Telomerase-Dependent Ageing In The Zebrafish Brain
Abstract
Decreased telomerase expression, telomere shortening, senescence-associated markers and inflammation have all been independently observed in the ageing brain and associated with disease. However, causality between limited telomerase expression and brain senescence and neuro-inflammation in the natural ageing setting is yet to be established. Here, we address these questions using the zebrafish as an ageing model which, akin to humans, displays premature ageing and death in the absence of telomerase and where telomere shortening is a driver of cellular senescence.
Our work shows for the first time that telomerase deficiency (tert-/-) accelerates key hallmarks of ageing identified in the Wild Type (WT) zebrafish brain at transcriptional, cellular, tissue and functional levels. We show that Tert-dependent transcriptomic changes associated with dysregulation of gene expression, stress response and dysregulation of immune genes are accompanied by accelerated accumulation of senescence-associated markers and inflammation in the aged brain. Importantly, In vivo, these changes correlate with increased blood-brain barrier permeability and altered cognitive behaviour. Of note, telomerase-dependent accumulation of senescence-associated markers in the brain occurs not only in the expected proliferative areas but also in non-proliferative ones, where it is unlikely due to telomere-dependent replicative exhaustion, suggesting that non-canonical roles of telomerase may be involved.
Together, our work suggests that telomerase has a protective role in the zebrafish brain against the accumulation of senescence and neuro-inflammation and is required for blood brain barrier integrity.
GRAPHICAL ABSTRACT
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/493215v3_ufig1.gif" ALT="Figure 1"> View larger version (19K): [email protected]@1df753org.highwire.dtl.DTLVardef@1588c0eorg.highwire.dtl.DTLVardef@530a99_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical Abstract: The zebrafish brain displays telomerase-dependent transcriptional hallmarks of ageing which associate with telomerase-dependent accumulation of senescence-associated markers and inflammation in the brain. Importantly, in vivo, telomerase deficiency accelerates dysfunction of the blood brain barrier and behavioural change with ageing.
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Research summary
The paper investigates the role of telomerase in the ageing process of the zebrafish brain, specifically focusing on its protective effects against senescence and neuro-inflammation. This addresses a fundamental aspect of the biological aging process, making it relevant to longevity research. However, while the findings contribute to our understanding of telomerase's role in brain aging, the study primarily provides solid research without introducing groundbreaking concepts or methodologies, thus limiting its overall impact.
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