Study shows how mitochondria regulate lifespan by activating the immune system

Findings published by researchers at the University of São Paulo may point to novel therapeutic targets for aging-related disorders such as neurodegenerative and cardiovascular diseases.

By Karina Ninni  |  Agência FAPESP – Mitochondria are cell organelles that play a vital role in the organism, generating most of the energy needed to power the body’s biochemical reactions from food. Paradoxically, there is evidence that mild impairment of mitochondrial functioning is associated with an increase in longevity.

A study by an international group of researchers shows how this happens. Reported in an article published in The Embo Journal, it is the first study to confirm involvement of the innate immune system, the front line of defense against pathogens, in lifespan extension, the authors claim.

“Below-optimal performance by the mitochondria stresses the cells and triggers a series of responses that protect the organism against pathogens so that it lives longer. However, there’s a limit, and the system can collapse if mitochondrial functioning is severely impaired,” said Juliane Campos, first author of the article. Campos is currently on a postdoctoral internship at Harvard Medical School in the United States with a scholarship from FAPESP. 

“We now know that in response to mild mitochondrial stress [like that induced by physical exercise], cells reorganize biochemically to offset this imbalance and thereby become more prepared to cope with future adverse situations. However, if mitochondrial stress is excessive and prolonged [as in chronic degenerative diseases], these substitutes are insufficient and the result is collapse and cell death,” said Júlio Cesar Batista Ferreira, a co-author of the article. Ferreira is a professor at the University of São Paulo’s Biomedical Sciences Institute (ICB-USP) and Medical School (FM-USP) in Brazil.

According to Campos, mitochondrial dysfunction usually has a trigger. “There are mutations in humans that lead to sustained dysfunction, typically in the most severe cases,” she said. “There are also some conditions [such as caloric restriction] that can temporarily reduce mitochondrial functioning, but this differs from one person to another. Our goal is to understand the mechanisms whereby mild mitochondrial disruption extends lifespan because it will then be possible to identify future therapeutic targets.”

Experimental model

To investigate the link between mild mitochondrial dysfunction, longevity and the innate immune system, the group chose the nematode Caenorhabditis elegans, one of the most widely used experimental models for the study of aging, given several advantages such as a 17-day average lifespan.

“A rodent typically lives for two and a half years, and a fruit fly for four months. So the short lifespan of C. elegans is an advantage for research purposes,” Campos explained. “In addition, C. elegans is transparent. Its organs can easily be seen, and fluorescent proteins can be inserted to help identify phenotypes inside it. Although it’s distant from humans in the evolutionary chain, its genome is very similar to ours. Up to 80% of its genes are homologs of human genes. Yet another advantage is that it feeds on bacteria, and specific genes can easily be manipulated.”

For the experiment, the scientists cultured a bacterium and used it to delete a gene in C. elegans. The modified microorganism was offered as food, and when ingested by the worm it switched off a specific gene. Ferreira noted that there are two ways to analyze the role of a gene. “You remove it from the system and see what happens, or you increase its expression in the system and evaluate the effect,” he said.

The group wanted to know why the animal lives longer when its mitochondria undergo mild metabolic stress, but this is no easy task. “Thousands of genes produce proteins, which act in a coordinated and hierarchical manner in cells. We, therefore, focused on identifying the critical genes involved in lifespan extension due to mild mitochondrial dysfunction. As proof of concept, we switched off these genes one by one, and observed whether the animals lived longer when mitochondrial functioning was mildly impaired,” Campos said.

The conclusion was that activating the innate immune system was a prerequisite for longevity. Mild mitochondrial impairment activated the system, and this was necessary for the animal to live longer or protect itself from pathogens.

“In short, stressed mitochondria send a warning signal to the immune system, and this signal makes the organism live longer. When we deleted genes associated with the innate immune system or prevented their activation in the animals with mild mitochondrial dysfunction, all of this beneficial response was abolished,” she said.

Previous research published by the group had already established that two transcription factors (proteins that control gene transcription) were involved in lifespan extension: DAF-16 in C. elegans or FOXO3 in humans; and ATFS-1 or ATF5 respectively. These proteins coordinate different pathways, however.

“We knew mild mitochondrial dysfunction increased lifespan, and these two transcription factors coordinated the process, but we wanted to find out which pathways were involved,” Campos explained. “Given that the transcription factors also control the innate immune system, we assumed they were also involved in this phenotype. Our latest study showed that both the signaling pathway mediated by the protein p38 and the signaling pathway mediated by the mitochondrial unfolded protein response [mitoUPR] act together on the same innate immunity genes to promote resistance to pathogens and longevity. The mitochondria can prolong lifespan by signaling via these pathways. We also discovered that transcription factor ATF5 is able to warn immune system genes that they need to form new proteins, which will coordinate this immune system activation cascade in cells.”

Therapeutic approaches

According to Ferreira, most human diseases are associated with mitochondrial collapse, and a deeper understanding of how mitochondria function under stress, and of their links with other cellular compartments, is essential to the development of pharmacological and non-pharmacological strategies to prevent, mitigate or reverse this collapse in order to treat disease.

Life expectancy has been increasing for some time, he added, but extending lifespan is an ambitious goal. “I don’t know if we can achieve it, but I believe we’ll certainly improve the quality of people’s lives in the meantime. We know certain diseases are associated with aging, such as Parkinson’s, Alzheimer’s, and cardiovascular disorders. A better understanding of compensatory and deleterious mitochondrial responses in aging will therefore serve as a basis for the development of therapies that go to the heart of these diseases. Our latest study completes one more piece of the puzzle,” he said.

Another point he stressed is the possibility of modulating the innate immune system, which could contribute to healthy aging. “The challenge now is to validate this for the entire life course. Our experimental model lives for 20 days, whereas we live for 80 years, so we must now find out how our discovery affects human beings,” he said.

The article “Mild mitochondrial impairment enhances innate immunity and longevity through ATFS-1 and p38 signaling” is at: www.embopress.org/doi/full/10.15252/embr.202152964.