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Telomerase activity is restricted in humans and telomere attrition occurs in several tissues accompanying natural aging. Critically short telomeres trigger DNA damage responses and activate p53 which leads to apoptosis or replicative senescence. These processes reduce cell proliferation and disrupt tissue homeostasis, thus contributing to systemic aging. Similarly, zebrafish have restricted telomerase expression, and telomeres shorten to critical length during their lifespan. Telomerase-deficient zebrafish (tert -/-) is a premature model of aging that anticipates aging phenotypes due to early telomere shortening. tert -/- zebrafish have impaired cell proliferation, accumulation of DNA damage markers and p53 response. These cellular defects lead to disruption of tissue homeostasis, resulting in premature infertility, gastrointestinal atrophy, sarcopenia and kyphosis. Such consequences contribute to its premature death. Here we reveal a genetic interdependence between tp53 and telomerase function. Mutation of tp53 abrogates premature aging of tert -/- zebrafish, prolonging male fertility and lifespan. However, it does not fully rescue healthspan. tp53mut tert -/- zebrafish retain high levels of inflammation and increased spontaneous cancer incidence. Conversely, loss of telomerase prolongs the lifespan of tp53mut single mutants. Lack of telomerase reduces two-fold the cancer incidence in double mutants and increases lifetime survival. Thus, we observe a reciprocal rescue of tp53mut and tert -/- that ameliorates lifespan but not spontaneous cancer incidence of tp53mut, likely due to higher levels of inflammation., (© 2024. The Author(s).)

Telomere length, unlike most genetic traits, is epigenetic, in the sense that it is not fully coded by the genome. Telomeres vary in length and randomly assort to the progeny leaving some individuals with longer and others with shorter telomeres. Telomerase activity counteracts this by extending telomeres in the germline and during embryogenesis but sizeable variances remain in telomere length. This effect is exacerbated by the absence of fully active telomerase. Telomerase heterozygous animals (tert+/-) have reduced telomerase activity and their telomeres fail to be elongated to wild-type average length, meaning that - with every generation - they decrease. After a given number of successive generations of telomerase-insufficient crosses, telomeres become critically short and cause organismal defects that, in humans, are known as telomere biology disorders. Importantly, these defects also occur in wild-type (tert+/+) animals derived from such tert+/- incrosses. Despite these tert+/+ animals being proficient for telomerase, they have shorter than average telomere length and, although milder, develop phenotypes that are similar to those of telomerase mutants. Here, we discuss the impact of this phenomenon on human pathologies associated with telomere length, provide a brief overview of telomere biology across species and propose specific measures for working with telomerase-deficient zebrafish., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Telomere shortening is a hallmark of aging and is counteracted by telomerase. As in humans, the zebrafish gut is one of the organs with the fastest rate of telomere decline, triggering early tissue dysfunction during normal zebrafish aging and in prematurely aged telomerase mutants. However, whether telomere-dependent aging of an individual organ, the gut, causes systemic aging is unknown. Here we show that tissue-specific telomerase expression in the gut can prevent telomere shortening and rescues premature aging of tert -/- . Induction of telomerase rescues gut senescence and low cell proliferation, while restoring tissue integrity, inflammation and age-dependent microbiota dysbiosis. Averting gut aging causes systemic beneficial impacts, rescuing aging of distant organs such as reproductive and hematopoietic systems. Conclusively, we show that gut-specific telomerase expression extends the lifespan of tert -/- by 40%, while ameliorating natural aging. Our work demonstrates that gut-specific rescue of telomerase expression leading to telomere elongation is sufficient to systemically counteract aging in zebrafish., (© 2023. The Author(s).)

One of the hallmarks of cancer is its unlimited replicative potential that needs a compensatory mechanism for the consequential telomere erosion. Telomerase promoter (TERTp) mutations were recently reported as a novel mechanism for telomerase re-activation/expression in order to maintain telomere length. Pancreatic endocrine tumors (PETs) were so far recognized to rely mainly on the alternative lengthening of telomeres (ALT) mechanism. It was our objective to study if TERTp mutations were present in pancreatic endocrine tumors (PET) and could represent an alternative mechanism to ALT. TERTp mutations were detected in 7% of the cases studied and were mainly associated to patients harbouring hereditary syndromes. In vitro, using PET-derived cell lines and by luciferase reporter assay, these mutations confer a 2 to 4-fold increase in telomerase transcription activity. These novel alterations are able to recruit ETS transcription factor members, in particular GABP-α and ETV1, to the newly generated binding sites. We report for the first time TERTp mutations in PETs and PET-derived cell lines. Additionally, our data indicate that these mutations serve as an alternative mechanism and in an exclusive manner to ALT, in particular in patients with hereditary syndromes.

