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

WelcomeCutting Healthcare Costs Through Prevention:

Measuring the Efficacy, Safety, and Cost Savingsof Dietary Supplements

Richard Sharpee, PhDSymposium Planning Chairman

Natural Health Research Institute

Scientific Research ManagerNow Health Group, Inc.

Artemis P. Simopoulos, MD

PresidentThe Center for Genetics,

Nutrition & Health

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

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

Relationships between genes, environment, and development are dynamic

Genotype Environment

Phenotype

Development

Childs, B. (1990). Genetic Variation and Nutrition. World Rev Nutr Diet, Vol 63.

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.

The desaturation and elongation of ω3 and ω6 fatty acids

(FADS 2)

(FADS 1)

Ratios of dietary ω6:ω3 fatty acids in the late Paleolithic period and in current Western

dietary patterns (g/d) a,b

Paleolithic Western

LA:ALA 0.70 18.75

AA+DTA:EPA+DPA+DHA 1.79 3.33

Total 0.79 16.74

aData from Eaton et al. (1998), World Rev Nutr Diet.

bAssuming an energy intake of 35:65 of animal:plant sources.

ω6:ω3 ratios in various populations

Population ω6:ω3 Reference

Paleolithic 0.79 a,b Eaton et al, 1998

Greece prior to 1960 1.00-2.00 Simopoulos, 1999

Current United States 16.74 Eaton et al, 1998

United Kingdom and northern Europe

15.00 Sanders, 2000

Japan 4.00 Sugano and Hirahana, 2000

India rural 5-6.1 Pella et al, 2003

India urban

38-50 Pella et al, 2003aData from Eaton et al. (1998), World Rev Nutr Diet.

bAssuming an energy intake of 35:65 of animal: plant sources.

GREECE SPAIN ITALY PORTUGAL U.S. EEC/OTHER

OLIVE OIL CONSUMPTION PER PERSON

The Mediterranean Region

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.

Life expectancy and disease rates in the United States and Greece in the 1960’s

Life expectancy and disease rates

Gender United States Greece

Life expectancy at age 45 M 27 31

F 33 34

Coronary heart disease M 189 33

F 54 14

Cerebrovascular diseases M 30 26

F 24 23

Breast cancer F 22 8

Stomach cancer M 6 10

F 3 6

Colorectal cancer M 11 3

F 10 3

Total cancers M 102 83

F 87 61

Dietary characteristics in the United States and Greece in the 1960s

Dietary characteristics United States Greece

Fat (% energy) 39 37

Saturated fat (% energy) 18 8

Vegetables (g/day) 171 191

Fruits (g/day) 233 463

Legumes (g/day) 1 30

Breads and cereals (g/day) 123 453

Potatoes (g/day) 124 170

Meat* (g/day) 273 35

Fish (g/day) 3 39

Eggs (g/day) 40 15

Alcohol (g/day) 6 23

* Includes poultry

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

Nature’s nutrients: The purslane plant

Fatty acid content of plants*

Fatty acid Purslane Spinach Buttercrunch Lettuce

Red Leaf Lettuce

Mustard

14:0 0.16 0.03 0.01 0.03 0.02

16:0 0.81 0.16 0.07 0.10 0.13

18:0 0.20 0.01 0.02 0.01 0.02

18:1ω9 0.43 0.04 0.03 0.01 0.01

18:2ω6 0.89 0.14 0.10 0.12 0.12

18:3ω3 4.05 0.89 0.26 0.31 0.48

20:5ω3 0.01 0.00 0.00 0.00 0.00

22:6ω3 0.00 0.00 0.001 0.002 0.001

Other 1.95 0.43 0.11 0.12 0.32

Total fatty acid content

8.50 1.70 0.601 0.702 1.101

*mg/g of wet weight

A.P. Simopoulos and N. Salem, Jr. (1986). New England Journal of Medicine, 315:833.

