Understanding Flavonoids and Their Role in Health

Understanding Flavonoids and Their Role in Health Johanna Dwyer, DSc, RD, Tufts University John Erdman, PhD, University of Illinois Barbara Lyle, PhD, ILSI North America, moderator Sponsored by ILSI North America & American Society for Nutrition August 2015 ASN Membership Benefits Are you dedicated to research and the application of nutrition science to improve public health and quality of life? Journal Access Free online access to The American Journal of Clinical Nutrition (AJCN), The Journal of Nutrition and Advances in Nutrition - #1 and #3 ranked scholarly pubs in nutrition/dietetics Research & Clinical Communities - Fifteen Research Interest Sections (RIS) - Three Scientific Councils: Global Nutrition, Medical Nutrition and Nutritional Sciences Multimedia content at www.nutrition.org - Journal access - Teaching resources, podcasts and webinars Networking - Advance your career! ASN members include researchers, medical practitioners, allied health professionals, international scientists and clinicians, postdoctoral/young professionals, students, and industry 1

A Few Reminders CPE Credit ASN designates this educational activity for a maximum of 1.5 CPEUs. Dietitians and Dietetic Technicians, Registered should only claim credit commensurate with the extent of their participation in the activity. To claim credit, please take the post webinar evaluation to be emailed after the webinar. Questions & Answers Submit questions by typing them in the questions box on your Go To Meetings screen. Submit your questions at any time during today s webinar and we will cover them at the end. 2

International Life Sciences Institute North American Branch A public, non-profit scientific organization that advances the understanding and application of science related to the nutritional quality and safety of the food supply. Sponsored research Professional & educational programs Seminars, workshops, and publications ILSI North America's programs are funded primarily by its industry membership. This webinar was sponsored by the ILSI NA Technical Committee on Bioactives Flavonoids, Polyphenols, and Carotenoids. ILSI s tri-partite structure creates a neutral forum for discussing scientific issues that impact the health of the public. Dr. Eric Hentges, PhD, Executive Director Dr. Barbara Lyle, PhD, Sr. Nutrition Advisor 6 3

Disclosures for Johanna Dwyer 7 Disclosures for John Erdman 8 4

Outline Definition, classification, and structure of flavonoids Possible health benefits by subclass Food sources Dietary recommendations 9 Objectives Participants will be able to: 1 2 3 State what flavonoids are State food sources of flavonoids Describe the putative role of flavonoids in health 10 5

Overview Flavonoids have always been around, but our understanding of them is in the early stages. Over 4,000 flavonoids have been identified in foods - occurring in fruit, vegetables, legumes and beverages. 1 New research and databases have allowed us to gain insight and expand application of knowledge 2 3 Still much work to ascertain absolute values for recommendations Clarification is needed about how to make accurate claims by differentiating between whole foods and specific flavonoids 11 The Big Picture of Bioactives THE DIVERSITY OF BIOACTIVE PHENOLS S P E C I F I C I T Y Phenolics Polyphenolics Flavonoids Bioactives are constituents in foods, other than those to meet basic nutritional needs, that are responsible for a change in human health.* *(Office of Disease Prevention & Health Promotion) Phenolics and their many derivatives are an example of one large group of these bioactives. Though often used interchangeably, there are important chemical differences between these groups of bioactive phenols and their safety. 12 6

Polyphenol Family Polyphenols Tannins Coumarins Stilbenes Flavonoids Flavones Flavanones Isoflavones Flavonols Parsley, thyme, oregano, some exotic fruits Oranges, tangerines, tangelos Soy, tempeh, miso, okra Tea, onions, berries, greens Flavanols & Proanthocyanidins Cocoa, tea, red wine, berries Anthocyanidins Blueberries, cranberries, grapes, red wine 13 What are flavonoids? Flavonoids are polyphenolic compounds that are ubiquitous in nature and are categorized, according to chemical structure into: Flavones Flavanones Isoflavones Flavonols Flavanols and Proanthocyanidins Anthocyanins Phenol groups Antioxidant Activities of Flavonoids Department of Environmental and Molecular Toxicology Oregon State University 7

Classification of Flavonoids B A C Basic flavan ring structure 15 Subclass Structures Flavones Isoflavones Anthocyanidins Flavanones Flavonols Flavanols 16 8

