Maximizing Omega-3 Health Benefits

There are now close to 20,000 published studies on the benefits of omega-3 fatty acids. As researchers continue to discover new longevity mechanisms such as reducing brain shrinkage, protecting memory and improving endothelial function, scientists have begun to analyze how different omega-3 sources affect the body.

Emerging evidence suggests that omega-3s from fish oil as well as krill oil, provide complementary effects upon different cellular targets.¹ In addition, scientists are finding that cellular uptake of omega-3 fatty acids from fish and krill oil occur at different rates depending on their destination.²

Intriguing data suggest that combining fish oil and krill oil may provide enhanced support for cardiovascular health and the nervous system, including the brain. This is due to the different levels and rates of uptake observed for omega-3 fatty acids from fish and krill oil in plasma, platelets, and red blood cells.

As scientists continue to study uptake of marine oils into various cells and tissue components in the body, the evidence suggests that by combining both fish and krill oil, you may optimize the protective benefits provided by these different sources of omega-3 fatty acids.

syndrome, and even osteoporosis and arthritis.

Benefits Of Both Fish Oil And Krill Oil

Fish oil and krill oil share many important similarities, such as effectively reducing the ratio of omega-6 to omega-3 fatty acids in the body. This is an important biomarker associated with lower levels of chronic inflammation.² Both krill and fish oil also increase plasma and cell membrane concentrations of omega-3 fats.^3.4

However, there are differences. What scientists have found is that the uptake of omega-3 fatty acids from fish oil and krill oil is different for the plasma, platelets, and red blood cells.⁵

For example, clinical data from human test subjects suggest that omega-3 fatty acids like DHA from fish oil result in a more rapid uptake into plasma triglyceride and platelet phospholipids,⁶ which offers benefits given the effects of plasma triglycerides and platelet function on endothelial function, and cardiovascular health in general.

In comparison, the omega-3s found in krill appear to be more rapidly incorporated into red blood cell phospholipids.⁷ This is important, because not only do scientists view the uptake of essential fatty acids in red blood cells as a biomarker for uptake into the brain,⁸ but additional research suggests that when omega-3 fatty acids such as DHA are bound to phospholipids as they are with krill, it increases their uptake to the brain.⁹ This is further supported by human clinical research, which suggests ingestion of phospholipid-bound EPA and DHA increase cognitive function scores to a greater degree compared with scores obtained when the fatty acids in the ingested oil were provided in the triglycerides storage form.¹⁰

When combined, krill and fish oil appear to offer enhanced benefits for both the cardiovascular and nervous system than either form by itself.

Let’s now look at how fish oil and krill oil work together to provide the broadest spectrum of coverage for brain health, heart health, and much more.

Omega-3s And Brain Health

Both omega-3 fatty acids DHA and EPA are well known to provide systemic benefits throughout the body and reduce the risk of early death.¹¹

DHA is vital for early brain development and maintenance, while EPA seems to be closely related to behavior and mood. Together, both molecules provide critical neuroprotective benefits.¹¹ These neuroprotective effects are important for the prevention of age-related brain shrinkage (cortical atrophy). Aging adults with brain shrinkage often experience memory loss, cognitive decline, and an increase in depression.^12-14

Studies show that people with higher levels of omega-3 fatty acids in their blood experience brain benefits such as better cognitive outcomes, larger gray matter volume for their age, fewer signs of brain blood flow disturbances, and lower rates of dementia, compared with those having lower omega-3 fatty acid levels.^15-20

Those with lower DHA levels have poorer scores on cognitive testing, smaller brain volumes, and more “white matter hyperintensity” (also called leukoaraiosis), a condition that is associated with accelerated brain aging.²¹

One important way omega-3 fatty acids protect your brain is by shielding the chief memory processing area of your brain, the hippocampus. Studies show that people with lower total omega-3 levels have smaller hippocampus volumes.²²

Because patients with depression experience rapid shrinking of their hippocampus, many strategies for relieving depression focus on increasing new brain cell growth in that specific area of the brain.²³ There’s now evidence that increasing omega-3 intake, especially DHA, may be an effective way of treating or preventing depression, partly by protecting the hippocampus from further shrinkage.²³

In addition to depression, chronic stress leads to loss of volume of the hippocampus—and also causes enlargement of the amygdala, the portion of the brain that regulates anxiety and anger.²⁴ When rats were supplemented with omega-3s during exposure to stress, they showed lower corticosterone levels (a marker of stress), and improved learning on a maze—indicating that the omega-3s helped preserve memory and reduce anxiety.²⁴

Diabetes is a key factor in accelerated brain aging. Neuroprotective and cognition-improving effects have been shown in diabetic animals when they were supplemented with omega-3s.²⁵

Omega-3s are also credited with slowing the rate of cognitive decline in patients with very mild early Alzheimer’s disease. This study demonstrates the importance of early intervention with omega-3s for aging adults.²⁶

Krill Oil’s Additional Brain Benefits

Both krill and fish oil are rich in the long-chain fatty acids EPA and DHA.

