Canonical and extra-telomeric functions of telomerase: Implications for healthy ageing conferred by endurance...

Telomerase preserves genomic integrity by maintaining and protecting the telomeres. Seminal findings from 1985 revealed the canonical role of telomerase and motivated investigations into potential therapeutic strategies to combat one of the hallmarks of ageing-telomere attrition. Since then, the field of telomere biology has rapidly expanded, with telomerase serving essential roles in cancer and cell development through its canonical function. However, telomerase also exerts critical extra-telomeric functions through its protein (telomerase reverse transcriptase, TERT) and RNA components (telomerase RNA component, TERC). Telomerase re-activation or ectopic expression promotes survival and permits unlimited proliferation in tumours and healthy non-malignant cells. TERT gene therapies improve health and lifespan in ageing mice and mouse models of age-related diseases. The extra-telomeric functions of telomerase are critical to ageing. These include protection against oxidative stress, orchestration of chromatin modifications and transcription, and regulation of angiogenesis and metabolism (e.g. mitochondrial function and glucose control). Given these biological functions are key adaptations to endurance training and the recent meta-analytical findings that indicate exercise up-regulates TERT and telomerase, a comprehensive discussion on the implications of the canonical and extra-telomeric roles of telomerase is warranted. This review highlights the therapeutic benefits of telomerase-based treatments for idiopathic and chronic diseases that are linked to ageing. Discussion on the canonical and extra-telomeric roles of telomerase are presented, followed by a detailed summary of the evidence on how exercise influences telomerase. Finally, the potential cell signalling underpinning the exercise-induced modulation of telomerase are discussed with directions for future research.