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Filtering fish oil fact from fiction
Nina Bailey BSc MSc, PhD RNutr
In 1992, the BNF Task Force on Unsaturated Fatty Acids
suggested a desirable population intake for EPA and DHA of
0.5% of energy, which equates to about 8g/week (1.14g/day) for women and 10g/week (1.42g/day) for men,
equivalent to 2-3 medium servings of oil-rich fish per week
For a 77kg individual to raise their omega-3 index from 4.2% to 8% they would need a daily dose of 16mg/kg
omega-3 (equivalent to 1.25g) (Flock et al. 2013)
British Nutrition Foundation. Unsaturated fatty acids nutritional and physiological significance: the report of the British Nutrition Foundation's task force. New York: Chapman & Hall, 1992.
https://www.gov.uk/government/statistics/ndns-results-from-years-5-and-6-combined
Flock MR, Skulas-Ray AC, Harris WS, Etherton TD, Fleming JA, Kris-Etherton PM. Determinants of erythrocyte omega-3 fatty acid content in response to fish oil supplementation: a dose-response randomized controlled trial. J Am Heart Assoc. 2013 Nov 19;2(6):e000513.
Stark KD, Van Elswyk ME, Higgins MR, Weatherford CA, Salem N Jr. Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the bloodstream of healthy adults. Prog Lipid Res. 2016 Jul;63:132-52.
Current UK omega-3 recommendations
450mg EPA and DHA daily (2 portions fish
weekly, of which one should be oily)
However...........
Is omega-3 ‘deficiency’ a global burden?
Mean consumption of oily fish (all age groups) was
below the recommended one portion (140g) per week
(rolling programme for 2012 and 2013 to 2013 and 2014)
and equivalent to 13 to 29 grams per week in children and
54 to 87 grams per week in adults
Sprague M, Dick JR, Tocher DR. Impact of sustainable feeds on omega-3 long-chain fatty acid
levels in farmed Atlantic salmon, 2006-2015. Sci Rep. 2016 Feb 22;6:21892.
4Sprague M, Dick JR, Tocher DR. Impact of sustainable feeds on omega-3 long-chain fatty acid levels in farmed Atlantic salmon, 2006-2015.
Sci Rep. 2016 Feb 22;6:21892.
Changes in the levels of fatty acids (% of total fatty acids), of either marine (- - -) or terrestrial
origin (___), in the flesh of Scottish Atlantic salmon farmed between 2006–2015 (mean ± SD)   
LA
DHA
EPA
ALA
Oleic acid
5Sprague M, Dick JR, Tocher DR. Impact of sustainable feeds on omega-3 long-chain fatty acid levels in farmed Atlantic salmon, 2006-2015.
Sci Rep. 2016 Feb 22;6:21892.
Number of portions required (mean ± SD) to obtain a weekly intake of 3.5 g EPA+         
DHA (ISSFAL, 2004), based on a 130 g serving 
Using omega-3 at a dose of 1g – is this enough?
• Many fish oil clinical trials have used a dose of 1 g/d in all treated subjects
• An omega-3 dose 1 g/d, (as Omacor) in the study by Rupp et al, increased omega-3 index from a mean of
3.6 % to 5.4 % but approximately 16 % of the subjects achieved an EPA+DHA blood level less than 4.8 %.   
• The AA to EPA ratio was reduced from 20 to 7.2 and after withdrawal, EPA and DHA plasma levels
approach baseline values within 10 days
• This is clinically relevant since it has been noted that an omega-3 index>5 % is the range in which   
dramatic reduction in sudden coronary death reduction can be observed
• Individual variability in blood level response to such a common dose could leave a substantial number of
patients at elevated CHD risk due to failure to achieve a therapeutic EPA+DHA blood level   
Rupp H, Wagner D, Rupp T, Schulte LM, Maisch B. Risk stratification by the “EPA+DHA level” and the “EPA/AA ratio” Herz. 2004;29:673–685.   
Superko HR, Superko AR, Lundberg GP, Margolis B, Garrett BC, Nasir K, Agatston AS. Omega-3 Fatty Acid Blood Levels Clinical Significance Update.
Curr Cardiovasc Risk Rep. 2014;8(11):407. Review.
Donadio JV, Bergstralh EJ, Bibus DM, Grande JP. Is body size a biomarker for optimizing dosing of omega-3 polyunsaturated fatty
acids in the treatment of patients with IgA nephropathy? Clin J Am Soc Nephrol. 2006;1:933–939.
 In IgA Nephropathy patients, 2 years of treatment with 3.35 g/d total omega-3 fatty acids (Omacor
4g) EPA levels increased from 0.8±0.5 to 3.1±1.3 % after treatment and DHA from 3.7±1.6 to 6.5±               
1.3 %.
 Treatment with 6.70 g/d of omega-3 fatty acids (Omacor 8g) increased blood EPA levels from 0.9±0.6   
to 5.2±1.8 % and blood DHA from 3.5±1.4 to 7.1±1.6 %           
 In patients with IgA nephropathy, treated with 4 g/d fish oil, the mean EPA/AA ratio increased from
approximately 0.09±0.07 to 0.45±0.40 with a wide range of individual variability       
Using omega-3 at a doses of >1g impact on omega-3 index and
AA to EPA ratio
4g Omacor (EPA 1.8 g, DHA 1.47 g) 8g Omacor (EPA 3.6g; DHA ; 2.94g)
AA EPA DHA Omega-3 index AA to EPA ratio AA EPA DHA Omega-3 index AA to EPA ratio
Base line 10 0.8 3.7 4.5 10 9.8 0.9 3.5 4.4 10
6 weeks 8.5 3.6 6.7 10.2 2 8.0 4.9 7.4 12.3 1.7
6 months 8.5 3.1 6.5 9.6 2 7.7 5.2 7.5 12.9 1.4
Donadio JV, Bergstralh EJ, Bibus DM, Grande JP. Is body size a biomarker for optimizing dosing of omega-3 polyunsaturated fatty
acids in the treatment of patients with IgA nephropathy? Clin J Am Soc Nephrol. 2006;1:933–939.
Plasma phospholipid levels of EPA, DHA, and EPA/AA ratios were significantly inversely correlated with
increasing body weight and BMI in the Omacor 4-g dosage group but not in the Omacor 8-g dosage group
The levels of EPA, DHA, omega-3 index increased significantly with increasing dose of Omacor
The plotted line is a smoother (running average) and identifies a plateauing effect at a dosage of
approximately 0.07 g/kg
4g Omacor (EPA 1.8 g, DHA 1.47 g) 8g Omacor (EPA 3.6g; DHA ; 2.94g)
AA EPA DHA Omega-3 index AA to EPA ratio AA EPA DHA Omega-3 index AA to EPA ratio
Base line 10 0.8 3.7 4.5 10 9.8 0.9 3.5 4.4 10
6 weeks 8.5 3.6 6.7 10.2 2 8.0 4.9 7.4 12.3 1.7
6 months 8.5 3.1 6.5 9.6 2 7.7 5.2 7.5 12.9 1.4
Blood levels (mean±SD) of EPA and DHA as % of total fatty acids pre- and post dosing
 Blood levels (mean ± SD) of EPA & DHA as % of total fatty acids pre- and post dosing
 Data points are identified by author and ranked by daily dose (low to high)
 Fish oil doses were as follows: Rupp, 1 g/d; Di Stasi, 1 g/d; Poppitt, 1.2 g/d; Vedin, 2.3 g/d; Donadio, 3.35
g/d; Laidlow, 4 g/d; Donadio, 6.7 g/d
 Red line indicates the level of DHA above which it is suggested that atrial fibrillation risk may be reduced
Superko HR, Superko SM, Nasir K, Agatston A, Garrett BC. Omega-3 fatty acid blood levels: clinical significance and controversy. Circulation. 2013 Nov
5;128(19):2154-61.
Blood levels (mean±SD) of EPA/AA at baseline and after treatment.
Superko HR, Superko SM, Nasir K, Agatston A, Garrett BC. Omega-3 fatty acid blood levels: clinical significance and controversy. Circulation. 2013 Nov
5;128(19):2154-61.
 Doses were as follows: Shintani, 1800 mg/d; Matsuzaki, 1800 mg/d; Donadio, 3.5 g/d; Laidlow, 4.0 g/d;
Donadio, 6.7 g/d
 The red line indicates a risk level suggested by Itakura et al.5 EPA/AA indicates eicosapentaenoic
acid/arachidonic acid; and SD, standard deviation.
Maternal health and
outcomes
200mg/day
Brain and eye development
and function
200mg/day
Promotes maternal DHA
status
Supports normal gestational
period
Increases DHA breast milk
content
Promotes foetal growth and
development
Cardiovascular, visual
and cognition
250mg/day
Cardiovascular, visual
and cognition
250mg/day
Promotes visual acuity
Promotes cognitive
performance
Cardiovascular heath
Cognitive function
Low DHA associated with
increased risk of cognitive
decline, dementia and
age related macular
degeneration
DHA requirements through the life stages
The developing brain
DHA accumulates rapidly in the normally growing
foetal brain, at around 67 mg/day in the last
trimester.
Total brain volume undergoes an initial rapid
spurt, reaching 80% of its maximum volume by
around 1.5 years.
Further growth spurts are believed to occur
between 2–4 years and between 6–8 years of
age.Groeschel S, Vollmer B, King MD, Connelly A.
2010 Developmental changes in cerebral grey and white matter
volume from infancy to adulthood. Int J Dev Neurosci. 28:481-9.
Anti-inflammatory
eicosanoid production
DGLA
GLA
LA
EPA
ETA
SDA
ALA
Delta -6 desaturase
Delta -5 desaturase
Cyclooxygenase (COX)/lipoxygenase (LOX)
Elongase
Series-2 prostaglandins
Series-2 thromboxanes
Series-4 leukotrienes
Hydroxy fatty acids
AA
COX/LOX
Omega-6 Omega-3 Eicosanoids, including prostaglandins and
leukotrienes, are biologically active lipids
derived from AA and EPA that have been
implicated in various pathological processes,
such as inflammation and cancer
The relationship between AA and EPA is
therefore significant when considering omega-
3 intervention strategies
Key structural role &
anti-inflammatory
docosanoid production
Resolvins
Protectins
DHA
Elongase &
desaturase
Pro-inflammatory
eicosanoid production
Series-3 prostaglandins
Series-3 thromboxanes
Series-5 leukotrienes
Hydroxy fatty acids
Resolvins
Primary structural function &
anti-inflammatory docosanoid
production
Anti-inflammatory eicosanoid
production
REDUCED INFLAMMATION
DHAEPA
Pro-inflammatory eicosanoid
production
INFLAMMATION
AA
AA to EPA ratio
direct antagonism
The relationship between the omega-3 index and the AA to EPA ratio
Omega-3 index
EPA and DHA incorporation
• The preferential uptake of EPA and DHA by
specific phospholipids is significant
• PC is located mainly in the outer membrane
whereas PE is primarily on the inside
• The distribution of these PLs determines the
enzymes with which they interact
– EPA is preferentially incorporated into PC with
some incorporation into PE
– DHA is preferably incorporated into PE with some
incorporation into PC
15
DHA ‘issues’?
• Membranes enriched with DHA are most susceptible to oxidative damage, and
oxidative alterations of membranes have many potential consequences in
human pathophysiology
• DHA has antioxidant and pro-oxidant effects at low and high levels of
incorporation, respectively
– At low concentration, DHA lowers lipid peroxidation and is generally incorporated in PE
(inside membrane)
– At higher doses DHA can be incorporated into PC where it may exhibit proinflammatory
effects (outside membrane)
• DHA therefore has different effects on cell function, depending on its
phospholipid accumulation which differs according to its concentration
Véricel E, Polette A, Bacot S, Calzada C, Lagarde M. Pro- and antioxidant activities of docosahexaenoic acid on human blood platelets. J
Thromb Haemost. 2003 Mar;1(3):566-72.
Is there an optimal EPA to DHA ratio?
2:1 EPA to DHA proportions demonstrated to be more effective treatments to produce an
antiinflammatory response compared with 1:2 EPA to DHA
6 :1 EPA to DHA ratio may be optimal for correcting omega-3 deficiency, with concomitant
positive effects on lipid profiles and on inflammatory indices
EPA in excess of DHA is optimal!
As much as 13% of DHA is retroconverted to EPA
Monitor DHA levels and supplement accordingly?
Dasilva G, Pazos M, García-Egido E, Pérez-Jiménez J, Torres JL, Giralt M, Nogués MR, Medina I. Lipiomics to analyse the influence of diets with different ratios of EPA to DHA in
the progression of metabolic syndrome using SHTOB rats. Food Chem. 2016 Aug 15;205:196-203.
