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Negative Effects of Omega-3 Fatty Acids; EPA, DHA. March 4, 2012 at 11:25pm What is Fish Oil?

Fish oil (Omega 3 fatty acids) are produced out of the flesh of oily fish. Fish do not in fact generate omega-3 fatty acids. Instead they build up omega-3 in two ways: Either from eating micro algae which create essential fatty acids (with fish such as sardines and herrings) or else from eating larger pelagic and predatory fish which themselves have built up omega-3 fatty acids through eating micro-algae. Fish Oil consists of the omega-3 fatty acids, eicosapentaenoic acid (EPA), as well as docosahexaenoic acid (DHA). Fish Oil. Pharmacy Direct. Retrieved 1996-2012 ======================// Understanding the Relationship of Fats. To understand the present issues regarding fats in nutrition and medicine it's helpful to look at the historical development of biochemical and physiological fat research in a variety of contexts, including agriculture and economics, as well as considering the effects of the changing ideas about cell structure, vitamins, hormones, immunology, brain development, and the growing understanding of the way physiology interacts with ecology. We need to recognize the complexity of the physiology of fats, to appreciate the complexity of the living organism. If you've been following the Mainstream Media or reading biased Medical Journals, it's easy to get the idea that fish oil is something any sensible healthy person should use. It's rare to see anything suggesting that it could be dangerous. The FDA has gone from warning against the consumption of too much of these omega-3 oils to sponsoring biased industry claims, there has been considerable accumulation of information about the dangers of fish oils and omega-3 fatty acids. The reason linseed oil and fish oil were used for making varnishes and paints was that they are drying oils, reacting with oxygen to polymerize and harden. The physical and chemical properties of the oils are fairly well understood, and among the polyunsaturated fatty acids (PUFA) the omega -3 fatty acids react most easily with oxygen. Heat, light, and moisture increase their spontaneous interactions with oxygen, and besides polymerizing, these oils produce a variety of reactive particles, including acrolein, which combine with other substances, such as cellular proteins and DNA, with highly toxic effects. At low temperatures and low oxygen concentrations these oils are not highly reactive. Fats that harden at low temperatures (as saturated fats do) wouldn't be convenient for organisms that live in a cool environment, and so organisms regulate the type of fat they synthesize according to the temperature of their tissues. The fact that certain types of polyunsaturated fatty acids function nicely in fish, worms, and insects, doesn't mean that they are ideal fats for mammals. Another way of arguing for the use of fish oil or other omega-3 fats is to show a correlation between disease and a decreased amount of EPA, DHA, or arachidonic acid in the tissues, and to say "these oils are deficient, the disease is caused by a deficiency of essential fatty acids." Those oils are extremely susceptible to oxidation, so they tend to spontaneously disappear in response to tissue injury, cellular excitation, the increased energy demands of stress, exposure to toxins or ionizing radiation, or even exposure to light. That spontaneous oxidation is what made them useful as varnish or paint medium. But it is what makes them sensitize the tissues to injury. Their "deficiency" in the tissues frequently

corresponds to the intensity of oxidative stress and lipid peroxidation; it is usually their presence, rather than their deficiency, that created the disposition for the disease. Ultimately, all systems of the body are harmed by an excess of omega - 3. There are two reasons for this. One is that the plants produce omega - 3 for protection, not only to store energy for the germination of the seed; To defend the seeds from animals, the oils block the digestive enzymes in the stomach. Digestion is one of our most basic functions, and evolution has built many other systems by using variations of that system; as a result, all of these systems are damaged by the substances which damage the digestive system. The other reason is that the seeds are designed to germinate in early spring, so their energy stores must be accessible when the temperatures are cool, and they normally don't have to remain viable through the hot summer months. Unsaturated oils are liquid when they are cold, and this is necessary for any organism that lives at low temperatures. For example, fish in cold water would be stiff if they contained saturated fats. Omega - 3 oils easily go rancid (spontaneously oxidize) when they are warm and exposed to oxygen. Seeds contain a small amount of vitamin E to delay rancidity. When the oils are stored in our tissues, they are much warmer, and more directly exposed to oxygen, than they would be in the seeds, and so their tendency to oxidize is greatly increased. These oxidation processes can damage enzymes and other parts of cells, and especially their ability to produce energy. ===========================================// Major Negative Effect of Supplementing Fish Oil Long Term. (over 2 weeks) Fish Oil inhibits NF-kb which in the long term causes Cancer, Inflammatory and Autoimmune Diseases, Septic Shock, Viral Infection, improper Immunity Development, Synaptic Plasticity and Memory Loss. The observable short term benefits of consuming Fish Oil are due to the activation of PPARa, which promotes fat loss due to nutrient deficient Ketogenic Pathways which normally activate under conditions of energy deprivation and malnourishment. NF-kB Inhibitors should only be used short term when treating patients with cancer due to its ability to increase the effectiveness of Chemotherapy, as it disables the cells ability to defend itself. Additionally, most viruses inhibit NF-kb to either enhance replication or contribute to viral pathogenicity. NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls the transcription of DNA. NF-B is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-B plays a key role in regulating the immune response to infection (kappa light chains are critical components of immunoglobulins). Incorrect regulation of NF-kappaB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-kappaB has also been implicated in processes of synaptic plasticity and memory. ( NF-B is important in regulating cellular responses because it belongs to the category of "rapid-acting" primary transcription factors, i.e., transcription factors that are present in cells in an inactive state and do not require new protein synthesis to be activated (other members of this family include transcription factors such as c-Jun, STATs, and nuclear hormone receptors). This allows NF-B to be a first responder to harmful cellular stimuli. Known inducers of NF-B activity are highly variable and include reactive oxygen species (ROS), tumor necrosis factor alpha (TNF), interleukin 1-beta (IL-1), bacterial lipopolysaccharides (LPS), isoproterenol, cocaine, and ionizing radiation. ( =====================//

