Welcome
Cutting Healthcare Costs Through Prevention:
Measuring the Efficacy, Safety, and Cost Savings
of Dietary Supplements
Richard Sharpee, PhD
Symposium Planning Chairman
Natural Health Research Institute
Scientific Research Manager
Now Health Group, Inc.
Artemis P. Simopoulos, MD
President
The 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
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, 2003
Greece prior to 1960
aData
from Eaton et al. (1998), World Rev Nutr Diet.
bAssuming
an energy intake of 35:65 of animal: plant sources .
OLIVE OIL CONSUMPTION PER PERSON
GREECE
SPAIN
ITALY
PORTUGAL
U.S.
EEC/OTHER
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
M
27
31
F
33
34
M
189
33
F
54
14
M
30
26
F
24
23
Breast cancer
F
22
8
Stomach cancer
M
6
10
F
3
6
M
11
3
F
10
3
M
102
83
F
87
61
Life expectancy at age 45
Coronary heart disease
Cerebrovascular diseases
Colorectal cancer
Total cancers
Greece
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
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
6
23
Legumes (g/day)
Alcohol (g/day)
* 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 EGG
SUPERMARKET
EGG
FATTY ACID
GREEK EGG
SUPERMARKET
EGG
Omega-6 fatty acids
Saturated fats
14:0
15:0
16:0
17:0
18:0
TOTAL
16.00
-0.17
0.46
5.40
0.70
0.29
23.02
26.14
0.25
0.36
0.47
5.02
0.37
1.20
33.81
18:3ω3
6.90
0.52
0.04
20:3ω3
20:5ω3
22:5ω3
22:6ω3
0.16
1.20
2.80
6.60
0.03
-0.09
1.09
115.36
TOTAL
17.66
1.73
1.10
-77.60
0.66
21.33
100.66
0.70
0.07
56.66
0.34
22.88
80.65
16:1ω7
18:1
20:1ω9
22:1ω9
21.70
120.50
0.58
--
4.67
109.97
0.68
--
24:1ω9
--
TOTAL
142.78
Mono-unsaturated fats
18:2ω6
18:3ω6
20:2ω6
20:3ω6
20:4ω6
22:4ω6
22:5ω6
TOTAL
Omega-3 fatty acids
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%
Cheddar American Swiss
Milk
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 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
ω6 Polyunsaturates
18:2ω6
20:2ω6
20:3ω6
20:4ω6
22:4ω6
22:5ω6
Total
ω3 Polyunsaturates
18:3ω3
20:4ω3
20:5ω3
22:5ω3
22:6ω3
Total
ω6/ω3 Ratio
Control Fat-1
14.2 a
1.2 a
1.6 a
15.2 a
4.4 a
0.2 a
36.8 a
9.2 b
0.3 b
0.4 b
4.1 b
1.0 b
0.0 b
15.0 b
0.2 b
0.0 b
0.1 b
1.2 b
1.0 a
2.5 b
14.7 a
3.6 a
0.6 a
6.1 a
5.8 a
1.3 a
17.4 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
Lipid Mediators
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
Key cellular actions of lipoxins and resolvins
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.
Spite M, Serhan CN. Circ Res. 2010;107:1-15.
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
Effect of ω-3
Fatty Acid
Function
Factor
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.
Effect of ω-3 fatty acids on factors involved in the
pathophysiology of atherosclerosis, inflammation, and the
metabolic syndrome
Effect of ω-3
Fatty Acid
Function
Factor
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
Effect of ω-3 fatty acids on factors involved in the
pathophysiology of atherosclerosis, inflammation, and
the metabolic syndrome
Effect of ω-3
Fatty Acid
Function
Factor
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 insulinsensitizing adipokine
Effect of ω-3 fatty acids on factors involved in the
pathophysiology of atherosclerosis, inflammation, and the
metabolic syndrome
Effect of ω-3
Fatty Acid
Function
Factor
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
Effect of ω-3 fatty acids on factors involved in the
pathophysiology of atherosclerosis, inflammation, and the
metabolic syndrome
Effect of ω-3
Fatty Acid
Function
Factor
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
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
Effects of PUFA on several genes encoding enzyme proteins
involved in inflammation, adhesion molecules, cell growth, early
gene expression, β-oxidation, and growth factors
Fatty
acid
Cell growth
and early gene
expression
c-fos, Egr-1
Adhesion
molecules
VCAM-1
mRNA**
Inflammation
IL-1B
mRNA
β-oxidation
acyl-CoA
oxidase
mRNA**
Growth
Factors
PDGF
mRNA
LA
LNA
AA
***
EPA
*
DHA
*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
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 αLinolenic 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
• 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
Marchioli R., Barzi F., Bomba E. et al. Circulation 2002; 105: 1897-1903.
Early benefit of ω3 PUFA therapy: Total mortality
Marchioli R., Barzi F., Bomba E. et al. Circulation 2002; 105: 1897-1903.
Early benefit of ω3 PUFA therapy: Sudden death
Marchioli R., Barzi F., Bomba E. et al. Circulation 2002; 105: 1897-1903.
Early benefit of ω3 PUFA therapy:
Coronary heart disease mortality
Marchioli R., Barzi F., Bomba E. et al. Circulation 2002; 105: 1897-1903.
Early benefit of ω3 PUFA therapy:
Cardiovascular mortality
Marchioli R., Barzi F., Bomba E. et al. Circulation 2002; 105: 1897-1903.
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.
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
Ambring A, Johansson M, Axelsen M, et al., Am J Clin Nutr 2006; 83: 575-81.
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.
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 agematched 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 Longterm 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 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
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
ω-3 supplementation is associated with a
reduced risk of
•
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
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
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
Before ω-3
After ω-3
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.
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.
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.
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.
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 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
2.00
1.0
(Upper limit)4
--
< 8.0
MONOs5
--
--
TRANS-FA
(Upper limit)3
SAT
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