An important difference, however, is that EPA and DHA found in krill oil are bound to phospholipids, a form of fat that makes up the cell membrane. Phospholipids also enhance cell signaling, which is especially important for the healthy functioning of the nervous system and the brain.

Studies show that when omega-3 fatty acids such as DHA are bound to phospholipids as they are with krill, it increases their uptake to the brain.²⁷

In lab experiments, animals given krill showed improved navigation skills. What this means is that they achieved higher levels of cognition and memory required to navigate complex territory.²⁸ In addition, research shows that animals supplemented with krill oil showed significantly fewer signs of depression and resignation. This improvement in mood was equivalent to the effect of the prescription anti-depressant drug imipramine (Tofranil^®).²⁹

Human studies also confirm cognition and memory improvement with omega-3 supplementation. For example, a study showed that both fish oil and krill oil enhanced cognitive function in a group of older men by increasing oxygen delivery to their brains. Interestingly, for those taking krill oil this effect was more prominent than those taking fish oil, though both groups were significantly better than placebo.³⁰ As we pointed out earlier, because the omega-3 DHA is bound to phospholipids in krill it may be more effectively incorporated into the critical cell membrane in brain cells.

Enhanced Cardio Protection With Fish And Krill Oil

It has long been known that higher levels of omega-3 fatty acids like EPA and DHA are strongly linked to improved cardiovascular health; while lower levels of omega-3s in the blood are linked to increased rates of hypertension and risk of heart attack. That association continues to grow stronger in a host of heart disease-related areas.

Ample evidence from animal studies supports regular supplementation with omega-3 oils as a means of lowering long-term cardiovascular risk. This may be due to omega-3 fatty acids’ effects on reducing inflammation, lowering triglycerides, reducing blood pressure, improving endothelial function, inducing new blood vessel formation after heart attack or stroke, and favorable modification of obesity-related inflammatory molecules.^35-39

Human clinical trials also abound demonstrating the benefits of omega-3s for heart health. Here are a few highlights:

• Taking 4 grams per day of a prescription EPA supplement led to marked reductions in plasma triglyceride levels, especially in people with very high levels; reductions of 33 to 45% have been reported.^40-42
• Similarly, 4 grams per day of prescription EPA led to significant reduction in triglycerides and other dangerous lipids in people already on statin-type lipid-lowering medications.^43,44
• Taking 4 grams per day of prescription EPA led to significant reduction in oxidized LDL-cholesterol and C-reactive protein (CRP), measures of oxidation and inflammation, respectively.⁴⁵  
• In patients with cardiac complications from metabolic syndrome, taking 1,440 mg/day of omega-3 fatty acid supplements led to improvements in endothelial function, including improved blood flow resulting in vessel dilation.⁴⁶
• Taking 520 mg/day of DHA and 120 mg/day of EPA led to decreased platelet aggregation (clot-forming).⁴⁷
• In obese adults, 4 grams per day of a 46% EPA, 38% DHA supplement, and diet changes led to increases in both large and small artery elasticity.⁴⁸

Additional Heart Health With Fish Oil

Both fish oil and krill oil are rich sources of heart-healthy omega-3 fatty acids. However, fish oil may provide advantages for cardiovascular health beyond those found in krill oil.

An interesting human study directly compared the ingestion of phospholipid-bound DHA found in krill with the form of DHA naturally found in fish oil. The results showed that the DHA found in fish oil was absorbed much quicker than the phospholipid-bound DHA uptake into plasma from krill by almost 3-fold.⁴⁹

This data has important implications and suggests that the form of DHA found naturally in fish oil provides a more rapid uptake into plasma triglycerides, as well as platelet phospholipids, both of which are important considerations for optimizing cardiovascular health.

The omega-3 fatty acids found in krill oil and bound to phospholipids provide additional cardio- vascular benefits, as you will see in the next section.

Heart Benefits From Krill Oil

To these impressive heart health findings on fish oil, we can now add complementary cardiovascular benefits from krill oil.

