Age is widely recognised as a major factor in the development of cancer. This is partly because, over time, cells accumulate random mutations that can lead to cancer. However, other factors beyond these cell mutations also seem to influence cancer rates in older adults. One of these factors is the accumulation of senescent cells, which are cells that have stopped dividing and contribute to chronic inflammation, promoting tumour growth and invasiveness.

As we age, our telomeres—the protective caps on the ends of our chromosomes—shorten and become damaged. This leads to an increase in senescent cells. People with genetic conditions that affect telomere maintenance, known as telomeropathies, experience premature telomere shortening, have shorter lifespans, and are at a higher risk of developing cancer. Similarly, mice that lack the enzyme telomerase exhibit premature aging, reduced lifespans, and an increased incidence of tumours.

Recently, zebrafish have emerged as a valuable model for studying the role of telomeres in aging and cancer. Unlike mice, zebrafish have telomere lengths similar to humans, which shorten significantly as they age. We have shown that telomerase mutant zebrafish, which have shorter telomeres, display premature aging and an increased risk of developing cancer, much like humans with telomeropathies.

One of the first organs to show critical telomere shortening during aging is the gut, due to its high cell turnover rate. In our studies, we have observed that telomerase mutant zebrafish exhibit loss of gut tissue integrity and increased intestinal permeability, similar to conditions seen in patients with inflammatory bowel disease (IBD). This gut dysfunction can drive systemic inflammation and increase cancer risk. Importantly, we found that restoring telomerase expression specifically in the gut of zebrafish can restore gut health, counteract aging in other organs, and even extend lifespan.

Based on this evidence, we propose that aging of the gut contributes to the increased cancer incidence seen with age. This project lead by Dr. Miguel FERREIRA aims to test whether gut telomere shortening is necessary and sufficient to induce local and systemic inflammation and create a tumour-prone environment. The team will investigate how gut dysfunction sends signals throughout the body that lead to higher cancer rates. Specifically, we will examine which senescence-associated or inflammatory signals are involved in this process and determine if the immune system plays a key role in spreading these inflammatory signals.

By understanding these mechanisms, we hope to develop new strategies to reduce cancer risk and improve health in older adults.