Clinical Medicine Insights Received 27 Mar 2021 | Revised 25 Apr 2021 | Accepted 28 May 2021 | Published Online 30 Jun 2021 DOI: https://doi.org/10.52845/CMI/2021-2-2-5 CMI JOURNAL 2 (2), 124−143 (2021) ISSN (O) 2694-4626 REVIEW ARTICLE Exercise and Non-Communicable Diseases: Part II Cancer, Diabetes Mellitus, Kidney Diseases, Alzheimer’s Disease, Arthritis Shashi K. Agarwal, MD ∗ 12227 US Highway 1, #309 North Brunswick, NJ 08902,USA Abstract Non-communicable diseases (NCDs) are the leading global cause of death and disproportionately afflict those living in low-income and lower-middle-income countries. Healthy lifestyle behaviors, includ- ing eating a high-quality diet, non-smoking, engaging in moderate to vigorous physical activity, and drinking alcohol in moderation, have been associated with a lower risk of NCDs, a decline in worsening, and a reduction in associated mortality. The first part of this two- part series discussed exercise and its effects on cardiovascular and respiratory diseases, obesity, depression, and liver ailments. This sec- ond part discusses the deleterious effects of smoking on five non- communicable diseases, viz., cancer, diabetes mellitus, chronic kidney disease, Alzheimer’s disease, and arthritis. This manuscript highlights the benefits of exercise, in reducing the incidence, progression, and premature mortality of NCDs. Keywords: exercise, non-communicable diseases, cancer, diabetes mel- litus, chronic kidney disease, Alzheimer’s disease, arthritis Copyright : © 2021 The Authors. Published by Medical Editor and Educational Research Publishers Ltd. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/). 1 INTRODUCTION Exercise (or lack of it) is fast becoming a major lifestyle factor in the prevention and treatment of major non-communicable diseases1. It is also used to treat back pain2 sports injuries3, osteoporosis4, inflammatory bowel disease5, neurodegenerative diseases (such as Parkinson’s disease)6, Huntington’s disease7, mul- tiple sclerosis8, anxiety disorders9, and many other ailments10−11. Exercise helps increase confidence, improve socialization, brings happiness, and helps improve sleep12,13. The overall quality of life is also improved14. A recent US study suggested that moderate to vigorous physical activity could significantly reduce general premature mortality and increase life expectancy15. CMI JOURNAL 2 (2), 124−143 MEERP LTD 125 Open Access Journal https://doi.org/10.52845/CMI/2021-2-3-11 https://orcid.org/0000-0003-0007-5582 https://creativecommons.org/licenses/by-nc-nd/4.0/ https://medicineinsights.info/index.php/cmi/index MEERP LTD SHASHI K. AGARWAL, MD The World Health Organization recommends that adult men and women should accumulate at least 150 min of moderate-intensity physical exercise per week, while young people aged 5–17 years should accumulate at least 60 min of physical exercise of moderate to vigorous intensity daily16. 2 DISCUSSION Chronic NCDs are common conditions affecting humans17. They are gradually replacing infectious diseases as the leading health burden across the world18. The Centers for Disease Control and Pre- vention (CDC) of USA defines chronic diseases as “conditions that last 1 year or more and require ongoing medical attention or limit activities of daily living or both”19. They estimate that six in ten adults in the USA have a chronic disease, while four in ten have two or more chronic diseases19. In a recent study, Ng et al reported that most individuals develop at least one chronic disease during their lifetime20. Rosella et al found that in the Ontario population, two-thirds of individuals had four or more chronic conditions at the time of their death21. More and more deaths globally, are now attributable to chronic NCDs22. According to the World Health Organiza- tion (WHO), chronic NCDs accounted for 71% of the 57 million global deaths in 201623. Chronic non-communicable diseases include car- diovascular diseases (CVDs) (such as hyperten- sion, coronary artery disease, stroke, and heart fail- ure), cancer, chronic respiratory diseases (such as chronic obstructive pulmonary disease, sleep apnea, and asthma), diabetes mellitus, Alzheimer’s disease, chronic kidney disease (CKD), arthritis, depression, obesity, and liver diseases (such as nonalcoholic Supplementary information The online version of this article (10.52845/CMI/2021-2-2-5) contains supplementary material, which is available to autho- rized users. Corresponding Author: Shashi K. Agarwal, MD Shashi K. Agarwal, MD 2227 US Highway 1, #309 North Brunswick, NJ 08902,USA Email: usacardiologist@gmail.com and alcoholic hepatitis, viral hepatitis, cirrhosis of liver)24. There is overwhelming evidence that exer- cise also confers significant benefits in the preven- tion and management of these diseases25,26. As dis- cussed in part I of this two-part manuscript, it has sig- nificant benefits for cardiovascular diseases, respira- tory diseases, obesity, depression, and liver diseases. This manuscript will discuss its benefits for cancer, diabetes mellitus, kidney diseases, Alzheimer’s dis- ease, and arthritis. Cancer was diagnosed in 18 million individuals in 201827. Cancers of the lung (2.09 million cases), breast (2.09million cases), and prostate (1.28million cases) were themost common in this group27. Cancer was responsible for 9.6 million deaths globally in 201828. Today, cancer-related mortality exceeds that caused by communicable diseases such as human im- munodeficiency virus/acquired immunodeficiency syndrome, tuberculosis, and malaria, combined29. Diabetes mellitus (DM) is also a common chronic disease30. It is mainly categorized into 2 major sub- types, type I DM (T1D) and type II DM (T2D)31. T1D is an autoimmune disorder, with several ge- netic, epigenetic, and environmental factors playing a role in its genesis32. T2D is characterized by insulin resistance and accounts for 90-95% of all diabetes cases31. It often leads to the development of several microvascular (retinopathy, nephropathy, and neu- ropathy) andmacrovascular (coronary artery disease, stroke, peripheral artery disease) complications33. Deaths from DM continue to increase all over the world34. CKD has an estimated prevalence of 10.6%- 13.4%35, and its prevalence is growing rapidly36. CKD progresses to end-stage kidney disease requir- ing a kidney transplant, and these numbers are also on the increase37. It is estimated that the number of people requiring renal replacement will double to 5.4 million by 203038. This population has a mortality rate that is over 100-fold compared to that seen in the normal population39. DM continues to be the leading cause of CKD40. Dementia affects around 50 mil- lion people worldwide and this number is projected to increase to 152 million by 205041. Alzheimer’s disease (AD) is the most common dementia and is caused by amyloid-beta peptide accumulation in the medial temporal lobe and neocortical structures42. Treatment for AD is symptomatic as there is no MEERP LTD CMI JOURNAL 2 (2), 124−143 (2021) 126 mailto:usacardiologist@gmail.com EXERCISE AND NON-COMMUNICABLE DISEASES: PART II CANCER, DIABETES MELLITUS, KIDNEY DISEASES, ALZHEIMER’S DISEASE, ARTHRITIS cure available at this time43. Arthritis is of over 100 types, the most common being rheumatoid arthritis, osteoarthritis, psoriatic arthritis, and inflammatory arthritis44. Osteoarthritis (OA) is the most prevalent chronic joint disease and is associated with cartilage loss45,46. It usually affects the knees, although it can affect any joint45,46. It is a major cause of dis- ability in older adults47. Rheumatoid arthritis (RA) is a chronic, systemic, immune-inflammatory dis- ease, especially affecting the synovial joints resulting in synovitis, joint erosion, and cartilage damage48. Its etiology includes several genetic, environmental, and endogenous factors49. Lifestyle changes can beneficially modify chronic NCDs50. The detrimental but modifiable lifestyle factors include tobacco smoking, inadequate veg- etable and fruit consumption, excessive alcohol con- sumption, physical inactivity, and obesity51. Part I reviewed the benefits of exercise for cardiovascular diseases, respiratory diseases, obesity, depression, and liver diseases. This manuscript will discuss its benefits for cancer, diabetes mellitus, kidney dis- eases, Alzheimer’s disease, and arthritis. 