Laboratory studies in rats showed that krill oil reduced harmful triglyceride concentrations in the liver more than the fish oil.^50-53

Krill oil was able to reduce structural and molecular changes found in the hearts of rats after a heart attack. After the heart attack, only the rats supplemented with krill oil were observed to have a significant reduction in heart weight, inflammation, and left ventricle dilation as compared to controls.⁵⁴

Omega-3 Fights Metabolic Syndrome And Diabetes

People with metabolic syndrome (the combination of central obesity, high blood pressure, disturbed lipid profile, and impaired glucose tolerance) are at increased risk of death from cardiovascular disease, diabetes, cancer, and other apparently “age-related” disorders. Because metabolic syndrome is closely associated with chronic low-grade inflammation, the powerful anti-inflammatory effects of omega-3 fats are especially important as a means of slowing or stopping the progression of this deadly disorder.

Studies indicate that supplementing with omega-3s can reduce various factors involved in the metabolic syndrome. The following is a list of the benefits of supplementing with omega-3s to reduce the impact of metabolic syndrome:

• Reduces body weight^55,56
• Lowers blood pressure⁵⁵
• Normalizes lipid profiles (lowering LDL, total cholesterol, and triglycerides)^55,57
• Reduces fasting and after-meal glucose and insulin levels while improving insulin sensitivity,^38,56-60 and
• Reduces total body inflammatory status, as measured by elevated cytokines and other markers of inflammation such as C-reactive protein.^55,57,61,62

An exciting animal study recently showed that, in diabetic rats, DHA supplementation not only helped to prevent diabetic eye disease, but also increased the survival rate of animals by around 25%, compared with the diabetic rats supplemented with soybean oil.⁶³

Krill Oil And Weight Loss

Animal studies show potent reduction of liver fat stores, glucose levels, and cholesterol levels in mice supplemented with krill oil while being fed a high fat diet.^64,65 While many of these effects are seen with fish oil as well, studies show that krill oil, with its unique phospholipid structure, had the added benefit of increasing fat-burning in mitochondria while reducing new glucose production in the liver.^66,67 As with so many other complex disease processes, utilizing multiple pathways to reduce disease is a highly effective strategy.⁶⁷

Synergy In Bone And Joint Health

People used to believe that osteoporosis and osteoarthritis were the result of aging and reduced intake of calcium and milk products. Science has now shown that these bone and joint disorders are, in part, due to inflammation. Because of this, bones and joints are prime targets for the anti-inflammatory properties of omega-3 oils from both fish and krill.

In both animal and human studies, omega-3s from fish oil have been found to reduce post-menopausal bone loss.^68-71 This effect appears to be related mainly to a decrease in the number and activity of bone-destroying cells, due to reduced inflammation because of increased levels of omega-3s.^72-77

On the other hand, people with lower blood levels of omega-3s are more likely to experience arthritis-related cartilage loss, compared to those with higher levels.⁷⁸

And in osteoarthritis, when a DHA/EPA formulation was added to chondroitin sulfate, people experienced more complete relief of symptoms such as stiffness and pain. One study found a significant increase in walking speed in people who supplemented with fish oil versus those who did not.^79,80 As with the beneficial results seen in people with bone loss, these positive findings may have been the result of the decreased inflammatory destruction of joint cartilage.⁸¹

In arthritis-prone guinea pigs, omega-3 supplementation significantly reduced the occurrence of the disease. In addition, omega-3 supplementation in osteoarthritic dogs and cats led to increased levels of daily activity.^82-84

Krill oil is joining the toolkit for fighting arthritis, thanks to its exceptional anti-inflammatory properties resulting from its phospholipid form of omega-3s. A study in mice with experimental arthritis showed that krill oil supplements reduced arthritis scores and markedly diminished joint swelling. When examined under a microscope, the animals’ joints were remarkably free of inflammatory infiltrates of immune system cells.⁸⁵

A study on humans has also shown the benefits of krill oil on arthritis.⁸⁶ In a double-blind, randomized, placebo-controlled study, 90 patients who had cardiovascular disease and/or rheumatoid or osteoarthritis along with high levels of C-reactive protein (CRP, an indicator of inflammation), received either 300 mg/day of krill oil or placebo.

After just seven days, those supplementing with krill had their CRP levels reduced by 19.3%, while in the placebo group, CRP levels rose by 15.7%. Even more impressive, the krill benefit was long-lasting. The krill group’s CRP levels continued to fall by 29.7% at 14 days, and 30.9% at 30 days. More importantly from the patients’ points of view, the krill oil supplement reduced pain scores by 28.9%, reduced stiffness by 20.3%, and reduced functional impairment by 22.8%.

Summary

Growing evidence suggests that fish oil omega-3s are complemented by those from krill oil, which occur naturally in a form that can be readily taken up by cell membranes.

Fish oil and krill oil have now been shown to provide superior neuroprotection, protecting vital brain areas from age-related shrinkage and dysfunction. Such measures may prevent memory loss, dementia, and even depression.

