Clinical Medicine Insights Received 25 Jul 2021 | Revised 22 Aug 2021 | Accepted 18 Sept 2021 | Published Online 01 Oct 2021 DOI: https://doi.org/10.52845/CMI/2021-2-4-1 CMI JOURNAL 2 (4), 201−223 (2021) ISSN (O) 2694-4626 REVIEW ARTICLE Diet and Non-Communicable Diseases: Part I Cardiovascular Diseases, Respiratory Diseases, Obesity, Depression, Liver Diseases Shashi K. Agarwal, MD ∗ 12227 US Highway 1, #309 North Brunswick, NJ 08902, USA Abstract Diet is involved in the development and progression of several chronic diseases. These include diseases that are responsible for a major health burden globally, such as cancer, cardiovascular diseases, obesity, di- abetes mellitus, and depression. The scientific world is replete with studies on the impact of dietary factors and common diets on these ailments. Prudent dietary habits sever both preventive and therapeutic roles in several non-communicable diseases. Healthy diets are primarily plant-based, and low in red and processed meats and sugar-sweetened beverages. This manuscript discusses our understanding of the modulation of diet in order to mitigate cardiovascular diseases, respiratory diseases, obesity, depression, and liver diseases. Keywords: diet, non-communicable diseases, cardiovascular diseases, respiratory diseases, obesity, depression, liver diseases 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 I t is estimated that almost 10% of the global burden of disease is related to poor diet1. The influence of diet has been noted with several ailments, including cardiovascular diseases2,3, di- abetes mellitus4,5, cancer6,7, lung diseases8,9, gas- trointestinal diseases10−12, kidney diseases13,14, neu- rological diseases15,16, mental disorders17−19, and arthritis20,21, and many others22−25. A poor diet re- duces the quality of life26. It is also one of the leading causes of accelerated aging27, disability28, and excess mortality29. The seven countries study, reevaluated in 2017, highlighted the substantial in- fluence of diet on health30. Dietary interventions have become a core aspect of primary and secondary prevention of the most common non-communicable diseases (NCDs)31. Besides caloric restriction to avoid overweight and obesity (a body mass index below 25 kg/m2)32, a healthy diet is well balanced and consists of high consumption of non-starchy vegetables, fruits, whole grains, and legumes, a lim- CMI JOURNAL 2 (4), 201−223 MEERP LTD 201 Open Access Journal https://doi.org/10.52845/CMI/2021-2-3-7 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 ited to moderate consumption of nuts, seafood lean meats, low-fat dairy products, and vegetable oil rich in mono and polyunsaturated fats, and limitation or elimination of trans-fats, saturated fats, fried foods, sodium, red meat, refined carbohydrates, and sugar- sweetened beverages33−35. Several diets have become popular for their bene- ficial health effects36−38. The most common ones are the Mediterranean39, Dietary Approaches to Stop Hypertension (DASH)40, and vegetarian41 diets. The Mediterranean diet is commonly followed in the olive-growing areas of the Mediterranean region. These residents have a high intake of vegetables, whole grains, legumes, fresh fruit, non-refined ce- reals, nuts, and extra virgin olive oil. They have a moderate consumption of fish, poultry, and dairy, and a low intake of red meats (usually reserved for special occasions only) and sweets. Their intake of alcohol is moderate and usually limited to red wine consumed during their main meals36,39. Meta- analysis of cohort studies on this diet revealed a 10% reduction in cardiovascular events and 8% reduction in mortality39. The DASH diet is low in sodium (< 2300mg/day) and has been promoted by theNational Institutes of Health to treat hypertension. It also encourages consumption of fruits and vegetables of different colors, fat-free or low-fat dairy prod- ucts, whole grains, and various protein sources (e.g., seafood, lean meats, eggs, legumes, nuts, seeds, and soya) while limiting added sugars (< 10% of calories per day), saturated fats (< 10% of calories per day), and alcohol (≤ 1 drink per day for women and ≤ 2 drinks per day for men). Besides effects on blood pressure, it also helps in improving other risk factors for CVD and diabetes mellitus37,40. A vegetarian diet is a plant-based diet, rich in whole grains, cereals, legumes, fruits, leafy ground vegetables, nuts, seeds, Supplementary