Telomeres are repeated sequences at the end of chromosomes. A little of that length is lost with each cell division, and in this way telomere length acts as a countdown. Somatic cells become senescent or self-destruct when telomere length becomes too short, thanks in large part to the activity of TP53. This is a protective mechanism, removing cells that can become cancerous or otherwise harmful. Stem cells employ telomerase to maintain long telomeres, and supply a tissue with new daughter somatic cells to take the place of those lost to telomere shortening. Thus a tissue has some turnover of cells, allowing a degree of protection from the most harmful cell malfunctions. This study provides some insight into how these relationships play out in practice by sabotaging telomerase and p53, and observing the results.
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 model of premature 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.
Link: https://doi.org/10.1...598-024-56153-8
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