Shaikh NA, Yantha J, Shaikh S, Rowe W, Laidlaw M, Cockerline C, Ali A, Holub B, Jackowski G: Efficacy of a unique omega-3 formulation on the correction of nutritional deficiency
and its effects on cardiovascular disease risk factors in a randomized controlled VASCAZEN((R)) REVEAL Trial. Molecular and cellular biochemistry 2014, 396:9-22.
 
EPA and DHA utilisation differences
 High DHA intake reduces delta-6-desaturase activity
 Studies often report no increase in DHA levels with pure EPA
supplementation – DHA saturation?
 In some cases [depression/neurodevelopmental disorders] high
DHA supplementation has been shown to worsen health outcomes
 12 week intervention with 1.8 g omega-3 (1.2g EPA + 0.6g
DHA) in young healthy males aged 18-25
 During the washout period, EPA and DHA levels decreased
back to baseline levels, with EPA levels rapidly returned to
baseline levels within 2 weeks of stopping fish oil
supplementation, while serum DHA returned to baseline
levels only by the end of the washout period
Suggests high EPA requirements? Time (weeks)
Roke K, Mutch DM. The role of FADS1/2 polymorphisms on cardiometabolic markers and fatty acid profiles in young adults consuming fish oil
supplements. Nutrients. 2014 Jun 16;6(6):2290-304.
0 4 8 12 20
0
1
2
3
4
Time (weeks)
EPA in mononuclear cell PL (%)
0 4 8 12 20
1
2
3
4
Time (weeks)
DHA in mononuclear cell PL (%)
Effect of stopping intake of EPA and DHA
Healthy volunteers given fish oil for 12 weeks; then 8 week washout
• Yaqoob P, Pala HS, Cortina-Borja M, Newsholme EA, Calder PC. Encapsulated fish oil enriched in alpha-tocopherol alters plasma phospholipid and mononuclear cell
fatty acid compositions but not mononuclear cell functions. Eur J Clin Invest. 2000 Mar;30(3):260-74
Benefits of the Opti-O-3
 Knowledge of baseline levels will guide the practitioner recommendations—
unsurprisingly, low baseline values may require a larger dose than a high baseline
value!
 The omega-3 index and AA to EPA ratio are invaluable for assessing both baseline
risk and the change in risk (as function of intake – retesting is advisable ≥6 months)
 Dose response studies show us that high doses of omega-3 are required to reduce
the AA to EPA ratio and achieve an omega-3 index ≥8%, especially where the
baseline levels are suboptimal ≤4%
Use in conjunction with Pharmepa RESTORE & MAINTAIN
 Pre-loading with pure EPA for 6 months (RESTORE) is advised to reduce the AA to EPA
ratio, before the introduction of EPA/DHA with GLA (MAINTAIN) for long-term
support of the omega-3 index
DHA
EPA
ETA
SDA
ALA
Delta -6 desaturase
Delta -5 desaturase
Elongase
DPA
 EPA converts to DPA
 DPA acts as a reservoir for EPA (retroconversion
back to EPA)
 DHA retroconversion to EPA
X EPA conversion to DHA?????
In the brain, low DHA is seen by an increase in DPA
‘Healthy DHA to EPA ratio of RBC = 3:1/4:1
Opti-O-3 average is 2.4 (most people are low in DHA)
Supplementation:
 Pure EPA increases EPA and reduces DHA
 Pure DHA increases EPA and DHA
 EPA and DHA increases both EPA and DHA
Supplementing with omega-3
22
1%
3% 3% 3% 3%
10% 10% 10% 10%
A B C D
A
B
C
D
Omega-3 index = 4
AA to EPA ratio = 10
2%
4%
3%
Omega-3 index = 5
AA to EPA ratio = 5
Omega-3 index = 6
AA to EPA ratio = 3.3
Omega-3 index = 7
AA to EPA ratio = 2.5
3%
10%
E
5%
D
Omega-3 index = 8
AA to EPA ratio = 2
What’s the best omega-3 index?
EPA
DHA
AA
23
1%
3%
4%
5% 5%
10% 10% 10% 10%
A B C D
A
B
C
D
Omega-3 index = 4
AA to EPA ratio = 10
1%
2%
1%
Omega-3 index = 5
AA to EPA ratio = 10
Omega-3 index = 6
AA to EPA ratio = 10
Omega-3 index = 7
AA to EPA ratio = 5
5%
10%
E
3%
D
Omega-3 index = 8
AA to EPA ratio = 3.3
What’s the best omega-3 index?
EPA
DHA
AA
Optimising the EPA to DHA ratio with Pharmepa
1 RESTORE 2 RESTORE 3 RESTORE 4 RESTORE 1 MAINTAIN 2 MAINTAIN 3 MAINTAIN 4 MAINTAIN
0
500
1000
1500
2000
2500
GLA (mg) DHA (mg) EPA (mg)
1 RESTORE 2 RESTORE 3 RESTORE 4 RESTORE 1 MAINTAIN 2 MAINTAIN 3 MAINTAIN 4 MAINTAIN
EPA (mg) 500 1000 1500 2000 250 500 750 1000
DHA (mg) 0 0 0 0 83 167 250 333
GLA (mg) 0 0 0 0 20 40 60 80
Vitamin E (mg) 5 10 15 20 3 6 9 12
Vitamin D (µg) 0 0 0 0 10 20 30 40
EPA to DHA ratio - - - - 3 3 3 3
Total Omega-3 (mg) 500 1000 1500 2000 333 666 1000 1333
1 RESTORE 1 RESTORE 1 RESTORE 1 RESTORE 2 RESTORE 2 RESTORE 2 RESTORE 2 RESTORE
1 MAINTAIN 2 MAINTAIN 3 MAINTAIN 4 MAINTAIN 1 MAINTAIN 2 MAINTAIN 3 MAINTAIN 4 MAINTAIN
EPA (mg) 750 1000 1250 1500 1250 1500 1750 2000
DHA (mg) 83 167 250 333 83 167 250 333
GLA (mg) 20 40 60 80 20 40 60 80
Vitamin E (mg) 8 11 14 17 13 16 19 22
Vitamin D (µg) 10 20 30 40 10 20 30 40
EPA to DHA ratio 9 6 5 5 15 9 7 6
Total Omega-3 (mg) 833 1167 1500 1833 1333 1667 2000 2333
0
500
1000
1500
2000
2500
3000
GLA (mg) DHA (mg) EPA (mg)
1 RESTORE 1 RESTORE 1 RESTORE 1 RESTORE 2 RESTORE 2 RESTORE 2 RESTORE 2 RESTORE
1 MAINTAIN 2 MAINTAIN 3 MAINTAIN 4 MAINTAIN 1 MAINTAIN 2 MAINTAIN 3 MAINTAIN 4 MAINTAIN
Optimising the EPA to DHA ratio with Pharmepa
How much omega-3 is too much?
 AA levels during administration of various types of EPA/DHA preparations have shown that
phospholipid AA levels rise initially when the total dose of EPA and DHA administered is
relatively small
 A fall in AA levels only comes later when the cumulative amount of EPA, EPA/DHA
administered is high
 Doses of up to about 2 g/day pure omega-3 fatty acid lead to a rise in RBC AA levels while 4
g/day lead to a fall
 Higher (>2g) EPA may be ineffective compared to lower doses (1-2g) because higher doses
create a drop in AA levels and that the suppression of AA levels may not be helpful
 Both AA and DHA are require to maintain optimal cell membrane fluidity and for the
production of SPMs and therefore it may be as much of a mistake to suppress omega-6 levels
by raising omega-3 intakes too high
 DHA clearance is at a slower rate than EPA (post supplementation) which reflects retention of
PUFAs for membrane integrity
Horrobin DF, Jenkins K, Bennett CN, Christie WW. Eicosapentaenoic acid and arachidonic acid: collaboration and not antagonism is 
the key to biological understanding. Prostaglandins Leukot Essent Fatty Acids. 2002 Jan;66(1):83-90.
Benefits of the Opti-O-3
 Knowledge of baseline levels will guide the practitioner recommendations—
unsurprisingly, low baseline values may require a larger dose than a high baseline
value!
 The omega-3 index and AA to EPA ratio are invaluable for assessing both baseline
risk and the change in risk (as function of intake – retesting is advisable ≥6 months)
 Dose response studies show us that high doses of omega-3 are required to reduce
the AA to EPA ratio and achieve an omega-3 index ≥8%, especially where the
baseline levels are suboptimal ≤4%
Use in conjunction with Pharmepa RESTORE & MAINTAIN
 Pre-loading with pure EPA for 6 months (RESTORE) is advised to reduce the AA to EPA
ratio, before the introduction of EPA/DHA with GLA (MAINTAIN) for long-term
support of the omega-3 index
Question
What is the best form of omega-3 to take from an ethical,
financial and therapeutic potential standpoint?
Is krill oil actually any good? – what about phospholipids?
Basically no – phospholipids are great but you simply
cannot get enough omega-3 into your cells with Krill –
unless you want to take 10s of grams daily!
Krill is a great source of antioxidant – this may be a
contributing factor to the health benefits of krill – but as a
tool for raising levels it’s a no no!!
% increase in serum EPA+DHA content following 2 weeks of
EPA and DHA supplementation Av. 3.3g per day.
Bioavailability of EPA+DHA from rTG was superior (124%)
compared with natural fish oil, whereas the bioavailability
from EE was inferior (73%)
rTG oil delivered biggest increase in serum lipid content in
the lowest volume of oil and lowest total dose of EPA+DHA
rTG FBO (TG) CLO (TG) FFA EE CO
Capsule size (mg) 650 1000 500 650 650 650
Capsules/day 10 13 24 10 10 10
EPA (g/day) 1.85 2.04 1.38 2.18 1.87 0
DHA (g/day) 1.29 1.48 1.87 1.4 1.39 0
EPA+DHA (g/day) 3.1 3.5 3.2 3.6 3.3 0
Total oil (g) 6.5 13 12 6.5 6.5 6.5
Omega-3 concentration (%) 48 27 27 55 50 n/a
rTG = re-esterified triglyceride; FBO = fish body oil; CLO = cod liver
oil; FFA = free fatty acid; EE=ethyl ester; CO =corn oil
Dyerberg J, Madsen P, Møller JM, Aardestrup I, Schmidt EB. Bioavailability of marine n-3 fatty acid formulations. Prostaglandins Leukot Essent Fatty
Acids. 2010 Sep;83(3):137-41.
Bioavailability depends on the fatty acid structure
Maki et al., 2009
Krill vs fish oil in ‘like for like’
dosing
2g krill oil vs 2g fish oil
4-week randomised
double-blind intervention
in ‘healthy’ but overweight
individuals
(krill n=26 vs fish oil n=25
Krill oil 2.0 g/day
216mg EPA + 90mg DHA
Fish oil 2.0 g/day
EPA 212mg EPA + 178mg DHA
Olive oil (control)
At the end of the treatment period, the mean plasma
EPA concentration was higher in the krill oil group
compared with the fish oil group (377 vs 293 μmol/L),
whereas the mean plasma DHA concentrations were
comparable (476 vs 478 μmol/L)
EPA and DHA from krill oil are absorbed at least as well
as that from fish oil
Ulven et al., 2011
Comparing krill with fish oil
3.0g krill oil vs 1.8g fish oil
7-week intervention
‘healthy’ individuals
(krill n=26 vs fish oil n=40)
Krill oil (3.0 g/day)
543mg EPA + DHA
Fish oil (1.8 g/day)
864 mg EPA + DHA
Control group no supplementation
No significant differences in plasma EPA, DPA and DHA
between the krill and fish oil groups
The authors therefore suggest that krill and fish oil
represent comparable dietary sources of omega-3 even
if the EPA and DHA dose in the krill oil was 62.8% of
that in the fish oil but doesn’t support the ‘less is
more’
Schuchardt et al., 2011
Comparing krill, rTG and EE at
comparative doses
EPA and DHA 1680mg
Double-blinded cross over
– single dose (n=12)
1680mg total omega-3
7.0g krill oil (1050 mg EPA: 630mg DHA
3.4g fish oil EE (1008mg EPA: 672mg)
3.4g fish oil rTG (1008mg EPA: 672mg)
EPA and DHA were absorbed in the following order
Krill oil > triglyceride > ethyl ester
krill oil contained high amounts of EPA and DHA as free
fatty acids rather than as total phospholipid (22% EPA
and 21% DHA)
However, due to high standard deviation values, there
were no statistically significant difference in uptake
between the three treatments
Ramprasath et al., 2013
Krill vs fish oil in ‘like for like
omega-3’ dosing
600mg of omega-3
Double blinded,
randomized, placebo-
controlled, crossover trial
(4 week intervention, 8
week washout )
Three treatment phases:
3g krill oil (600mg of omega-3)
3g fish oil (600mg of omega-3)
3g placebo control (corn oil)
Consumption of 3g/day krill oil for 4 weeks increased
plasma and RBC omega-3 index and decreased the
omega-6/ -3 ratio compared with fish and corn oil
Authors conclude that krill is superior to fish oil in
increasing omega-3, decreasing the omega-6 to omega-
Krill bioavailability studies
It is concluded that there is at present no evidence for greater bioavailability of krill vs. Fish oil
and that more carefully controlled human trials must be performed to establish their relative
efficacies after chronic administration
Norman Salem, Jr, Connye N Kuratko A reexamination of krill oil bioavailability studies Lipids Health Dis. 2014; 13: 137.