Fish and krill oils combined also optimize cardiovascular health to lower blood lipids, reduce the risk of arrhythmias, and prevent heart attacks and the damage they cause. Similarly, the marine oils lower risk for obesity, diabetes, and metabolic syndrome, which in turn can lower chances of developing diseases from cancer to stroke. And now there’s evidence that these oils can ameliorate osteoporosis and painful arthritis.

Thus, both fish oil and krill oil offer secure, complementary coverage to safeguard the health of our aging bodies.

If you have any questions on the scientific content of this article, please call a Life Extension^® Wellness Specialist at 1-866-864-3027.

References

1. Available at: http://www.jlr.org/content/40/10/1867.long#xref-ref-23-1.Accessed March 25, 2014.
2. Available at: http://www.jlr.org/content/40/10/1867.long#xref-ref-23-1. Accessed March 25, 2014.
3. Ramprasath VR, Eyal I, Zchut S, Jones PJ. Enhanced increase of omega-3 index in healthy individuals with response to 4-week n-3 fatty acid supplementation from krill oil versus fish oil. Lipids Health Dis. 2013;12(1):178.
4. Ulven SM, Kirkhus B, Lamglait A, et al. Metabolic effects of krill oil are essentially similar to those of fish oil but at lower dose of EPA and DHA, in healthy volunteers. Lipids. 2011 Jan;46(1):37-46.
5. Available at: http://www.jlr.org/content/40/10/1867.long#xref-ref-23-1. Accessed March 25, 2014.
6. Available at: http://www.jlr.org/content/40/10/1867.long#xref-ref-23-1. Accessed March 25, 2014.
7. Available at: http://www.jlr.org/content/40/10/1867.long#xref-ref-23-1. Accessed March 25, 2014.
8. Innis S M. Plasma and red blood cell fatty acid values as indexes of essential fatty acids in the developing organs of infants fed with milk or formulas. J Pediatr. 1992;120: S78–S86.
9. Thies F, Pillon C, Moliere P, Lagarde M, Lecerf J. Preferential incorporation of sn-2 lysoPC DHA over unesterified DHA in young rat brain. Am J Physiol. 1994;36:R1273–9.
10. Vaisman N, Kaysar N, Zaruk-Adasha Y, et al. Correlation between changes in blood fatty acid composition and visual sustained attention performance in children with inattention: effect of dietary n-3 fatty acids containing phospholipids. Am J Clin Nutr. 2008;87:1170–80.
11. Kidd PM. Omega-3 DHA and EPA for cognition, behavior, and mood: clinical findings and structural-functional synergies with cell membrane phospholipids. Altern Med Rev. 2007 Sep;12(3):207-27.
12. Fotuhi M, Do D, Jack C. Modifiable factors that alter the size of the hippocampus with ageing. Nat Rev Neurol. 2012 Apr;8(4):189-202.
13. Tsopelas C, Stewart R, Savva GM, et al. Neuropathological correlates of late-life depression in older people. Br J Psychiatry. 2011 Feb;198(2):109-14.
14. Zahodne LB, Gongvatana A, Cohen RA, Ott BR, Tremont G. Are apathy and depression independently associated with longitudinal trajectories of cortical atrophy in mild cognitive impairment? Am J Geriatr Psychiatry. 2013 Nov;21(11):1098-106.
15. Titova OE, Sjogren P, Brooks SJ, et al. Dietary intake of eicosapentaenoic and docosahexaenoic acids is linked to gray matter volume and cognitive function in elderly. Age (Dordr). 2013 Aug;35(4):1495-505.
16. Bowman GL, Silbert LC, Howieson D, et al. Nutrient biomarker patterns, cognitive function, and MRI measures of brain aging. Neurology. 2012 Jan 24;78(4):241-9.
17. Albanese E, Dangour AD, Uauy R, et al. Dietary fish and meat intake and dementia in Latin America, China, and India: a 10/66 Dementia Research Group population-based study. Am J Clin Nutr. 2009 Aug;90(2):392-400.
18. Walhovd KB, Storsve AB, Westlye LT, Drevon CA, Fjell AM. Blood markers of fatty acids and vitamin D, cardiovascular measures, body mass index, and physical activity relate to longitudinal cortical thinning in normal aging. Neurobiol Aging. 2013 Nov 21.
