Ingredients in Clinical Practice. Zhaoping Li, M.D., Ph.D. Professor of Medicine David Geffen School of Medicine UCLA

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1 Ingredients in Clinical Practice Zhaoping Li, M.D., Ph.D. Professor of Medicine David Geffen School of Medicine UCLA

2 In the Beginning.. There were Plants and Herbs Soil

3 Then The Plants Made Oxygen Using Energy of the Sun O2 O2 Water AS OXYGEN BUILT UP, THEY NEEDED TO PROTECT THEMSELVES FROM THE BAD EFFECTS OF TOO MUCH OXYGEN

4 So Each Plant Protected Itself from Extra Oxygen by Making... COLORFUL NATURAL PLANT NUTRIENTS (ANTIOXIDANTS)

5 PEOPLE CAME AND ATE THE PLANTS AND LIFE WAS GOOD!!!

6 Diets 50,000 Years Ago Fruits, nuts, seeds, roots, tubers, flowers, leaves, stalks, beans Fish, small animals 1/2 the fat 2-3x the protein No dairy or refined flour No processed foods No alcohol, no tobacco

7 Ratio of ω-6 to ω-3 Paleolithic Man 2:1 Traditional Chinese 1:1 to 2:1

8 Diets Today Potato, refined pasta, cereals white rice & flour, corn Added fat and sugar High fat proteins Ice cream, cheese and whole milk Processed foods

9 Ratio of ω-6 to ω-3 Current American 15:1 to 30:1 WHO recommendation 5:1 to 10:1

10 Injured surface (%) All Americans studied had some atherosclerosis by age 15 Heart damage starts in childhood Start Early For Primary Prevention Age (yrs). abdominal aorta coronary artery Heart attacks/1000 PDAY results; Strong et al. JAMA1999; 281:

11 Heart Attack Death Rate Americans have high omega-6 in HUFA & an omega-3 deficit CHD Mortality CHD Mortality and Tissue HUFA y = x R 2 = Quebec Urban USA = USA quintiles 100 Quebec Cree 50 Japan Quebec Inuit 0 Greenland % n-6 HUFA in Total HUFA Lands, Lipids 2003 (Apr.); 38:

n-6 and n-3 PUFA contents of human mononuclear

12 n-6 and n-3 PUFA contents of human mononuclear cell phospholipids % of total fatty acids Linoleic acid (18:2w-6) 10 DGLA (20:3w-6) 1.5 Arachidonic acid (20:4w-6) 20 a-linolenic acid (18:3w-3) < 0.5 EPA (20:5w-3) 1.0 DHA (22:6w-3) 2.5 Yaqoob et al. (2000) Eur. J. Clin. Invest. 30,

13 25-yr.CHD mortality (%) Blood cholesterol is a poor predictor of CHD worldwide 35 %n-6inhufa No.Europe-80% USA-75% Serbia-65% So.Europe-60% Crete-50% Japan-40% Serum TC (mg/dl)

15 Opposing Roles of 6 s and 3 s Omega-6 eicosonoids pro-inflammatory pro-aggregatory pro-vasoconstriction Il-6, TNF-α Omega-3 eicosomoids less-inflammatory less aggregatory favor vasodilation

16 n-3 Fatty Acids in Human Health -Membrane structure -Brain and visual development -Cognitive and neurological function (during development & with aging) - Regulation of - blood pressure - platelet function, thrombosis, fibrinolysis - blood lipid (especially triglyceride) - vascular function - cardiac rhythm - inflammation - immune response - bone health - insulin sensitivity

17 Inflammation Resolution

18 Inflammation Resolution

19 Resolvins & related compounds EPA DHA E-series resolvins D-series resolvins, (neuro)protectins etc. Anti-inflammatory; inflammation resolving Serhan (2004) Lipids 39,

