Exercise and Alternative Mechanisms of Telomerase
Evolution tends towards reuse of component parts, and as a result no gene has just one function. Telomerase in particular is involved in far more than just extending telomeres, the caps that the ends of chromosomes that are reduced with each cell division. In humans, stem cells express telomerase to maintain long telomeres, while all other cells can replicate only a limited number of times. What are the other functions of telomerase? As first noted some years ago, telomerase may be protective of mitochondrial function, and the paper here lists a few other interesting line items as well: angiogenesis, metabolism, regulation of gene expression, and so forth.
When we see evidence for a large upregulation of telomerase expression achieved via gene therapy to extend life in mice, is this taking place only because increased telomerase expression is extending telomeres, or are other mechanisms also participating to a significant degree? Separately, it is noted that exercise increases telomerase expression, though evidently nowhere near enough to produce the same extension of mouse life span as has been achieved via the use of telomerase gene therapies. Nonetheless, to what degree are the benefits of exercise mediated by telomerase? These are presently questions without firm answers.
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 that 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.