2.1 CANCER In 1986, Winningham et al suggested that physical activity may play a major role in oncology52. The cancer modulating effect of exercise has been con- firmed by several subsequent studies53−55. Behrens and the group found that low physical activity ac- counted for 6% of all cancers in Germany53. They re- ported that physical inactivity resulted in an increase in endometrial cancer by 15%, renal cancer by 17%, liver cancer by 24%, and lung cancer by 19%53. Ac- cording to Islami and the group, physical inactivity accounted for 2.9% of all cancer cases in the US54. They estimated that physical inactivity accounted for 26.7% of uterine cancers, 16.3% of colorectal cancers, and 3.9% of female breast cancers54. A re- cent umbrella review, including 19 reviews, 26meta- analyses, and 541 original studies, evaluating phys- ical activity and cancer risk, concluded that regular physical activity is beneficial in preventing 7 major cancers (colon, breast, endometrium, lung, esoph- agus, pancreas, and meningioma)55. The greatest beneficial impact appears to be on breast and colon cancer56. In a meta-analysis of 38 cohort studies in 2016 by Pizot et al, breast cancer risk was reduced by 12-21% in the most physically active women than in those who were least physically active57. In another more recent study, exercising 7 hours a week reduced colon cancer risk by 40%58. Several studies have also reported significant reductions in physical activity in cancers of the stomach59, kidney60, bladder60, and endometrium61. Minimal amounts of exercise may have protective effects62, although there appears to be a dose-dependent relationship63−65. Following a cancer diagnosis, exercise is associ- ated with better clinical outcomes66−69. Animal stud- ies have demonstrated a decrease in cancer tumor growth with exercise67. Exercise therapy before the initiation of chemotherapy is associated with im- provements in tolerance to cancer treatment68. Ben- efits are also noted with exercise pre-surgery69. Pre- treatment exercise results in mitigation of the sig- nificant functional decline often noted in cancer patients68,69. Exercise during treatment also demonstrates clin- ical benefits70−83. These patients notice an im- proved tolerance to chemotherapy and surgery69.70. Their hospital stay is decreased69. They have fewer side effects and less fatigue71,72. Their aerobic en- durance, strength, flexibility, and body composi- tion improves73. They become more physically fit and have increased energy levels and vitality74. There is an improvement in sleep quality75 and a reduction in depression76 and anxiety77, often ex- perienced by these patients. Exercising cancer pa- tients also improve their self-esteem71. Their QOL improves78. Exercise helps decrease metastasis and cancer recurrence79,80. Benefits of exercise have also been seen in individuals after metastasis has occurred81. Survival is increased82,83. Regular exer- cise continues to be recommended by various world health organizations for cancer patients84−88. Physical activity induces several cancer-preventive changes in the human body, including reducing adi- pose tissue, improving insulin resistance, reducing inflammation, enhancing immune function, modu- lating sex hormones and growth factors, and en- hancing resistance to oxidative stress and DNA damage89. In patients with established malignant CMI JOURNAL 2 (2), 124−143 (2021) MEERP LTD 127 MEERP LTD SHASHI K. AGARWAL, MD tumors, physical activity/exercise paradigms regu- late intra-tumoral vascular maturity and perfusion, hypoxia, and metabolism and augment the antitumor immune response90. More than 40% of patients diagnosed with cancer have comorbid NCDs, such as diabetes, obesity, chronic obstructive pulmonary disease, and heart failure91. Cancer itself may increase the risk of devel- oping some of these diseases92,93. Breast cancer sur- vivors experience an increased risk of cardiovascu- lar disease92 and cardiovascular mortality93. Patients with nonmetastatic breast cancer demonstrate a 23% adjusted reduced risk of cardiovascular events, with exercise94. Exercise benefits for cancer, therefore, also extend to coexisting NCDs. 2.2 DIABETES MELLITUS Several studies have stressed the value of regular physical activity as part of lifestyle changes to help prevent or delay type 2 diabetes95,96. Church et al found that a weight loss of only 5%-7% achieved with physical activity at least 150–175 min/week and dietary energy restriction demonstrate reduc- tions of 40%–70% in the risk of developing type 2 diabetes in people with impaired glucose tolerance97. A systemic review of randomized controlled trials found that lifestyle changes, including