A Snapshot seminar hosted by the School of Physiology, Pharmacology and Neuroscience

Host: Chrissy Hammond

Abstract: Telomerase, the enzyme capable of elongating telomeres, is usually restricted in human somatic cells, which contributes to progressive telomere shortening with cell-division and ageing. T and B-cells cells, along with cancer cells are somatic cells that can break this rule and can re-activate telomerase expression. Whether telomerase expression modulation is beneficial or detrimental to a cell or tissue is highly context dependent. The mechanisms, kinetics and tissue-specificity underlying the protective or deleterious mechanisms of telomerase, in humans, however, remain largely unresolved.

Our work, using the zebrafish model which, similarly to humans, depends on telomerase for health and lifespan, combines RNA sequencing, immunofluorescence, in situ hybridisation and in vivo functional assays throughout the life course to shed light on telomerase-dependent and -independent changes with ageing across tissues, aiming to unravel potential common underlying pathways and inter-connections.

Our recent work show that limiting levels of telomerase lead to alterations in gut immunity, impacting on the ability to clear pathogens in vivo. These are accompanied by increased gut permeability, which, together, are likely contributors to local and systemic tissue degeneration and increased susceptibility to infection with ageing. Additionally, we performed whole tissue RNA sequencing of gut and brain, in naturally aged zebrafish alongside prematurely aged telomerase null mutants (tert-/-), throughout their lifespan. We identified key telomerase-dependent and independent common gene and pathway changes between the gut and brain at the early stages of ageing, highlighting potential early intervention therapeutic targets for preventing age-associated dysfunction in both tissues. These correlate with our recent and unpublished work that identified telomerase-dependent increase in inflammation and senescence in the brain, which accompany functional dysfunction.