Telomerase activity is restricted in humans. Consequentially, telomeres shorten in most cells throughout our lives. Telomere dysfunction in vertebrates has been primarily studied in inbred mice strains with very long telomeres that fail to deplete telomeric repeats during their lifetime. It is, therefore, unclear how telomere shortening regulates tissue homeostasis in vertebrates with naturally short telomeres. Zebrafish have restricted telomerase expression and human-like telomere length. Here we show that first-generation tert(-/-) zebrafish die prematurely with shorter telomeres. tert(-/-) fish develop degenerative phenotypes, including premature infertility, gastrointestinal atrophy, and sarcopaenia. tert(-/-) mutants have impaired cell proliferation, accumulation of DNA damage markers, and a p53 response leading to early apoptosis, followed by accumulation of senescent cells. Apoptosis is primarily observed in the proliferative niche and germ cells. Cell proliferation, but not apoptosis, is rescued in tp53(-/-)tert(-/-) mutants, underscoring p53 as mediator of telomerase deficiency and consequent telomere instability. Thus, telomerase is limiting for zebrafish lifespan, enabling the study of telomere shortening in naturally ageing individuals., Competing Interests: The authors have declared that no competing interests exist.

Telomerase activity is restricted in humans and telomere attrition occurs in several tissues accompanying natural aging. Critically short telomeres trigger DNA damage responses and activate p53 which leads to apoptosis or replicative senescence. These processes reduce cell proliferation and disrupt tissue homeostasis, thus contributing to systemic aging. Similarly, zebrafish have restricted telomerase expression, and telomeres shorten to critical length during their lifespan. Telomerase-deficient zebrafish (tert −/−) is a premature model of aging that anticipates aging phenotypes due to early telomere shortening. tert −/− zebrafish have impaired cell proliferation, accumulation of DNA damage markers and p53 response. These cellular defects lead to disruption of tissue homeostasis, resulting in premature infertility, gastrointestinal atrophy, sarcopenia and kyphosis. Such consequences contribute to its premature death. Here we reveal a genetic interdependence between tp53 and telomerase function. Mutation of tp53 abrogates premature aging of tert −/− zebrafish, prolonging male fertility and lifespan. However, it does not fully rescue healthspan. tp53mut tert −/− zebrafish retain high levels of inflammation and increased spontaneous cancer incidence. Conversely, loss of telomerase prolongs the lifespan of tp53mut single mutants. Lack of telomerase reduces two-fold the cancer incidence in double mutants and increases lifetime survival. Thus, we observe a reciprocal rescue of tp53mut and tert −/− that ameliorates lifespan but not spontaneous cancer incidence of tp53mut, likely due to higher levels of inflammation. [ABSTRACT FROM AUTHOR]

Telomeres and telomerase prevent the continuous erosion of chromosome‐ends caused by lifelong cell division. Shortened telomeres are associated with age‐related pathologies. While short telomere length is positively correlated with increased lethality at the individual level, in comparisons across species short telomeres are associated with long (and not short) lifespans. Here, we tested this contradiction between individual and evolutionary patterns in telomere length using African annual killifish. We analysed lifespan and telomere length in a set of captive strains derived from well‐defined wild populations of Nothobranchius furzeri and its sister species, N. kadleci, from sites along a strong gradient of aridity which ultimately determines maximum natural lifespan. Overall, males were shorter‐lived than females, and also had shorter telomeres. Male lifespan (measured in controlled laboratory conditions) was positively associated with the amount of annual rainfall in the site of strain origin. However, fish from wetter climates had shorter telomeres. In addition, individual fish which grew largest over the juvenile period possessed shorter telomeres at the onset of adulthood. This demonstrates that individual condition and environmentally‐driven selection indeed modulate the relationship between telomere length and lifespan in opposite directions, validating the existence of inverse trends within a single taxon. Intraindividual heterogeneity of telomere length (capable to detect very short telomeres) was not associated with mean telomere length, suggesting that the shortest telomeres are controlled by regulatory pathways other than those that determine mean telomere length. The substantial variation in telomere length between strains from different environments identifies killifish as a powerful system in understanding the adaptive value of telomere length. [ABSTRACT FROM AUTHOR]