Proanthocyanidins B-linked proanthocyanidin (grape, cocoa, apples, pears, blueberries) A-linked proanthocyanidin (cranberry, nuts and nut skins, cinnamon, plums) 17 Flavones (Luteolin, apigenin) Found in Juniper berries, kumquats, oregano, parsley, celery seed, and thyme Epidemiological studies show consumption is associated inversely with and inflammation and mortality Intervention studies show: Improved lipid profiles, antioxidant status and endothelial function in patients with mild hyperlipidemia Improved levels of blood antioxidant enzymes 18 9

Flavones Sources and Levels Food Per 100 g/100ml Per std. serving Celery Seed 900 mg 36 mg/tsp Oregano (fresh) 3 4 mg 0.1 0.2 mg/tsp Oregano (dried) Parsley (dried) Thyme (fresh) 1100 mg 4500 mg 45 mg 40 45 mg/tsp 150 200 mg/tsp 2 mg/tsp Sage (fresh) 15 mg 0.5 mg/tsp Flavanones (Hesperetin, Naringenin) Intervention studies show: Found in citrus fruits, such as oranges, and their juices Epidemiological studies show association between consumption and reduced risk of CHD, ischemic stroke, acute coronary events, and improved lipid profiles A significant increase in HDL C and improved LDL:HDL ratio Sweetie juice (a hybrid of pummelo and grapefruit) reduced systolic blood pressure in individuals with Stage I hypertension; reduced total, LDL C and triglycerides in individuals with existing CVD Improved flow mediated dilation, improved inflammatory markers, total cholesterol, and increased HDL in individuals with metabolic syndrome Chronic daily consumption of flavanone rich 100% orange juice over 8 week was beneficial for cognitive function in healthy older adults. 20 10

Flavanones Sources and Levels Food Grapefruit (whole) Grapefruit juice Orange Orange juice Lemon Tangelo juice Per 100 g/100ml 20 50 mg 15 20 mg 40 45 mg 15 30 mg 50 mg 100 125 mg Per std. serving 30 75 mg/average size (150 g) 35 50 mg/8 oz. 35 40 mg/small orange (96 g) 35 75 mg/8 oz. 3 mg/wedge 240 300 mg/8 oz. Isoflavones (Daidzein, Genistein) Intervention studies show: Found in soybeans; small amounts in chickpeas, fava beans, pistachios, peanuts & other fruits and nuts Epidemiological studies show an association with improved cardiovascular and women s health Bind weakly to estrogen receptors and can have estrogenic & anti estrogenic effects May reduce incidence of hot flashes in postmenopausal women Modest effects on maintaining bone density May slow progression of plaque in artery walls Improved blood vessel function Some may slow cancer cell growth in animals 22 11

Isoflavones Sources and Levels Food Soybeans (edamame) Soymilk Veggie Patty/Burger (textured soy protein) Soy Sauce Tofu, cooked (silken firm) Soy cheese (mozzarella, swiss) Per 100 g/100ml 80 150 mg 7 11 mg 4 6 mg 1 2 mg 20 40 mg 6 8 mg Per std. serving 50 100 mg per ½ cup 18 28 mg/8 oz. 3 4 mg/patty <0.3 mg/tbsp. 22 45 mg/4 oz. 2 3 mg per 1 oz. Flavonols (Quercetin, Isorhamnetin, Kaempferol, Myricetin) Found in almost every plant based food at some level, including onions, cranberries, tea, beans, & greens Epidemiological studies show mixed results; some evidence shows consumption associated inversely with risk of CVD and stroke Intervention studies show: Inhibited platelet aggregation and thrombus formation Lowered systolic blood pressure and plasma oxidized LDL concentrations in overweight individuals with a high CVD risk 24 12