exercise, had a preventive effect on the development of T2D in people with impaired glucose tolerance. While the control group had a diabetes incidence of 9.3% to 67.7%, in this study, the lifestyle intervention group demonstrated a reduced incidence of 3% to 46%98. A recent systematic review of 53 studies done by Balk et al found that, compared with usual care, diet and physical activity promotion programs improved several cardiometabolic risk factors and reduced the incidence of type 2 diabetes99. Exercise, especially moderate to vigorous, confers several benefits on patients with both type I and type II diabetes100. Aerobic exercise in type I di- abetes helps by decreasing insulin resistance and improving lipid levels and endothelial function101. In T2D, aerobic exercise reduces blood glucose, A1C, triglycerides, blood pressure, and insulin resistance102. Both T1D and T2D patients lose weight and become more cardio-metabolically fit with aerobic exercise. As a result, the cardiovas- cular risk diminishes103−105. The latter is impor- tant as diabetics have a higher risk of developing CVDs106. CVDs are responsible for most deaths in these patients107. Many diabetic patients are obese, and exercise also helps them get more physically fit and function better108. Resistance exercises are also helpful in T2D109,110. These patients generate more muscle mass, more bone mineral density, and become stronger109. There is also improvement in the cardiometabolic profile109. Resistance exercises in T1D, if done before aerobic exercises, minimize the risk of exercise-induced hypoglycemia110. Flex- ibility and balance exercises help diabetics improve their joint mobility, which often deteriorates with the combination of hyperglycemia and aging111. Stretch- ing exercises increase the range of motion of joints and improve flexibility in these patients112. Diabetics may have gait and balance problems, especially if peripheral neuropathy is present113. Balance training in these patients can therefore help reduce the risk of falls114. Both Yoga and Tai Chi may help improve glycemic control and many QOL parameters115,116. Aerobic activity also helps reduce mortality in both types I and type 2 diabetes117. Exercise stress testing before starting an exercise program is recommended for previously sedentary diabetics or those with car- diovascular autonomic neuropathy118. 2.3 CHRONIC KIDNEY DISEASE The role of sedentary behavior and exercise on GFR and albuminuria, or both, has been extensively studied119−123. Sedentary behavior increases the risk of developing CKD, while physical exercise reduces this risk124−126. In a prospective analysis of the Car- diovascular Health Study, greater baseline physical activity was associated with a lower risk of GFR decline >3 mL/min/1.73 m2 per year over 7 years of follow-up127. In the Second National Health and Nu- tritional Examination Survey, highly active people, when compared with inactive people, demonstrated a reduced risk for developing kidney failure or dying of CKD over a mean of 13 years128. A recent study has also confirmed the preventive benefits of exer- cise in CKD129 . MEERP LTD CMI JOURNAL 2 (2), 124−143 (2021) 128 EXERCISE AND NON-COMMUNICABLE DISEASES: PART II CANCER, DIABETES MELLITUS, KIDNEY DISEASES, ALZHEIMER’S DISEASE, ARTHRITIS Once CKD has developed, physical activity in the affected individual slows down130. This deteriora- tion in physical performance is evidenced by a de- creased walking capacity, muscle strength, balance, and fine motor skills131−134. With the initiation of dialysis, physical functioning does not improve135 and continues to deteriorate136 usually becoming a major disability137. The National Kidney Foundation recommends that patients with CKD on dialysis be “counseled and regularly encouraged by nephrology and dialysis staff to increase their level of physical activity”138. This is because several studies have demonstrated that physical activity benefits patients with CKD139. Exercise in these patients is associ- ated with not only a slower decline in eGFR, but often an improvement140,141. In a meta-analysis of 13 RCTs totaling 421 patients with CKD, Zhang et al concluded that exercise therapy was associated with a +2.6 mL/min increase in eGFR142. Greenwood et al in a retrospective longitudinal cohort study estimated that each extra hour of