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

Fatty acid levels in various chicken egg yolks (mg fatty acid/g hard-boiled egg yolk)

FATTY ACID GREEK EGGSUPERMARKET

EGG

Saturated fats

14:0 1.10 0.70

15:0 -- 0.07

16:0 77.60 56.66

17:0 0.66 0.34

18:0 21.33 22.88TOTAL 100.66 80.65

Mono-unsaturated fats

16:1ω7 21.70 4.67

18:1 120.50 109.97

20:1ω9 0.58 0.68

22:1ω9 -- --

24:1ω9 -- 0.04

TOTAL 142.78 115.36

FATTY ACID GREEK EGGSUPERMARKET

EGG

Omega-6 fatty acids

18:2ω6 16.00 26.1418:3ω6 -- 0.2520:2ω6 0.17 0.3620:3ω6 0.46 0.4720:4ω6 5.40 5.0222:4ω6 0.70 0.3722:5ω6 0.29 1.20TOTAL 23.02 33.81

Omega-3 fatty acids

18:3ω3 6.90 0.52

20:3ω3 0.16 0.0320:5ω3 1.20 --22:5ω3 2.80 0.09

22:6ω3 6.60 1.09

TOTAL 17.66 1.73

P 40.68 = 0.4 35.55 = 0.44 Omega-6 23.02 = 1.3 33.81 = 19.4

S 100.66 80.65 Omega-3 17.66 1.73

A.P. Simopoulos and N. Salem, Jr. (1989). New England Journal of Medicine, 321:1412.

Fatty acid composition of selected cheeses (amount in grams/100 grams, edible portion)

2% Milk

Cheddar American SwissGreek

MyzithraGreek

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 mg 10 mg

Eicosapentaenoic Acid

-- -- -- 18 mg 14 mg

Docosapentaenoic Acid

-- -- -- 31 mg 23 mg

Docosahexaenoic Acid

-- -- -- 5.5 mg 5.1 mg

Fatty acid composition of snails

Origin 18:0 18:1(9) 18:2(6) 18:3(3) 20:2(6) 20:4(6) 20:5(3)

Crete 7.3 19.9 17.2 9.7 7.0 8.8 1.1

Greece 8.6 12.7 18.7 10.6 7.2 9.2 1.2

France 10.9 10.3 14.3 4.9 10.6 16.2 1.7

Weight of a snail = 10 to 15 g Lipids = 0.15 to 0.19 g

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 ± 0.1 p < 0.001

18:0 0.7 ± 0.0 1.1 ± 0.0 p < 0.001

18:1ω9 31.0 ± 0.3 21.4 ± 0.4 p < 0.001

18:2ω6 41.9 ± 0.4 53.1 ± 0.7 p < 0.001

18:3ω3 0.9 ± 0.1 0.3 ± 0.0 p < 0.001

Modified from Sandker, G.W. et al. (1993). Eur J Clin Nutr, 47: 201-208.

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.

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.

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 acids Control Fat-1ω6 Polyunsaturates18:2ω6 14.2 a 9.2 b

20:2ω6 1.2 a 0.3 b

20:3ω6 1.6 a 0.4 b

20:4ω6 15.2 a 4.1 b

22:4ω6 4.4 a 1.0 b

22:5ω6 0.2 a 0.0 b

Total 36.8 a 15.0 b

ω3 Polyunsaturates18:3ω3 0.2 b 3.6 a

20:4ω3 0.0 b 0.6 a

20:5ω3 0.1 b 6.1 a

22:5ω3 1.2 b 5.8 a

22:6ω3 1.0 a 1.3 a

Total 2.5 b 17.4 a

ω6/ω3 Ratio 14.7 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.

Eicosanoid Formation and Metabolism

Catabolic pathways of arachidonic acid

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.

EPA Resolvins of E series

DHA Resolvins of D series

DHA Protectins D

DHA Neuroprotectin D1

AA Lipoxins A4, B4

Lipid Mediators

Key cellular actions of lipoxins and resolvins

Spite M, Serhan CN. Circ Res. 2010;107:1-15.

LXA₄ 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 (PGI₂.