information The online version of this article (10.52845/CMI/2021-2-4-1) 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 sea vegetables38,41. The term semi-vegetarians is sometimes used to describe individuals who con- sume meat up to or less than once a week. Lacto- vegetarians eat dairy products, ovo-vegetarians eat eggs, lacto-ovo vegetarians eat both dairy products and eggs, while a pesco-vegetarian eats fish, in ad- dition to the plants42. A vegan usually consumes no food from animal sources43. The nature of veg- etarianism often varies between different cultures and regions44−46. Most European and North Amer- ican vegetarians eat dairy products and eggs and are therefore lacto-ovo-vegetarians44. Asian Indian vegetarians are mainly lacto-vegetarians45. Dairy in- take is much less in Chinese vegetarians when com- pared to Western vegetarians46. Vegetarian diets are specifically linked to a lower risk of coronary artery disease and type 2 diabetes43,47, while vegan diets, in addition, also help in losing weight43. The impact of diet on common chronic medical conditions is discussed in this two-part manuscript. Part I discusses the relationship between diet and cardiovascular diseases (CVD), chronic obstructive pulmonary disease (COPD), obesity, depression, and liver diseases. Part II discusses its impact on cancer, diabetes mellitus (DM), kidney diseases, Alzheimer’s disease, and arthritis. 2 DISCUSSION CDC defines chronic diseases as “conditions that last 1 year or more and require ongoing medical attention or limit activities of daily living or both”48 Most chronic diseases are NCDs, and their incidence and prevalence is growing all over the world49. Diet is an important modifiable risk factor for chronic diseases development and progression50−52. Cardio- vascular diseases (CVDs) are a heterogeneous group of diseases of the heart and the circulatory system53. CVDs are associated with extremely high morbid- ity and continue to be the leading cause of pre- mature mortality worldwide54. It is estimated that by the year 2030, 23.6 million people will die of CVDs per year55. The underlying cause is usually atherosclerosis56. Chronic respiratory diseases are common non-communicable diseases57 and include chronic obstructive pulmonary disease (COPD), MEERP LTD CMI JOURNAL 2 (4), 201−223 (2021) 202 mailto:usacardiologist@gmail.com DIET AND NON-COMMUNICABLE DISEASES: PART I CARDIOVASCULAR DISEASES, RESPIRATORY DISEASES, OBESITY, DEPRESSION, LIVER DISEASES asthma, interstitial lung diseases, pulmonary sar- coidosis, and pneumoconiosis such as silicosis and asbestosis58. It is estimated that 545 million peo- ple in the world suffered from chronic respiratory diseases in 201759. They remain a leading cause of death and disability worldwide60. They caused more than 3.8 million deaths in 2017, which ac- counted for 7% of all global deaths and 9% of all NCD deaths61. Obesity is an increasing public health problem worldwide62. Besides its epidemic influence in adults, it is increasingly affecting chil- dren and adolescents63. Obesity leads to a wide array of illnesses such as type 2 diabetes mellitus (DM)64, hepatic steatosis65, gallbladder diseases66, osteoarthritis67, and several cancers (such as those of the endometrium, breast, ovary, prostate, liver, gallbladder, kidney, and colon)68, in addition to the diseases discussed in this manuscript. Even modest weight loss—5%decrease in bodyweight—has been shown to lower the risk of chronic disease69,70. Its etiology is multifactorial, but diet plays an important role71. Obesity increases mortality72. Depressive dis- orders are the leading cause of global disability73. It is usually associated with a low mood, sadness, lack of energy, and an inability to enjoy life74. It also affects physical health75. Overall, depression leads to a considerable reduction in the quality of life, med- ical comorbidity, and mortality76,77. Chronic liver diseases have become a major international pub- lic health concern78−80. It is estimated that non- alcoholic fatty liver disease (NAFLD) has a preva- lence of around 25% of the general population81. Diet also plays a major role in alcoholic liver dis- ease (ALD)82 . Diet also is associated with liver cancer83. Chronic liver diseases cause more than 2 million deaths per year57. These diseases and their relationship with diet are discussed below. 