By: Sairah Sheikh, PharmD Candidate c/o 2024

Increased physical activity is often touted as a lifestyle choice that improves bodily health dramatically. Over recent years, there has been an increase in research showing that exercise can help to prevent chronic diseases. Physical activity exerts its benefit through a wide variety of mechanisms.

Exercise can improve the health of cancer patients undergoing chemotherapy, immunotherapy, or radiation. Research conducted by Memorial Sloan Kettering’s Exercise Oncology Service revealed that patients who had been treated with chemotherapy for three months experienced a 15% decline in their fitness levels, which is equal to physically aging 10 years in three months. When observing the effect of regularly exercising during treatment periods, these researchers found that it significantly decreased physical aging.¹ Additionally, a study published in the National Library of Medicine showed the benefits of exercise in mice with cancer. In this study, mice were injected with 4T1 mammary carcinoma, equivalent to triple-negative breast cancer. They were then split into two groups: an active and a sedentary group. The active group ran on the treadmill for 30 minutes per day for five days a week, while the other mice were kept in their home cages. Both groups were treated with radiotherapy and programmed cell death-1 (PD-1)-blocking immunotherapy. The study determined that tumor growth was substantially lower in the mice that exercised, with an average tumor size of 203 + 52 mm³ versus 325 + 83 mm³ in the sedentary control group.² This occurred as a result of a reduction in myeloid-derived suppressor cells (MDSCs) along with an increase in natural killer (NK) and CD8 T-cell activation. MDSCs are immunosuppressive and ultimately promote the growth of tumors, as well as bodily resistance against immunotherapy.³ The power of exercise is not limited to the treatment of oncology patients.

Another mechanism behind the health benefits of exercise involves the hypothalamic-pituitary-adrenal axis (HPA) and its interaction with the sympathetic nervous system (SNS).⁴ These systems mediate the body’s stress response, with the HPA axis releasing glucocorticoids such as cortisol, and the SNS releasing epinephrine and norepinephrine.⁴ Heightened glucocorticoid levels normally stimulate the mobilization of immune cells. However, with prolonged glucocorticoid activation, immunosuppressive effects take place to prevent high inflammation due to the overactivity of these cells. Glucocorticoid resistance can also develop as a result of sustained high cortisol levels, which can eventually culminate in chronic inflammation and a higher risk of developing inflammatory disorders.⁴

Exercise buffers against these effects by optimizing HPA and SNS responses.⁴ It has been observed that physically active individuals have a different physiological response to stress-inducing situations when compared to non-physically active individuals. In situations with high physical and non-physical stress, physically fit people have been observed to experience significantly lower HPA responses. They had decreased cortisol and heart rate, along with significantly improved mood.⁴ SNS reactivity has been seen to be improved as well because those who are more physically active exhibit a more rapid recovery from stressors compared to less physically active individuals.⁴ Less physically fit individuals demonstrated higher HPA responses, higher cortisol and heart rate responses, less calmness, and higher anxiety overall. This shows how effective exercise is in improving a person’s overall physical and mental health in the presence of stressors, which is especially critical in society today. The effect physical activity has on lowering inflammation in the body should also not be overlooked.

Exercise has a positive impact on cardiovascular function as well. Since cardiovascular disease is the leading cause of death in the world,⁵ it is important to note the mechanisms behind exercise as a method to improve cardiac activity. One mechanism is the mitochondrial adaptations that occur in the body. Exercise can improve VO₂ max, which is the maximum amount of oxygen our body takes in when performing any physical activity and is used to measure long-term cardiorespiratory fitness. It does this by “increasing the mitochondrial content and desaturation of myoglobin in skeletal muscle tissue.”⁵ Exercise also enhances mitochondrial biogenesis in cardiomyocytes, which may be due to increased activation of AMP-activated protein kinase (AMPK) which leads to increased mitochondrial PGC-1α expression.⁵ PGC-1α is a protein that helps regulate cellular energy metabolism by stimulating mitochondrial biogenesis to make the muscle tissue more oxidative and less glycolytic.⁶ Additionally, exercise helps the heart as it causes mitochondria to increase oxidation of fatty acids leading to an increase in the capacity for adenosine triphosphate (ATP) synthesis.⁵ Exercise has also been found to increased expression of endothelial nitric oxide synthase (eNOS), which is associated with inhibition of platelet aggregation and reduction in the onset of atherosclerosis, thrombosis, ischemia, or other cardiac events.^5,6 