Flavonols* Sources and Levels Food Per 100 g/100ml Per std. serving Tea Apples Cranberry juice Onions Blueberries Tomato (fresh & raw) 3 5 mg 5 10 mg 1 4 mg 10 40 mg 10 12 mg 1 mg 8 13 mg 8 oz. cup 9 18 mg/med. apple (180 g) 4 10 mg (8 oz. glass) 1 4 mg/1 Tbsp. (10g) 15 18 mg/1 c. (148 g) 1 2 mg/med. tomato (123 g) * Widely distributed in foods; found in nearly all plant-based foods 25 Flavanols & Proanthocyanidins* Found in cocoa, tea, grape products (juice, wine), and berries (including cranberries) Epidemiological studies show consumption associated inversely with risk of cardiovascular disease and stroke Intervention studies show: Improved nitric oxide dependent vascular function Inhibition of platelet aggregation Improved blood pressure Improved lipid profiles Improved cognitive function Type A proanthocyanidins in cranberry reduced adhesion of pathogenic bacteria and demonstrated of reduced occurrence of urinary tract infections *(polymeric form of flavanols) 26 13

Flavanols & Proanthocyanidins Sources and Levels Food Apples (whole w. skin) Apple juice Blueberries Cranberry juice Grapes (red w. skin) Red Wine Natural Cocoa Powder Dark Chocolate Brewed Tea (black/green) Peanut Butter Per 100 g/100ml 40 80 mg 12 15 mg 100 150 mg 15 mg 15 20 mg 10 20 mg 1300 mg 230 mg 60 120 mg 10 15 mg Per std. serving 70 145 mg per med. apple (180 g) 20 30 mg per 6 oz. 80 120 mg per 1 cup 30 mg per 6 oz. 14 18 mg per cup (92 g) 14 30 mg per 5 fl. oz. 65 mg per 1 Tbsp. 90 mg per 40 g bar 110 230 mg per 6 oz. 3 5 mg per 2 Tbsp. Anthocyanidins-Cyaninidin, Delphinidin, Malvidin, Pelargoindin) Intervention studies show: Found in berries, grapes, cherries, purple carrots, and red cabbage Epidemiological studies show consumption associated with improved cardiovascular health outcomes, stroke, as well as, cognitive outcomes (including those related to declines with aging) Improved lipid metabolism Improved insulin resistance Improved vascular function Lowering of markers of inflammation Improved cognitive function 28 14

Anthocyanidins: Sources and Levels Food Blackberries Blueberries Pear Strawberries Cranberries Raspberries Red cabbage Plums Per 100 g/100ml 20 50 mg 300 350 mg 10 12 mg 30 40 mg 90 100 mg 40 50 mg 70 80 mg 10 12 mg Per std. serving 30 70 mg/1 cup (144 g) 220 260 mg/1 cup (150 g) 18 22 mg med fruit (178 g) 40 60 mg per cup (144 g) 90 100 mg per cup (100 g) 50 60 mg per cup (122 g) 100 125 mg per cup, shredded (70 g) 7 8 mg per sm. plum (66 g) Sample Menu Flavonoids Breakfast 1 small whole wheat bagel 2 tablespoons peanut butter 1 medium orange 43 1 cup fat free milk 1 cup black tea 280 Lunch Arugula salad made with: 4 cups of fresh arugula leaves 55 1 sliced pear 32 1/2 cup canned mandarin orange sections 18 1/3 cup unsalted peanuts 2 tablespoons reduced fat red wine vinaigrette Dinner Herb crusted baked cod, 3 ounces (blend of 1 tsp parsley, oregano, and celery seed) 100 12 reduced sodium wheat crackers 1 cup fat free milk 1/2 cup brown rice pilaf 1 cup edamame, steamed 180 1 small sourdough roll 1 teaspoon trans fat free margarine 1 cup fresh sweet cherries (with pits) 58 Brewed white iced tea (2c) 350 Snack (anytime) 1 cup lowfat yogurt 1 oz dark chocolate 45 Total 1178 30 15

Summary Flavonoids are naturally occurring and present in a wide variety of plant-based foods. Different types of foods contain different types of flavonoids No two foods exactly the same Diet diversity diversifies flavonoid intakes Flavonoids are demonstrated bioactive compounds in foods. Although studied for over two decades, the science on the benefits of flavonoids to health is promising, but still emerging. 31 Summary Research suggests that these dietary bioactive components may have a role in supporting improved health, including cardiovascular-related benefits anti-cancer benefits cognitive gastrointestinal and urinary tract health anti-inflammatory benefits Despite the emerging science, there is not yet today a quantified recommended intake level for flavonoids, or for any specific sub-class of flavonoids. 32 16

