1. Welcome Cutting Healthcare Costs Through Prevention: Measuring the Efficacy, Safety, and Cost Savings of Dietary Supplements

2. Richard Sharpee, PhD Symposium Planning Chairman Natural Health Research Institute Scientific Research Manager Now Health Group, Inc.

3. Artemis P. Simopoulos, MD President The Center for Genetics, Nutrition & Health

4. Artemis P. Simopoulos, M.D. President The Center for Genetics, Nutrition and Health Washington DC, USA Economic and Health Implications of Changing America’s Oil: The Omega-3 Opportunity Natural Health Research Institute Symposium Chicago, Illinois October 28, 2011

5. The concept of positive health Positive health requires a knowledge of man’s primary constitution (what today we would call genetics) and of the powers of various foods, both those natural to them and those resulting from human skill (today’s processed food). But eating alone is not enough for health. There must also be exercise, of which the effects must likewise be known. The combination of these two things makes regimen, when proper attention is given to the season of the year, the changes of the winds, the age of the individual and the situation of his home. If there is any deficiency in food or exercise the body will fall sick. ~Hippocrates

6. Relationships between genes, environment, and development are dynamic GenotypeEnvironment Phenotype Development Childs, B. (1990). Genetic Variation and Nutrition. World Rev Nutr Diet, Vol 63.

7. Hypothetical scheme of fat, fatty acid (ω6 and ω3, trans and total) intake (as percent of calories from fat) and intake of vitamins E and C (mg/d) Simopoulos AP: Genetic variation and evolutionary aspects of diet. In: Antioxidant Status, Diet, Nutrition, and Health, Papas AM (Editor), CRC Press, Boca Raton, 1999, pp. 65-88.

8. The desaturation and elongation of ω3 and ω6 fatty acids (FADS 2) (FADS 1)

9. Ratios of dietary ω6:ω3 fatty acids in the late Paleolithic period and in current Western dietary patterns (g/d) a,b PaleolithicWestern LA:ALA0.7018.75 AA+DTA:EPA+DPA+DHA1.793.33 Total0.7916.74 a Data from Eaton et al. (1998), World Rev Nutr Diet. b Assuming an energy intake of 35:65 of animal:plant sources.

10. ω6:ω3 ratios in various populations Populationω6:ω3Reference Paleolithic0.79 a,b Eaton et al, 1998 Greece prior to 19601.00-2.00Simopoulos, 1999 Current United States16.74Eaton et al, 1998 United Kingdom and northern Europe 15.00Sanders, 2000 Japan4.00Sugano and Hirahana, 2000 India rural5-6.1Pella et al, 2003 India urban 38-50Pella et al, 2003 a Data from Eaton et al. (1998), World Rev Nutr Diet. b Assuming an energy intake of 35:65 of animal: plant sources.

11. GREECE SPAIN ITALY PORTUGAL U.S.EEC/OTHER OLIVE OIL CONSUMPTION PER PERSON

12. The Mediterranean Region

13. The Mediterranean Diets Although Greece and the Mediterranean countries are usually considered to be areas of medium-high death rates (14.0-18.0 per 1000 inhabitants), death rates on the island of Crete have been below this level continuously since before 1930. No other area in the Mediterranean basin has had as low a death rate as Crete, according to data compiled by the United Nations in their demographic yearbook for 1948. It was 11.3-13.7 per 1000 inhabitants before World War II and about 10.6 in 1946-1948. Cancer and heart disease caused almost three times as many deaths proportionally in the United States as in Crete. The diet of Crete represents the traditional diet of Greece before 1960. Allbaugh LG (1953). Crete: A case study of an underdeveloped area. Princeton, NJ: Princeton University Press.