Cancer incidence increases exponentially with age when human telomeres are shorter. Similarly, telomerase reverse transcriptase (tert) mutant zebrafish have premature short telomeres and anticipate cancer incidence to younger ages. However, because short telomeres constitute a road block to cell proliferation, telomere shortening is currently viewed as a tumor suppressor mechanism and should protect from cancer. This conundrum is not fully understood. In our current study, we report that telomere shortening promotes cancer in a noncell autonomous manner. Using zebrafish chimeras, we show increased incidence of invasive melanoma when wild-type (WT) tumors are generated in tert mutant zebrafish. Tissues adjacent to melanoma lesions (skin) and distant organs (intestine) in tert mutants exhibited higher levels of senescence and inflammation. In addition, we transferred second generation (G2) tert blastula cells into WT to produce embryo chimeras. Cells with very short telomeres induced increased tumor necrosis factor1-a (TNF1-a) expression and senescence in larval tissues in a noncell autonomous manner, creating an inflammatory environment. Considering that inflammation is protumorigenic, we transplanted melanoma-derived cells into G2 tert zebrafish embryos and observed that tissue environment with short telomeres leads to increased tumor development. To test if inflammation was necessary for this effect, we treated melanoma transplants with nonsteroid anti-inflammatory drugs and show that higher melanoma dissemination can be averted. Thus, apart from the cell autonomous role of short telomeres in contributing to genome instability, we propose that telomere shortening with age causes systemic chronic inflammation leading to increased tumor incidence. [ABSTRACT FROM AUTHOR]

A correction to the article "Telomerase Is Required for Zebrafish Lifespan" by Catarina M. Henriques and colleagues that was published in the previous issue, is presented.

Telomerase expression is restricted in human cells and so telomeres shorten throughout our lives, providing a tumour suppressor mechanism that limits cell proliferation. As a trade-off, continuous telomere erosion results in replicative senescence and contributes to ageing. Recently, telomerase therapies were proposed as a valid approach to rescue degenerative phenotypes caused by telomere dysfunction. However, systemic effects initiated by short telomeres may prove dominant in limiting tissue renewal in the whole organism. Most of our knowledge of telomere biology derives from mouse models that do not rely on telomere exhaustion for controlling cell proliferation and tissue homeostasis. In order to understand the impact of telomere shortening in natural ageing, we need to investigate animal models that, like humans, have evolved to have telomere length as a cell division clock. [Copyright &y& Elsevier]

Each round of DNA replication results in the erosion of telomeres, the ends of linear chromosomes. Telomerase counteracts telomere shortening by synthesizing new DNA sequences in a time period restricted to late S a d G2 cell-cycle phases, even though the enzyme is active throughout the cell cycle. A recent study directly implicates cyclin dependent kinase (Cdk1) in the regulation of telomere elongation during the cell cycle. [ABSTRACT FROM AUTHOR]

Summary: The dramatic telomerase-dependent overelongation of telomeres in cells lacking Taz1 (ortholog of human TRF1/TRF2) or Rap1 implicates these proteins in restraint of telomerase activity. However, the modes by which these proteins regulate telomerase remain mysterious. Here we show that the mechanisms underlying excessive telomerase activity differ markedly between taz1Δ and rap1Δ strains. Despite allowing elevated telomerase access, rap1Δ telomeres are processed and synthesized in a cell-cycle-constrained manner similar to that of wild-type cells. In contrast, taz1Δ telomeres are processed with little cell-cycle dependency and recruit telomerase over an abnormally wide range of cell-cycle stages. Furthermore, although taz1Δ telomeres experience transient attrition mediated by replication fork stalling, this is balanced not only by temporal expansion of the telomerase activity period, but also by markedly increased recruitment of telomerase and its accessory factor Est1, suggesting that stalled forks generate robust substrates for telomerase. [ABSTRACT FROM AUTHOR]