IMMUNOLOGY AND INFLAMMATION

Biological activities of interleukin-1

Figure courtesy of Dr. Jos W. M. van der Meer, Nijmegen, the Netherlands

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

Effect of ω-3 fatty acids on factors involved in the pathophysiology of atherosclerosis, inflammation, and the

metabolic syndrome

Factor FunctionEffect of ω-3 Fatty Acid

Arachidonic Acid Eicosanoid precursor; aggregates platelets; stimulates white blood cells

Thromboxane A2 Platelet aggregation; vasoconstriction; increase of intracellular Ca++

Prostacyclin (PGI 2/3) Prevents platelet aggregation; vasodilation; increase cAMP

Leukotriene (LTB4) Neutrophil chemoattractant; increase of intracellular Ca++

Tissue plasminogen activator

Increases endogenous fibrinolysis

Fibrinogen Blood clotting factor

Platelet activating factor (PAF)

Activates platelets and white blood cells

Simopoulos AP.


Platelet-derived growth factor (PDGF)

Chemoattractant and mitogen for smooth muscles and macrophages

Oxygen free radicals Cellular damage; enhance LDL uptake via scavenger pathway; stimulate arachidonic acid metabolism

Lipid hydroperoxides Stimulate eicosanoid formation

Interleukin 1 and tumor necrosis factor

Stimulate neutrophil O2 free radical formation; stimulate lymphocyte proliferation; stimulate PAF; express intercellular adhesion molecule-1 on endothelial cells; inhibit plasminogen activator- thus procoagulants

Interleukin-6 Stimulates the synthesis of all acute phase proteins involved in the inflammatory response: C-reactive protein; serum amyloid A; fibrinogen; α₁-chymotrypsin; and haptoglobin


metabolic syndrome


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

PPARγ Genes involved in insulin sensitivity

GLUT-2/GLUT-4 Glucose transport

IRS-1/IRS-2 Insulin receptor signaling

Adiponectin Anti-inflammatory and insulin-sensitizing adipokine

Effect of ω-3 fatty acids on factors involved in the pathophysiology of atherosclerosis, inflammation, and

the metabolic syndrome


AMPK phosphorylation

A fuel sensing enzyme and a gatekeeper of the energy balance

Hepatic statosis

Obesity induced insulin resistance

VLDL

HDL Decreases the risk for coronary heart disease

Lp(a) Lipoprotein(a) is a genetically determined protein that has atherogenic and thrombogenic properties


metabolic syndrome


Trigylcerides and chylomicrons

Contribute to postprandial lipemia

Telomeres Have 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

PPAR Upregulates the expression of genes involved in lipid metabolism and downregulates the expression of genes involved in inflammation and suppresses NFkB


metabolic syndrome

PLASMA LIPIDS AND LIPOPROTEINS

THROMBOSIS AND ATHEROSCLEROSIS

Omega-3 fatty acids

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

CELL MEMBRANE FUNCTION AND METABOLISM THROUGHOUT

THE LIFE CYCLE

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 decrease induce 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.

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

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

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).

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

Early benefit of ω3 PUFA therapy: Total mortality


Early benefit of ω3 PUFA therapy: Sudden death


Early benefit of ω3 PUFA therapy: Coronary heart disease mortality


Early benefit of ω3 PUFA therapy: Cardiovascular mortality


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.


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.

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


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.


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..

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.

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.

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.

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

Dietary ratio of n-6 to n-3 polyunsaturated fattyacids 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

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.

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

• 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 adirect action of W-3’s on the CNS

ω-3 supplementation is associated with a reduced risk of

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)

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

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


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

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


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.

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.


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.


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 5th 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.

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.

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.

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.

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.

Relationships between genes, environment, and development are dynamic

Genotype Environment

Phenotype

Development

Childs, B. (1990). Genetic Variation and Nutrition. World Rev Nutr Diet, Vol 63.

Adequate intakes (AI) for adults

Fatty Acid Grams/day (2000 kcal diet) % Energy

LA 4.44 2.0

(Upper Limit)1 6.67 3.0

LNA 2.22 1.0

DHA + EPA 0.65 0.3

DHA to be at least2 0.22 0.1

EPA to be at least 0.22 0.1

TRANS-FA

(Upper limit)3 2.00 1.0

SAT

(Upper limit)4 -- < 8.0

MONOs5 -- --

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.

Adequate intake (AI) for infant formula/ diet

Fatty Acid Percent of Fatty Acids

LA1 10.00

LNA 1.50

AA2 0.50

DHA 0.35

EPA3

(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.

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

Documents

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