Research that shows that telomeres, mitochondria and inflammation work together to prevent cancer could lead to interventions to offset the harmful consequences of aging.

The relationship between cancer and aging is a complicated one; age is the single biggest risk factor for cancer, but cancer – and its treatment – may contribute to an accelerated aging phenotype. And despite the risk of cancer increasing with age, adults with the longest longevity are actually less likely to develop cancer. [1] The Hallmarks of Aging [2] were inspired by the Hallmarks of Cancer [3], and aging and cancer share many hallmarks, such as genomic instability.

Now scientists at the Salk Institute have further teased out the relationship between aging pathways and cancer, and it could lead to novel interventions that counter the harmful effects of aging [4].

Longevity.Technology: As we age, the end caps of our chromosomes, called telomeres, gradually shorten. Now, Salk scientists have discovered that when telomeres become very short, they communicate with mitochondria, the cell’s powerhouses. This communication triggers a complex set of signaling pathways and initiates an inflammatory response that destroys cells that could otherwise become cancerous.

The findings, published last week in Nature, could lead to new ways of preventing and treating cancer as well as designing better interventions to offset the harmful consequences of aging.

The discovery is the result of a collaboration between co-senior authors and Salk Professors Jan Karlseder and Gerald Shadel, who teamed up to explore similarities they had each found in inflammatory signaling pathways. Karlseder’s lab studies telomere biology and how telomeres prevent cancer formation. Shadel’s lab studies the role mitochondria play in human disease, aging, and the immune system.

“We were excited to discover that telomeres talk to mitochondria,” says Karlseder, holder of the Donald and Darlene Shiley Chair. “They clearly synergize in well-controlled biological processes to initiate cellular pathways that kill cells that could cause cancer.”

When telomeres shorten to a point where they can no longer protect chromosomes from damage, a process called “crisis” occurs, and cells die. This beneficial natural process removes cells with very short telomeres and unstable genomes and is known to be a powerful barrier against cancer formation. Karlseder and the study’s first author Joe Nassour, a senior research associate in the Karlseder lab, previously discovered that cells in crisis are removed by autophagy, the process by which the body rids itself of damaged cells.

Autophagy declines with age, and is thought to contribute to the accumulation of damaged macromolecules and organelles that happens during aging. Failing autophagy has been associated with the worsening of aging-associated diseases, including neurodegeneration and cancer [5].

In this study, the team wanted to know how autophagy-dependent cell-death programs are activated during crisis, when telomeres are extremely short. By conducting a genetic screen using human skin cells called fibroblasts, the scientists discovered interdependent immune sensing and inflammatory signaling pathways – similar to the ones by which the immune system combats viruses – that are crucial for cell death during crisis. Specifically, they found that RNA molecules emanating from short telomeres activate immune sensors called ZBP1 and MAVS in a unique way on the outer surface of mitochondria.

The findings demonstrate important links between telomeres, mitochondria and inflammation and underscore how cells can bypass crisis (thereby evading destruction) and become cancerous when the pathways are not functioning properly.

“Telomeres, mitochondria, and inflammation are three hallmarks of aging that are most often studied in isolation,” says Shadel, holder of the Audrey Geisel Chair in Biomedical Science and director of the San Diego Nathan Shock Center of Excellence in the Basic Biology of Aging. “Our findings showing 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.”

“Cancer formation is not a simple process,” says Nassour. “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 plan to further examine the molecular basis of these pathways and explore the therapeutic potential of targeting these pathways to prevent or treat cancer and hopefully further explore and leverage the relationship between telomeres and mitochondria.

Main image shows telomeres (green) and DNA (blue) during DNA repair activities. Credit: Salk Institute.

[1] https://pubmed.ncbi.nlm.nih.gov/15571545/
[2] https://www.cell.com/cell/fulltext/S0092-8674(13)00645-4
[3] https://www.cell.com/cell/fulltext/S0092-8674(00)81683-9
[4] https://www.nature.com/articles/s41586-023-05710-8
[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333684/