Telomerase-Dependent Ageing In The Zebrafish Brain

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. RNA-Sequencing of whole brain tissues, throughout the lifespan of WT and telomerase-deficient (tert-/-) fish. The data 4 age-groups of WT (2, 9, 22 and >30 months), corresponding to young, adult, median lifespan and old; and 3 age-groups of telomerase-deficient fish (2, 9, and 22 months), which correspond to young, medium lifespan and old. Each group has a sample size of 3 animals. To identify signatures of ageing, WT brain samples were subjected separately to DESEq2 analysis, comparing the time points 9, 22 and >30 months with the time-point of 2 months. Then, tert-/- samples at 2, 9 and 22 months were compared with WT at 2 months, to identify telomerase-dependent ageing processes.