2.1 CARDIOVASCULAR DISEASES Poor eating habits are a major modifiable risk factor for cardiovascular diseases (CVD)84−86. A plethora of scientific studies indicates that red and processed meat87, fried foods88, sugar-sweetened beverages89, excess alcohol intake90 and obesity91 have detrimen- tal effects on CVDs, while fruits and vegetables92,93, whole grains94, fiber95, tree nuts96, chocolate97, and coffee98 are cardioprotective. The most effective dietary intervention is probably salt restriction99. This leads to blood pressure (BP) reduction, which is associated with a substantial re- duction in morbidity and mortality from CVDs100. According to major US cardiology associations, a reduction of salt intake to <1500 mg/d101 should bring the BP down by about -5/6 mm Hg systolic and -2/3 mm Hg diastolic102. Obesity is closely re- lated to hypertension (HTN)103, and weight reduc- tion in obese individuals, via calorie restriction, or other dietary changes, is also associated with BP reduction104. The AHA estimates that every 1 Kg (2.2 lbs) weight reduction is associated with about a 1mmHg reduction in systolic BP105. A change in the quality of diet also helps105,106. A diet rich in fruits, vegetables, whole grains, low-fat dairy products and with a reduction in saturated and total fat has also been estimated to reduce systolic BP by -11 mm Hg and diastolic BP by – 3mm Hg105. Both the DASH diet107 and theMediterranean diet108, help reduce BP in patients with HTN. Controlling HTN helps reduce several CVDs, including stroke109, heart failure110, and cardiac arrhythmias111. The major beneficial impact of a drop in BP is, however, on coronary artery disease112,113. In a recent longitudinal study of 153,082 US veterans, the DASH diet was in- versely associated with the incidence of coronary artery disease (CAD)114. Another study, a meta- analysis of cohort studies determined that adherence to the DASH diet resulted in a 21% reduced risk of CAD115. The Lyon Diet Heart Study, which evalu- ated the impact of the Mediterranean diet on CAD, found a reduction in coronary mortality of 65% after 46 months116. Benefits of a healthy diet have also been recorded with stroke117, heart failure118, peripheral arterial disease119, and vasculogenic erec- tile dysfunction120. A high-fat diet has also been linked to an increase in cardiac arrhythmias121, and SCD122. A cardiovascular healthy diet also helps reduce hypercholesterolemia123, DM124, and chronic kidney disease125 – all major risk factors for CVDs. 2.2 RESPIRATORY DISEASES The adverse association between obesity and COPD is well known126,127. Obesity risks increase with the CMI JOURNAL 2 (4), 201−223 (2021) MEERP LTD 203 MEERP LTD SHASHI K. AGARWAL, MD consumption of an energy-dense, high fat, and low- fiber diet, resulting in excess caloric intake128. The quality of diet also appears to influence COPD129,130. Several diets appear to reduce the development of COPD from 25% to 54%131−133. The most impor- tant beneficial component of these diets appears to be a higher intake of fruits and vegetables134. con- sumption of fish135, and a lower intake of processed meats136. A diet rich in a higher intake of meat and potatoes, and a lower intake of soy and cereal has been associated with lower forced expiratory volume in one second (FEV1) and an increased prevalence of COPD137. In patients with diagnosed COPD, pa- tients on a diet with high consumption of fruits and vegetables demonstrated an annual increase in their FEV1 while those on a usual diet showed a decrease in FEVI during 3 years of followup138. Several recent studies have confirmed the beneficial effects of fruits and vegetables in retarding the development and progression of COPD139−141. Several micronutrients are present in high amounts in fruits and vegeta- bles, are associated with better lung parameters and their presence may explain their beneficial effect in patients with COPD142,143. These include vita- min C142, alpha-tocopherol140, and beta-carotene143. Their benefits have been attributed to a reduction in inflammation and oxidative stress144. Fish oils are anti-inflammatory and are protective against the de- velopment of COPD145. Micronutrients like calcium, phosphorus, iron, potassium, and selenium also ap- pear to be beneficial in these patients146. Vitamin D supplementation, especially in those with severe de- ficiency, also helps in reducing the number of COPD exacerbations147. Diet also influences