14. Life expectancy and disease rates in the United States and Greece in the 1960’s Life expectancy and disease rates GenderUnited StatesGreece Life expectancy at age 45M2731 F3334 Coronary heart diseaseM18933 F5414 Cerebrovascular diseasesM3026 F2423 Breast cancerF228 Stomach cancerM610 F36 Colorectal cancerM113 F103 Total cancersM10283 F8761

15. Dietary characteristics in the United States and Greece in the 1960s Dietary characteristicsUnited StatesGreece Fat (% energy)3937 Saturated fat (% energy)188 Vegetables (g/day)171191 Fruits (g/day)233463 Legumes (g/day)130 Breads and cereals (g/day)123453 Potatoes (g/day)124170 Meat* (g/day)27335 Fish (g/day)339 Eggs (g/day)4015 Alcohol (g/day)623 * Includes poultry

16. National Geographic, September 1969, Vol. 136, No. 3.

18. Nature’s nutrients: The purslane plant

19. Fatty acid content of plants* Fatty acidPurslaneSpinachButtercrunch Lettuce Red Leaf Lettuce Mustard 14:00.160.030.010.030.02 16:00.810.160.070.100.13 18:00.200.010.020.010.02 18:1ω90.430.040.030.01 18:2ω60.890.140.100.12 18:3ω34.050.890.260.310.48 20:5ω30.010.00 22:6ω30.00 0.0010.0020.001 Other1.950.430.110.120.32 Total fatty acid content 8.501.700.6010.7021.101 *mg/g of wet weight A.P. Simopoulos and N. Salem, Jr. (1986). New England Journal of Medicine, 315:833.

20. Summary: Nutritional value of purslane One serving of fresh leaves (100 g) contains: 300-400 mg 18:3ω3 12 mg alpha-tocopherol 27 mg ascorbic acid 2 mg beta-carotene 15 mg glutathione

21. Fatty acid levels in various chicken egg yolks (mg fatty acid/g hard-boiled egg yolk) FATTY ACIDGREEK EGG SUPERMARKET EGG Saturated fats 14:01.100.70 15:0--0.07 16:077.6056.66 17:00.660.34 18:021.3322.88 TOTAL100.6680.65 Mono-unsaturated fats 16:1ω721.704.67 18:1120.50109.97 20:1ω90.580.68 22:1ω9-- 24:1ω9--0.04 TOTAL142.78115.36 FATTY ACIDGREEK EGG SUPERMARKET EGG Omega-6 fatty acids 18:2ω616.0026.14 18:3ω6--0.25 20:2ω60.170.36 20:3ω60.460.47 20:4ω65.405.02 22:4ω60.700.37 22:5ω60.291.20 TOTAL23.0233.81 Omega-3 fatty acids 18:3ω36.900.52 20:3ω30.160.03 20:5ω31.20-- 22:5ω32.800.09 22:6ω36.601.09 TOTAL17.661.73 P40.68=0.435.55=0.44Omega-623.02=1.333.81=19.4 S100.6680.65Omega-317.661.73 A.P. Simopoulos and N. Salem, Jr. (1989). New England Journal of Medicine, 321:1412.

22. Fatty acid composition of selected cheeses (amount in grams/100 grams, edible portion) 2% Milk CheddarAmericanSwiss Greek Myzithra Greek Feta Total polyunsaturated fat.07 g.94 g.99 g.62 g.80 g.58 g 18:2.04 g.58 g.61 g.34 g.38 g.29 g 18:3.03 g.36 g.38 g.28 g.30 g.20 g Arachidonic Acid-- 14 mg10 mg Eicosapentaenoic Acid -- 18 mg14 mg Docosapentaenoic Acid -- 31 mg23 mg Docosahexaenoic Acid -- 5.5 mg5.1 mg

23. Fatty acid composition of snails Origin18:018:1(9)18:2(6)18:3(3)20:2(6)20:4(6)20:5(3) Crete7.319.917.29.77.08.81.1 Greece8.612.718.710.67.29.21.2 France10.910.314.34.910.616.21.7 Weight of a snail = 10 to 15 gLipids = 0.15 to 0.19 g

24. Fatty acid composition of serum cholesterol esters (Percent, X ± SD) Crete (n = 92)Zutphen (n = 97)Significance 16:0 11.1 ± 0.1 11.9 ± 0.1p < 0.001 18:0 0.7 ± 0.0 1.1 ± 0.0p < 0.001 18:1ω9 31.0 ± 0.3 21.4 ± 0.4p < 0.001 18:2ω6 41.9 ± 0.4 53.1 ± 0.7p < 0.001 18:3ω3 0.9 ± 0.1 0.3 ± 0.0p < 0.001 Modified from Sandker, G.W. et al. (1993). Eur J Clin Nutr, 47: 201-208.

