Our chromosomes’ end caps, known as telomeres, increasingly shrink as we become older. Salk researchers have now shown that when telomeres are very short, they talk to the mitochondria, which are the cell’s powerhouses.

This communication sets off a sophisticated network of signaling channels and starts an inflammatory reaction that kills cells that may otherwise develop into cancer.

The results, which were published in Nature today, might lead to new strategies for preventing and treating cancer, as well as the development of more effective therapies to counteract the negative effects of aging.

The discovery was made by co-senior authors and Salk Professors Jan Karlseder and Gerald Shadel, who worked together to look for similarities in the inflammatory signaling pathways they had each found on their own. Karlseder’s research group is interested in the biology of telomeres and how they play a role in preventing cancer. Shadel’s lab looks at how mitochondria affect disease, getting older, and the immune system.

“We were excited to discover that telomeres talk to mitochondria,” adds Karlseder. “They clearly synergize in well-controlled biological processes to initiate cellular pathways that kill cells that could cause cancer.”

Crisis develops and cells perish when telomeres get too short to prevent damage to chromosomes.

This advantageous natural mechanism eliminates cells with unstable genomes and extremely short telomeres, and it is well-known to be a good barrier against the development of cancer.

Karlseder and the study’s first author, Joe Nassour, a senior research associate in Karlseder’s lab, had already found that the body gets rid of damaged cells through a process called autophagy when cells are in trouble.

The goal of this work was to determine how telomere-shortening crises trigger autophagy-dependent cell-death systems.

Scientists used human skin cells called fibroblasts to do a genetic screen. They found interdependent immune sensing and inflammatory signaling pathways, which are similar to the ones the immune system uses to fight viruses and are important for cell death in times of stress.

In particular, they discovered that RNA molecules released by short telomeres activate immunological sensors ZBP1 and MAVS in a manner distinct from that of other types of mitochondria.

The results underline how cells may skip crisis (thus escaping elimination) and becoming malignant when the pathways are not working correctly and show significant connections between telomeres, mitochondria, and inflammation.

“Telomeres, mitochondria, and inflammation are three hallmarks of aging that are most often studied in isolation,” remarks Shadel. 

The findings of the study show “that stressed telomeres send an RNA message to mitochondria to cause inflammation highlights the need to study interactions between these hallmarks to fully understand aging and perhaps intervene to increase health span in humans.”

Nassour claims that cancer development is not a straightforward process. 

“It is a multistep process that requires many alterations and changes throughout the cell. A better understanding of the complex pathways linking telomeres and mitochondria may lead to the development of novel cancer therapeutics in the future.”

Next, the scientists want to learn more about how these pathways work at the molecular level and look into how they might be used to prevent or treat cancer.

Source: 10.1038/s41586-023-05710-8

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