COPD-related mortality148. Walda et al noted an inverse trend for 20-year COPD mortality, and a 100 g increase in fruit intake at baseline resulted in a 24% lower COPD mortality risk149. Obesity, which is usually associated with an energy- dense, low fiber, and high-fat diet, is common in asthma patients150 with harmful effects151,152. Ex- cess body weight is associated with reduced lung volumes, poorer asthma control and outcomes, and poorer quality of life151,152. Excess adipose tissue induces immunometabolism disarray, increased ox- idative stress, and decreased bioavailability of nitric oxide, producing or aggravating airway disease153. Reduction in weight helps, as has been demonstrated by bariatric surgery studies that have resulted in dramatic improvements in asthma control and lung function154. A weight-reducing diet is therefore ben- eficial in asthma patients155. Asthma is an inflam- matory disease156, and the latter can be beneficially modulated with a judicious diet157. In adults with severe asthma, higher fat and lower fiber intake have been associated with increased eosinophilic airway inflammation158. Reduction of dietary sat- urated fat intake reduces this inflammation159. In contrast, fruits, vegetables, and their antioxidants help lower airway inflammation160,161. A study from Mexico demonstrated that fruit and vegetable in- take was inversely associated with IL-8 protein in nasal lavage of asthmatic children, indicating re- duced inflammation162. In asthmatic adults, intake of tomato juice, which is abundant in the antioxi- dant lycopene, reduced airway neutrophil influx and sputum neutrophil elastase activity after just seven days of supplementation157. On the other hand, a diet characterized by highly processed foods, with high intakes of refined grains, processed and red meats, desserts and sweets, fried foods, and high-fat dairy products, with low intake of fruits and vegetables has harmful effects on asthma in children163−165. Several case–control studies indicate that a diet rich in vegetables and fruits, may exert some protective effect against lung cancer166,167. Cruciferous vegeta- bles, such as broccoli, are rich in isothiocyanates, and these have cancer-preventive activity166. A high intake of total or saturated fat does not appear to increase the risk of lung cancer, as a pooled analysis of eight cohort studies showed168. However, high levels of nitrosamines (formed during cooking) in fried or well-done red meat, appear to increase lung cancer risk169,170. 2.3 OBESITY Excess caloric intake without corresponding energy burn results inweight gain171. An imbalance between energy intake and expenditure, results in an increase in the number (hyperplasia) and size (hypertrophy) of adipocytes172,173. In other words, individuals con- suming more calories than the recommended daily allowance according to the METs expended, are MEERP LTD CMI JOURNAL 2 (4), 201−223 (2021) 204 DIET AND NON-COMMUNICABLE DISEASES: PART I CARDIOVASCULAR DISEASES, RESPIRATORY DISEASES, OBESITY, DEPRESSION, LIVER DISEASES likely to become overweight or obese171. Excess calories are easier to consume with food rich is fats and sugars, and low in fiber174. Ultra-processed foods are typical examples - they are highly pro- cessed foods high in total energy, free sugars, sat- urated fats, sodium, and additives, and low in fiber, protein, phytochemicals, and micronutrients – with additives primarily to increase their shelf life without increasing their cost175. The foods include chips, car- bonated soft drinks, sweet or savory snacks, confec- tionary, mass-produced packaged bread, buns, pas- tries, cakes, biscuits and desserts, prepacked break- fast cereals, preprepared meals, including pies, pasta and pizza dishes, reconstituted meat and meat prod- ucts, ‘instant’ soup, and noodle dishes175. Ultra- processed foods account for about 50–60 % of the energy content in the usual diet of the average US, Canadian, or British consumer176−178. Several epidemiological studies have examined dif- ferences in body weight based on dietary patterns. Findings from AHS, EPIC and the Swedish Mam- mography Cohort studies found that omnivores had the highest prevalence of overweight and obesity compared to individuals eating less meat, such as plant-based diets179. The EPIC-PANACEA study showed that an increase in 250 g/day of meat led to a 2 kg weight gain after 5 years180. In a study