The Long‐Term Effects of Exercise Mitigate Deleterious Healthspan Changes and Cancer Incidence in Mice Following Diet‐Induced Obesity and Radiation Exposure

Abstract

There are nearly 16 million cancer survivors living in the United States today, with two‐thirds of them having received radiation therapy as part of their treatment. Furthermore, there is a concurrent increase in obesity and physical inactivity among this population. Combined with the effects of ionizing radiation (IR), these host factors are increasing the risk of secondary, treatment‐induced cancers and may contribute to poor healthspan outcomes in cancer survivors. As such, a critical need exists to develop a better understanding of how these host factors interact with radiation exposure, such that we can provide cancer survivors with better lifestyle recommendations to enhance their overall quality of life and decrease their secondary cancer risk. Male CBA mice were randomly divided into a control diet group (CTRL) or a 45% high fat diet group (HFD) to induce obesity. At nine weeks of age, half of the mice in each dietary group began a treadmill exercise training intervention (EX), or remained sedentary (SED), and were then all exposed to ionizing radiation (3 Gy) at 13 weeks of age. Healthspan was measured in each group at 17 months of age by assessing: endurance performance, metabolic and locomotor activity, depression‐like behaviour, forelimb grip strength and plasma clinical chemistry. Endurance performance was significantly greater in CTRL/EX compared to both HFD groups 5 days pre‐IR and compared to both SED groups 5 months post‐IR (both p<0.05). Metabolic analysis revealed a significant increase in the respiratory exchange ratio in CTRL compared to HFD mice (p<0.05), but there were no significant differences in O2 consumption, CO2, or heat production (p>0.05). There was also a trend for an increase in locomotor activity in the CTRL/EX compared to CTRL/SED group during their light and dark cycle (p = 0.06 and p = 0.108, respectively). Further, there was a significant decrease in depression‐like behaviour among HFD compared to CTRL mice, and EX compared to SED mice (p<0.05), as well as a significant decrease in forelimb grip strength normalized to body weight among HFD compared to CTRL mice (p<0.05). Additionally, there was a significant increase in total cholesterol levels among HFD compared to CTRL mice (p<0.05). Interestingly, the CTRL/EX and HFD/EX groups had a 20% decrease in cancer incidence compared to the HFD/SED group, and EX mice had a 17.5% decrease in cancer incidence compared to SED mice, independent of diet (both p>0.05). Our current findings suggest that long‐term exercise and dietary interventions should be implemented in cancer survivors exposed to radiation therapy in order to improve healthspan and potentially protect against secondary cancer incidence. Support or Funding Information The American Institute of Cancer Research (AICR), The Natural Sciences and Engineering Research Council of Canada (NSERC), and The Canadian Institutes of Health Research (CIHR)