25. Omega-3 fatty acids in traditional diets In traditional diets, omega-3 fatty acids are found throughout the food chain Eggs have a ratio of omega-6:omega-3 of 1:1 Pasta made with eggs and milk that is rich in omega-3 fatty acids is enriched in omega-3’s Pasta made with water and flour, or regular milk, is not enriched in omega-3’s.

26. Mediterranean α-linolenic acid rich diet in secondary prevention of CHD: End points (27 months mean follow up) de Lorgeril, M. et al. Lancet 1994; 343: 1454-59.

27. Polyunsaturated fatty acid composition of total cellular lipids from the control heart cells and the transgenic cells expressing a C. elegans fat-1 cDNA Mol % of total fatty acidsControlFat-1 ω6 Polyunsaturates 18:2ω614.2 a 9.2 b 20:2ω61.2 a 0.3 b 20:3ω61.6 a 0.4 b 20:4ω615.2 a 4.1 b 22:4ω64.4 a 1.0 b 22:5ω60.2 a 0.0 b Total36.8 a 15.0 b ω3 Polyunsaturates 18:3ω30.2 b 3.6 a 20:4ω30.0 b 0.6 a 20:5ω30.1 b 6.1 a 22:5ω31.2 b 5.8 a 22:6ω31.0 a 1.3 a Total2.5 b 17.4 a ω6/ω3 Ratio14.7 a 0.9 b Values are means of four measurements. Values for each fatty acid with the same letter do not differ significantly (p<0.01) between control and fat-1. Kang, J.X. (2003), World Rev Nutr Diet, Vol. 92.

28. Eicosanoid Formation and Metabolism

29. Catabolic pathways of arachidonic acid

30. Uncontrolled inflammation is now appreciated in the pathogenesis of many diseases that were not previously considered classic inflammatory diseases- Atherosclerosis, cancer, and several neurological disorders such as Alzheimer’s disease and Parkinson’s disease. EPAResolvins of E series DHAResolvins of D series DHAProtectins D DHANeuroprotectin D 1 AALipoxins A 4, B 4 Lipid Mediators

31. Key cellular actions of lipoxins and resolvins Spite M, Serhan CN. Circ Res. 2010;107:1-15. LXA ₄ is generated from AA, whereas omega-3 fatty acids, EPA and DHA serve as precursors for E-series and D-series resolvins, respectively. Lipoxins and resolvins act in a stereospecific manner on distinct cell types through interaction with GPCRs to stimulate nonphlogistic macrophage phagocytosis, increase antiinflammatory cytokines, and decrease proinflammatory cytokine generation in macrophages, neutrophils (PMNs) endothelial cells, and dendritic cells. Lipoxins and resolvins also stimulate endothelial production of nitric oxide (NO) and vasoprotective prostacyclin (PGI ₂.

32. IMMUNOLOGY AND INFLAMMATION

33. Biological activities of interleukin-1 Figure courtesy of Dr. Jos W. M. van der Meer, Nijmegen, the Netherlands

34. Chronic inflammatory diseases Rheumatoid Arthritis Ulcerative Colitis Psoriasis Lupus Erythematosus Diabetes (I & II) Obesity Atherosclerosis Cancer IL-1 (IL-α AND IL-1-β), IL-1ra TNF are elevated

35. Effect of ω-3 fatty acids on factors involved in the pathophysiology of atherosclerosis, inflammation, and the metabolic syndrome Factor Function Effect of ω-3 Fatty Acid Arachidonic AcidEicosanoid precursor; aggregates platelets; stimulates white blood cells Thromboxane A 2 Platelet aggregation; vasoconstriction; increase of intracellular Ca ++ Prostacyclin (PGI 2/3 )Prevents platelet aggregation; vasodilation; increase cAMP Leukotriene (LTB 4 )Neutrophil chemoattractant; increase of intracellular Ca ++ Tissue plasminogen activator Increases endogenous fibrinolysis FibrinogenBlood clotting factor Platelet activating factor (PAF) Activates platelets and white blood cells Simopoulos AP.