19. Blondeau N, Pétrault O, Manta S, Giordanengo V, Gounon P, Bordet R, Lazdunski M, Heurteaux C. Polyunsaturated fatty acids are cerebral vasodilators via the TREK-1 potassium channel. Circ Res. 2007 Jul 20;101(2):176-84.
20. Sinn N., Howe P.R.C. Mental health benefits of omega-3 fatty acids may be mediated by improvements in cerebral vascular function. Biosci Hypotheses. 2008;1:103–8.
21. Tan ZS, Harris WS, Beiser AS, et al. Red blood cell omega-3 fatty acid levels and markers of accelerated brain aging. Neurology. 2012 Feb 28;78(9):658-64.
22. Pottala JV, Yaffe K, Robinson JG, Espeland MA, Wallace R, Harris WS. Higher RBC EPA + DHA corresponds with larger total brain and hippocampal volumes: WHIMS-MRI Study. Neurology. 2014 Jan 22.
23. Kang JX, Gleason ED. Omega-3 Fatty acids and hippocampal neurogenesis in depression. CNS Neurol Disord Drug Targets. 2013 Jun;12(4):460-5.
24. Perez MA, Terreros G, Dagnino-Subiabre A. Long-term omega-3 fatty acid supplementation induces anti-stress effects and improves learning in rats. Behav Brain Funct. 2013 Jun 14;9(1):25.
25. Jia D, Heng LJ, Yang RH, Gao GD. Fish oil improves learning impairments of diabetic rats by blocking PI3K/AKT/nuclear factor-kappaB-mediated inflammatory pathways. Neuroscience. 2013 Nov 16.
26. Freund-Levi Y, Eriksdotter-Jonhagen M, Cederholm T, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006 Oct;63(10):1402-8.
27. Thies F, Pillon C, Moliere P, Lagarde M, Lecerf J. Preferential incorporation of sn-2 lysoPC DHA over unesterified DHA in young rat brain. Am J Physiol. 1994 Nov;36: R1273–9.
28. Park HJ, Shim HS, Kim KS, et al. Enhanced learning and memory of normal young rats by repeated oral administration of Krill Phosphatidylserine. Nutr Neurosci. 2013 Mar;16(2):47-53.
29. Wibrand K, Berge K, Messaoudi M, et al. Enhanced cognitive function and antidepressant-like effects after krill oil supplementation in rats. Lipids Health Dis. 2013;12:6.
30. Konagai C, Yanagimoto K, Hayamizu K, Han L, Tsuji T, Koga Y. Effects of krill oil containing n-3 polyunsaturated fatty acids in phospholipid form on human brain function: a randomized controlled trial in healthy elderly volunteers. Clin Interv Aging. 2013;8:1247-57.
31. Hayakawa S, Yoshikawa D, Ishii H, et al. Association of plasma omega-3 to omega-6 polyunsaturated fatty acid ratio with complexity of coronary artery lesion. Intern Med. 2012;51(9):1009-14.
32. Huang T, Shou T, Cai N, Wahlqvist ML, Li D. Associations of plasma n-3 polyunsaturated fatty acids with blood pressure and cardiovascular risk factors among Chinese. Int J Food Sci Nutr. 2012 Sep;63(6):667-73.
33. Wu JH, Lemaitre RN, King IB, et al. Association of plasma phospholipid long-chain omega-3 fatty acids with incident atrial fibrillation in older adults: the cardiovascular health study. Circulation. 2012 Mar 6;125(9):1084-93.
34. Hara M, Sakata Y, Nakatani D, et al. Low levels of serum n-3 polyunsaturated fatty acids are associated with worse heart failure-free survival in patients after acute myocardial infarction. Circ J. 2013;77(1):153-62.
35. Jung SB, Kwon SK, Kwon M, et al. Docosahexaenoic acid improves vascular function via up-regulation of SIRT1 expression in endothelial cells. Biochem Biophys Res Commun. 2013 Jul 19;437(1):114-9.
36. Lluis L, Taltavull N, Munoz-Cortes M, et al. Protective effect of the omega-3 polyunsaturated fatty acids: Eicosapentaenoic acid/Docosahexaenoic acid 1:1 ratio on cardiovascular disease risk markers in rats. Lipids Health Dis. 2013;12(1):140.
37. Turgeon J, Dussault S, Maingrette F, et al. Fish oil-enriched diet protects against ischemia by improving angiogenesis, endothelial progenitor cell function and postnatal neovascularization. Atherosclerosis. 2013 Aug;229(2):295-303.
38. Younan SM, Rashed LA, Abd El Aziz OM. Cardioprotective modulation of cardiac adiponectin and adiponectin receptors by omega-3 in the high-fat fed rats. Chin J Physiol. 2013 Apr 30;56(2):65-76.