examining a cohort of 49,098 Taiwanese adults, the percentage of participants with a BMI ≥ 27 kg/m2 was significantly lower among those following a vegetarian diet (10.9%) as compared to those fol- lowing a non-vegetarian diet (15.4%)181. The Ad- ventist Health Study also demonstrated that BMI increases as the number of animal foods in the diet increased182. In this study, vegans had the lowest BMI, followed by vegetarians, pesco-vegetarians, semi-vegetarians, and omnivores182. The European Prospective Investigation into Cancer and Nutri- tion (EPIC-Oxford) study found that vegans gain significantly less weight as they age compared to omnivores183. Plant-based diets also help in weight loss184,185, Huang et al in ameta-analytic study found significant weight loss with plant based diets184, while Barnard et al reported in another meta-analysis that plant-based diets were associated with a mean weight loss of −3.4 kg to 4.6 kg185. Several sub- sequent clinical trials, including the New DIETs study186, HER Health Study187, and the VA BEACH Diet Study188, have also confirmed the weight loss benefit associated with plant-based diets. A prudent diet – plant based or restricted in calories, should ide- ally include 60% carbohydrate intake, 25% protein intake, and 15% fat intake189. Weight loss in these patients is enhanced by combining exercise190 - reg- ular moderate-intensity aerobic exercise for at least 150 min per week or more than 300 min per week. Resistance exercises at moderate intensity two times per week with 10 to 15 resistance exercise repetitions should also be part of this exercise regimen. 2.4 DEPRESSION Diet is a well-known factor associated with depression191−194. As mentioned before, a calorie- rich diet may result in obesity128. Obesity is harmful to depression195. The prevalence of depression in obese individuals is twice as high as in those of normal weight196,197. An improvement in the diet, especially with calorie restriction resulting in weight loss may help with an improvement in depression symptoms198,199. Depression can also lead to obesity, indicating that there is a bidirectional causality200−202. The quality of diet also has a major impact on depression203. Lassale et al. in a review and analysis of 20 longitudinal and 21 cross-sectional studies, concluded that an inverse association between healthy diet and depression204. A recent meta-analysis confirmed that ‘healthy’ dietary patterns (regardless of the type) may contribute to the prevention of depressive symptoms205 . and this appears to be related in a linear dose-response fashion198. Diets low in fruit and vegetables206, fish207, or legumes208, are associated with an increase in depression. Diets rich in sugar, sodium, saturated fat209,210, meat, and eggs211,212 are associated with more depression. A diet with lower intakes of low-calorie foods is similarly harmful213. An unhealthy diet is often poor in several micronutrients, including tryptophan, inositol, magnesium, fiber, folate, and omega-3 fatty acids which are important for proper mental wellbeing214. However, dietary supplements do not appear to be very effective in reducing depression215. Improper diet and obesity result CMI JOURNAL 2 (4), 201−223 (2021) MEERP LTD 205 MEERP LTD SHASHI K. AGARWAL, MD in HPA axis dysregulation216. They also increase inflammation, oxidative stress, and other endocrine dysfunctions217. 2.5 LIVER DISEASES Nonalcoholic fatty liver disease (NAFLD) is a pro- gressive disease of the liver that ranges from hep- atic steatosis (liver fat >5% of liver weight) to more severe steatohepatitis, (NASH, hepatocellular inflammation}, with progression to fibrosis and end- stage cirrhosis218. Weight loss via caloric restriction remains the most viable option in the treatment of NAFLD and fibrosis219. Reducing body weight by 7- 10%with hypocaloric diets is the most efficacious in the treatment of NAFLD/NASH and fibrosis220,221, with greater weight loss (≥10%) being associated with the highest rates of NAFLD/NASH resolution and fibrosis regression222. However, histological im- provements are also observed with as little as 3- 5% weight loss223,224. A healthy diet, besides a diet that prevents excess body weight, is also impor- tant. Several diets, including the Mediterranean Pa- leolithic, ketogenic, high-protein, plant-based, low- carbohydrate, and intermittent fasting approaches all have shown beneficial health outcomes