36. Factor Function Effect of ω-3 Fatty Acid Platelet-derived growth factor (PDGF) Chemoattractant and mitogen for smooth muscles and macrophages Oxygen free radicalsCellular damage; enhance LDL uptake via scavenger pathway; stimulate arachidonic acid metabolism Lipid hydroperoxidesStimulate eicosanoid formation Interleukin 1 and tumor necrosis factor Stimulate neutrophil O 2 free radical formation; stimulate lymphocyte proliferation; stimulate PAF; express intercellular adhesion molecule-1 on endothelial cells; inhibit plasminogen activator- thus procoagulants Interleukin-6Stimulates the synthesis of all acute phase proteins involved in the inflammatory response: C-reactive protein; serum amyloid A; fibrinogen; α ₁ -chymotrypsin; and haptoglobin Effect of ω-3 fatty acids on factors involved in the pathophysiology of atherosclerosis, inflammation, and the metabolic syndrome

37. Factor Function Effect of ω-3 Fatty Acid C-reactive protein (CRP) An acute phase reactant and an independent risk factor for cardiovascular disease Endothelial-derived relaxation factor (EDRF) Reduces arterial vasoconstrictor response Insulin sensitivity PPARγGenes involved in insulin sensitivity GLUT-2/GLUT-4Glucose transport IRS-1/IRS-2Insulin receptor signaling AdiponectinAnti-inflammatory and insulin- sensitizing adipokine Effect of ω-3 fatty acids on factors involved in the pathophysiology of atherosclerosis, inflammation, and the metabolic syndrome

38. Factor Function Effect of ω-3 Fatty Acid AMPK phosphorylation A fuel sensing enzyme and a gatekeeper of the energy balance Hepatic statosis Obesity induced insulin resistance VLDL HDLDecreases the risk for coronary heart disease Lp(a)Lipoprotein(a) is a genetically determined protein that has atherogenic and thrombogenic properties Effect of ω-3 fatty acids on factors involved in the pathophysiology of atherosclerosis, inflammation, and the metabolic syndrome

39. Factor Function Effect of ω-3 Fatty Acid Trigylcerides and chylomicrons Contribute to postprandial lipemia TelomeresHave anti-aging effects whereas LA promotes shortening of telomeres and aging Resolvins E1-E2 (EPA)Anti-inflammatory important in the resolution of inflammation Resolvin D1-D2 (DHA)Anti-inflammatory important in the resolution of inflammation Neuroprotectin (DHA)Protects brain; important in the patients with strokes or trauma PPARUpregulates the expression of genes involved in lipid metabolism and downregulates the expression of genes involved in inflammation and suppresses NFkB Effect of ω-3 fatty acids on factors involved in the pathophysiology of atherosclerosis, inflammation, and the metabolic syndrome

40. PLASMA LIPIDS AND LIPOPROTEINS

41. THROMBOSIS AND ATHEROSCLEROSIS

42. Omega-3 fatty acids The antiarrhythmic effects in animal and human studies could explain the reduced mortality of postmyocardial infarction patients given these acids.

43. CELL MEMBRANE FUNCTION AND METABOLISM THROUGHOUT THE LIFE CYCLE

44. DHA *EPA ***AA LNA LA Growth Factors PDGF mRNA β-oxidation acyl-CoA oxidase mRNA** Inflammation IL-1B mRNA Adhesion molecules VCAM-1 mRNA** Cell growth and early gene expression c-fos, Egr-1 Fatty acid *EPA has no effect by itself but enhances the effect of DHA. ** Monounsaturates also suppress VCAM-1 mRNA, but to a lesser degree than DHA, and induce acyl-CoA oxidase mRNA ***AA suppresses VCAM-1 mRNA, but to a lesser degree than DHA suppress or decreaseinduce or increase Effects of PUFA on several genes encoding enzyme proteins involved in inflammation, adhesion molecules, cell growth, early gene expression, β-oxidation, and growth factors Simopoulos AP. Annals of Nutrition and Metabolism 1996;40:303-311.

