1. Omega-3 Fatty Acids : Naming, sources, intakes, metabolism and health benefits Philip Calder Professor of Nutritional Immunology University of Southampton

2. This lecture will cover ä Fatty acid structure, nomenclature, sources, and intakes  Metabolic relationship between  -linolenic acid and long chain omega-3 fatty acids ä Omega-3 fatty acids and cardiovascular health ä Omega-3 fatty acids and visual and brain development ä Recommendations for omega-3 fatty acid intake

3. Fats in the diet CH2.O.CO.R1 CH2.O.CO.R1 R2.CO.OCH CH2.O.CO.R3 CH2.O.CO.R3 Triglycerides Also sphingolipids cholesterol and cholesterol esters CH2.O.CO.R1 CH2.O.CO.R1 R2.CO.OCH CH2.O.POO.O.Base CH2.O.POO.O.Base Phospholipids

4. COOH H3CH3C Fatty acid structure

5. Fatty acid structure and nomenclature COOH H3CH3C H3CH3C H3CH3C Stearic acid18:0 Oleic acid 18:1  -9 Linoleic acid 18:2  -6  -Linolenic acid18:3  -3 H3CH3C COOH Mammals cannot insert double bonds in here 9 6 3 Omega =  - = n-

6. 0 20 40 60 80 100 Sunflower oil Corn oil Soybean oil Olive oil Pig fat Beef fat Butter Saturated Monounsaturated Polyunsaturated

7. Latest fatty acid intake data for adults in UK (g/day) MalesFemales Total fat87 (36% energy)61 (35% energy) Saturated3323 Trans32 Monounsaturated2920 Omega-6 PUFA139 Omega-3 PUFA2.31.7

8. H3CH3C COOH H3CH3C H3CH3C H3CH3C Omega-3 PUFAs  -Linolenic acid (18:3  -3) EPA (20:5  -3) DPA (22:5  -3) DHA (22:6  -3)

9. These have different dietary sources and their intake differs markedly

10.  -Linolenic acid (18:3  -3) ä Found in green plant tissues ä Found in some vegetable oils (e.g. soybean, rapeseed) ä Found in some nuts (e.g. walnut) ä Found in linseed (flaxseed) and linseed oil  Contributes 85 to 95% of  -3 PUFA intake in UK adults (ca. 2.1 g/day in males; 1.5 g/day in females)

11. Long chain  -3 PUFAs (EPA, DPA, DHA) - oily fish are the only rich source of preformed long chain  -3 PUFAs - adults in the UK consume on average 1/3 of a portion of oily fish per week (53 g/week) - fish consumers consume 1.3 portions of oily fish per week (about 195 g/week) - average long chain  -3 PUFA intake is < 0.2 g/day (200 mg/day) - long chain  -3 PUFAs are found in fish oils

12. Long chain  -3 PUFA content of fish EPADPADHA Total (g/100 g food)g/portion Cod0.080.010.16 0.30 Haddock0.050.010.10 0.19 Herring0.510.110.69 1.56 Mackerel0.710.121.10 3.09 Salmon0.550.140.86 1.55 Crab0.470.080.45 0.85 Prawns0.060.010.04 0.06

13.  -linolenic acid is metabolically related to long chain  -3 PUFAs Delta 6-desaturase Elongase Delta 5-desaturase  -Linolenic acid (18:3  -3) 18:4  -3 20:4  -3 EPA (20:5  -3) DPA (22:5  -3) DHA (22:6  -3)

14.  -Linolenic acid EPA DHA This pathway does not work very well in humans

15. Key points (so far)   -6 and  -3 PUFAs are distinct fatty acid families  Most  -3 PUFA in the diet is in the form of  - linolenic acid  Long chain  -3 PUFAs are found in oily fish (fish oil capsules)  Average intake of long chain  -3 PUFAs is < 0.2 g/day   -Linolenic acid is poorly converted to long chain  -3 PUFAs in humans

16. Omega-3 PUFAs and human health

18. DiseaseExpected Actual Myocardial infarction 40 3 Psoriasis 40 2 Bronchial asthma 25 1 Diabetes 9 1 Multiple sclerosis 2 0 From a survey of distribution of diseases in Greenland Eskimos Kromann & Green (1980) Acta Med. Scand. 208, 410-406

