercício físico], the cell biochemically reorganizes itself to compensate for such an imbalance and this makes it more prepared to deal with future adverse situations. Now, if mitochondrial stress is excessive and prolonged [caso das doenças crônico-degenerativas]these substitutes become insufficient, resulting in the collapse and, consequently, in cell death”, explains Júlio Cesar Batista Ferreira, associate professor at the Institute of Biomedical Sciences and at the Faculty of Medicine at USP (University of São Paulo) and co-author of the work .

According to Campos, mitochondrial dysfunction usually has a trigger. “There are mutations in humans that lead to sustained dysfunction, usually in more severe cases. [como a restrição calórica] that can transiently reduce mitochondrial function and this is different from individual to individual. The idea is to understand the mechanisms by which this slight mitochondrial disturbance increases longevity because, then, future therapeutic targets can be identified”, he summarizes.

experimental model

To understand the connection between mild mitochondrial dysfunction, longevity and the innate immune system, the group used a soil worm, the Caenorhabditis elegans. It is one of the best known experimental models for the study of aging, as it offers some advantages. One of them is the average life expectancy of just 17 days.

“The lifespan of a rodent is two and a half years; of a drosophila, four months. So, thinking in terms of research time, this is an advantage. C. elegans it is transparent, which makes it possible to visualize organs and couple fluorescent proteins to identify some phenotype within that organism. And, despite being far from humans in the evolutionary chain, it has a high homology with the human genome. Up to 80% of its genes have human counterparts. Another advantage: it feeds on bacteria, so it is very easy to manipulate a specific gene in this organism”, explains the researcher.

For the experiment, the scientists grew a bacterium and, inside it, inserted a machinery capable of deleting a gene in the Ç. elegans. The modified microorganism was offered as food to the worm. Upon ingesting it, this machinery began to act and turned off a specific gene. Ferreira recalls that in genetics there are two ways of understanding the role of a gene. “Either you take it out of the system and see what happens; or you increase its expression in the system and evaluate the effect.”

The group wanted to know why the animal lives longer when the mitochondria are under slight metabolic stress. But this task is not easy. “There are thousands of genes producing proteins, which work in a coordinated and hierarchical way in cells. In this sense, we identified the critical genes involved in increasing longevity due to slight mitochondrial dysfunction. As a proof of concept, we individually turned off these genes and saw that the animals stopped living longer in the face of slight mitochondrial dysfunction”, explains Campos.

The conclusion is that activating the innate immune system is a prerequisite for longevity: when the mitochondria have a slight dysfunction, it is activated and this is necessary for the animal to live longer or protect itself against pathogens.

“In short, mitochondria under stress send a warning signal to the immune system. And this signal makes the organism live longer. When we delete genes related to the innate immune system or prevent them from being activated in this animal with mild dysfunction mitochondria, all this beneficial response is abolished.”

In previous work published by the team, it had already been established that two transcription factors (proteins that control the transcription of genes) were involved in increasing the longevity of these animals: DAF-16 (in Ç. elegans) or FOXO3 (in humans) and ATFS-1 (in Ç. elegans) or ATF5 (in humans). But these proteins coordinate several pathways.

“We knew that mild mitochondrial dysfunction increased longevity and that these two transcription factors coordinated the process, but we wanted to know in what ways they did so. Knowing that these factors also control the innate immune system, we assumed that they would also be involved in the process. This new work demonstrates that both the signaling pathway mediated by the p38 protein and the signaling pathway mediated by mitochondrial misfolded proteins [que em inglês são conhecidas pela sigla mitoUPR] act together on the same innate immunity genes to promote pathogen resistance and longevity. And mitochondria can prolong longevity by signaling through these pathways. We also discovered that the transcription factor ATF 5 is able to warn the immune system genes that they need to form new proteins, which will coordinate this cascade of activation of the immune system in the cell”, says Campos.

Therapeutic approaches

According to Ferreira, most of the diseases we develop are associated with mitochondrial collapse. In this sense, a better understanding of the functioning of mitochondria under stress conditions, as well as its connections with other cellular compartments, is essential to develop pharmacological and non-pharmacological strategies capable of preventing, mitigating or reversing such collapse and, consequently, treating patients.

According to the researcher, improving life expectancy is something we’ve seen for a long time, but increasing longevity is an ambitious goal. “I don’t know if we will actually get there, but I believe that we will certainly be able to make the individual live better for the same period, that is, promote an improvement in the quality of life. We know that there are certain diseases associated with aging, such as Parkinson’s, Alzheimer’s and cardiovascular disorders In this sense, the understanding of the compensatory and deleterious responses of mitochondria associated with aging will serve as a foundation for the development of therapies that act at the heart of these diseases.

The researcher highlights the possibility of modulating the innate immune system, which could contribute to a healthier aging process. “The challenge now is to validate this throughout evolution. Our experimental model lives for 20 days and we live for 80 years. So, now, we have to verify what the impact of our discovery is for humans.”

The article “Mild mitochondrial impairment enhances innate immunity and longevity through ATFS-1 and p38 signaling” can be read online.

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