45. Mechanisms of Omega-6/Omega-3 Fatty Acids Linoleic Acid Inhibits Eicosapentaenoic Acid Incorporation from Dietary Fish Oil Supplements in Human Subjects Linoleic Acid Increases Low-Density Lipoprotein Oxidation and Severity of Coronary Atherosclerosis As the Omega-6/Omega-3 Ratio Decreases, So Does the Platelet Aggregation

46. Mechanisms of Omega-6/Omega-3 Fatty Acids Omega-3 Fatty Acids downregulate the expression of genes involved in inflammation and obesity A Lower Omega-6/Omega-3 Ratio as part of a Mediterranean Diet Decreases Vascular Endothelial Growth Factor Decreasing Linoleic Acid with Constant α- Linolenic Acid in Dietary Fat Increases Eicosapentaenoic Acid in Plasma Phospholipids in Healthy Men

47. 25-year CHD mortality in the Seven Countries Study Verschuren, W.M. et al. (1995). Serum total cholesterol and long-term coronary heart disease mortality in different cultures: Twenty five-year follow-up of the seven countries study. JAMA, 274 (2).

48. Early protection against sudden death by ω3 polyunsaturated fatty acids after myocardial infarction: Time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione Marchioli R., Barzi F., Bomba E. et al. Circulation 2002; 105: 1897-1903. 11,323 patients were randomly assigned to supplements of omega-3 PUFAs 850 mg/d- ratio of EPA:DHA = 2.1 Vitamin E = 300 mg/d Both omega-3 and vitamin E None (control) On top of optimal pharmacological treatment, lifestyle advice Survival curves for omega-3 PUFA treatment diverged early after randomization and total mortality was significantly lowered after 3 months of treatment A similar significant, although delayed pattern after 6 to 8 months of treatment was observed for cardiovascular, cardiac and coronary death

49. Early benefit of ω3 PUFA therapy: Total mortality Marchioli R., Barzi F., Bomba E. et al. Circulation 2002; 105: 1897-1903.

50. Early benefit of ω3 PUFA therapy: Sudden death Marchioli R., Barzi F., Bomba E. et al. Circulation 2002; 105: 1897-1903.

51. Early benefit of ω3 PUFA therapy: Coronary heart disease mortality Marchioli R., Barzi F., Bomba E. et al. Circulation 2002; 105: 1897-1903.

52. Early benefit of ω3 PUFA therapy: Cardiovascular mortality Marchioli R., Barzi F., Bomba E. et al. Circulation 2002; 105: 1897-1903.

53. Early protection against sudden death by ω3 polyunsaturated fatty acids after myocardial infarction: Conclusion The early effect of low dose 850 mg/d omega-3 PUFAs on total mortality and sudden death supports the hypothesis of an antiarrhythmic effect of omega-3 fatty acids. Such a result is consistent with the wealth of evidence coming from laboratory experiments on isolated myocytes, animal models, epidemiological and clinical studies. Marchioli R., Barzi F., Bomba E. et al. Circulation 2002; 105: 1897-1903.

55. Mediterranean-inspired diet lowers the ratio of serum phospholipid n-6 to n-3 fatty acids, the number of leukocytes and platelets, and vascular endothelial growth factor in healthy subjects Reduced cardiovascular disease mortality and morbidity has been shown in populations adhering to a Mediterranean diet. Design 32 subjects: 10 women and 22 men Placed on Mediterranean diet or ordinary Swedish diet 4 weeks, crossover design Concentrations of fatty acids and lipids C-reative protein (CRP), interleukin-6 (IL-6), both before and after lipopolysaccharide simulation; number of leukocytes and platelets, vascular endothelial growth factor (VEGF), monocyte chemoattractant protein 1 (MCP-1) Ambring A, Johansson M, Axelsen M, et al., Am J Clin Nutr 2006; 83: 575-81.