20 PGE 2 concentration (ng/ml) Increased oral intake of EPA and DHA Decreases arachidonic acid levels in inflammatory cells Increases EPA and DHA levels in inflammatory cells Inhibits arachidonic acid metabolism Neutrophil PL; 12 weeks supplementation Healy et al. (2000) Lipids 35, Effect on PGE 2 production (human mononuclear cells; LPS) wk 12 wk EPA dose (g/day) Rees et al. (2006) Am. J. Clin. Nutr. 83,

Mortality (Probability) Potential Cardiovascular Benefits of n-3 Fatty Acids Reduced sudden death Reduced arrhythmias Triglyceride lowering

21 Mortality (Probability) Potential Cardiovascular Benefits of n-3 Fatty Acids Reduced sudden death Reduced arrhythmias Triglyceride lowering Anti-thrombotic 1.0 Anti-inflammatory Anti-hypertensive GISSI Omega-3 FA >20% P = Placebo Months Marchioli, R. et al. Circulation

22 n-3 FA/Fish Intakes and Stroke Outcome Study Population/ Dependent Variables Mozaffarian 05 USA/ fish intake Effects on stroke prevention ++ (1, total and ischemic subtype) He 02 USA/ fish intake ++ (1, ischemic subtype) Bouzan 05 USA + Spain/ fish intake + (1, total ) Yamagishi 08 Japan/ fish or n-3 intake - (1, total) Nakamura 05 Japan/ fish intake - (1, total) Sauvaget 03 Japan/ fish intake - (1, ischemic subtype) Wennberg 07 Sweden/ dietary EPA/DHA intake - (1, total) Tanaka 08 Japan/ EPA supplement + (2, recurrent total) Mayurasakorn K,..., Deckelbaum RJ. Curr Opin Clin Nutr Metab Care

Depression Worldwide, lower serum omega-3 fatty acids significantly correlate with depression Double-blind, placebo-controlled studies show efficacy of omega 3

23 Depression Worldwide, lower serum omega-3 fatty acids significantly correlate with depression Double-blind, placebo-controlled studies show efficacy of omega 3 (from fish oil) in unipolar and bipolar depression Eicosapentanoic acid (EPA) more critical omega-3 fatty acid than docosahexanoic acid (DHA) Typical EPA dose >2.5 gm/day

DHA May Boosts Memory People who eat a lot of fatty fish score better on memory tests and are less likely to develop Alzheimer s disease Animal research

24 DHA May Boosts Memory People who eat a lot of fatty fish score better on memory tests and are less likely to develop Alzheimer s disease Animal research credited docosahexanoic acid (DHA) DHA 900 mg daily for six months had almost double the reduction in errors on a test that measures learning and memory skills

25 UCLA Study Rats fed on n-3 deficient diet Showed memory deficits in the Barnes Maze Exacerbated by fructose intake Increase in the ratio of n-6/n-3 fatty acid composition Ameliorated by the presence of dietary DHA Modulating insulin receptor signaling

Cancer Marine-derived fatty acids have been found to inhibit proliferation and promote apoptosis in breast, prostate, and colon cancer cell lines Studies in animal models of cancer also indicate that

26 Cancer Marine-derived fatty acids have been found to inhibit proliferation and promote apoptosis in breast, prostate, and colon cancer cell lines Studies in animal models of cancer also indicate that increased intake of EPA and DHA decreases the occurrence and progression of mammary, prostate, and intestinal tumors In humans few have demonstrated significant inverse relationships between fish or omega-3 fatty acid intake and the risk for breast, prostate, or colorectal cancers

27 Prostate Cancer Eating fish more than three times per week was associated with a reduced risk of prostate cancer Each additional daily intake of 0.5 g of marine fatty acid from food was associated with a 24% decreased risk of metastatic cancer. Fish oil 3 grams daily decreased prostate cancer cell proliferation Cancer Epidemiol Biomarkers Prev 2003;12:64-67.

when omega-3 fatty acid intake is low Studies in animals indicate

28 Docosahexaenoic acid (DHA) Found in very high concentrations in the cell membranes of the retina It conserves and recycles DHA even when omega-3 fatty acid intake is low Studies in animals indicate that DHA is required for the normal development and function of the retina

