A subset of gut leukocytes have telomerase-dependent “hyper-long” telomeres and require telomerase for function in zebrafish

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. Using the zebrafish model, we show that subsets gut immune cells have telomerase-dependent 'hyper-long' telomeres, which we identified as being predominantly macrophages and dendritics (mpeg1.1+ and cd45+mhcII+). Notably, mpeg1.1+ macrophages have much longer telomeres in the gut than in their haematopoietic tissue of origin, suggesting that there is a gut-specific modulation of telomerase in these cells. Moreover, we show that a subset of gut mpeg1.1+ cells express telomerase (tert) in young WT zebrafish, but that the relative proportion of these cells decreases with ageing. Importantly, this is accompanied by telomere shortening and DNA damage responses with ageing and a telomerase-dependent decrease in expression of autophagy and immune activation markers. Finally, these telomerase-dependent molecular alterations are accompanied by impaired phagocytosis of E.coli and increased gut permeability in vivo. Together, our data show that limiting levels of telomerase lead to changes in gut immunity and gut permeability, which, together, are likely contributors to local and systemic tissue degeneration and increased susceptibility to infection with ageing.

A subset of gut leukocytes has telomerase-dependent “hyper-long” telomeres and require telomerase for function in zebrafish

“…Telomerase has been described to have both canonical (telomere elongation) and non-canonical (telomere elongation-independent) functions. We therefore set out to determine the key molecular changes occurring in gut mpeg + cells in the absence of telomerase (tert), at the young age of c.5 months, where the levels of critically short telomeres are not yet sufficient to induce a significant accumulation of DNA damage response markers [56,72]. This means that most changes that we detect in the gut of young tert −/− animals are more likely to be due to absence of tert itself and its noncanonical functions, rather than telomere-induced DNA damage.…”

“…Genotyping was performed by PCR of the tert gene [29,30]. The telomerase null mutant (tert −/− ) zebrafish, extensively characterised elsewhere [29][30][31]72], displays no telomerase activity and has significantly shorter telomeres from birth, ageing and dying prematurely [29]. While tert −/− fish have a lifespan of c.12-20 months, WT fish typically die between 36-42 months of age [29,30].…”

Transcriptomic Signatures of Telomerase-Dependent and -Independent Ageing, in the Zebrafish Gut and Brain

“…As recently showed in (Dambroise et al, 2016), zebrafish age following the two-phase model first proposed flies (Tricoire & Rera, 2015), based on the age-related intestinal permeability assessed using the Smurf assay they previously described (Rera, Clark, & Walker, 2012). Moreover, we have recently shown that gut permeability with ageing, in zebrafish, is accelerated in the absence of telomerase (tert -/-) (Pam S. Ellis, 2022).…”

“…As recently showed in (Dambroise et al, 2016), zebrafish age following the two-phase model first proposed flies (Tricoire & Rera, 2015), based on the age-related intestinal permeability assessed using the Smurf assay they previously described (Rera, Clark, & Walker, 2012). Moreover, we have recently shown that gut permeability with ageing is accelerated in the absence of telomerase (tert -/-) (Pam S. Ellis, 2022). Following this model and considering the longevity curve from the population we sampled, the proportion of Smurfs might have been approximately, <10% at 2 month, 25% at 9 month, 50% at 22 months and >80% at 35 months.…”