56. Mediterranean-inspired diet: Results Plasma ratio of omega-6/omega-3 was substantially lowered after the Mediterranean diet Omega-6/omega-3 = 4.72 ± 0.19 (Swedish diet); 2.60 ± 0.17 (Mediterranean diet) p < 0.0001 No change in CRP or IL-6 Total number of leukocytes was 10% lower after Mediterranean diet; total number of platelets was 15% lower after Mediterranean diet Serum VEGF were lower after the Mediterranean diet 237 ± 30 →206 ± 25 pg/mL; p = 0.0014 Ambring A, Johansson M, Axelsen M, et al., Am J Clin Nutr 2006; 83: 575-81.

57. Mediterranean-inspired diet: Conclusion A Mediterranean-inspired diet (MID) reduces the number of platelets and leukocytes and VEGF concentrations in healthy subjects. This may be linked to higher serum concentrations of omega-3 fatty acids, which promote a favorable composition of phospholipids. Ambring A, Johansson M, Axelsen M, et al., Am J Clin Nutr 2006; 83: 575-81.

58. A Reduced Omega-6/Omega-3 Fatty Acid Dietary Ratio Increases Adiponectin Concentration and Fatty Acid Oxidation in Healthy Subjects Guebre-Egziabher et al. carried out a ten week dietary intervention in 17 healthy subjects. The dietary intervention decreased the LA/ALA ratio from 32.2 (s.d. 3.7) versus post-intervention 2.2 (s.d. 0.1). Guebre-Egziabher F, et al. Nutritional intervention to reduce the n-6/n-3 fatty acid ratio increases adiponectin concentration and fatty acid oxidation in healthy subjects. Eur J Clin Nutr 2007..

59. Inflammation and Autoimmune Diseases The first evidence of the important role of dietary intake of omega-3 polyunsaturated fatty acids (PUFAs) in inflammation was derived from epidemiological observations of the low incidence of autoimmune and inflammatory disorders, such as psoriasis, asthma and type-1 diabetes, as well as the complete absence of multiple sclerosis, in a population of Greenland Eskimos compared with gender- and age- matched groups living in Denmark. Most of these diseases are characterized by inappropriate activation of T cells resulting on and ultimately destruction of host tissues. Kromann N, Green A. Acta Med Scan 1980;208:401-406.

60. IgA Nephropathy IgA nephropathy is the most common glomerular disease in the world. In patients with IgA nephropathy, treatment with fish oil for two years retards the rate at which renal function is lost. The omega-3 fatty acids in fish oil affect eicosanoid metabolism and cytokine production, two important classes of inflammatory modulators, and therefore have the potential to alter renal hemodynamics and inflammation. Donadio Jr JV et al. N Engl J Med 1994;331:1194-1199.

61. Lupus Erythematosus Omega-3 fatty acids lower plasma triglycerides and improve red cell flexibility in patients with lupus nephritis. Clark WF et al. Kidney Int. 1993;44:75-86.

62. Dietary Omega-3 Fatty Acid, Ratio of Omega-6 to Omega-3 Intake, Inflammation, and Survival in Long- term Hemodialysis Patients Higher dietary omega-6 to omega-3 ratio appears to be associated with both worsening inflammation over time and a trend toward higher death risk in hemodialysis patients. Additional studies including interventional trials are needed to examine the association of dietary fatty acids with clinical outcomes in these patients. Noori N et al. Am J Kidney Dis. 2011;58(2):248-56

63. Dietary ratio of n-6 to n-3 polyunsaturated fatty acids and periodontal disease in community-based older Japanese: A 3-year follow-up study A high dietary n-6 to n-3 PUFAs ratio was significantly associated with greater number of periodontal disease events. The findings suggest the dietary n-6 to n-3 PUFAs ratio is associated with periodontal disease among older Japanese. Iawasaki M et al. Prostaglandins Leukot Essent Fatty Acids. 2011;85(2):107-12

64. Obesity-induced insulin resistance and hepatic steatosis are alleviated by omega-3 fatty acids: a role for resolvins and protectins Figure 3. w-3-PUFAs up-regulate the expression of insulin-sensitizing genes in adipose tissue and liver in ob/ob mice. Expression of PPARγ, IRS-1, and GLUT-4 in adipose tissue (A) and their counterparts in the liver (i.e., PPARγ, IRS-2, and GLUT-2) (B) was determined by real-time RT-PCR in samples from ob/ob mice receiving either a control diet (n=8) or a diet enriched with w-3 PUFAs (n=16). Results are expressed as means ± SE; P values vs. CT group. González-Périz A et al. FASEB J. 2009;23(6):1946-57.

