Figure 3. Hypothetical model of how aerobic exercise can attenuate the induction of cellular senescence and thus aspects of aging.

Hypothetical trajectory of telomere shortening determined by lifestyle. Telomere attrition is attenuated by a physically active lifestyle resulting in telomeres reaching a critically shortened length and thus inducing cellular senescence at an older age compared individuals with a sedentary lifestyle (A). Reactive oxygen species (ROS) and c-MYC expression are known to be increased by acute aerobic exercise. Transcription of TERT is upregulated by ROS and/or c-MYC expression. Epigenetic changes can be induced by exercise and are involved in the upregulation of TERT transcription, but they remain uninvestigated following exercise at the TERT loci. Following aerobic exercise, TERT isoforms including full-length and alternatively spliced isoforms will be generated. By transient upregulation of full-length TERT, telomerase activity would be increased and thus reduce telomere shortening compared to sedentary individuals. Telomere elongation is the canonical function of telomerase and only full-length TERT can generate telomerase that can elongate telomeres. However, non -canonical functions of TERT can be achieved by both full-length and alternatively spliced TERT isoforms. Regulation of TERT isoform expression could be related to the attenuation of aspects of aging, and here we show six different non-canonical functions of TERT that could be related to exercise induced TERT isoforms (both full-length and alternatively spliced variants). Overall, this hypothetical model indicates that exercise induces changes in telomere biology driven by TERT and telomerase that help maintain telomere length and prevent DNA damage response-induced cellular senescence and thus attenuate aspects of the aging process and promote health in physically active humans. Created with BioRender.com.