39. Hoshi T, Wissuwa B, Tian Y, et al. Omega-3 fatty acids lower blood pressure by directly activating large-conductance Ca(2)(+)-dependent K(+) channels. Proc Natl Acad Sci USA. 2013 Mar 19;110(12):4816-21.
40. Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial). Am J Cardiol. 2011 Sep 1;108(5):682-90.
41. Jacobson TA. A new pure omega-3 eicosapentaenoic acid ethyl ester (AMR101) for the management of hypertriglyceridemia: the MARINE trial. Expert Rev Cardiovasc Ther. 2012 Jun;10(6):687-95.
42. Tatsuno I, Saito Y, Kudou K, Ootake J. Efficacy and safety of TAK-085 compared with eicosapentaenoic acid in Japanese subjects with hypertriglyceridemia undergoing lifestyle modification: the omega-3 fatty acids randomized double-blind (ORD) study. J Clin Lipidol. 2013 May-Jun;7(3):199-207.
43. Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012 Oct 1;110(7):984-92.
44. Ballantyne CM, Braeckman RA, Soni PN. Icosapent ethyl for the treatment of hypertriglyceridemia. Expert Opin Pharmacother. 2013 Jul;14(10):1409-16.
45. Bays HE, Ballantyne CM, Braeckman RA, Stirtan WG, Soni PN. A new pure omega-3 eicosapentaenoic acid ethyl ester (AMR101) for the management of hypertriglyceridemia: the MARINE trial. Am J Cardiovasc Drugs. 2013 Feb;13(1):37-46.
46. Bozcali E, Babalik E, Himmetoglu S, Mihmanli I, Toprak S. omega-3 fatty acid treatment in cardiac syndrome X: a double-blind, randomized, placebo-controlled clinical study. Coron Artery Dis. 2013 Jun;24(4):328-33.
47. McEwen BJ, Morel-Kopp MC, Chen W, Tofler GH, Ward CM. Effects of omega-3 polyunsaturated fatty acids on platelet function in healthy subjects and subjects with cardiovascular disease. Semin Thromb Hemost. 2013 Feb;39(1):25-32.
48. Wong AT, Chan DC, Barrett PH, Adams LA, Watts GF. Supplementation with n3 fatty acid ethyl esters increases large and small artery elasticity in obese adults on a weight loss diet. J Nutr. 2013 Apr;143(4):437-41.
49. Available at: http://www.jlr.org/content/40/10/1867.long#ref-17. Accessed March 25, 2014.
50. Batetta B, Griinari M, Carta G, et al. Endocannabinoids may mediate the ability of (n-3) fatty acids to reduce ectopic fat and inflammatory mediators in obese Zucker rats. J Nutr. 2009 Aug;139(8):1495-501.
51. Flores A, Maldonado R, Berrendero F. Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far. Front Neurosci. 2013;7:256.
52. Karatsoreos IN, Thaler JP, Borgland SL, Champagne FA, Hurd YL, Hill MN. Food for thought: hormonal, experiential, and neural influences on feeding and obesity. J Neurosci. 2013 Nov 6;33(45):17610-6.
53. Piscitelli F, Carta G, Bisogno T, et al. Effect of dietary krill oil supplementation on the endocannabinoidome of metabolically relevant tissues from high-fat-fed mice. Nutr Metab (Lond). 2011;8(1):51.
54. Fosshaug LE, Berge RK, Beitnes JO, et al. Krill oil attenuates left ventricular dilatation after myocardial infarction in rats. Lipids Health Dis. 2011;10:245.
55. Ebrahimi M, Ghayour-Mobarhan M, Rezaiean S, et al. Omega-3 fatty acid supplements improve the cardiovascular risk profile of subjects with metabolic syndrome, including markers of inflammation and auto-immunity. Acta Cardiol. 2009 Jun;64(3):321-7.
56. Ludwig T, Worsch S, Heikenwalder M, Daniel H, Hauner H, Bader BL. Metabolic and immunomodulatory effects of n-3 fatty acids are different in mesenteric and epididymal adipose tissue of diet-induced obese mice. Am J Physiol Endocrinol Metab. 2013 Jun 1;304(11):E1140-56.
57. Derosa G, Cicero AF, Fogari E, et al. Effects of n-3 PUFAs on postprandial variation of metalloproteinases, and inflammatory and insulin resistance parameters in dyslipidemic patients: evaluation with euglycemic clamp and oral fat load. J Clin Lipidol. 2012 Nov-Dec;6(6):553-64.
58. Rafraf M, Mohammadi E, Asghari-Jafarabadi M, Farzadi L. Omega-3 fatty acids improve glucose metabolism without effects on obesity values and serum visfatin levels in women with polycystic ovary syndrome. J Am Coll Nutr. 2012 Oct;31(5):361-8.