19. Many studies report an inverse correlation between fish consumption or  -3 PUFA status and CHD Kromhout et al. 1985Fish  CVD mortality Shekelle et al. 1985Fish  CVD mortality Norelle et al. 1986Fish  CVD mortality Dolecek et al. 1992Dietary  -3 PUFA  CVD mortality Feskens et al. 1993Fish  CVD mortality Siscovik et al. 1995Fish  CVD mortality Kromhout et al. 1995Fish  CVD mortality Daviglus et al. 1997Fish  CVD mortality Albert et al. 1998Fish  sudden cardiac death Pedersen et al. 2000Adipose tissue  -3 PUFA  MI mortality Albert et al. 2002Whole blood  -3 PUFA  sudden death Hu et al. 2002Fish and  -3 PUFA intake  CHD mortality Hu et al. 2002Fish and  -3 PUFA intake  non-fatal MI Tavani et al. 2001Fish and  -3 PUFA intake  non-fatal MI Gualler et al. 2003Adipose tissue DHA  first MI Lemaitre et al. 2003Plasma EPA and DHA  CHD mortality

20. Prospective: Long chain  -3 PUFA status and sudden death 10.80.60.40.20 1 23 4 Relative risk of sudden death Quartile of blood  -3 PUFAs Adjusted for age & smoking Also adjusted for BMI, diabetes, hypertension, hypercholesterolemia, alcohol, exercise & family history of MI Albert et al. (2002) New Engl J Med 346, 1113-1118

21. Risk factors for atherosclerosis Elevated blood lipids Endothelial dysfunction Inflammation LDL-cholesterolTriglycerides Hypertension

22. Meta-analysis of trials of fish oil and blood pressure Geleijnse et al. (2002) J. Hypertens. 20, 1493-1499 36 controlled trials reviewed incl. 22 double blind Fish oil: - decreased systolic BP by 2.1 mm Hg (95% CI 1.0, 3.2; P < 0.01) - decreased diastolic BP by 1.6 mm Hg (95% CI 1.0, 2.2; P < 0.01) Effects greater in older subjects Effects greater in hypertensive subjects Conclusion “increased intake of fish oil may lower BP, especially in older and hypertensive subjects”

23. Relationship between dietary long chain  -3 PUFAs and blood TAG concentrations ä Review of 72 placebo-controlled human trials ä All > 2 weeks duration ä Harris (1996) Lipids 31, 243-252 TAG < 2 mM TAG > 2 mM TAG > 2 mM -30 -20 -10 010 % Change Placebo Fish oil Difference

24. Endothelium dependent coronary vasodilatation in patients with CHD before and after fish oil (4 months) Acetylcholine Increase in coronary blood flow (%) 3002001000 CHD patients after fish oil Controls CHD patients before fish oil

25. Fish oil and an inflammatory marker (sVCAM-1) ä Healthy subjects aged > 55 y ä Supplemented diet with a moderate amount of fish oil (= 1.2 g EPA+DHA/day) for 12 weeks ä Plasma soluble VCAM-1 concentrations measured Placebo FO FO 0 200 400 600 8001000 sVCAM-1 (ng/ml) PrePost Miles et al. (2001) Clinical Science 100, 91-100 *

26. Risk factors for atherosclerosis Elevated blood TAG Endothelial dysfunction Inflammation N-3 PUFA Hypertension

27. Secondary prevention: DART ä 1015 men aged < 70 y who had had a MI ä Advised to eat oily fish or take fish oil capsules vs. no advice ä Cardiovascular events and mortality followed for 2 years ä Relative risk death 0.77 ä Relative risk IHD death 0.84 8006004002000 85 90 95100 Time (days) % Surviviors Burr et al. (1989) Lancet ii, 757-761 Oily fish No advice

28. Secondary prevention: GISSI Study  2836 men who had had a MI within the last 3 months assigned to fish oil (0.85 g LC  -3 PUFA/day) vs. placebo ä Follow up for two years ä 356 deaths and non- fatal CV events in fish oil group vs. 414 in placebo group GISSI Prevenzione Investigators (1999) Lancet 354, 447-455 Relative risk in fish oil group Relative risk in fish oil group All fatal events0.80 CV death0.70 Coronary death0.65 Sudden death0.55

