Filtering fish oil fact from fiction

Filtering fish oil fact from fiction Nina Bailey BSc MSc, PhD RNutr

1

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?

2

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.

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.

Pregnancy

Infants and

children

Children and adults

AdultsMaternal 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 brainDHA 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

ALADelta -6 desaturase

Delta -5 desaturase

Cyclooxygenase (COX)/lipoxygenase (LOX)

Elongase

Series-2 prostaglandinsSeries-2 thromboxanesSeries-4 leukotrienes

Hydroxy fatty acids

AACOX/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 productionResolvins Protectins

DHAElongase &desaturase

Pro-inflammatory eicosanoid production

Series-3 prostaglandinsSeries-3 thromboxanesSeries-5 leukotrienes Hydroxy fatty acids

Resolvins

Primary structural function & anti-inflammatory docosanoid

production


REDUCED INFLAMMATION

DHAEPA


INFLAMMATION

AA

AA to EPA ratiodirect 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

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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

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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.

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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 12 200

1

2

3

4

Time (weeks)

EPA

in m

onon

ucle

ar c

ell P

L (%

)

0 4 8 12 201

2

3

4

Time (weeks)D

HA

in m

onon

ucle

ar c

ell P

L (%

)

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

ALADelta -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 = 4AA to EPA ratio = 10

2%

4%3%


Omega-3 index = 6AA to EPA ratio = 3.3

Omega-3 index = 7AA to EPA ratio = 2.5

3%

10%

E

5%

D Omega-3 index = 8AA 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


1%

2%1%




5%

10%

E

3%

DOmega-3 index = 8AA 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 MAINTAIN0

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 1000DHA (mg) 0 0 0 0 83 167 250 333GLA (mg) 0 0 0 0 20 40 60 80

Vitamin E (mg) 5 10 15 20 3 6 9 12Vitamin D (mg) 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 2000DHA (mg) 83 167 250 333 83 167 250 333GLA (mg) 20 40 60 80 20 40 60 80

Vitamin E (mg) 8 11 14 17 13 16 19 22Vitamin D (mg) 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

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QuestionWhat 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 COCapsule size (mg) 650 1000 500 650 650 650Capsules/day 10 13 24 10 10 10EPA (g/day) 1.85 2.04 1.38 2.18 1.87 0DHA (g/day) 1.29 1.48 1.87 1.4 1.39 0EPA+DHA (g/day) 3.1 3.5 3.2 3.6 3.3 0Total oil (g) 6.5 13 12 6.5 6.5 6.5Omega-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/dayEPA 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 groupsThe 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 DHA3.4g 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 esterkrill 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-3 ratio and improving the omega-3 index

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)

Concentrated fish oil (EE)

Standard fish oil (TG)

Krill oil (PL) 0

200

400

600

800

1000

1200

DHA EPA

Om

ega-

3 d

ose

(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 284

4.5

5

5.5

6

6.5

7

Concentrated fish oil (rTG) Concentrated fish oil (EE)

Standard fish oil (TG) Krill oil (PL)

Om

ega-

3 in

dex

rTG = reesterified triglyceride; EE=ethyl-ester; TG=triglyceride; PL=phospholipid

Day 0 Day 28 ∆ ChangeConcentrated fish oil (rTG)

4.17 6.82 2.65


4.13 5.77 1.64

Salmon oil (TG) 4.13 4.93 0.80

Krill oil (PL) 4.27 4.76 0.49


AA to

EPA

ratio

Day 0 Day 284

5

6

7

8

9

10

11

12

13

Concentrated fish oil (rTG) Concentrated fish oil (EE)Standard fish oil (TG) Krill oil (PL)

Day 0 Day 28 ∆ ChangeConcentrated fish oil (rTG)

11.886 4.738 -7.148


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


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 theproduction of unfavourable LPOs

i.e., the high content of astaxanthinin krill oil is possibly due to the presence of unstable free fatty acids

Regular split-dosing with small capsules ismore 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 (ω-6 PUFA-derived LPOs) and hydroxyhexenals (ω-3 PUFA-derived LPOs).

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

39

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 capsulesUnlike 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-dosingHigh 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 foodCapsules 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, & EPhenolsPolyphenols - flavonoids - isothiocyanates - stilbenes - phenolic acids - lignans - carotenoids - resveratrol

Enzymatic antioxidants require: SeleniumVitamin DCopperManganeseMagnesiumZincAmino 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 baselinelevels in EPA+DHA, and treated with fixed doses, ignoring the largeinter-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.. 44

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

45

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.

https://www.ncbi.nlm.nih.gov/pubmed/24602409

• 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 ratioLow omega-3 status

CytokinesCortisol

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 EPA

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-proliferationDown 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

AngiogenesisTF-kB & VEGF

Invasion and metastasisSTAT-3 & MMPs

Anti-proliferationCounteract LTB4.

down stream molecular targets are currently unclear

Cancer riskCancer progression

Cancer riskCancer 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. 53

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


REDUCED INFLAMMATION

DHAEPA


INFLAMMATION

AA

AA to EPA ratiodirect antagonism

The relationship between the omega-3 index and the AA to EPA ratio

Omega-3 index

Therapeutic

Wellbeing

Additional nutrients

Our products range

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 survivalEnergy metabolismNeurotrophinsNeurotransmissionMembrane fluidityCell membrane integrity Glucose transportNutrient synthesisNutrient metabolismGene expressionMethylationCerebral blood flow

Blood pressureOxidative damageNeuronal cell deathNeuroinflammationFree 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

A simple, expertly formulated, 1-a-day dual capsule system

Ultra concentrated MindCare® omega-3 EPA & DHA capsules with vitamins D & EPrecisely 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

MindCare® 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 forms

MindCare® 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® FOCUSAcetyl-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 capsulesupports 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-3WILD 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 USEAdults: 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 TullyNutrition Education

[email protected]

Dr Nina Bailey Head of Nutrition

[email protected] @DrNinaBailey

mailto:[email protected]

Filtering fish oil fact from fiction

Health & Medicine

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