Where do these foods fit? Because many flavonoid-rich foods (like fruits, vegetables, legumes) are also nutrient-rich, including a range of plant-based foods means getting vitamins, minerals, and fiber, along with flavonoids! Consumers are increasingly hearing about the benefits of flavonoids, so you can use their interest to reinforce the benefits of including a range of plant-based foods in their diet to get these phytochemicals they want, plus the essential nutrients they need to support good health. 33 Focus on Dietary Guidelines Flavonoids are becoming increasingly recognized as an important beneficial dietary component, as noted several times by the Dietary Guidelines Advisory Committee in 2010: It is possible that nutrients are most beneficial to health when they are consumed in their natural form and in combination with each other, such as in vegetables (including cooked dry beans and peas), fruits, and whole grains. These foods contain not only the essential vitamins and minerals that are often targeted in nutrient supplement pills, but also hundreds of naturally-occurring phytonutrients and other substances, including flavonoids. p.125 Beneficial effects of chocolate have been attributed to polyphenolic compounds, in particular flavonoids. P.244 High-flavanol chocolate or cocoa significantly lowered systolic and diastolic BP p.244 34 17

What you can recommend Takeaway messages: There is currently no recommended level of intake for flavonoids (including subclasses of flavonoids), but there is emerging science to suggest that the inclusion of a range of flavonoids in the diet can support overall health. Eat a mixed diet with nutrient rich fruit, vegetables, legumes, and whole grains in order to get the essential nutrients that your body needs, as well as a range of flavonoids, that can help support your overall health. Don t forget to include herbs and spices like parsley, oregano, cinnamon, and thyme as a regular part of the diet simple and tasty ways to get more flavonoids in your diet. Many real fruit juices, red wine, and even dark chocolate contain flavonoids all tasty options for getting some flavonoids but do so in moderation as part of a balanced diet. 35 Many Thanks ILSI NA thanks Drs. Catherine Kwik Uribe, Mars, Incorporated & Doug Balentine, Unilever, along with the ILSI NA committee scientists for collaborating with Drs. Dwyer and Erdman in developing this webinar This slide deck, webinar and reference recommendations are available on the ILSI NA website. 36 18

Questions & Answers Please submit your questions via the questions box on your screen. Useful Resources Special Article in Am J Clin Nutr. 2015. http://ajcn.nutrition.org/content/early/2015/04/08/ajcn.113.071274.abstract 38 19

Useful Resources 1. USDA-Iowa State University Database on the Isoflavone Content of Foods, Release 2.0 2008 http://www.ars.usda.gov/news/docs.htm?docid=6382 2. U.S. Department of Agriculture, Agricultural Research Service. 2013. USDA. Database for the Flavonoid Content of Selected Foods, Release 3.1. http://www.ars.usda.gov/news/docs.htm?docid=6231 3. USDA Database for the Proanthocyanidin Content of Selected Foods, 2004. http://www.ars.usda.gov/news/docs.htm?docid=5843 4. Phenol-Explorer database, v 3.6 http://phenol-explorer.eu/ 39 Selected References FLAVONOIDS: Flavonoids and Related Compounds: Bioavailability and Function (Oxidative Stress and Disease). Oxidative Stress and Disease (Book 29). CRC Press; 1 edition (April 24, 2012). 472. Harborne, J.B. and H. Baxter, The handbook of the natural flavonoids. 1999, Chichester ; New York: Wiley. Harborne, J.B. and C.A. Williams, Advances in flavonoid research since 1992. Phytochemistry, 2000. 55(6): p. 481-504. FLAVONES Hirvonen, T., et al., Intake of flavonols and flavones and risk of coronary heart disease in male smokers. Epidemiology, 2001. 12(1): p. 62-7. Hirvonen, T., et al., Flavonol and flavone intake and the risk of intermittent claudication in male smokers. Eur J Epidemiol, 2004. 19(4): p. 305-11. Cassidy, A., et al., Habitual intake of flavonoid subclasses and incident hypertension in adults. American Journal of Clinical Nutrition, 2011. 93(2): p. 338-347. Landberg, R., et al., Selected dietary flavonoids are associated with markers of inflammation and endothelial dysfunction in U.S. women. J Nutr, 2011. 141(4): p. 618-25. Peterson, J.J., et al., Associations between flavonoids and cardiovascular disease incidence or mortality in European and US populations. Nutr Rev, 2012. 70(9): p. 491-508. Jennings, A., et al., Intakes of anthocyanins and flavones are associated with biomarkers of insulin resistance and inflammation in women. J Nutr, 2014. 144(2): p. 202-8. 40 20