Concentrated fish oil (rTG) Standard fish oil (TG)
0
200
400
600
800
1000
1200
DHA EPA
Omega-3dose(mg/day)
EPA DHA Total omega-3
Concentrated fish oil (rTG) 650 450 1100
Concentrated fish oil (EE) 756 228 984
Salmon oil (TG) 180 220 400
Krill oil (PL) 150 90 240
Laidlaw M, Cockerline CA, Rowe WJ. A randomized
clinical trial to determine the efficacy of
manufacturers’ recommended doses of omega-3 fatty
acids from different sources in facilitating
cardiovascular disease risk reduction. Lipids Health
Dis. 2014;13:99.
Day 0 Day 28
4
4.5
5
5.5
6
6.5
7
Concentrated fish oil (rTG) Concentrated fish oil (EE)
Standard fish oil (TG) Krill oil (PL)
Omega-3index
rTG = reesterified triglyceride; EE=ethyl-ester;
TG=triglyceride; PL=phospholipid
Day 0 Day 28 ∆ Change
Concentrated
fish oil (rTG)
4.17 6.82 2.65
Concentrated
fish oil (EE)
4.13 5.77 1.64
Salmon oil (TG) 4.13 4.93 0.80
Krill oil (PL) 4.27 4.76 0.49
Laidlaw M, Cockerline CA, Rowe WJ. A randomized
clinical trial to determine the efficacy of
manufacturers’ recommended doses of omega-3 fatty
acids from different sources in facilitating
cardiovascular disease risk reduction. Lipids Health
Dis. 2014;13:99.
AAtoEPAratio
Concentrated fish oil (rTG) Concentrated fish oil (EE)
Standard fish oil (TG) Krill oil (PL)
Day 0 Day 28 ∆ Change
Concentrated
fish oil (rTG)
11.886 4.738 -7.148
Concentrated
fish oil (EE)
12.164 5.058 -7.107
Salmon oil (TG) 11.576 8.836 -2.740
Krill oil (PL) 11.568 8.963 -2.606
rTG = reesterified triglyceride; EE=ethyl-ester;
TG=triglyceride; PL=phospholipid
Laidlaw M, Cockerline CA, Rowe WJ. A randomized
clinical trial to determine the efficacy of
manufacturers’ recommended doses of omega-3 fatty
acids from different sources in facilitating
cardiovascular disease risk reduction. Lipids Health
Dis. 2014;13:99.
Fatty acid absorption
Flooding the body with concentrated high doses of omega-3 can increase
inflammation (more so in nutritionally compromised individuals) due to creation of
non-enzymatic oxidation end products
Antioxidants can reduce the
production of unfavourable LPOs
i.e., the high content of astaxanthin
in krill oil is possibly due to the
presence of unstable free fatty acids
Regular split-dosing with small capsules is
more favourable for delivery of high doses than single large doses
Non-enzymatic oxidation is caused by ROS attack of PUFAs and produces manifold potentially harmful LPOs, such
as malondialdehyde (general LPO measure), 8-isoprostane (LPO generated by AA peroxidation), and
hydroxynonenals ( -6 PUFA-derived LPOs) and hydroxyhexenals ( -3 PUFA-derived LPOs).ω ω
Assies J, Mocking RJ, Lok A, Ruhé HG, Pouwer F, Schene AH. Effects of oxidative stress on fatty acid- and one-carbon-metabolism in psychiatric and cardiovascular
disease comorbidity. Acta Psychiatr Scand. 2014 Sep;130(3):163-80.
4-hydroxynonenal (HNE) is a lipid peroxidation by product, derived from membrane
lipid oxidation by ROS
At physiological or low stress levels the major 4-HNE detoxification step is via
glutathione; if glutathione levels are compromised 4-HNE accumulates, causing
irreversible cell damage
Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signalling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal.
Oxid Med Cell Longev. 2014;2014:360438.
 Even small amounts of oxidised DHA are sufficient to reverse the beneficial effects of
DHA, emphasising the importance of preventing DHA from oxidation in nutritional
approaches
 This might also explain the different results obtained in epidemiological studies
dealing with DHA, where small contamination of oxidised DHA could lead to
negative/neutral study results
Omega-3 should be combined with appropriate antioxidants in high-risk individuals
Grimm MO, Haupenthal VJ, Mett J, Stahlmann CP, Blümel T, Mylonas NT, Endres K, Grimm HS, Hartmann T. Oxidized Docosahexaenoic Acid Species and
Lipid Peroxidation Products Increase Amyloidogenic Amyloid Precursor Protein Processing. Neurodegener Dis. 2016;16(1-2):44-54.
PV AV TOTOX
Oxidation of food grade oils
Time
Peroxide value (PV) = primary oxidation products - max value = 5
Ansidine value (AV) = secondary oxidation products - max value = 26
The oxidation of oil over time as
measured by peroxide value (PV),
anisidine value (AV) and TOTOX
value.
PV can decrease over time so AV
and/or TOTOX calculation is needed
to appreciate the whole oxidation
story
 Smaller capsules
Unlike our competitors, we keep our capsules small, making them not only easier to swallow but
to encourage and highlight the importance of split dosing
 Split-dosing
High doses of EPA should be distributed throughout the day. Not only does this help with
digestion and uptake of the fatty acids within the oil, but it also ensures that blood levels are
sustained throughout the day
 Taking the supplements with food
Capsules should never be taken on an empty stomach. Taking E-EPA with food (and ideally in the
presence of other dietary oil/fat) will increase the body’s natural ability to digest and absorb the
fatty acids
 Inclusion of vitamin E
We add vitamin E to all of our EPA products to protect the free fatty acids from oxidation both
pre and post digestion
 Adding an appropriate antioxidant may can offer additional benefits / protection
Supplement considerations when dosing
Taking an appropriate antioxidant overcomes potential issues
with peroxidation of highly concentrated omega-3s in ‘high-risk’
individuals
+
Brain structure & function
with antiinflammatory
benefits
Potent
antioxidant
Supports
methylation,
transulfation
etc
Comprehensive
support
Taking an appropriate antioxidant overcomes potential issues with
peroxidation of highly concentrated omega-3s in ‘high-risk’ individuals
Non enzymic antioxidants
Vitamins A, C, & E
Phenols
Polyphenols
- flavonoids
- isothiocyanates
- stilbenes
- phenolic acids
- lignans
- carotenoids
- resveratrol
Enzymatic antioxidants
require:
Selenium
Vitamin D
Copper
Manganese
Magnesium
Zinc
Amino acids (i.e. taurine)
Brain proteins, lipids and
DNA are vulnerable to
oxidative damage
Prevent, inhibit, repair ROS damage
Metabolism and exogenous
damage contribute to the
formation of ROS
Parletta N, Milte CM, Meyer BJ. Nutritional modulation of cognitive function and mental health. J Nutr Biochem. 2013 May;24(5):725-43.
Why fish oils sometimes ‘fail’
• Study participants are often recruited irrespective of their baseline
levels in EPA+DHA, and treated with fixed doses, ignoring the large
inter-individual variability in omega-3 status or variability in uptake
• It is often the case that individuals with the lowest omega-3 levels are the best ‘responders’ to fish oil
supplementation
• Omega-3 digested, absorbed and subsequently incorporated into cells and tissues – taking an omega-3 is
not the same as increasing omega-3 levels
• Such factors may contribute to the tendency towards neutral results in many intervention trials. The
omega-3 index has many features that qualify it as not only a biomarker of intake, but also as risk marker
and most importantly, a risk factor and target for intervention
• The potential impact of an intervention may well be determined by successful cellular uptake of omega-3
and the failure to reach an optimal omega-3 index may go towards explaining inconsistencies reported in
many clinical trials
• Establishing base line ‘biomarker’ levels may make it possible to identify ‘responders’ within the clinical trial
setting by monitoring the changes in biomarker levels
von Schacky C. Omega-3 fatty acids in cardiovascular disease--an uphill battle. Prostaglandins Leukot Essent Fatty Acids. 2015 Jan;92:41-7.
.
Inflammation and depression??
• In association with many physical illnesses behavioural changes occur such as
decreased appetite, weight loss, fatigue, sleep disturbances, impaired cognitive
abilities and depressed mood
• These symptoms appear to result from immune activation and mediated by
inflammatory cytokines (i.e., IL-1, IL-6, and TNF-α) and named ‘sickness
behaviour’
• Similar symptoms can be induced artificially by the administration of bacterial
endotoxin and cytokines such as TNF-α (given therapeutically for hepatitis C)
• These TNF-α induced symptoms can be successfully treated with SSRI
antidepressants suggesting that the production of inflammatory cytokines may
also underpin the development of depressive illness
Omega-3 in the management of mood disorders
• In patients with hepatitis C treated with IFN-α up to 45% will develop
depression
• Rates of IFN-α-induced depression is significantly lower in EPA-treated
but not in DHA-treated patients
• Meta-analysis support the use of 1g EPA in he management of major
depressive disorder
• EPA supplements are more likely to be ‘effective’ where there is pre-
existing inflammation
Lotrich, F. E., B. Sears, et al. (2013). "Anger induced by interferon-alpha is moderated by ratio of arachidonic acid to omega-3 fatty acids." J Psychosom Res 75(5): 475-483.
Mocking RJ, Harmsen I, Assies J, Koeter MW, Ruhé HG, Schene AH. Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for
major depressive disorder. Transl Psychiatry. 2016 Mar 15;6:e756.
Rapaport, M. H., A. A. Nierenberg, et al. (2015). "Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof of-concept
study." Molecular psychiatry. 2016 Jan;21(1):71-9.
Su KP, Lai HC, Yang HT, Su WP, Peng CY, Chang JP, Chang HC, Pariante CM. Omega-3 fatty acids in the prevention of interferon-alpha-induced depression: results from
a randomized, controlled trial. Biol Psychiatry. 2014 Oct 1;76(7):559-66. 
• Increased HPA-axis activity
• Increased cortisol production
• Increased IDO/TMO/KMO activity
• The kynurenine (KYN)/tryptophan ratio
• Increased SERT activity/low serotonin
• Decreased neurotrophins
• Decreased neurogenesis
• Increased hippocampal atrophy
• Decreased delta-6 desaturase activity
• Increased COX-2, PLA2 & PGE2 activity
Neuroinflammation in mood disorders
High AA to EPA ratio
Low omega-3 status
Cytokines
Cortisol
EPA and DHA as individual fatty acids
 Although EPA and DHA are both long-chain polyunsaturated fatty acids
(PUFAs), the molecules are often reported to produce biochemical and
physiological responses that are qualitatively and quantitatively different
from each other
 The kinetics of EPA and DHA differ between different cell types
 The marked differences between the effects of EPA and DHA indicate
that it is an over-simplification to generalise the effects of omega-3 PUFA
on cell function
 It is the EPA in excess of DHA that is the active component in fish oil
[treating depression]
Growing number of pure EPA studies
 JELIS - Japan EPA Lipid Intervention Study
• CVD - Hypercholesterolaemia subjects
• E-EPA 1.8g/daily – 2 years1.8g/day
• E-EPA + statins reduced incidence of major CVD events by 19%
• Compared with DHA, EPA administration reduced the EPA/AA ratio and the (PGI2 + PGI3)/TXA2
balance to a state that inhibits the onset and/or progression of CVD
 MARINE trial
• CVD – Hypertriglyceridaemia (≥ 500 mg/dL)
• E-EPA @ 2g & 4g/daily – 12 weeks
• E-EPA @ 4 g/day significantly reduced triglycerides , large VLDL, total LDL, small LDL, and total HDL
particle concentrations and VLDL particle size
 ANCHOR trial
• CVD – triglycerides ≥ 200 to < 500 mg/dL
• E-EPA 4g/daily with statins
• Significant reduction in triglycerides, large VLDL, total LDL, small LDL, and total HDL particle
concentrations and VLDL particle size
 REDUCE-IT (Reduction of Cardiovascular Events Outcomes trial) – ongoing
• CVD –high-risk patients with mixed dyslipidemia currently using statins
• E-EPA 4g/daily
Growing number of pure EPA studies
 Huntington’s disease
• E-EPA 1g/daily – 1 year
•Significant reduction in brain atrophy, particularly in the caudate and thalamus
•Stable or improved motor function
 SeAFood polyp prevention trial (ongoing)
• Colorectal cancer
• Pharmepa RESTORE - rTG EPA 2 g/daily – 1 year
 EMT2 (EPA for Metastasis) trial (starts October 2015)
• Colorectal cancer recurrence and survival after surgery for resectable liver
metastases
•Pharmepa RESTORE rTG EPA 2g/daily – 2 years
© CNELM
Lovaza -each 1g capsule contains
0.84g ethyl ester as EPA (0.465 g) and
DHA (0.375 g)
Epanova each 1g capsule contains
0.75g free fatty acids as EPA (0.55g)
and DHA (0.2g)
Vasepa each capslue contains 1g ethyl
ester as pure EPA
All products reduce TGs but EPA
alone appears to minimally decrease
or have a neutral effect on LDL-C,
while DHA/EPA combination products
have been shown to increase LDL-C,
which may be an important
consideration for patients with
atherosclerotic disease and/or risk
factors for CV disease
Ito MK. A Comparative Overview of Prescription Omega-3 Fatty Acid Products.