65. ω -3 Fatty acid and the brain may play a role in nervous system activity improve cognitive development and reference memory-related learning increase neuroplasticity of nerve membranes contribute to synaptogenesis and are involved in synaptic transmission

66. Impaired cognitive functions (Salem 2003) dementia (Freeman 2000) cognitive decline (Heude. Am J Clin Nutr. 2003 improve cognitive development (Neuringer. Willats) improve reference memory related learning (Gamoh- Neuroscience 1999) improve mood states (Freeman 2000) increase vigor and a sense of well being (Fontani 2005) The above studies strengthen the hypothesis of a direct action of W-3’s on the CNS ω -3 supplementation is associated with a reduced risk of

67. Omega-3’s improve mental disorders Decrease in the number of relapses of cocaine addicts Decrease in aggressiveness Depression Bipolar disorders Suicide Alcoholics required lower doses of benzodiazepines for detoxification and faster cognitive improvement than the placebo group (effects on neurotransmitters, hepatic damage, tolerance)

68. ω -3’s in Development Maternal intake of W-3’s during pregnancy and lactation may favor the later mental development of children (Helland et al. Pediatrics. 2003 Jan;111:39-44) important in visual and cognitive development

69. ω -3’s in Healthy Subjects 33 healthy subjects, 13 M, 20 F, 22-51 yrs (mean =33 ±7yrs) Subjects were tested at the beginning of the experiment and after 35 days. Supplemented with 4 grams of fish oil (1.60g EPA + 0.80 DHA + 0.4g of other W-3’s). Control consisted of 4g olive oil (indistinguishable by packaging, shape or taste). Fontani et al. Eur J Clin Invest. Nov; 35 (11) : 691-699

70. ω -3’s in Healthy Subjects Olive Oil Fish Oil Day 1: AA/EPA = 16.39 ± 8.32 mean value vs. 16.17 ± 10.63 Day 35: AA/EPA = 14.26 ± 8.87 mean value vs. 4.29 ± 2.60 P>0.0001

71. Profile of Mood States (POMS). Comparison before and after Omega-3 supplementation. Mean ± standard error (subjects n = 33). Paired samples t-test: **** P < 0·0001, *** P < 0·001, ** P < 0·01, * P < 0·04. Fontani et al 2005. Before ω-3 After ω-3

72. ω -3’s in Healthy Subjects The mood profile improved after W-3’s with increased vigor and reduced anger, anxiety and depression states. An EEG frequency shift towards the theta and alpha band were recorded in all tests after W-3’s Conclusion W-3 supplementation is associated with an improvement of attentional and physiological functions, particularly those involving complex cortical processing.

73. Cost Effectiveness of Rx with Omega-3’s GISSI Study – 2˚ prevention after MI based on morbidity and mortality data and the use of resources obtained prospectively during the 3.5 yr follow up period. Took into account the number of life years gained, hospital admissions Dx tests and drugs. The value of money of Omega-3 Rx was assessed using the cost-effectiveness ratio and the number needed to treat (NNT) approach. Ref: Franzoni, M. G et al. Pharmacoeconomics 2001;(19(4):411-20.

74. Cost Effectiveness of Rx with Omega-3’s 172 pts would need to be treated per year at an annual cost of E68,000, in order to save 1 patient, which is comparable with the NNT value and associated annual cost for simvastatin but less costly than that for pravastatin. Conclusion: The effectiveness of long term Rx with Omega-3s is comparable with other drugs in the routine care of 2˚ prevention after MI. Since the clinical benefit of omega-3s is additive they should be added to the established routine practice, with additive costs. Ref: Franzoni, M. G et al. Pharmacoeconomics 2001;(19(4):411-20.