29. There are also non-cardiovascular actions of long chain  -3 PUFAs

30. DHA concentration in different human tissues AdiposeErythrocytePlacentaLiverTestisBrainRetina 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 % Total fatty acids

31. DHA status and infant mental development (1 year of age) 1401201008060 Bayley Mental Development Index 3 6 9 12 Infant red cell DHA (%) Gibson et al. (1997) Eur. J. Clin. Nutr. 51, 578-584

32. “Maternal supplementation with very long chain n-3 fatty acids during pregnancy and lactation augments childrens IQ at 4 years of age” Placebo vs. 2.4 g long chain  -3 PUFAs/day (50:50 EPA & DHA) from week 18 of pregnancy until 3 months post partum Kaufman Assessment Battery for Children performed at 4 years of age - a measure of intelligence and achievement designed for children aged 2.5 to 12.5 years At 4 years of age: Children of mothers in control group = 102.3 (11.3) Children of mothers in fish oil group = 106.4 (7.4) Helland et al. (2003) Pediatrics 111, 39-44

33. Omega-3s in children with ADHD Burgess et al. (2000) Am. J. Clin. Nutr. 71, 327S-330S 0.250.20.150.10.050 Control Few ADHD Many ADHD EPA in plasma phospholipids

34. The Durham Trial A randomised controlled trial of fish oil supplementation (vs. placebo) in children (5 – 12 years old) with developmental co-ordination disorder (n = 117) Placebo vs. 550 mg EPA + 175 mg DHA/day for 3 months Then all onto EPA + DHA for a further 3 months Richardson & Montgomery (2005) Pediatrics 115, 1360-1366

35. Reading ageSpelling age Baseline 3 mo 6 mo 120 110 100 90 Omega 3 PlaceboPlacebo then Omega-3 Baseline 3 mo 6 mo 105 100 95 90

36. Omega 3 PlaceboPlacebo then Omega-3 Baseline 3 mo 6 mo Hyperactivity 63 61 59 57 55

37. - membrane structure - brain and visual development - maintenance of cognitive and neurological function (during development & with aging) - regulation of - blood pressure - platelet function, thrombosis, fibrinolysis - blood lipid concentrations - blood lipid concentrations - vascular function - cardiac rhythmn - inflammation - immune response - bone health - insulin sensitivity Long chain  -3 PUFAs are important in:

38. - optimal brain growth - optimal visual and neural function Long chain  -3 PUFAs promote

39. - hypertension - hypertriglyceridemia - thrombosis - vascular dysfunction - cardiac arrhythmias - cardiovascular disease - inflammatory conditions - allergic conditions - immune dysfunction - insulin resistance - psychiatric and neurological diseases of children and adults - neurodegenerative diseases of ageing - bone loss - some cancers Long chain  -3 PUFAs are (or may be) protective against

40. Summary: Long chain  -3 PUFAs -  Long chain  -3 PUFAs have a number of physiological effects ä Through their physiological effects they alter risk of a wide range of human diseases ä Lowered disease risk occurs through plausible biological mechanisms  There are newly emerging mechanisms of action of long chain  -3 PUFAs in some conditions  Long chain  -3 PUFAs exert health benefits right through the life cycle (womb to tomb!)

41. Long chain  -3 PUFAs Current intakes vs. Recommendations (g/day) Current av. UK intake < 0.2 ISSFAL 19990.65 BNF 1999 1.0-1.4 AHA 2003*1.0 AHA 2003**2 to 4 SACN/COT 20040.45 (minimum) *For patients with CHD **For patients with hypertriglyceridaemia

42. What about  -linolenic acid?

43. Sanderson et al. (2002) Brit. J. Nutr. 88, 573-579 “The studies …. suggested little, if any, benefit of  -linolenic acid, relative to linoleic acid, on risk factors for cardiovascular disease ….” Consensus statement

44. However,  -linolenic acid may exert health benefits through conversion to longer chain derivatives But, this may require high intakes of  -linolenic acid