Molecular regulation of telomeric elongation and TERT splicing in planarians

Planarians, flatworms renowned for their extraordinary regenerative capacity, depend on a population of adult pluripotent stem cells known as neoblasts. Unlike most adult stem cells in mammals, neoblasts maintain sustained telomerase activity throughout adulthood. This allows for continuous telomere elongation without apparent shortening. This feature is associated with lifelong regeneration, negligible aging, and striking resistance to spontaneous tumor formation. This review summarizes the current knowledge of the molecular mechanisms that govern telomere elongation in planarians and other organisms, particularly focusing on telomerase regulation. We discuss the molecular function of telomerase reverse transcriptase (TERT) and highlight alternative splicing of the tert gene as a potential evolutionary strategy to fine-tune telomerase catalytic activity in planarians. Additionally, we examine telomere-associated proteins that are functionally analogous to the shelterin complex described in humans. These proteins are involved in chromosome end protection and the regulation of telomerase access to telomeres. Notably, while constitutive telomerase activity and unlimited proliferative capacity are hallmarks of many human cancers-often driven by mutations or deregulation of TERT-planarians do not develop spontaneous malignant neoplasms. Tumor-like phenotypes only arise under experimental conditions, such as exposure to carcinogens or disruption of tumor-suppressor pathways. Together, this evidence supports a model in which the coordinated regulation of telomerase catalytic competence and accessibility sustains regeneration while restraining tumorigenic processes. This positions planarians as valuable models for studying aging and cancer biology.