sedentary behavior was associated with a worsening of kidney function, while each extra hour of total physical activity was associated with a better kidney function143. Exercise training in dialysis patients prevents muscle atro- phy and improves functional capacity and quality of life144,145. Benefits of exercise have also been noted in renal transplant patients146. Besides the benefits for the kidneys, exercise in CKD patients improves aerobic and functional capacity147,148. It improves peak/maximum oxy- gen consumption, strength, fine motor skills, and balance149,150. There is a reduction in cardiovascular outcomes151. Several benefits have also been noted with exercise following renal transplantation152. Overall, exercise in CKD patients imparts a bet- ter prognosis, a better quality of life, and better survival153−155. Exercise (aerobic, resistance, and flexibility) has been recommended for CKD patients by major kidney organizations156−158. Exercise is usually feasible, and well-tolerated in CKD patients, including those on dialysis and those following renal transplantation159−161. Physical activity may be associated with GFR and albuminuria via mechanisms such as modulation of inflammation, endothelial function, the renin- angiotensin system, and renal sympathetic nerve activity162−164. The beneficial change in GFR and albuminuria may also be mediated by modifica- tion of risk factors such as T2DM blood pressure, adiposity, and dyslipidemia, by increased physical activity165−168. 2.4 ALZHEIMER'S DISEASE Exercise and brain health are intricately associated169. Several cross-sectional, longitudinal observational studies and narrative reviews have discussed the benefits of exercise on cognitive function170−172. Meta-analytic reviews have con- cluded that older adults are protected against cognitive decline if they engage in exercise173−175. Northey and his group noted after analyzing 36 studies that physical exercise, in people over the age of 50, improved cognitive function, irrespective of their baseline cognitive status173. Falck et al conducted a systematic review and meta-analysis of 48 studies involving adults aged 60 or older and noted that exercise was associated with an improvement in cognitive function174. Chen et al recently performed a meta-analysis of 33 RCT studies and concluded that exercise interventions improve executive function175. Executive functions mainly originate in the prefrontal cortex and include attentional control, working memory, inhibition, and problem-solving. They are all important aspects of cognition. Hamer and Chida in a systematic review involving 163,000 non-psychotic participants found that the risk of dementia and AD was lowered by 28% and 45% with physical activity176. Lautenschlager et al found that in older adults with mild cognitive im- pairment, 142minutes of extra exercise per week im- proved cognition177. Twomore recent meta-analyses have also confirmed the slowing effects of aerobic exercise on cognitive decline, in patients with MCI or even AD178,179. Zheng et al evaluated 11 studies involving 1497 participants and found that in patients with MCI, aerobic exercise improved global cogni- tive ability and memory178. Panza and colleagues in a meta-analysis of nineteen studies, which included 1,145 subjects, reported that exercise training may delay the decline in cognitive function that occurs in individuals who are at risk of or have devel- CMI JOURNAL 2 (2), 124−143 (2021) MEERP LTD 129 MEERP LTD SHASHI K. AGARWAL, MD oped AD179. In patients with AD, exercise results in an improvement in cognitive function180, decreased neuropsychiatric symptoms, and a slower decline in activities of daily living181. And, consequently, reduced caregiver burden182. Patients with AD ex- perience fewer side effects183 and better adherence to medications184, with exercise. The mechanisms behind the exercise-related improvement in brain health have been well studied185,186. Exercise preserves neurogenesis187,188 and helps beneficial neuroplasticity189. Exercise also helps improve diabetes, hypertension, obesity, stress, depression, and inflammation, which are also risk factors for dementia190. In conclusion, physical activity is inversely associated with the risk of developing and the progression of dementia. 