P T. 2015 Dec;40(12):826-57.
Pro-inflammatory Anti-inflammatory
COX-1/COX2 COX-1/COX2
5-LOX 5-LOX
AA
EP
A
PGE3
LTB5
PGE2
LTB4
Proliferation Hypermethylation
of tumour suppressor genes,
increases expression of
aromatase
Migration & invasion
Activation of E4 receptor and
PI3k/Akt/mTOR pathway
Anti-proliferation
Down regulates COX-2 and ERK
1 / 2 pathway
Anti-anigogenic
Inhibits Ang2 an MMP-9
Proliferation Activation of BLT1
& BLT2 receptors,
MEK/ERKPI3K/Akt pathway
Angiogenesis
TF-kB & VEGF
Invasion and metastasis
STAT-3 & MMPs
Anti-proliferation
Counteract LTB4.
down stream molecular
targets are currently unclear
Cancer risk
Cancer progression
Cancer risk
Cancer progression
Better outcomes
Poorer outcomes
AA and EPA metabolism contribute to cancer
risk and progression through pro-and anti-
inflammatory lipid metabolites that stimulate
cell proliferation, angiogenesis, and migration
Azrad M, Turgeon C, Demark-Wahnefried W. Current evidence linking polyunsaturated Fatty acids with cancer risk and progression. Front Oncol. 2013 Sep 4;3:224.
Inflammation creates the ideal “tumour microenvironment” and is now
widely recognised as an enabling characteristic of cancer in regard to
enhanced cell proliferation, cell survival, cell migration and angiogenesis
Mahmoudabadi MM, Rahbar AR. Effect of EPA and vitamin C on superoxide dismutase, glutathione peroxidase, total antioxidant capacity and malondialdehyde
in type 2 diabetic patients. Oman Med J. 2014 Jan;29(1):39-45. doi: 10.5001/omj.2014.09.
Mahmoudabadi MM, Djalali M, Djazayery SA, Keshavarz SA, Eshraghian MR, Yaraghi AA, Askari G, Ghiasvand R, Zarei M.Effects of eicosapentaenoic acid and vitamin C on
glycemic indices, blood pressure, and serum lipids in type 2 diabetic Iranian males.J Res Med Sci. 2011 Mar;16 Suppl 1:S361-7.
Thota RN, Acharya SH, Abbott KA, Garg ML. Curcumin and long-chain Omega-3 polyunsaturated fatty acids for Prevention of type 2 Diabetes (COP-D): study protocol for a
randomised controlled trial. Trials. 2016 Nov 29;17(1):565.
Pure EPA supplementation has benefits in type II diabetics
• Lower levels of omega-3 are associated with, insulin resisitance, metabolic
syndrome, type II diabetes and associated health risks
• EPA has anti-thrombotic, anti-inflammatory and anti-arrhythmic effects, as
lowers blood pressure and reduces plasma triglyceride levels glycosylated
haemoglobin
• The higher EPA quantities in the phospholipid cell membranes could be
related to increased insulin sensitivity
• EPA reduces oxidative stress and increases superoxide dismutase,
glutathione peroxidase and total antioxidant capacity and decreases
malondialdehyde levels significantly
• Synergistic benefits with curcumin for the prevention of diabetes?
Primary structural function &
anti-inflammatory docosanoid
production
Anti-inflammatory eicosanoid
production
REDUCED INFLAMMATION
DHAEPA
Pro-inflammatory eicosanoid
production
INFLAMMATION
AA
AA to EPA ratio
direct antagonism
The relationship between the omega-3 index and the AA to EPA ratio
Omega-3 index
Therapeutic
Wellbeing
Additional nutrients
Our pr oduct s r ange
Olive oil
Fruit
Vegetables
Oily fish
Nuts & seeds
Legumes &
cereals
Monounsaturated fat
(oleic acid)
Antioxidants
(i.e. polyphenols)
Vitamin A,B,C & E
Vitamin D
Omega-3 fatty acids
(ALA, EPA & DHA)
Minerals
(i.e. selenium, iron &
iodine)
Amino acids
(i.e. taurine, tyrosine &
tryptophan)
Moderate red
wine
Lean meat
Moderate dairy
Neuronal survival
Energy metabolism
Neurotrophins
Neurotransmission
Membrane fluidity
Cell membrane
integrity
Glucose transport
Nutrient synthesis
Nutrient metabolism
Gene expression
Methylation
Cerebral blood flow
Blood pressure
Oxidative damage
Neuronal cell death
Neuroinflammation
Free radicals
Parletta N, Milte CM, Meyer BJ. Nutritional modulation of cognitive function and mental health. J Nutr Biochem. 2013 May;24(5):725-43.
Asimple,expertlyformulated,1-a-daydualcapsulesystem
Ultra concentrated
Mi ndCar e® omega-3 EPA
& DHA capsules with
vitamins D & E
Precisely formulated to target and support
brain function (250mg DHA plus 410 mg EPA
per capsule) using the body-ready rTG form of
omega-3 that is nature-identical and easily
absorbed by the body
Mi ndCar e® micronutrient
capsules contain:
full B complex plus zinc,
selenium, vitamin C and
targeted ACTIVES
Target distinct areas of brain health with a
comprehensive blend of synergistic vitamins,
minerals and specialist actives at proven,
effective levels and in super-bioavailable
 Mi ndCar e® is based on cutting-edge nutrition science and combines premium
triglyceride omega-3 fish oil containing 80% active doses of EPA and DHA with
scientifically proven nutrients for various aspects of brain health
MindCare® BALANCE
Magnesium glycinate and L-
Theanine with their natural
calming effects act as relaxants,
reduce feelings of stress and
reduce anxiety
MindCare® FOCUS
Acetyl-L-Carnitine, L-Theanine,
taurine and caffeine heighten
mental alertness and support
concentration, memory and
focus
MindCare® LIFT
Magnesium glycinate and 5-HTP
help to regulate
neurotransmitters required for
mood balance
MindCare® PROTECT
N-Acetyl L-Cysteine, alpha-lipoic
acid and resveratrol help
protect against
neuroinflammation and
improve and support energy
metabolism in the brain
Highly bioavailable micronutrients (vitamins C , D3 & E; vitamins B1, B2, B3, B5, B6, B7, B12 & folate; minerals zinc & selenium)
support immune & detoxification enzyme-mediated pathways. They support homocysteine recycling required for the production of
neurotransmitters, enhance neurotransmission via regulation of receptors, transporters and ion channels, support natural stress
response pathways, ensure optimal delivery of fuel to the brain, enhance cognition, relaxation, sleep, mental focus and reduce stress
and oxidative stress
Ultra concentrated MindCare® omega-3 EPA & DHA capsule
supports cognitive function, mental performance
MindCare® micronutrient capsules
ADVANCED
MULTIVITAMIN &
MINERALS
Pure Essentials Advanced Multivitamin &
Minerals is a comprehensive multi-nutrient
supplement, featuring full spectrum body-
ready methylated B-vitamins and active
mineral forms. Enhanced with a slow-release
delivery system, this supplement steadily
releases nutrients for optimal absorption and
uptake into the bloodstream. This advanced
formula is the ideal all-round multivitamin &
mineral supplement to support optimal
wellbeing.
Each capsule provides 410 mg EPA, 250 mg
DHA and 1000 iu vitamin D3 for intensive
daily support. The omega-3 is provided in the
superior rTG form, which is body-ready and
delivers higher levels of omega-3 into cells
faster than standard fish oil and krill oil.
This ultra-pure supplement is sourced
from wild, sustainable anchovies and the oil
is purified to remove all trace of mercury,
dioxins and PCBs. Natural lemon oil prevents
fish reflux.
SUPER CONCENTRATED
OMEGA-3
WILD FISH OIL &
VITAMIN D3
Serving size: 1 capsule Per serving % RI*
Longvida® optimised curcumin
extract from turmeric root
(min. 20% curcuminoids)
500 mg n/a
DIRECTIONS FOR USE
Adults: take 1 capsule daily with food. For intensive support,
take 2 capsules daily as a split dose. Do not exceed the dose
unless advised by a healthcare practitioner.
NUTRITIONAL INFORMATION
INGREDIENTS:
Longvida® optimised curcumin extract; capsule shell (emulsifier:
hydroxypropyl methylcellulose); stearic acid; soy lecithin;
maltodextrin; ascorbyl palmitate; silicon dioxide.
Free from: dairy, gluten, lactose, soya protein, wheat, yeast,
artificial colours and flavours; not tested on animals; non-GMO;
suitable for vegetarians & vegans; halal & kosher.
* % Reference Intake
Product information
Longvida optimized curcumin delivery system
 Longvida curcumin is able to survive the harsh digestive pH conditions and doesn’t get destroyed by
the acidic environment of the stomach
 The small particle size of Longvida curcumin ensures its easy passage across the intestinal cell
membrane
 Longvida provides a unique coating (of highly purified fatty acids and phospholipids) that surrounds
the curcumin molecule and enables it to be transported into the lymphatic system rather than the
circulatory system
 Unlike the circulatory system, the lymphatic system bypasses the liver (the major organ for
metabolism) so less curcumin is exposed to metabolic enzymes and remains in a free form
 The sole purpose of these metabolic enzymes is to attach large groups (called glucuronides or
sulphates) to the curcumin molecule, making it very bulky but also highly water soluble so it can be
rapidly excreted by the kidneys and out of the body in urine
 In contrast, the free form of curcumin stays in the body longer because it isn’t metabolised and
doesn’t have these water soluble groups attached to it so, it has a longer duration of action
Education Technical
Sophie Tully
Nutrition Education
Manager
sophiet@igennus.com
Dr Nina Bailey
Head of Nutrition
ninab@igennus.com
Twitter @DrNinaBailey

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Filtering fish oil fact from fiction

  • 1. Filtering fish oil fact from fiction Nina Bailey BSc MSc, PhD RNutr
  • 2. In 1992, the BNF Task Force on Unsaturated Fatty Acids suggested a desirable population intake for EPA and DHA of 0.5% of energy, which equates to about 8g/week (1.14g/day) for women and 10g/week (1.42g/day) for men, equivalent to 2-3 medium servings of oil-rich fish per week For a 77kg individual to raise their omega-3 index from 4.2% to 8% they would need a daily dose of 16mg/kg omega-3 (equivalent to 1.25g) (Flock et al. 2013) British Nutrition Foundation. Unsaturated fatty acids nutritional and physiological significance: the report of the British Nutrition Foundation's task force. New York: Chapman & Hall, 1992. https://www.gov.uk/government/statistics/ndns-results-from-years-5-and-6-combined Flock MR, Skulas-Ray AC, Harris WS, Etherton TD, Fleming JA, Kris-Etherton PM. Determinants of erythrocyte omega-3 fatty acid content in response to fish oil supplementation: a dose-response randomized controlled trial. J Am Heart Assoc. 2013 Nov 19;2(6):e000513. Stark KD, Van Elswyk ME, Higgins MR, Weatherford CA, Salem N Jr. Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the bloodstream of healthy adults. Prog Lipid Res. 2016 Jul;63:132-52. Current UK omega-3 recommendations 450mg EPA and DHA daily (2 portions fish weekly, of which one should be oily) However........... Is omega-3 ‘deficiency’ a global burden? Mean consumption of oily fish (all age groups) was below the recommended one portion (140g) per week (rolling programme for 2012 and 2013 to 2013 and 2014) and equivalent to 13 to 29 grams per week in children and 54 to 87 grams per week in adults
  • 3. Sprague M, Dick JR, Tocher DR. Impact of sustainable feeds on omega-3 long-chain fatty acid levels in farmed Atlantic salmon, 2006-2015. Sci Rep. 2016 Feb 22;6:21892.
