Exercise-induced metabolic programming of NK cells: the mTORC1 pathway or adrenergic signalling

Abstract

Tumorigenesis involves profound changes in intracellular mechanisms in different tissues,including metabolic disturbance, disruption of cell cycle, and resistance to apoptosis, being closelyrelated to external factors, such as smoking, alcoholism and lifestyle. The higher prevalence ofcancer in elderly individuals points to an immunosenescence role. Antitumor events are triggeredby natural killer cells, that inhibit the growth and proliferation of tumor cells and perform immunesurveillance. Based on our previous results, we hypothesized that lifelong physical exerciseremodels the energy metabolism of different cells, including NK cells, creating a favorablemetabolic environment that improves immune surveillance. Thus, we hope to demonstrate thatphysical training carried out for more than 20 years has a potential anti-immunosenescence effectand greater anti-tumor immunity. Thus, master athletes would exhibit a preserved immuneresponse to exercise, and would be better prepared to respond, i.e., immune respond, to newchallenges. In this sense, this project will examine the functional activity of NK cells and themolecular and metabolic mechanisms involved in their activation in master athletes, contributingto a better understanding of how regular physical exercise can enhance a better anti-tumorresponse. The experiments in this project are organized to answer 3 main questions: 1) Doathletes' NK cells have a better antitumor response regardless of training history length? 2) Whatare the phenotypes and the pattern of cytokine production in lymphocytes of master athletes? 3)Can regular physical exercise create a metabolic and immune environment that suppressestumorigenesis? We hope to demonstrate that the NK cells of master athletes have a phenotypic,metabolic and functional profile more associated with antitumor activity and find further evidencethat lifelong exercise can be a new non-pharmacological therapy in cancer prevention. (AU)