Preprint reports that telomerase in blood-forming cells extended lifespan in immunodeficient fish without detectable telomere lengthening

Preprint reports that telomerase in blood-forming cells extended lifespan in immunodeficient fish without detectable telomere lengthening

In a preprint on Research Square posted on October 9 that has yet to undergo peer review, biologists described an experiment in zebrafish with a defective rag1 gene. These fish lack adaptive immunity and develop intestinal and microbiota abnormalities with age. The researchers increased expression of tert, the gene encoding the catalytic component of telomerase, in blood-forming tissue and monitored survival, blood cells, and organ health.

Telomerase maintains telomeres, the protective ends of chromosomes. The intervention increased mean lifespan in rag1-deficient fish, although measurements in blood-forming tissue showed no statistically significant change in telomere length.

These fish had a more permeable intestinal barrier, and their microbial communities diverged further from those of healthy fish as they aged. The researchers tested the role of the microbiota through two interventions. Starting at three months of age, the fish received a combination of antibiotics each week. This reduced bacterial numbers, improved survival, and decreased the activity of inflammation-related genes in the intestine and blood-forming tissue. In the reverse experiment, microbiota from the mutant fish became established in healthy fish and transferred some of the molecular signs of inflammation and intestinal dysfunction.

The researchers then increased tert expression specifically in blood-forming tissue, where blood cells are produced. Mean lifespan in rag1-deficient fish increased by approximately eight months. Expression of stress- and inflammation-related genes changed in blood-forming tissue, while the proportions of the major blood cell groups remained largely unchanged. At the same time, there were fewer dying cells in the intestine and fewer vacuoles, or cavities within cells, in the liver. The microbiota composition also shifted partway toward that of healthy fish.

In a 2023 study, activating tert in the intestine of fish lacking their own telomerase lengthened telomeres in that tissue and extended lifespan. In the present study, increasing tert expression in blood-forming tissue altered gene expression there, along with the condition of the intestine and the microbiota. Measurements detected no widespread telomere lengthening in blood-forming tissue.