Selected References FLAVANONES Mink, P.J., et al., Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. Am J Clin Nutr, 2007. 85(3): p. 895-909. Landberg, R., et al., Selected Dietary Flavonoids are Associated with Markers off Inflammation and Endothelial Dysfunction in U.S. Women. Journal of Nutrition, 2011. 141(4): p. 618-625. Duluc, L., et al., Mitochondria as potential targets of flavonoids: focus on adipocytes and endothelial cells. Curr Med Chem, 2012. 19(26): p. 4462-74. Kean, R.J., et al., Chronic consumption of flavanone-rich orange juice is associated with cognitive benefits: an 8-wk, randomized, double-blind, placebo-controlled trial in healthy older adults. Am J Clin Nutr, 2015. 101(3): p. 506-14. Sun, Q., et al., Urinary Excretion of Select Dietary Polyphenol Metabolites Is Associated with a Lower Risk of Type 2 Diabetes in Proximate but Not Remote Follow-Up in a Prospective Investigation in 2 Cohorts of US Women. J Nutr, 2015. Gorinstein, S., et al., Preventive effects of diets supplemented with sweetie fruits in hypercholesterolemic patients suffering from coronary artery disease. Prev Med, 2004. 38(6): p. 841-7. Morand, C., et al., Hesperidin contributes to the vascular protective effects of orange juice: a randomized crossover study in healthy volunteers. Am J Clin Nutr, 2011. 93(1): p. 73-80. 41 Selected References ISOFLAVONES Aubertin-Leheudre, M., et al., Effect of 6 months of exercise and isoflavone supplementation on clinical cardiovascular risk factors in obese postmenopausal women: a randomized, double-blind study. Menopause, 2007. 14(4): p. 624-9. Messina, M., A brief historical overview of the past two decades of soy and isoflavone research. J Nutr, 2010. 140(7): p. 1350S-4S. Hoshida, S., et al., Different effects of isoflavones on vascular function in premenopausal and postmenopausal smokers and nonsmokers: NYMPH study. Heart Vessels, 2011. 26(6): p. 590-5. North American Menopause, S., The role of soy isoflavones in menopausal health: report of The North American Menopause Society/Wulf H. Utian Translational Science Symposium in Chicago, IL (October 2010). Menopause, 2011. 18(7): p. 732-53. Cai, Y., et al., Soya isoflavone consumption in relation to carotid intima-media thickness in Chinese equol excretors aged 40-65 years. Br J Nutr, 2012. 108(9): p. 1698-704. Chan, Y.H., et al., Prospective observational study of isoflavone and the risk of stroke recurrence: potential clinical implications beyond vascular function. J Nutr Health Aging, 2012. 16(4): p. 383-8. Curtis, P.J., et al., Chronic ingestion of flavan-3-ols and isoflavones improves insulin sensitivity and lipoprotein status and attenuates estimated 10-year CVD risk in medicated postmenopausal women with type 2 diabetes: a 1-year, double-blind, randomized, controlled trial. Diabetes Care, 2012. 35(2): p. 226-32. Shi, L., et al., Urinary isoflavone concentrations are inversely associated with cardiometabolic risk markers in pregnant U.S. women. J Nutr, 2014. 144(3): p. 344-51. 42 21