59. Lamping KG, Nuno DW, Coppey LJ, et al. Modification of high saturated fat diet with n-3 polyunsaturated fat improves glucose intolerance and vascular dysfunction. Diabetes Obes Metab. 2013 Feb;15(2):144-52.
60. Lanza IR, Blachnio-Zabielska A, Johnson ML, et al. Influence of fish oil on skeletal muscle mitochondrial energetics and lipid metabolites during high-fat diet. Am J Physiol Endocrinol Metab. 2013 Jun 15;304(12):E1391-403.
61. Spencer M, Finlin BS, Unal R, et al. Omega-3 fatty acids reduce adipose tissue macrophages in human subjects with insulin resistance. Diabetes. 2013 May;62(5):1709-17.
62. Yan Y, Jiang W, Spinetti T, et al. Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity. 2013 Jun 27;38(6):1154-63.
63. Tikhonenko M, Lydic TA, Opreanu M, et al. N-3 polyunsaturated Fatty acids prevent diabetic retinopathy by inhibition of retinal vascular damage and enhanced endothelial progenitor cell reparative function. PLoS One. 2013;8(1):e55177.
64. Maki KC, Reeves MS, Farmer M, et al. Krill oil supplementation increases plasma concentrations of eicosapentaenoic and docosahexaenoic acids in overweight and obese men and women. Nutr Res. 2009 Sep;29(9):609-15.
65. Tandy S, Chung RW, Wat E, et al. Dietary krill oil supplementation reduces hepatic steatosis, glycemia, and hypercholesterolemia in high-fat-fed mice. J Agric Food Chem. 2009 Oct 14;57(19):9339-45.
66. Burri L, Berge K, Wibrand K, Berge RK, Barger JL. Differential effects of krill oil and fish oil on the hepatic transcriptome in mice. Front Genet. 2011;2:45.
67. Ferramosca A, Conte A, Burri L, et al. A krill oil supplemented diet suppresses hepatic steatosis in high-fat fed rats. PLoS One. 2012;7(6):e38797.
68. Sakaguchi K, Morita I, Murota S. Eicosapentaenoic acid inhibits bone loss due to ovariectomy in rats. Prostaglandins Leukot Essent Fatty Acids. 1994 Feb;50(2):81-4.
69. Kruger MC, Coetzer H, de Winter R, Gericke G, van Papendorp DH. Calcium, gamma-linolenic acid and eicosapentaenoic acid supplementation in senile osteoporosis. Aging (Milano). 1998 Oct;10(5):385-94.
70. Salari Sharif P, Asalforoush M, Ameri F, Larijani B, Abdollahi M. The effect of n-3 fatty acids on bone biomarkers in Iranian postmenopausal osteoporotic women: a randomized clinical trial. Age (Dordr). 2010 Jun;32(2):179-86.
71. Bonnet N, Ferrari SL. Effects of long-term supplementation with omega-3 fatty acids on longitudinal changes in bone mass and microstructure in mice. J Nutr Biochem. 2011 Jul;22(7):665-72.
72. Fernandes G, Lawrence R, Sun D. Protective role of n-3 lipids and soy protein in osteoporosis. Prostaglandins Leukot Essent Fatty Acids. 2003 Jun;68(6):361-72.
73. Sun D, Krishnan A, Zaman K, Lawrence R, Bhattacharya A, Fernandes G. Dietary n-3 fatty acids decrease osteoclastogenesis and loss of bone mass in ovariectomized mice. J Bone Miner Res. 2003 Jul;18(7):1206-16.
74. Bhattacharya A, Rahman M, Banu J, et al. Inhibition of osteoporosis in autoimmune disease prone MRL/Mpj-Fas(lpr) mice by N-3 fatty acids. J Am Coll Nutr. 2005 Jun;24(3):200-9.
75. Rahman MM, Bhattacharya A, Fernandes G. Docosahexaenoic acid is more potent inhibitor of osteoclast differentiation in RAW 264.7 cells than eicosapentaenoic acid. J Cell Physiol. 2008 Jan;214(1):201-9.
76. Rahman MM, Bhattacharya A, Banu J, Kang JX, Fernandes G. Endogenous n-3 fatty acids protect ovariectomy induced bone loss by attenuating osteoclastogenesis. J Cell Mol Med. 2009 Aug;13(8b):1833-44.
77. Li Y, Seifert MF, et al. Dietary conjugated linoleic acids alter serum IGF-I and IGF binding protein concentrations and reduce bone formation in rats fed (n-6) or (n-3) fatty acids. J Bone Miner Res. 1999 Jul;14(7):1153-62.
78. Baker KR, Matthan NR, Lichtenstein AH, et al. Association of plasma n-6 and n-3 polyunsaturated fatty acids with synovitis in the knee: the MOST study. Osteoarthritis Cartilage. 2012 May;20(5):382-7.