  • 4. 4Sprague M, Dick JR, Tocher DR. Impact of sustainable feeds on omega-3 long-chain fatty acid levels in farmed Atlantic salmon, 2006-2015. Sci Rep. 2016 Feb 22;6:21892. Changes in the levels of fatty acids (% of total fatty acids), of either marine (- - -) or terrestrial origin (___), in the flesh of Scottish Atlantic salmon farmed between 2006–2015 (mean ± SD)    LA DHA EPA ALA Oleic acid
  • 5. 5Sprague M, Dick JR, Tocher DR. Impact of sustainable feeds on omega-3 long-chain fatty acid levels in farmed Atlantic salmon, 2006-2015. Sci Rep. 2016 Feb 22;6:21892. Number of portions required (mean ± SD) to obtain a weekly intake of 3.5 g EPA+          DHA (ISSFAL, 2004), based on a 130 g serving 
  • 6. Using omega-3 at a dose of 1g – is this enough? • Many fish oil clinical trials have used a dose of 1 g/d in all treated subjects • An omega-3 dose 1 g/d, (as Omacor) in the study by Rupp et al, increased omega-3 index from a mean of 3.6 % to 5.4 % but approximately 16 % of the subjects achieved an EPA+DHA blood level less than 4.8 %.    • The AA to EPA ratio was reduced from 20 to 7.2 and after withdrawal, EPA and DHA plasma levels approach baseline values within 10 days • This is clinically relevant since it has been noted that an omega-3 index>5 % is the range in which    dramatic reduction in sudden coronary death reduction can be observed • Individual variability in blood level response to such a common dose could leave a substantial number of patients at elevated CHD risk due to failure to achieve a therapeutic EPA+DHA blood level    Rupp H, Wagner D, Rupp T, Schulte LM, Maisch B. Risk stratification by the “EPA+DHA level” and the “EPA/AA ratio” Herz. 2004;29:673–685.    Superko HR, Superko AR, Lundberg GP, Margolis B, Garrett BC, Nasir K, Agatston AS. Omega-3 Fatty Acid Blood Levels Clinical Significance Update. Curr Cardiovasc Risk Rep. 2014;8(11):407. Review.
  • 7. Donadio JV, Bergstralh EJ, Bibus DM, Grande JP. Is body size a biomarker for optimizing dosing of omega-3 polyunsaturated fatty acids in the treatment of patients with IgA nephropathy? Clin J Am Soc Nephrol. 2006;1:933–939.  In IgA Nephropathy patients, 2 years of treatment with 3.35 g/d total omega-3 fatty acids (Omacor 4g) EPA levels increased from 0.8±0.5 to 3.1±1.3 % after treatment and DHA from 3.7±1.6 to 6.5±                1.3 %.  Treatment with 6.70 g/d of omega-3 fatty acids (Omacor 8g) increased blood EPA levels from 0.9±0.6    to 5.2±1.8 % and blood DHA from 3.5±1.4 to 7.1±1.6 %             In patients with IgA nephropathy, treated with 4 g/d fish oil, the mean EPA/AA ratio increased from approximately 0.09±0.07 to 0.45±0.40 with a wide range of individual variability        Using omega-3 at a doses of >1g impact on omega-3 index and AA to EPA ratio 4g Omacor (EPA 1.8 g, DHA 1.47 g) 8g Omacor (EPA 3.6g; DHA ; 2.94g) AA EPA DHA Omega-3 index AA to EPA ratio AA EPA DHA Omega-3 index AA to EPA ratio Base line 10 0.8 3.7 4.5 10 9.8 0.9 3.5 4.4 10 6 weeks 8.5 3.6 6.7 10.2 2 8.0 4.9 7.4 12.3 1.7 6 months 8.5 3.1 6.5 9.6 2 7.7 5.2 7.5 12.9 1.4
  • 8. Donadio JV, Bergstralh EJ, Bibus DM, Grande JP. Is body size a biomarker for optimizing dosing of omega-3 polyunsaturated fatty acids in the treatment of patients with IgA nephropathy? Clin J Am Soc Nephrol. 2006;1:933–939. Plasma phospholipid levels of EPA, DHA, and EPA/AA ratios were significantly inversely correlated with increasing body weight and BMI in the Omacor 4-g dosage group but not in the Omacor 8-g dosage group The levels of EPA, DHA, omega-3 index increased significantly with increasing dose of Omacor The plotted line is a smoother (running average) and identifies a plateauing effect at a dosage of approximately 0.07 g/kg 4g Omacor (EPA 1.8 g, DHA 1.47 g) 8g Omacor (EPA 3.6g; DHA ; 2.94g) AA EPA DHA Omega-3 index AA to EPA ratio AA EPA DHA Omega-3 index AA to EPA ratio Base line 10 0.8 3.7 4.5 10 9.8 0.9 3.5 4.4 10 6 weeks 8.5 3.6 6.7 10.2 2 8.0 4.9 7.4 12.3 1.7 6 months 8.5 3.1 6.5 9.6 2 7.7 5.2 7.5 12.9 1.4
  • 9. Blood levels (mean±SD) of EPA and DHA as % of total fatty acids pre- and post dosing  Blood levels (mean ± SD) of EPA & DHA as % of total fatty acids pre- and post dosing  Data points are identified by author and ranked by daily dose (low to high)  Fish oil doses were as follows: Rupp, 1 g/d; Di Stasi, 1 g/d; Poppitt, 1.2 g/d; Vedin, 2.3 g/d; Donadio, 3.35 g/d; Laidlow, 4 g/d; Donadio, 6.7 g/d  Red line indicates the level of DHA above which it is suggested that atrial fibrillation risk may be reduced Superko HR, Superko SM, Nasir K, Agatston A, Garrett BC. Omega-3 fatty acid blood levels: clinical significance and controversy. Circulation. 2013 Nov 5;128(19):2154-61.
  • 10. Blood levels (mean±SD) of EPA/AA at baseline and after treatment. Superko HR, Superko SM, Nasir K, Agatston A, Garrett BC. Omega-3 fatty acid blood levels: clinical significance and controversy. Circulation. 2013 Nov 5;128(19):2154-61.  Doses were as follows: Shintani, 1800 mg/d; Matsuzaki, 1800 mg/d; Donadio, 3.5 g/d; Laidlow, 4.0 g/d; Donadio, 6.7 g/d  The red line indicates a risk level suggested by Itakura et al.5 EPA/AA indicates eicosapentaenoic acid/arachidonic acid; and SD, standard deviation.
  • 11. Maternal health and outcomes 200mg/day Brain and eye development and function 200mg/day Promotes maternal DHA status Supports normal gestational period Increases DHA breast milk content Promotes foetal growth and development Cardiovascular, visual and cognition 250mg/day Cardiovascular, visual and cognition 250mg/day Promotes visual acuity Promotes cognitive performance Cardiovascular heath Cognitive function Low DHA associated with increased risk of cognitive decline, dementia and age related macular degeneration DHA requirements through the life stages
  • 12. The developing brain DHA accumulates rapidly in the normally growing foetal brain, at around 67 mg/day in the last trimester. Total brain volume undergoes an initial rapid spurt, reaching 80% of its maximum volume by around 1.5 years. Further growth spurts are believed to occur between 2–4 years and between 6–8 years of age.Groeschel S, Vollmer B, King MD, Connelly A. 2010 Developmental changes in cerebral grey and white matter volume from infancy to adulthood. Int J Dev Neurosci. 28:481-9.
  • 13. Anti-inflammatory eicosanoid production DGLA GLA LA EPA ETA SDA ALA Delta -6 desaturase Delta -5 desaturase Cyclooxygenase (COX)/lipoxygenase (LOX) Elongase Series-2 prostaglandins Series-2 thromboxanes Series-4 leukotrienes Hydroxy fatty acids AA COX/LOX Omega-6 Omega-3 Eicosanoids, including prostaglandins and leukotrienes, are biologically active lipids derived from AA and EPA that have been implicated in various pathological processes, such as inflammation and cancer The relationship between AA and EPA is therefore significant when considering omega- 3 intervention strategies Key structural role & anti-inflammatory docosanoid production Resolvins Protectins DHA Elongase & desaturase Pro-inflammatory eicosanoid production Series-3 prostaglandins Series-3 thromboxanes Series-5 leukotrienes Hydroxy fatty acids Resolvins
  • 14. Primary structural function & anti-inflammatory docosanoid production Anti-inflammatory eicosanoid production REDUCED INFLAMMATION DHAEPA Pro-inflammatory eicosanoid production INFLAMMATION AA AA to EPA ratio direct antagonism The relationship between the omega-3 index and the AA to EPA ratio Omega-3 index
  • 15. EPA and DHA incorporation • The preferential uptake of EPA and DHA by specific phospholipids is significant • PC is located mainly in the outer membrane whereas PE is primarily on the inside • The distribution of these PLs determines the enzymes with which they interact – EPA is preferentially incorporated into PC with some incorporation into PE – DHA is preferably incorporated into PE with some incorporation into PC 15
  • 16. DHA ‘issues’? • Membranes enriched with DHA are most susceptible to oxidative damage, and oxidative alterations of membranes have many potential consequences in human pathophysiology • DHA has antioxidant and pro-oxidant effects at low and high levels of incorporation, respectively – At low concentration, DHA lowers lipid peroxidation and is generally incorporated in PE (inside membrane) – At higher doses DHA can be incorporated into PC where it may exhibit proinflammatory effects (outside membrane) • DHA therefore has different effects on cell function, depending on its phospholipid accumulation which differs according to its concentration Véricel E, Polette A, Bacot S, Calzada C, Lagarde M. Pro- and antioxidant activities of docosahexaenoic acid on human blood platelets. J Thromb Haemost. 2003 Mar;1(3):566-72.
  • 17. Is there an optimal EPA to DHA ratio? 2:1 EPA to DHA proportions demonstrated to be more effective treatments to produce an antiinflammatory response compared with 1:2 EPA to DHA 6 :1 EPA to DHA ratio may be optimal for correcting omega-3 deficiency, with concomitant positive effects on lipid profiles and on inflammatory indices EPA in excess of DHA is optimal! As much as 13% of DHA is retroconverted to EPA Monitor DHA levels and supplement accordingly? Dasilva G, Pazos M, García-Egido E, Pérez-Jiménez J, Torres JL, Giralt M, Nogués MR, Medina I. Lipiomics to analyse the influence of diets with different ratios of EPA to DHA in the progression of metabolic syndrome using SHTOB rats. Food Chem. 2016 Aug 15;205:196-203. Shaikh NA, Yantha J, Shaikh S, Rowe W, Laidlaw M, Cockerline C, Ali A, Holub B, Jackowski G: Efficacy of a unique omega-3 formulation on the correction of nutritional deficiency and its effects on cardiovascular disease risk factors in a randomized controlled VASCAZEN((R)) REVEAL Trial. Molecular and cellular biochemistry 2014, 396:9-22.
  • 18.   EPA and DHA utilisation differences  High DHA intake reduces delta-6-desaturase activity  Studies often report no increase in DHA levels with pure EPA supplementation – DHA saturation?  In some cases [depression/neurodevelopmental disorders] high DHA supplementation has been shown to worsen health outcomes  12 week intervention with 1.8 g omega-3 (1.2g EPA + 0.6g DHA) in young healthy males aged 18-25  During the washout period, EPA and DHA levels decreased back to baseline levels, with EPA levels rapidly returned to baseline levels within 2 weeks of stopping fish oil supplementation, while serum DHA returned to baseline levels only by the end of the washout period Suggests high EPA requirements? Time (weeks) Roke K, Mutch DM. The role of FADS1/2 polymorphisms on cardiometabolic markers and fatty acid profiles in young adults consuming fish oil supplements. Nutrients. 2014 Jun 16;6(6):2290-304.