Selected References FLAVONOLS Hirvonen, T., et al., Intake of flavonols and flavones and risk of coronary heart disease in male smokers. Epidemiology, 2001. 12(1): p. 62-7. Hollman, P.C., A. Geelen, and D. Kromhout, Dietary flavonol intake may lower stroke risk in men and women. J Nutr, 2010. 140(3): p. 600-4. Landberg, R., et al., Selected Dietary Flavonoids are Associated with Markers off Inflammation and Endothelial Dysfunction in U.S. Women. Journal of Nutrition, 2011. 141(4): p. 618-625. Vermeulen, E., et al., Dietary flavonoid intake and esophageal cancer risk in the European prospective investigation into cancer and nutrition cohort. Am J Epidemiol, 2013. 178(4): p. 570-81. Zamora-Ros, R., et al., The association between dietary flavonoid and lignan intakes and incident type 2 diabetes in European populations: the EPIC-InterAct study. Diabetes Care, 2013. 36(12): p. 3961-70. Zamora-Ros, R., et al., Dietary intakes of individual flavanols and flavonols are inversely associated with incident type 2 diabetes in European populations. J Nutr, 2014. 144(3): p. 335-43. 43 Selected References FLAVANOLS & PROANTHOCYANIDINS Heiss, C., et al., Acute consumption of flavanol-rich cocoa and the reversal of endothelial dysfunction in smokers. J Am Coll Cardiol, 2005. 46(7): p. 1276-83. Balzer, J., et al., Sustained benefits in vascular function through flavanol-containing cocoa in medicated diabetic patients a double-masked, randomized, controlled trial. J Am Coll Cardiol, 2008. 51(22): p. 2141-9. Williamson, G., et al., Functional foods for health promotion: state-of-the-science on dietary flavonoids. Extended abstracts from the 12th Annual Conference on Functional Foods for Health Promotion, April 2009. Nutr Rev, 2009. 67(12): p. 736-43. Berry, N.M., et al., Impact of cocoa flavanol consumption on blood pressure responsiveness to exercise. Br J Nutr, 2010. 103(10): p. 1480-4. de la Iglesia, R., et al., Healthy properties of proanthocyanidins. Biofactors, 2010. 36(3): p. 159-68. Schroeter, H., et al., Recommending flavanols and procyanidins for cardiovascular health: current knowledge and future needs. Mol Aspects Med, 2010. 31(6): p. 546-57. Hooper, L., et al., Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. Am J Clin Nutr, 2008. 88(1): p. 38-50. Spencer, J.P., The impact of fruit flavonoids on memory and cognition. Br J Nutr, 2010. 104 Suppl 3: p. S40-7. Ried, K., et al., Effect of cocoa on blood pressure. Cochrane Database Syst Rev, 2012. 8: p. CD008893. Blumberg, J.B., et al., The science of cocoa flavanols: bioavailability, emerging evidence, and proposed mechanisms. Adv Nutr, 2014. 5(5): p. 547-9. Mastroiacovo, D., et al., Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects: the Cocoa, Cognition, and Aging (CoCoA) Study--a randomized controlled trial. Am J Clin Nutr, 2015. 101(3): p. 538-48. 44 22

Selected References ANTHOCYANINS Cassidy, A., et al., Habitual intake of flavonoid subclasses and incident hypertension in adults. American Journal of Clinical Nutrition, 2011. 93(2): p. 338-347. Jennings, A., et al., Intakes of anthocyanins and flavones are associated with biomarkers of insulin resistance and inflammation in women. J Nutr, 2014. 144(2): p. 202-8. Spencer, J.P., The impact of fruit flavonoids on memory and cognition. Br J Nutr, 2010. 104 Suppl 3: p. S40-7. Cote, J., et al., Bioactive compounds in cranberries and their biological properties. Crit Rev Food Sci Nutr, 2010. 50(7): p. 666-79. de Pascual-Teresa, S., D.A. Moreno, and C. Garcia-Viguera, Flavanols and anthocyanins in cardiovascular health: a review of current evidence. Int J Mol Sci, 2010. 11(4): p. 1679-703. Wallace, T.C., Anthocyanins in cardiovascular disease. Adv Nutr, 2011. 2(1): p. 1-7. Jennings, A., et al., Higher anthocyanin intake is associated with lower arterial stiffness and central blood pressure in women. Am J Clin Nutr, 2012. 96(4): p. 781-8. Alvarez-Suarez, J.M., et al., One-month strawberry-rich anthocyanin supplementation ameliorates cardiovascular risk, oxidative stress markers and platelet activation in humans. J Nutr Biochem, 2014. 25(3): p. 289-94. 45 Thank you for joining us! Visit nutrition.org for upcoming events: December 4-6. Advances and Controversies in Clinical Nutrition. Long Beach, CA. meetings@nutrition.org. April 2-6, 2016. ASN s Scientific Sessions and Annual Meeting at EB 2016. 23