75. Cost Effectiveness of Rx with Omega-3’s Early Postoperatie enteral immunonutrition: clinical outcome and cost comparison analysis in surgical patients. To determine if early post-op feeding of pts with UGI malignancy supplemented with arginine dietary nucleotides and omega-3s  improved clinical outcome – (reduced infections, wound complications, and ↓ Rx costs compared to isocaloric isonitrogenous control diet. Post op complications 17 pts (77) in the Rx group and 24 pts (77) in the control group – During the 1-5 days complications were similar in both groups but after the 5 th post op day there were 5 pts in the Rx group and 13 in the control p <.05. Total costs of the Rx complications were 83, 563. German marks in the Rx group vs. 122, 430 in the control. Senekal M et al. Crit Care Med 1997;25(9):1489-96.

76. Conclusions and Recommendations The importance of omega-3 essential fatty acids in the diet is now evident, as well as the need to return to a more physiologic omega-6/omega-3 ratio of about 1-4/1 rather than the ratio of 20-16/1 provided by current Western diets. In order to improve the ratio of omega-6/omega-3 essential fatty acids, it will be necessary to decrease the intake of omega-6 fatty acids from vegetable oils and to increase the intake of omega-3 fatty acids by using oils rich in omega-3 fatty acids and increase the intake of fish to two to three times per week or take supplements.

77. Conclusions and Recommendations Omega-3 fatty acids have been part of our diet since the beginning of time. It is only for the past 150 years that omega-3 fatty acids have been decreased in Western diets due to agribusiness and food processing. The need to return the omega-3 fatty acids into the food supply has been recognized by industry, which is already producing omega-3 enriched products.

78. Further Research Needs There is a clear need for more carefully designed and controlled clinical trials in the therapeutic application of omega-3 fatty acids to human autoimmune and inflammatory conditions. In designing clinical interventions, genetic variation should be taken into consideration, since the level of cytokines is to a great extent genetically determined and the dose or amount of omega-3 fatty acids to suppress the proinflammatory state may vary.

79. Further Research Needs Because chronic diseases are multigenic and multifactorial it is essential in designing clinical trials that the background diet, the omega-6/omega-3 ratio and the genetic variants are taken into consideration.

80. Relationships between genes, environment, and development are dynamic GenotypeEnvironment Phenotype Development Childs, B. (1990). Genetic Variation and Nutrition. World Rev Nutr Diet, Vol 63.

81. Adequate intakes (AI) for adults Fatty AcidGrams/day (2000 kcal diet)% Energy LA4.442.0 (Upper Limit) 1 6.673.0 LNA2.221.0 DHA + EPA0.650.3 DHA to be at least 2 0.220.1 EPA to be at least0.220.1 TRANS-FA (Upper limit) 3 2.001.0 SAT (Upper limit) 4 --< 8.0 MONOs 5 -- 1. Although the recommendation is for AI, the Working Group felt that there is enough scientific evidence to also state an upper limit (UL) for LA of 6.67 g/d based on a 2000kcal diet or of 3.0% of energy. 2. For pregnant and lactating women, ensure 300 mg/d of DHA. 3.Except for dairy products, other foods under natural conditions do not contain trans-FA. Therefore, the Working Group does not recommend trans-FA to be in the food supply as a result of hydrogenation of unsaturated fatty acids or high temperature cooking (reused frying oils). 4.Saturated fats should not comprise more than 8% of energy. 5. The Working Group recommended that the majority of fatty acids are obtained from monounsaturates. The total amount of fat in the diet is determined by the culture and dietary habits of people around the world (total fat ranges from 15-40% of energy) but with special attention to the importance of weight control and the reduction of obesity.

82. Adequate intake (AI) for infant formula/ diet Fatty AcidPercent of Fatty Acids LA 1 10.00 LNA1.50 AA 2 0.50 DHA0.35 EPA 3 (Upper Limit)< 0.10 1.The Working Group recognizes that in countries like Japan, the breast milk content of LA is 6-10% of fatty acids and the DHA is higher, about 0.6%. The formula/ diet comparison described here is patterned on infant formula studies in Western countries. 2.The Working Group endorsed the addition of the principal long chain polyunsaturates, AA and DHA, to all infant formulas. 3.EPA is a natural constituent of breast milk, but in amounts more than 0.1% in infant formula may antagonize AA and interfere with infant growth.

83. Bernard Gesch, September 25, 2009, Volume 325, Science Magazine