  • 19. 0 4 8 12 20 0 1 2 3 4 Time (weeks) EPA in mononuclear cell PL (%) 0 4 8 12 20 1 2 3 4 Time (weeks) DHA in mononuclear cell PL (%) Effect of stopping intake of EPA and DHA Healthy volunteers given fish oil for 12 weeks; then 8 week washout • Yaqoob P, Pala HS, Cortina-Borja M, Newsholme EA, Calder PC. Encapsulated fish oil enriched in alpha-tocopherol alters plasma phospholipid and mononuclear cell fatty acid compositions but not mononuclear cell functions. Eur J Clin Invest. 2000 Mar;30(3):260-74
  • 20. Benefits of the Opti-O-3  Knowledge of baseline levels will guide the practitioner recommendations— unsurprisingly, low baseline values may require a larger dose than a high baseline value!  The omega-3 index and AA to EPA ratio are invaluable for assessing both baseline risk and the change in risk (as function of intake – retesting is advisable ≥6 months)  Dose response studies show us that high doses of omega-3 are required to reduce the AA to EPA ratio and achieve an omega-3 index ≥8%, especially where the baseline levels are suboptimal ≤4% Use in conjunction with Pharmepa RESTORE & MAINTAIN  Pre-loading with pure EPA for 6 months (RESTORE) is advised to reduce the AA to EPA ratio, before the introduction of EPA/DHA with GLA (MAINTAIN) for long-term support of the omega-3 index
  • 21. DHA EPA ETA SDA ALA Delta -6 desaturase Delta -5 desaturase Elongase DPA  EPA converts to DPA  DPA acts as a reservoir for EPA (retroconversion back to EPA)  DHA retroconversion to EPA X EPA conversion to DHA????? In the brain, low DHA is seen by an increase in DPA ‘Healthy DHA to EPA ratio of RBC = 3:1/4:1 Opti-O-3 average is 2.4 (most people are low in DHA) Supplementation:  Pure EPA increases EPA and reduces DHA  Pure DHA increases EPA and DHA  EPA and DHA increases both EPA and DHA Supplementing with omega-3
  • 22. 22 1% 3% 3% 3% 3% 10% 10% 10% 10% A B C D A B C D Omega-3 index = 4 AA to EPA ratio = 10 2% 4% 3% Omega-3 index = 5 AA to EPA ratio = 5 Omega-3 index = 6 AA to EPA ratio = 3.3 Omega-3 index = 7 AA to EPA ratio = 2.5 3% 10% E 5% D Omega-3 index = 8 AA to EPA ratio = 2 What’s the best omega-3 index? EPA DHA AA
  • 23. 23 1% 3% 4% 5% 5% 10% 10% 10% 10% A B C D A B C D Omega-3 index = 4 AA to EPA ratio = 10 1% 2% 1% Omega-3 index = 5 AA to EPA ratio = 10 Omega-3 index = 6 AA to EPA ratio = 10 Omega-3 index = 7 AA to EPA ratio = 5 5% 10% E 3% D Omega-3 index = 8 AA to EPA ratio = 3.3 What’s the best omega-3 index? EPA DHA AA
  • 24. Optimising the EPA to DHA ratio with Pharmepa 1 RESTORE 2 RESTORE 3 RESTORE 4 RESTORE 1 MAINTAIN 2 MAINTAIN 3 MAINTAIN 4 MAINTAIN 0 500 1000 1500 2000 2500 GLA (mg) DHA (mg) EPA (mg) 1 RESTORE 2 RESTORE 3 RESTORE 4 RESTORE 1 MAINTAIN 2 MAINTAIN 3 MAINTAIN 4 MAINTAIN EPA (mg) 500 1000 1500 2000 250 500 750 1000 DHA (mg) 0 0 0 0 83 167 250 333 GLA (mg) 0 0 0 0 20 40 60 80 Vitamin E (mg) 5 10 15 20 3 6 9 12 Vitamin D (µg) 0 0 0 0 10 20 30 40 EPA to DHA ratio - - - - 3 3 3 3 Total Omega-3 (mg) 500 1000 1500 2000 333 666 1000 1333
  • 25. 1 RESTORE 1 RESTORE 1 RESTORE 1 RESTORE 2 RESTORE 2 RESTORE 2 RESTORE 2 RESTORE 1 MAINTAIN 2 MAINTAIN 3 MAINTAIN 4 MAINTAIN 1 MAINTAIN 2 MAINTAIN 3 MAINTAIN 4 MAINTAIN EPA (mg) 750 1000 1250 1500 1250 1500 1750 2000 DHA (mg) 83 167 250 333 83 167 250 333 GLA (mg) 20 40 60 80 20 40 60 80 Vitamin E (mg) 8 11 14 17 13 16 19 22 Vitamin D (µg) 10 20 30 40 10 20 30 40 EPA to DHA ratio 9 6 5 5 15 9 7 6 Total Omega-3 (mg) 833 1167 1500 1833 1333 1667 2000 2333 0 500 1000 1500 2000 2500 3000 GLA (mg) DHA (mg) EPA (mg) 1 RESTORE 1 RESTORE 1 RESTORE 1 RESTORE 2 RESTORE 2 RESTORE 2 RESTORE 2 RESTORE 1 MAINTAIN 2 MAINTAIN 3 MAINTAIN 4 MAINTAIN 1 MAINTAIN 2 MAINTAIN 3 MAINTAIN 4 MAINTAIN Optimising the EPA to DHA ratio with Pharmepa
  • 26. How much omega-3 is too much?  AA levels during administration of various types of EPA/DHA preparations have shown that phospholipid AA levels rise initially when the total dose of EPA and DHA administered is relatively small  A fall in AA levels only comes later when the cumulative amount of EPA, EPA/DHA administered is high  Doses of up to about 2 g/day pure omega-3 fatty acid lead to a rise in RBC AA levels while 4 g/day lead to a fall  Higher (>2g) EPA may be ineffective compared to lower doses (1-2g) because higher doses create a drop in AA levels and that the suppression of AA levels may not be helpful  Both AA and DHA are require to maintain optimal cell membrane fluidity and for the production of SPMs and therefore it may be as much of a mistake to suppress omega-6 levels by raising omega-3 intakes too high  DHA clearance is at a slower rate than EPA (post supplementation) which reflects retention of PUFAs for membrane integrity Horrobin DF, Jenkins K, Bennett CN, Christie WW. Eicosapentaenoic acid and arachidonic acid: collaboration and not antagonism is  the key to biological understanding. Prostaglandins Leukot Essent Fatty Acids. 2002 Jan;66(1):83-90.
  • 27. Benefits of the Opti-O-3  Knowledge of baseline levels will guide the practitioner recommendations— unsurprisingly, low baseline values may require a larger dose than a high baseline value!  The omega-3 index and AA to EPA ratio are invaluable for assessing both baseline risk and the change in risk (as function of intake – retesting is advisable ≥6 months)  Dose response studies show us that high doses of omega-3 are required to reduce the AA to EPA ratio and achieve an omega-3 index ≥8%, especially where the baseline levels are suboptimal ≤4% Use in conjunction with Pharmepa RESTORE & MAINTAIN  Pre-loading with pure EPA for 6 months (RESTORE) is advised to reduce the AA to EPA ratio, before the introduction of EPA/DHA with GLA (MAINTAIN) for long-term support of the omega-3 index
  • 28. Question What is the best form of omega-3 to take from an ethical, financial and therapeutic potential standpoint? Is krill oil actually any good? – what about phospholipids? Basically no – phospholipids are great but you simply cannot get enough omega-3 into your cells with Krill – unless you want to take 10s of grams daily! Krill is a great source of antioxidant – this may be a contributing factor to the health benefits of krill – but as a tool for raising levels it’s a no no!!
  • 29. % increase in serum EPA+DHA content following 2 weeks of EPA and DHA supplementation Av. 3.3g per day. Bioavailability of EPA+DHA from rTG was superior (124%) compared with natural fish oil, whereas the bioavailability from EE was inferior (73%) rTG oil delivered biggest increase in serum lipid content in the lowest volume of oil and lowest total dose of EPA+DHA rTG FBO (TG) CLO (TG) FFA EE CO Capsule size (mg) 650 1000 500 650 650 650 Capsules/day 10 13 24 10 10 10 EPA (g/day) 1.85 2.04 1.38 2.18 1.87 0 DHA (g/day) 1.29 1.48 1.87 1.4 1.39 0 EPA+DHA (g/day) 3.1 3.5 3.2 3.6 3.3 0 Total oil (g) 6.5 13 12 6.5 6.5 6.5 Omega-3 concentration (%) 48 27 27 55 50 n/a rTG = re-esterified triglyceride; FBO = fish body oil; CLO = cod liver oil; FFA = free fatty acid; EE=ethyl ester; CO =corn oil Dyerberg J, Madsen P, Møller JM, Aardestrup I, Schmidt EB. Bioavailability of marine n-3 fatty acid formulations. Prostaglandins Leukot Essent Fatty Acids. 2010 Sep;83(3):137-41.
  • 30. Bioavailability depends on the fatty acid structure
  • 31.
  • 32. Maki et al., 2009 Krill vs fish oil in ‘like for like’ dosing 2g krill oil vs 2g fish oil 4-week randomised double-blind intervention in ‘healthy’ but overweight individuals (krill n=26 vs fish oil n=25 Krill oil 2.0 g/day 216mg EPA + 90mg DHA Fish oil 2.0 g/day EPA 212mg EPA + 178mg DHA Olive oil (control) At the end of the treatment period, the mean plasma EPA concentration was higher in the krill oil group compared with the fish oil group (377 vs 293 μmol/L), whereas the mean plasma DHA concentrations were comparable (476 vs 478 μmol/L) EPA and DHA from krill oil are absorbed at least as well as that from fish oil Ulven et al., 2011 Comparing krill with fish oil 3.0g krill oil vs 1.8g fish oil 7-week intervention ‘healthy’ individuals (krill n=26 vs fish oil n=40) Krill oil (3.0 g/day) 543mg EPA + DHA Fish oil (1.8 g/day) 864 mg EPA + DHA Control group no supplementation No significant differences in plasma EPA, DPA and DHA between the krill and fish oil groups The authors therefore suggest that krill and fish oil represent comparable dietary sources of omega-3 even if the EPA and DHA dose in the krill oil was 62.8% of that in the fish oil but doesn’t support the ‘less is more’ Schuchardt et al., 2011 Comparing krill, rTG and EE at comparative doses EPA and DHA 1680mg Double-blinded cross over – single dose (n=12) 1680mg total omega-3 7.0g krill oil (1050 mg EPA: 630mg DHA 3.4g fish oil EE (1008mg EPA: 672mg) 3.4g fish oil rTG (1008mg EPA: 672mg) EPA and DHA were absorbed in the following order Krill oil > triglyceride > ethyl ester krill oil contained high amounts of EPA and DHA as free fatty acids rather than as total phospholipid (22% EPA and 21% DHA) However, due to high standard deviation values, there were no statistically significant difference in uptake between the three treatments Ramprasath et al., 2013 Krill vs fish oil in ‘like for like omega-3’ dosing 600mg of omega-3 Double blinded, randomized, placebo- controlled, crossover trial (4 week intervention, 8 week washout ) Three treatment phases: 3g krill oil (600mg of omega-3) 3g fish oil (600mg of omega-3) 3g placebo control (corn oil) Consumption of 3g/day krill oil for 4 weeks increased plasma and RBC omega-3 index and decreased the omega-6/ -3 ratio compared with fish and corn oil Authors conclude that krill is superior to fish oil in increasing omega-3, decreasing the omega-6 to omega- Krill bioavailability studies It is concluded that there is at present no evidence for greater bioavailability of krill vs. Fish oil and that more carefully controlled human trials must be performed to establish their relative efficacies after chronic administration Norman Salem, Jr, Connye N Kuratko A reexamination of krill oil bioavailability studies Lipids Health Dis. 2014; 13: 137.
  • 33. Concentrated fish oil (rTG) Standard fish oil (TG) 0 200 400 600 800 1000 1200 DHA EPA Omega-3dose(mg/day) EPA DHA Total omega-3 Concentrated fish oil (rTG) 650 450 1100 Concentrated fish oil (EE) 756 228 984 Salmon oil (TG) 180 220 400 Krill oil (PL) 150 90 240 Laidlaw M, Cockerline CA, Rowe WJ. A randomized clinical trial to determine the efficacy of manufacturers’ recommended doses of omega-3 fatty acids from different sources in facilitating cardiovascular disease risk reduction. Lipids Health Dis. 2014;13:99.
  • 34. Day 0 Day 28 4 4.5 5 5.5 6 6.5 7 Concentrated fish oil (rTG) Concentrated fish oil (EE) Standard fish oil (TG) Krill oil (PL) Omega-3index rTG = reesterified triglyceride; EE=ethyl-ester; TG=triglyceride; PL=phospholipid Day 0 Day 28 ∆ Change Concentrated fish oil (rTG) 4.17 6.82 2.65 Concentrated fish oil (EE) 4.13 5.77 1.64 Salmon oil (TG) 4.13 4.93 0.80 Krill oil (PL) 4.27 4.76 0.49 Laidlaw M, Cockerline CA, Rowe WJ. A randomized clinical trial to determine the efficacy of manufacturers’ recommended doses of omega-3 fatty acids from different sources in facilitating cardiovascular disease risk reduction. Lipids Health Dis. 2014;13:99.
