Background

Telomeres, the repetitive DNA sequences at the ends of eukaryotic chromosomes, are incompletely duplicated and shorten with every round of cell division. To overcome this, a specialised DNA polymerase, telomerase (tert), elongates the ends of chromosomes by employing the telomerase RNA component (terc) as a template and adding repeated copies, thereby preventing replicative shortening. However, in humans, tert is repressed in most somatic cells after birth leading to a continuous shortening of telomeres throughout our lives. This then results in replicative senescence and contributes to aging pathologies. Zebrafish has emerged as a valuable model to study telomere biology since its telomeres shorten significantly over time similarly to humans and play an important role in tissue maintenance during its lifespan. In this preprint, the authors treated telomerase deficient zebrafish (tert-/-) with telomere-targeted antisense oligonucleotides (tASOs) and demonstrated their efficacy in rescuing premature aging phenotypes.

Key findings

Rescue of developmental and growth impairments

The authors used second-generation (G2) tert-/- zebrafish, which develop earlier and more severe phenotypes than first-generation fish (G1). tASOs were injected into one-cell-stage G2 tert-/- embryos and larval phenotypes were assessed at 2- and 5-days post-fertilization (dpf). tASO treatment significantly reduced the percentage of larvae with malformations and restored larval length to wild type (WT) levels.

 

Improvement in health and survival

Through behavioral and survival assays, the authors found that G2 tert-/- larvae displayed abnormal swirling motion, pericardial and yolk sac edemas (swelling from fluid accumulation), and increased lethality. tASO treatment improved motor behavior, reduced the incidence of edema, and significantly enhanced survival.

 

Restoration of fertility and sexual maturity

In zebrafish tert-/-, male fertility loss occurs earlier than in WT and testes atrophy is seen in 6 months old fish. Following tASO injection of G1 fish at the one-cell stage, the authors observed a notable rescue of testicular atrophy, as evidenced by increased sperm maturation. In parallel, treated females showed a fivefold increase in the number of fertilized eggs compared to untreated controls.

 

What I like about the preprint

The study highlights an interesting therapeutic avenue for tASO in aging-related diseases. I particularly appreciated the comprehensive phenotypic characterization across developmental and behavioral levels, along with the follow-up of long-term effects in adult zebrafish. The positive outcomes of the treatment in this model are encouraging and sparked my curiosity to deepen my knowledge further in this topic.

 

Future directions and questions for the authors

• You suggest that the abnormal swirling behavior in tert-/- larvae may be due to central nervous system dysfunction. Are you planning to further explore this phenotype and check whether tASO rescues some defected neural pathways involved in motor coordination?
• In your previous work, you’ve shown that p53 suppression alleviates senescence and inflammation in this model. Will you further assess whether tASO treatment exerts similar effects?

 

References

• Henriques, C. M., & Ferreira, M. G. (2024). Telomere length is an epigenetic trait – Implications for the use of telomerase-deficient organisms to model human disease. Disease Models & Mechanisms, 17(3). https://doi.org/10.1242/dmm.050581
• Henriques, C. M., Carneiro, M. C., Tenente, I. M., Jacinto, A., & Ferreira, M. G. (2013). Telomerase is required for zebrafish lifespan. PLoS Genetics, 9(1), e1003214. https://doi.org/10.1371/journal.pgen.1003214

Tags: aging, chromosomes, telomeres

doi: https://doi.org/10.1242/prelights.40782

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