Additionally, physical activity has been proven to have an immensely beneficial impact on neurological health. Higher amounts of gray and white matter in the brain allow for information processing and bodily processes to be carried out more effectively.⁷ Imaging studies have suggested that adequate exercise is linked with increased volume and integrity of gray and white matter integrity, especially in the prefrontal cortex and hippocampus.⁴ Additionally, regions of the brain that are associated with stress and aging seem to benefit from a physically active lifestyle which shows that exercise promotes cognitive activity. ⁴ If hippocampus volume increases due to exercise, it is also associated with higher BDNF levels. BDNF, or brain-derived neurotrophic factor, is a molecule that improves cognitive function and regulates heart function and energy metabolism.⁴ About 30% of the body’s interleukin 6 (IL-6) levels are found in adipose tissue, so if a person is physically fit, they will likely have less adipose tissue and thus have less inflammation in their body. Furthermore, in a Treatment with Exercise Augmentation for Depression (TREAD) study, inflammatory biomarkers such as C-reactive protein (CRP) were shown to be lower in physically fit persons compared to those who are not fit.⁸ Patients in the study who had major depressive disorder and whose symptoms did not improve after being given a selective serotonin reuptake inhibitor (SSRI) were given an exercise plan. Patients who followed their exercise plan were found to have significantly lessened depressive symptoms.⁸

The aforementioned mechanisms make it clear that exercise is beneficial in both preventing disease and reducing its severity. In a country where 60% of the adult population is battling a chronic disease,⁹ it is especially beneficial to become educated about healthy lifestyle choices such as exercise so that we can lessen symptom burden and improve quality of life. 

References

1. How exercise can help treat and prevent cancer. Memorial Sloan Kettering Cancer Center. https://www.mskcc.org/videos/how-exercise-can-help-treat-and-prevent. Accessed February 2, 2023. 
2. Wennerberg E, Lhuillier C, Rybstein MD, et al. Exercise reduces immune suppression and breast cancer progression in a preclinical model. Oncotarget. 2020;11(4):452-461. Published 2020 Jan 28. doi:10.18632/oncotarget.27464
3. Law AMK, Valdes-Mora F, Gallego-Ortega D. Myeloid-derived suppressor cells as a therapeutic target for cancer. Cells. 2020;9(3):561. Published 2020 Feb 27. doi:10.3390/cells9030561
4. Silverman MN, Deuster PA. Biological mechanisms underlying the role of physical fitness in health and resilience. Interface Focus. 2014;4(5):20140040. doi:10.1098/rsfs.2014.0040
5. Pinckard K, Baskin KK, Stanford KI. Effects of exercise to improve cardiovascular health. Front Cardiovasc Med. 2019;6:69. Published 2019 Jun 4. doi:10.3389/fcvm.2019.00069
6. Liang H, Ward WF. PGC-1alpha: A key regulator of energy metabolism. Adv Physiol Educ. 2006;30(4):145-151. doi:10.1152/advan.00052.2006
7. Filley CM, Fields RD. White matter and cognition: making the connection. J Neurophysiol. 2016;116(5):2093-2104. doi:10.1152/jn.00221.2016
8. Toups MSP, Greer TL, Kurian BT, et al. Effects of serum brain derived neurotrophic factor on exercise augmentation treatment of depression. J Psychiatr Res. 2011;45(10):1301-1306. doi:10.1016/j.jpsychires.2011.05.002
9. National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP). Chronic diseases in America. Centers for Disease Control and Prevention. Last Updated December 13, 2022. Accessed August 13, 2023. https://www.cdc.gov/chronicdisease/resources/infographic/chronic-diseases.htm

Published by Rho Chi Post