2.5 ARTHRITIS The beneficial role of exercise in osteoarthritis is also persuasive191−195. Improved pain and functional out- comes after exercise therapy in OA are well demon- strated by numerous meta-analytic studies191,192. Goh et al showed that exercise not only significantly reduced pain and improved function in patients with OA, but improved performance and QOL in these patients as compared with usual care at 8 weeks193. Both traditional exercises such as aerobic, resistance, and flexibility, and non-traditional exercises such as Tai Chi, Yoga, and aquatics are effective in the management of knee and hip osteoarthritis194. In their systematic review of 44 clinical trials involv- ing patients with knee osteoarthritis, there was an improvement in physical function and the quality of life, and these effects lasted up to six months after cessation of land-based therapeutic exercises195. Se- vere hip osteoarthritis is one of the main causes of disabling pain, functional impairment, and reduced quality of life in elderly patients196. In a review of 10 RCTs, researchers concluded that land-based therapeutic exercises can reduce pain and improve physical function among people with symptomatic hip OA197. Land- and aquatic-based physical activ- ities help patients with both knee and hip OA to reduce pain and increase mobility, muscle strength, joint flexibility, and aerobic endurance198. Initially, aquatic exercises may be deployed. The buoyancy of the water decreases joint loading, which can help decrease pain, and warm water may also have a therapeutic effect199. Once patients become more mobile, they can transition to land-based exercises. Exercise should be the main intervention for OA patients193,200. Weesandt and his group in a review concluded that osteoarthritis can be successfully managed and treated through exercise, with minimal risk of negative consequences201. Rheumatoid arthritis also responds well to physical exercise202−208. These patients notice an improve- ment in joint health and mobility. They increase their aerobic work capacity and become more physically active. They notice an improvement in endurance, strength, and dynamic balance. Rheumatoid fatigue and cachexia are reduced. There is also an improve- ment in psychological well-being. Increased physical activity and exercise also help reduce the impact of systemic manifestations of RA209, such as increased inflammation, disturbed vascular function, and in- creased cardiovascular risk in these patients210−212. Despite these benefits, RA patients have lower phys- ical activity levels than healthy individuals213−215, with 71 % of RA patients not participating in regular physical activity216. Exercise is relatively safe as compared with pharmacological treatments in the management of arthritis217. The American College of Rheumatol- ogy/Arthritis Foundation guidelines for the manage- ment of arthritis of the hip and knee emphasize the importance of regularly performed physical exercise as an important therapeutic intervention218. 3 CONCLUSION Exercise plays a major preventive and therapeutic role in most non-communicable diseases. It imparts positive physical and psychological health outcomes. It is safe and feasible for most NCD patients. It can help maintain or increase physical independence over time and decrease caregiver burden. Most pro- fessional associations of NCDs emphasize the incor- poration of exercise for the prevention and manage- ment of these diseases. Acknowledgment: None MEERP LTD CMI JOURNAL 2 (2), 124−143 (2021) 130 EXERCISE AND NON-COMMUNICABLE DISEASES: PART II CANCER, DIABETES MELLITUS, KIDNEY DISEASES, ALZHEIMER’S DISEASE, ARTHRITIS Funding: None Conflict of interest: None REFERENCES 1. Suzuki K. Chronic Inflammation as an Im- munological Abnormality and Effectiveness of Exercise. Biomolecules. 2019 Jun 7;9(6):223. doi: 10.3390/biom9060223. 2. Galán-Martín MA, Montero-Cuadrado F, Lluch-Girbes E, Coca-López MC, Mayo- Iscar A, Cuesta-Vargas A. Pain neuroscience education and physical exercise for patients with chronic spinal pain in primary healthcare: a randomised trial protocol. 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Clinical Medicine Insights. 2021;124−143. https://doi.or g /10.52845/CMI/2021-2-2-5 MEERP LTD CMI JOURNAL 2 (2), 124−143 (2021) 143 Introduction Discussion CANCER DIABETES MELLITUS CHRONIC KIDNEY DISEASE ALZHEIMER'S DISEASE ARTHRITIS CONCLUSION