  • 35. AAtoEPAratio Concentrated fish oil (rTG) Concentrated fish oil (EE) Standard fish oil (TG) Krill oil (PL) Day 0 Day 28 ∆ Change Concentrated fish oil (rTG) 11.886 4.738 -7.148 Concentrated fish oil (EE) 12.164 5.058 -7.107 Salmon oil (TG) 11.576 8.836 -2.740 Krill oil (PL) 11.568 8.963 -2.606 rTG = reesterified triglyceride; EE=ethyl-ester; TG=triglyceride; PL=phospholipid Laidlaw M, Cockerline CA, Rowe WJ. A randomized clinical trial to determine the efficacy of manufacturers’ recommended doses of omega-3 fatty acids from different sources in facilitating cardiovascular disease risk reduction. Lipids Health Dis. 2014;13:99.
  • 36. Fatty acid absorption Flooding the body with concentrated high doses of omega-3 can increase inflammation (more so in nutritionally compromised individuals) due to creation of non-enzymatic oxidation end products Antioxidants can reduce the production of unfavourable LPOs i.e., the high content of astaxanthin in krill oil is possibly due to the presence of unstable free fatty acids Regular split-dosing with small capsules is more favourable for delivery of high doses than single large doses Non-enzymatic oxidation is caused by ROS attack of PUFAs and produces manifold potentially harmful LPOs, such as malondialdehyde (general LPO measure), 8-isoprostane (LPO generated by AA peroxidation), and hydroxynonenals ( -6 PUFA-derived LPOs) and hydroxyhexenals ( -3 PUFA-derived LPOs).ω ω Assies J, Mocking RJ, Lok A, Ruhé HG, Pouwer F, Schene AH. Effects of oxidative stress on fatty acid- and one-carbon-metabolism in psychiatric and cardiovascular disease comorbidity. Acta Psychiatr Scand. 2014 Sep;130(3):163-80.
  • 37. 4-hydroxynonenal (HNE) is a lipid peroxidation by product, derived from membrane lipid oxidation by ROS At physiological or low stress levels the major 4-HNE detoxification step is via glutathione; if glutathione levels are compromised 4-HNE accumulates, causing irreversible cell damage Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signalling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev. 2014;2014:360438.
  • 38.  Even small amounts of oxidised DHA are sufficient to reverse the beneficial effects of DHA, emphasising the importance of preventing DHA from oxidation in nutritional approaches  This might also explain the different results obtained in epidemiological studies dealing with DHA, where small contamination of oxidised DHA could lead to negative/neutral study results Omega-3 should be combined with appropriate antioxidants in high-risk individuals Grimm MO, Haupenthal VJ, Mett J, Stahlmann CP, Blümel T, Mylonas NT, Endres K, Grimm HS, Hartmann T. Oxidized Docosahexaenoic Acid Species and Lipid Peroxidation Products Increase Amyloidogenic Amyloid Precursor Protein Processing. Neurodegener Dis. 2016;16(1-2):44-54.
  • 39. PV AV TOTOX Oxidation of food grade oils Time Peroxide value (PV) = primary oxidation products - max value = 5 Ansidine value (AV) = secondary oxidation products - max value = 26 The oxidation of oil over time as measured by peroxide value (PV), anisidine value (AV) and TOTOX value. PV can decrease over time so AV and/or TOTOX calculation is needed to appreciate the whole oxidation story
  • 40.  Smaller capsules Unlike our competitors, we keep our capsules small, making them not only easier to swallow but to encourage and highlight the importance of split dosing  Split-dosing High doses of EPA should be distributed throughout the day. Not only does this help with digestion and uptake of the fatty acids within the oil, but it also ensures that blood levels are sustained throughout the day  Taking the supplements with food Capsules should never be taken on an empty stomach. Taking E-EPA with food (and ideally in the presence of other dietary oil/fat) will increase the body’s natural ability to digest and absorb the fatty acids  Inclusion of vitamin E We add vitamin E to all of our EPA products to protect the free fatty acids from oxidation both pre and post digestion  Adding an appropriate antioxidant may can offer additional benefits / protection Supplement considerations when dosing
  • 41. Taking an appropriate antioxidant overcomes potential issues with peroxidation of highly concentrated omega-3s in ‘high-risk’ individuals +
  • 42. Brain structure & function with antiinflammatory benefits Potent antioxidant Supports methylation, transulfation etc Comprehensive support Taking an appropriate antioxidant overcomes potential issues with peroxidation of highly concentrated omega-3s in ‘high-risk’ individuals
  • 43. Non enzymic antioxidants Vitamins A, C, & E Phenols Polyphenols - flavonoids - isothiocyanates - stilbenes - phenolic acids - lignans - carotenoids - resveratrol Enzymatic antioxidants require: Selenium Vitamin D Copper Manganese Magnesium Zinc Amino acids (i.e. taurine) Brain proteins, lipids and DNA are vulnerable to oxidative damage Prevent, inhibit, repair ROS damage Metabolism and exogenous damage contribute to the formation of ROS Parletta N, Milte CM, Meyer BJ. Nutritional modulation of cognitive function and mental health. J Nutr Biochem. 2013 May;24(5):725-43.
  • 44. Why fish oils sometimes ‘fail’ • Study participants are often recruited irrespective of their baseline levels in EPA+DHA, and treated with fixed doses, ignoring the large inter-individual variability in omega-3 status or variability in uptake • It is often the case that individuals with the lowest omega-3 levels are the best ‘responders’ to fish oil supplementation • Omega-3 digested, absorbed and subsequently incorporated into cells and tissues – taking an omega-3 is not the same as increasing omega-3 levels • Such factors may contribute to the tendency towards neutral results in many intervention trials. The omega-3 index has many features that qualify it as not only a biomarker of intake, but also as risk marker and most importantly, a risk factor and target for intervention • The potential impact of an intervention may well be determined by successful cellular uptake of omega-3 and the failure to reach an optimal omega-3 index may go towards explaining inconsistencies reported in many clinical trials • Establishing base line ‘biomarker’ levels may make it possible to identify ‘responders’ within the clinical trial setting by monitoring the changes in biomarker levels von Schacky C. Omega-3 fatty acids in cardiovascular disease--an uphill battle. Prostaglandins Leukot Essent Fatty Acids. 2015 Jan;92:41-7. .
  • 45. Inflammation and depression?? • In association with many physical illnesses behavioural changes occur such as decreased appetite, weight loss, fatigue, sleep disturbances, impaired cognitive abilities and depressed mood • These symptoms appear to result from immune activation and mediated by inflammatory cytokines (i.e., IL-1, IL-6, and TNF-α) and named ‘sickness behaviour’ • Similar symptoms can be induced artificially by the administration of bacterial endotoxin and cytokines such as TNF-α (given therapeutically for hepatitis C) • These TNF-α induced symptoms can be successfully treated with SSRI antidepressants suggesting that the production of inflammatory cytokines may also underpin the development of depressive illness
  • 46. Omega-3 in the management of mood disorders • In patients with hepatitis C treated with IFN-α up to 45% will develop depression • Rates of IFN-α-induced depression is significantly lower in EPA-treated but not in DHA-treated patients • Meta-analysis support the use of 1g EPA in he management of major depressive disorder • EPA supplements are more likely to be ‘effective’ where there is pre- existing inflammation Lotrich, F. E., B. Sears, et al. (2013). "Anger induced by interferon-alpha is moderated by ratio of arachidonic acid to omega-3 fatty acids." J Psychosom Res 75(5): 475-483. Mocking RJ, Harmsen I, Assies J, Koeter MW, Ruhé HG, Schene AH. Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder. Transl Psychiatry. 2016 Mar 15;6:e756. Rapaport, M. H., A. A. Nierenberg, et al. (2015). "Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof of-concept study." Molecular psychiatry. 2016 Jan;21(1):71-9. Su KP, Lai HC, Yang HT, Su WP, Peng CY, Chang JP, Chang HC, Pariante CM. Omega-3 fatty acids in the prevention of interferon-alpha-induced depression: results from a randomized, controlled trial. Biol Psychiatry. 2014 Oct 1;76(7):559-66. 
  • 47. • Increased HPA-axis activity • Increased cortisol production • Increased IDO/TMO/KMO activity • The kynurenine (KYN)/tryptophan ratio • Increased SERT activity/low serotonin • Decreased neurotrophins • Decreased neurogenesis • Increased hippocampal atrophy • Decreased delta-6 desaturase activity • Increased COX-2, PLA2 & PGE2 activity Neuroinflammation in mood disorders High AA to EPA ratio Low omega-3 status Cytokines Cortisol
  • 48. EPA and DHA as individual fatty acids  Although EPA and DHA are both long-chain polyunsaturated fatty acids (PUFAs), the molecules are often reported to produce biochemical and physiological responses that are qualitatively and quantitatively different from each other  The kinetics of EPA and DHA differ between different cell types  The marked differences between the effects of EPA and DHA indicate that it is an over-simplification to generalise the effects of omega-3 PUFA on cell function  It is the EPA in excess of DHA that is the active component in fish oil [treating depression]
  • 49. Growing number of pure EPA studies  JELIS - Japan EPA Lipid Intervention Study • CVD - Hypercholesterolaemia subjects • E-EPA 1.8g/daily – 2 years1.8g/day • E-EPA + statins reduced incidence of major CVD events by 19% • Compared with DHA, EPA administration reduced the EPA/AA ratio and the (PGI2 + PGI3)/TXA2 balance to a state that inhibits the onset and/or progression of CVD  MARINE trial • CVD – Hypertriglyceridaemia (≥ 500 mg/dL) • E-EPA @ 2g & 4g/daily – 12 weeks • E-EPA @ 4 g/day significantly reduced triglycerides , large VLDL, total LDL, small LDL, and total HDL particle concentrations and VLDL particle size  ANCHOR trial • CVD – triglycerides ≥ 200 to < 500 mg/dL • E-EPA 4g/daily with statins • Significant reduction in triglycerides, large VLDL, total LDL, small LDL, and total HDL particle concentrations and VLDL particle size  REDUCE-IT (Reduction of Cardiovascular Events Outcomes trial) – ongoing • CVD –high-risk patients with mixed dyslipidemia currently using statins • E-EPA 4g/daily
  • 50. Growing number of pure EPA studies  Huntington’s disease • E-EPA 1g/daily – 1 year •Significant reduction in brain atrophy, particularly in the caudate and thalamus •Stable or improved motor function  SeAFood polyp prevention trial (ongoing) • Colorectal cancer • Pharmepa RESTORE - rTG EPA 2 g/daily – 1 year  EMT2 (EPA for Metastasis) trial (starts October 2015) • Colorectal cancer recurrence and survival after surgery for resectable liver metastases •Pharmepa RESTORE rTG EPA 2g/daily – 2 years
  • 51. © CNELM Lovaza -each 1g capsule contains 0.84g ethyl ester as EPA (0.465 g) and DHA (0.375 g) Epanova each 1g capsule contains 0.75g free fatty acids as EPA (0.55g) and DHA (0.2g) Vasepa each capslue contains 1g ethyl ester as pure EPA All products reduce TGs but EPA alone appears to minimally decrease or have a neutral effect on LDL-C, while DHA/EPA combination products have been shown to increase LDL-C, which may be an important consideration for patients with atherosclerotic disease and/or risk factors for CV disease Ito MK. A Comparative Overview of Prescription Omega-3 Fatty Acid Products. P T. 2015 Dec;40(12):826-57.