Disease Prevention: Impaired Visual and Neural Development Because the last trimester of pregnancy is a critical period for the accumulation of DHA in the brain

synthesize DHA from ALA, they can t synthesize enough to prevent declines in plasma and cellular DHA levels without additional dietary intake Preterm infants fed

29 Disease Prevention: Impaired Visual and Neural Development Because the last trimester of pregnancy is a critical period for the accumulation of DHA in the brain and retina, preterm infants are particularly vulnerable to adverse effects of insufficient DHA on visual and neural development Although preterm infants can synthesize DHA from ALA, they can t synthesize enough to prevent declines in plasma and cellular DHA levels without additional dietary intake Preterm infants fed formulas with DHA added had significantly improved measures of visual function compared to preterm infants fed DHA-free formulas in 5 out of 5 randomized controlled trials

30 Femeral neck BMD Benefit for Osteoporosis Baseline Week 12 Week Control n-3 Exercise n-3/exercise Tartibian et al. Nutr Metabolism 2011, 8:71 (15 October 2011)

31 Sources of n-3 Fatty Acids Fish Algae Krill Plants

32 EPA and DHA: Sources Food Serving EPA (g) DHA (g) Amt providing 1 g of EPA + DHA Herring, Pacific, cooked 3 ounces ounces Salmon, chinook, cooked 3 ounces ounces Salmon, Atlantic, cooked 3 ounces ounces Oysters, Pacific, cooked 3 ounces ounces Salmon, sockeye, cooked 3 ounces ounces Trout, rainbow, cooked 3 ounces ounces Tuna, white, packed in water 3 ounces ounces Crab, dungeness, cooked 3 ounces ounces Shrimp, cooked 3 ounces ounces Cod, Pacific, cooked 3 ounces ounces Fish oil, menhaden 1 gram grams Fish oil, salmon 1 gram grams

33 Methyl Mercury Content White (albacore) tuna Tilefish Shark Swordfish King mackerel 33

34 Are all n-3 fatty acids equal? DHA ALA ->EPA J Nutr Apr;137(4):973-8

Alpha-linolenic acid: Sources Food Serving Alpha-linolenic acid (g) Flaxseed oil 1 tablespoon 8.5 Walnuts, English 1 ounce 2.6 Flaxseeds 1 tablespoon 2.

35 Alpha-linolenic acid: Sources Food Serving Alpha-linolenic acid (g) Flaxseed oil 1 tablespoon 8.5 Walnuts, English 1 ounce 2.6 Flaxseeds 1 tablespoon 2.2 Walnut Oil 1 tablespoon 1.4 Canola Oil 1 tablespoon 1.2 Mustard Oil 1 tablespoon 0.8 Soybean Oil 1 tablespoon 0.9 Walnuts, Black 1 ounce 0.6 Olive Oil 1 tablespoon 0.1 Broccoli, raw 1 cup, chopped 0.1

36 Fatty Acid Composition of Plants Fatty Acid Purslane Spinach Buttercrunch Lettuce Red Leaf Lettuce Mustard mg/g of wet weight 14: : : :1w :2w :3w :5w :6w Other Total fatty acid content

37 Stearidonic Omega-3 from Soybeans Stearidonic has better oxidative stability than the more highly unsaturated EPA and DHA. Soybeans have inherent antioxidant protection systems that can allow for production of higher quality raw materials Encapsulated Oil Bodies Inherent Antioxidants Oxidation History

38 CONCLUSIONS Fish oil is the mostly recommended supplement in clinical practice Fish oil shows anti-inflammatory, antioxidant, anticancer, anti-atherosclerotic and antineurodegenerative properties. Fish oil may help to decrease cardiovascular risk preserve memory and neurological function

Future directions for nutritional and therapeutic research in omega-3 3 lipids

Future directions for nutritional and therapeutic research in omega-3 3 lipids Philip Calder Professor of Nutritional Immunology University of Southampton Aim To review dietary sources and intakes of long