Telomerase is required for zebrafish lifespan.

Area of Science:

• Genetics
• Cell Biology
• Gerontology

Background:

• Telomere shortening is a hallmark of aging, but its role in vertebrates with naturally short telomeres is understudied.
• Most vertebrate models, like mice, have long telomeres and limited telomere depletion, hindering research on telomere shortening's impact on tissue homeostasis.
• Zebrafish possess restricted telomerase expression and human-like telomere lengths, making them a suitable model for studying telomere dynamics.

Purpose of the Study:

• To investigate the role of telomerase in regulating tissue homeostasis and lifespan in zebrafish.
• To determine the consequences of telomere shortening in a vertebrate model with naturally short telomeres.
• To elucidate the molecular mechanisms, including the involvement of p53, linking telomere deficiency to aging phenotypes.

Main Methods:

• Generation of tert(-/-) zebrafish mutants lacking telomerase activity.
• Phenotypic analysis of tert(-/-) mutants, including lifespan, fertility, and tissue morphology.
• Assessment of cell proliferation, DNA damage markers, apoptosis, and senescence in mutant fish.
• Genetic analysis using tp53(-/-)tert(-/-) double mutants to evaluate the role of p53.

Main Results:

• First-generation tert(-/-) zebrafish exhibited significantly shorter telomeres and premature death.
• Mutant fish displayed degenerative phenotypes such as infertility, gastrointestinal atrophy, and sarcopenia.
• Impaired cell proliferation, increased DNA damage, and p53-mediated apoptosis followed by senescence were observed.
• Apoptosis was concentrated in proliferative niches and germ cells, while cell proliferation was restored in tp53(-/-)tert(-/-) mutants.

Conclusions:

• Telomerase activity is crucial for maintaining telomere length and limiting premature aging in zebrafish.
• Telomere shortening in zebrafish leads to a spectrum of age-related degenerative diseases.
• The p53 pathway is a key mediator of the cellular and organismal responses to telomere deficiency and instability.
• Zebrafish serve as a valuable model for studying telomere shortening and aging in naturally aging individuals.