in these patients225. Dietary ingredients that are beneficial include soluble and insoluble fiber, monounsaturated or polyunsaturated fatty acids, several micronutri- ents, vitamins E, C, and D, and several polyphenols (e.g., resveratrol, curcumin, caffeine, quercetin) are also helpful in NAFLD226,227. On the other hand, fructose and saturated fatty acids contribute to the pathogenesis of NAFLD228. Alcohol intake in ex- cess induces hepatic damage resulting in alcohol liver disease, which includes liver steatosis, fibrosis, cirrhosis, and alcoholic hepatitis229. These can be prevented by alcohol abstinence and the damaged liver can be helped with nutritional support. Patients with ALD usually suffer from malnutrition230, and this exacerbates the severity of the liver disease231. These patients may either have an intake of an unhealthy diet with too few essential nutrients or the alcohol may prevent the body from digesting and utilizing essential nutrients232. Many ALD pa- tients suffer from protein-calorie malnutrition233 which increases complications. The American Col- lege of Gastroenterology and the American As- sociation for the Study of Liver Diseases guide- lines recommend 1.2 to 1.5 g/kg per day of pro- tein intake and 35 to 40 kcal/kg per d of body weight for energy intake in patients with ALD82 Be- sides these macronutrients, ALD patients need sev- eral micronutrients to protect liver toxicity and dis- tant complications include zinc234, magnesium235, selenium236, vitamins D237, vitamin E238, folate239, niacin240, and thiamine241. A proper nutritional sup- port in patients with ALD helps reduce infectious complications and improves 1-year mortality in such patients242,243. There is a strong association between obesity and hepatocellular carcinoma244,245 .The re- sults show that diet plays an important role in HCC occurrence246. Several diets have been noted to lower the risk of hepatocellular carcinoma247,248. These di- ets are usually rich in foods such as vegetables249,250, poultry251, fish252, wholegrains253, nuts254, tea255, and caffeinated coffee256,257. Micronutrients such as vitamin E, vitamin B9, β-carotene, manganese, and potassium may help in reducing the develop- ment of HCC258. Some fats, including monoun- saturated fats259, may also have beneficial effects. However, data indicates that processed red meat consumption260 high-fat dairy foods261, and in- gestion of sugar-sweetened beverages262 may in- crease HCC risk. Heavy alcohol intake is also harmful263,264. 3 CONCLUSION A healthy diet should provide adequate macro and micronutrients, and avoid harmful saturated fat, pro- cessed meats, sugar-sweetened drinks, excess salt, and excess alcohol. The beneficial effects of a pru- dent diet on several NCDs are strong. Water is also an important component of diet265. It comprises from 75%bodyweight in infants to 55% in the elderly. Be- sides providing adequate hydration, plain water in- take is associated with a decrease in sugar-sweetened beverages, and a decrease in caloric intake. Water intake should not be forgotten as a beneficial com- ponent of a healthy diet. Acknowledgment: None Funding: None MEERP LTD CMI JOURNAL 2 (4), 201−223 (2021) 206 DIET AND NON-COMMUNICABLE DISEASES: PART I CARDIOVASCULAR DISEASES, RESPIRATORY DISEASES, OBESITY, DEPRESSION, LIVER DISEASES Conflict of interest: None 4 REFERENCES 1. Gakidou E, Afshin A, Abajobir AA, Abate KH, Abbafati C, Abbas KM, et al. Global, re- gional, and national comparative risk assess- ment of 84 behavioural, environmental and oc- cupational, and metabolic risks or clusters of risks, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2017;390(10100):1345-422. 2. D’Souza MS, Dong TA, Ragazzo G, Dhindsa DS, Mehta A, Sandesara PB, Freeman AM, Taub P, Sperling LS. 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European Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition, and Allergies. Scientific opinion on dietary reference values for water. EFSA J 2010;8:1459. How to cite this article: Agarwal S.K, MD DIET AND NON-COMMUNICABLE DISEASES: PART I Cardiovascular Diseases, Respiratory Dis-eases, Obesity, Depression, Liver Diseases. Clin-ical Medicine Insights. 2021;201−223. https://doi. org/10.52845/CMI/2021-2-4-1 CMI JOURNAL 2 (4), 201−223 (2021) MEERP LTD 223 Introduction Discussion CARDIOVASCULAR DISEASES RESPIRATORY DISEASES OBESITY DEPRESSION LIVER DISEASES CONCLUSION REFERENCES