79. Gruenwald J, Petzold E, Busch R, Petzold HP, Graubaum HJ. Effect of glucosamine sulfate with or without omega-3 fatty acids in patients with osteoarthritis. Adv Ther. 2009 Sep;26(9):858-71.
80. Hutchins-Wiese HL, Kleppinger A, Annis K, et al. The impact of supplemental n-3 long chain polyunsaturated fatty acids and dietary antioxidants on physical performance in postmenopausal women. J Nutr Health Aging. 2013 Jan;17(1):76-80.
81. Wann AK, Mistry J, Blain EJ, Michael-Titus AT, Knight MM. Eicosapentaenoic acid and docosahexaenoic acid reduce interleukin-1beta-mediated cartilage degradation. Arthritis Res Ther. 2010;12(6):R207.
82. Knott L, Avery NC, Hollander AP, Tarlton JF. Regulation of osteoarthritis by omega-3 (n-3) polyunsaturated fatty acids in a naturally occurring model of disease. Osteoarthritis Cartilage. 2011 Sep;19(9):1150-7.
83. Corbee RJ, Barnier MM, van de Lest CH, Hazewinkel HA. The effect of dietary long-chain omega-3 fatty acid supplementation on owner’s perception of behaviour and locomotion in cats with naturally occurring osteoarthritis. J Anim Physiol Anim Nutr (Berl). 2012 Aug 11.
84. Moreau M, Troncy E, Del Castillo JR, Bedard C, Gauvin D, Lussier B. Effects of feeding a high omega-3 fatty acids diet in dogs with naturally occurring osteoarthritis. J Anim Physiol Anim Nutr (Berl). 2012 Jul 14.
85. Ierna M, Kerr A, Scales H, Berge K, Griinari M. Supplementation of diet with krill oil protects against experimental rheumatoid arthritis. BMC Musculoskelet Disord. 2010;11:136.
86. Deutsch L. Evaluation of the effect of Neptune Krill Oil on chronic inflammation and arthritic symptoms. J Am Coll Nutr. 2007 Feb;26(1):39-48.
87. Holub BJ. Clinical nutrition: 4. Omega-3 fatty acids in cardiovascular care. CMAJ. 2002 Mar 5;166(5):608-15.
88. Angerer P, von Schacky C. n-3 polyunsaturated fatty acids and the cardiovascular system. Curr Opin Lipidol. 2000 Feb;11(1):57-63.
89. Schmidt EB, Skou HA, Christensen JH, Dyerberg J. N-3 fatty acids from fish and coronary artery disease: implications for public health. Public Health Nutr. 2000 Mar;3(1):91-8.
90. Marik PE, Varon J. Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review. Clin Cardiol. 2009 Jul;32(7):365-72.
91. Pauwels EK, Kostkiewicz M. Fatty acid facts, Part III: Cardiovascular disease, or, a fish diet is not fishy. Drug News Perspect. 2008 Dec;21(10):552-61.
92. Pittet YK, Berger MM, Pluess TT, Voirol P, Revelly JP, Tappy L, Chioléro RL. Blunting the response to endotoxin in healthy subjects: effects of various doses of intravenous fish oil. Intensive Care Med. 2010 Feb;36(2):289-95.
93. Dewailly E, Blanchet C, Gingras S, Lemieux S, Holub BJ. Fish consumption and blood lipids in three ethnic groups of Quebec (Canada). Lipids. 2003 Apr;38(4):359-65.
94. Albert CM, Campos H, Stampfer MJ, et al. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med. 2002 Apr 11;346(15):1113-8.
95. Harris WS, Von Schacky C. The Omega-3 Index: a new risk factor for death from coronary heart disease? Prev Med. 2004 Jul;39(1):212-20.111
96. von Schacky C, Harris WS. Cardiovascular benefits of omega-3 fatty acids. Cardiovasc Res. 2007 Jan 15;73(2):310-5.
97. Lemaitre RN, King IB, Mozaffarian D, Kuller LH, Tracy RP, Siscovick DS. n-3. Polyunsaturated fatty acids, fatal ischemic heart disease, and nonfatal myocardial infarction in older adults: the Cardiovascular Health Study. Am J Clin Nutr. 2003 Feb;77(2):319-25.
98. Zong G, Ye X, et al. Associations of erythrocyte palmitoleic acid with adipokines, inflammatory markers, and the metabolic syndrome in middle-aged and older Chinese. Am J Clin Nutr. 2012 Nov;96(5):970-6.
99. Kurotani K, Sato M, et al. High levels of stearic acid, palmitoleic acid, and dihomo-linolenic acid and low levels of linoleic acid in serum cholesterol ester are associated with high insulin resistance. Nutr Res. 2012 Sep;32(9):669-675.e3.