  • 52. Pro-inflammatory Anti-inflammatory COX-1/COX2 COX-1/COX2 5-LOX 5-LOX AA EP A PGE3 LTB5 PGE2 LTB4 Proliferation Hypermethylation of tumour suppressor genes, increases expression of aromatase Migration & invasion Activation of E4 receptor and PI3k/Akt/mTOR pathway Anti-proliferation Down regulates COX-2 and ERK 1 / 2 pathway Anti-anigogenic Inhibits Ang2 an MMP-9 Proliferation Activation of BLT1 & BLT2 receptors, MEK/ERKPI3K/Akt pathway Angiogenesis TF-kB & VEGF Invasion and metastasis STAT-3 & MMPs Anti-proliferation Counteract LTB4. down stream molecular targets are currently unclear Cancer risk Cancer progression Cancer risk Cancer progression Better outcomes Poorer outcomes AA and EPA metabolism contribute to cancer risk and progression through pro-and anti- inflammatory lipid metabolites that stimulate cell proliferation, angiogenesis, and migration Azrad M, Turgeon C, Demark-Wahnefried W. Current evidence linking polyunsaturated Fatty acids with cancer risk and progression. Front Oncol. 2013 Sep 4;3:224. Inflammation creates the ideal “tumour microenvironment” and is now widely recognised as an enabling characteristic of cancer in regard to enhanced cell proliferation, cell survival, cell migration and angiogenesis
  • 53. Mahmoudabadi MM, Rahbar AR. Effect of EPA and vitamin C on superoxide dismutase, glutathione peroxidase, total antioxidant capacity and malondialdehyde in type 2 diabetic patients. Oman Med J. 2014 Jan;29(1):39-45. doi: 10.5001/omj.2014.09. Mahmoudabadi MM, Djalali M, Djazayery SA, Keshavarz SA, Eshraghian MR, Yaraghi AA, Askari G, Ghiasvand R, Zarei M.Effects of eicosapentaenoic acid and vitamin C on glycemic indices, blood pressure, and serum lipids in type 2 diabetic Iranian males.J Res Med Sci. 2011 Mar;16 Suppl 1:S361-7. Thota RN, Acharya SH, Abbott KA, Garg ML. Curcumin and long-chain Omega-3 polyunsaturated fatty acids for Prevention of type 2 Diabetes (COP-D): study protocol for a randomised controlled trial. Trials. 2016 Nov 29;17(1):565. Pure EPA supplementation has benefits in type II diabetics • Lower levels of omega-3 are associated with, insulin resisitance, metabolic syndrome, type II diabetes and associated health risks • EPA has anti-thrombotic, anti-inflammatory and anti-arrhythmic effects, as lowers blood pressure and reduces plasma triglyceride levels glycosylated haemoglobin • The higher EPA quantities in the phospholipid cell membranes could be related to increased insulin sensitivity • EPA reduces oxidative stress and increases superoxide dismutase, glutathione peroxidase and total antioxidant capacity and decreases malondialdehyde levels significantly • Synergistic benefits with curcumin for the prevention of diabetes?
  • 54. Primary structural function & anti-inflammatory docosanoid production Anti-inflammatory eicosanoid production REDUCED INFLAMMATION DHAEPA Pro-inflammatory eicosanoid production INFLAMMATION AA AA to EPA ratio direct antagonism The relationship between the omega-3 index and the AA to EPA ratio Omega-3 index
  • 56. Olive oil Fruit Vegetables Oily fish Nuts & seeds Legumes & cereals Monounsaturated fat (oleic acid) Antioxidants (i.e. polyphenols) Vitamin A,B,C & E Vitamin D Omega-3 fatty acids (ALA, EPA & DHA) Minerals (i.e. selenium, iron & iodine) Amino acids (i.e. taurine, tyrosine & tryptophan) Moderate red wine Lean meat Moderate dairy Neuronal survival Energy metabolism Neurotrophins Neurotransmission Membrane fluidity Cell membrane integrity Glucose transport Nutrient synthesis Nutrient metabolism Gene expression Methylation Cerebral blood flow Blood pressure Oxidative damage Neuronal cell death Neuroinflammation Free radicals Parletta N, Milte CM, Meyer BJ. Nutritional modulation of cognitive function and mental health. J Nutr Biochem. 2013 May;24(5):725-43.
  • 57. Asimple,expertlyformulated,1-a-daydualcapsulesystem Ultra concentrated Mi ndCar e® omega-3 EPA & DHA capsules with vitamins D & E Precisely formulated to target and support brain function (250mg DHA plus 410 mg EPA per capsule) using the body-ready rTG form of omega-3 that is nature-identical and easily absorbed by the body Mi ndCar e® micronutrient capsules contain: full B complex plus zinc, selenium, vitamin C and targeted ACTIVES Target distinct areas of brain health with a comprehensive blend of synergistic vitamins, minerals and specialist actives at proven, effective levels and in super-bioavailable  Mi ndCar e® is based on cutting-edge nutrition science and combines premium triglyceride omega-3 fish oil containing 80% active doses of EPA and DHA with scientifically proven nutrients for various aspects of brain health
  • 58. MindCare® BALANCE Magnesium glycinate and L- Theanine with their natural calming effects act as relaxants, reduce feelings of stress and reduce anxiety MindCare® FOCUS Acetyl-L-Carnitine, L-Theanine, taurine and caffeine heighten mental alertness and support concentration, memory and focus MindCare® LIFT Magnesium glycinate and 5-HTP help to regulate neurotransmitters required for mood balance MindCare® PROTECT N-Acetyl L-Cysteine, alpha-lipoic acid and resveratrol help protect against neuroinflammation and improve and support energy metabolism in the brain Highly bioavailable micronutrients (vitamins C , D3 & E; vitamins B1, B2, B3, B5, B6, B7, B12 & folate; minerals zinc & selenium) support immune & detoxification enzyme-mediated pathways. They support homocysteine recycling required for the production of neurotransmitters, enhance neurotransmission via regulation of receptors, transporters and ion channels, support natural stress response pathways, ensure optimal delivery of fuel to the brain, enhance cognition, relaxation, sleep, mental focus and reduce stress and oxidative stress Ultra concentrated MindCare® omega-3 EPA & DHA capsule supports cognitive function, mental performance MindCare® micronutrient capsules
  • 59. ADVANCED MULTIVITAMIN & MINERALS Pure Essentials Advanced Multivitamin & Minerals is a comprehensive multi-nutrient supplement, featuring full spectrum body- ready methylated B-vitamins and active mineral forms. Enhanced with a slow-release delivery system, this supplement steadily releases nutrients for optimal absorption and uptake into the bloodstream. This advanced formula is the ideal all-round multivitamin & mineral supplement to support optimal wellbeing.
  • 60. Each capsule provides 410 mg EPA, 250 mg DHA and 1000 iu vitamin D3 for intensive daily support. The omega-3 is provided in the superior rTG form, which is body-ready and delivers higher levels of omega-3 into cells faster than standard fish oil and krill oil. This ultra-pure supplement is sourced from wild, sustainable anchovies and the oil is purified to remove all trace of mercury, dioxins and PCBs. Natural lemon oil prevents fish reflux. SUPER CONCENTRATED OMEGA-3 WILD FISH OIL & VITAMIN D3
  • 61. Serving size: 1 capsule Per serving % RI* Longvida® optimised curcumin extract from turmeric root (min. 20% curcuminoids) 500 mg n/a DIRECTIONS FOR USE Adults: take 1 capsule daily with food. For intensive support, take 2 capsules daily as a split dose. Do not exceed the dose unless advised by a healthcare practitioner. NUTRITIONAL INFORMATION INGREDIENTS: Longvida® optimised curcumin extract; capsule shell (emulsifier: hydroxypropyl methylcellulose); stearic acid; soy lecithin; maltodextrin; ascorbyl palmitate; silicon dioxide. Free from: dairy, gluten, lactose, soya protein, wheat, yeast, artificial colours and flavours; not tested on animals; non-GMO; suitable for vegetarians & vegans; halal & kosher. * % Reference Intake Product information
  • 62. Longvida optimized curcumin delivery system  Longvida curcumin is able to survive the harsh digestive pH conditions and doesn’t get destroyed by the acidic environment of the stomach  The small particle size of Longvida curcumin ensures its easy passage across the intestinal cell membrane  Longvida provides a unique coating (of highly purified fatty acids and phospholipids) that surrounds the curcumin molecule and enables it to be transported into the lymphatic system rather than the circulatory system  Unlike the circulatory system, the lymphatic system bypasses the liver (the major organ for metabolism) so less curcumin is exposed to metabolic enzymes and remains in a free form  The sole purpose of these metabolic enzymes is to attach large groups (called glucuronides or sulphates) to the curcumin molecule, making it very bulky but also highly water soluble so it can be rapidly excreted by the kidneys and out of the body in urine  In contrast, the free form of curcumin stays in the body longer because it isn’t metabolised and doesn’t have these water soluble groups attached to it so, it has a longer duration of action
  • 63. Education Technical Sophie Tully Nutrition Education Manager sophiet@igennus.com Dr Nina Bailey Head of Nutrition ninab@igennus.com Twitter @DrNinaBailey

Editor's Notes

  1. Used to be one portion to achieve 0.5g/day, now it’s possibly 2-3! &amp;lt;number&amp;gt;
  2. Blood levels (mean±SD) of EPA as a percentage of total fatty acids pre- and postdosing. Data points are identified by author and ranked by daily dose (low to high). Fish oil doses were as follows: Rupp, 1 g/d32; Di Stasi, 1 g/d16; Poppitt, 1.2 g/d29; Vedin, 2.3 g/d36; Donadio, 3.35 g/d17; Laidlow, 4 g/d22; Donadio, 6.7 g/d18. EPS indicates eicosapentaenoic acid; and SD, standard deviation.
  3. Blood levels (mean±SD) of EPA/AA at baseline and after treatment. Studies are ranked by daily dose low to high. Doses were as follows: Shintani, 1800 mg/d34; Matsuzaki, 1800 mg/d25; Donadio, 3.5 g/d17; Laidlow, 4.0 g/d22; Donadio, 6.7 g/d18. The red line indicates a risk level suggested by Itakura et al.5 EPA/AA indicates eicosapentaenoic acid/arachidonic acid; and SD, standard deviation.
  4. ALA and SDA can raise omega-3 EPA but with little impact on DHA Ingestion of 3 g/day ALA (from 5.1g flaxseed oil) for 12 weeks resulted in significant increases in plasma EPA (60%) and DPA (25%) but not DHA (Harper et al., 2005) &amp;lt;number&amp;gt;
  5. &amp;lt;number&amp;gt;
  6. As a biomarker, the AA to EPA ratio gives an indication of the inflammatory status Diet has the capacity to influence the amount of polyunsaturated fats within our cell membranes, so we also need a structural biomarker The omega-3 index = biomarker of intake, but also as risk marker, a risk factor and target for therapy Combining the AA to EPA ratio with the omega-3 index gives us a comprehensive overview of health status &amp;lt;number&amp;gt;
  7. 100,000 years ago &amp;lt;number&amp;gt;
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  12. Differences between end of study and baseline values of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and EPA plus DHA content in mg/L serum, in the sum of serum lipid fractions (cholesterol esters, triglycerides, and phospholipids). A bioavailability index of 100 is indicated in the EPA+DHA plot, corresponding to 150 EPA+DHA mg/l (solid line) indicating the mean value of increases (mg/L) after intake of natural fish oils: Fish body oil (FBO) and cod liver oil (CLO). The differences in the grand total of EPA plus DHA were significant when comparing EE with rTG (p=0.000I) and EE with fish body oil (p=0.024), but not when comparing EE with CLO (p=0.13) and EE with FFA (p=0.29). Values are means +SEM (bars). rTG=re-esterified triglycerides, FFA=free fatty acids, EE=ethyl esters, and CO=corn oil. &amp;lt;number&amp;gt;
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  15. Source naturals Arctic pure 150EPA 90DHA : MegaRed Krill 300mg (1 a day) EPA 50mg DHA 24 &amp;lt;number&amp;gt;
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  24. Low omega-3 status predicts &amp;lt;number&amp;gt;
  25. The role of cytokines on PLA2, COX-2 and PGE2 Cytokines such as IL-1, TNF-a increase COX-2 and stimulate signaling pathways leading to PLA2 phosphorylation and AA release (Sun et al., 2004) Increased levels of PLA2, COX-2 and PGE2 activity is observed in depression, bipolar and schizophrenia PLA2 has been implicated both in the breakdown and remodelling of phospholipid membranes, with increased activity directly associated with several brain structural alterations as observed in schizophrenia (Smesny et al., 2010) &amp;lt;number&amp;gt;
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  29. A new biomarker in cancer patients: the AA to EPA ratio To evaluate the potential value of tumour risk assessment in colon and breast cancer patients by determining the AA to EPA ratio  in plasma in a case-control study against healthy patients (Garassino et al.,  2006) These data suggest that AA to EPA ratio in plasma is strongly correlated with cancer disease Findings Colorectal cancer AA/EPA ratio was 22.232+1.852 compared to 14.25+1.083 for healthy subjects (median age 70; range 53 - 81) Breast cancer The AA/EPA ratio was 21.029+2.584 compared to 12.10+1.414 in healthy subjects (median age 77; range 44 - 86) &amp;lt;number&amp;gt;
  30. As a biomarker, the AA to EPA ratio gives an indication of the inflammatory status Diet has the capacity to influence the amount of polyunsaturated fats within our cell membranes, so we also need a structural biomarker The omega-3 index = biomarker of intake, but also as risk marker, a risk factor and target for therapy Combining the AA to EPA ratio with the omega-3 index gives us a comprehensive overview of health status &amp;lt;number&amp;gt;
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