Studies of NF-kB Inhibition and Fish Oil Redox Rep. 2002;7(6):369-78.Inhibition of leukocyte-endothelial interactions by oxidized omega-3 fatty acids: a novel mechanism for the anti-inflammatory effects of omega-3 fatty acids in fish oil. Sethi S. Oxidation of EPA and its activation of PPARalpha and subsequent inhibition of NF-kappaB is the underlying mechanism for the beneficial effects of fish oil. Arterioscler Thromb Vasc Biol. 2004 Sep;24(9):1621-7. Epub 2004 Jul 1.Oxidized omega-3 fatty acids inhibit NF-kappaB activation via a PPARalpha-dependent pathway. Mishra A, Chaudhary A, Sethi S. These studies show that the antiinflammatory effects of fish oil may result from the inhibitory effects of oxidized omega-3 fatty acids on NF-kappaB activation via a PPARalpha-dependent pathway. NATURE|Vol 441|25 May 2006|doi:10.1038/nature04870. Nuclear factor-B in cancer development and progression. NF-B inhibitors are more likely to be of use in cancer therapy, in which they can be administered intermittently for shorter durations, thereby avoiding immunosuppression associated with long-term inhibition. Although, in some cases, NF-B inhibition contributes to tumour development, the most likely outcome of its inhibition in existing tumours is increased cancer cell apoptosis. Trends in Neuroscience Volume 20, Issue 6, 1 June 1997, Pages 252258. doi:10.1016/S01662236(96)01035-1. NF-kB: a crucial transcription factor for glial and neuronal cell function. NF-kB is one of the best-characterized transcription factors. It is expressed ubiquitously and regulates the expression of many genes, most of which encode proteins that play an important and often determining role in the processes of immunity and inflammation... NF-kB is involved in brain function, particularly following injury and in neurodegenerative conditions such as Alzheimer's disease ... NF-kB can therefore be considered as one of the most important transcription factors characterized in brain to date and it might be as crucial for neuronal and glial cell function as it is for immune cells. J Mol Med. 2008 July; 86(7): 747759. Published online 2008 February 2. doi: 10.1007/s00109-0080308-4 NF-B signaling in skeletal muscle: prospects for intervention in muscle diseases J Clin Invest. 2001;107(2):135142. doi:10.1172/JCI11914. Blocking the NF-B pathway by the IB super-repressor enhances the sensitivity of cells to apoptosis-inducing stimuli. For example, TNF- treatment of cells induces the NF-B pathway and results in cellular apoptosis. Since NF-B protects cells from undergoing apoptosis, blocking this pathway enhances apoptosis. Thus, NF-B has an important role in the regulation of cellular proliferation, and inhibition of the NF-B pathway may enhance the efficacy of cancer chemotherapy. J Clin Invest. 2001;107(2):143151. doi:10.1172/JCI11918. Hostile takeovers: viral appropriation of the NF-kB pathway. viral proteins inhibit NF-kB activity and either enhance replication or contribute to viral pathogenicity. Many viruses have evolved mechanisms to target the NF-kB pathway to facilitate their replication, cell survival, and evasion of immune responses. Clin Chem. 1999 Jan;45(1):7-17. New Insights into the Role of Nuclear Factor-B, a Ubiquitous Transcription Factor in the Initiation of Diseases. a complete and persistent blockage of NF-B activation will lead to immune deficiencies and the apoptosis of healthy cells. ===================// Most common Fish Oil "Benefits:" Promotes Cardiovascular Health & Protects Against Heart Attack and Stroke.

Reduces Inflammation/Pain and Promotes Healthy Joints. Supports Mental Focus & Long-Term Cognitive Function. Supports Positive Mood & Emotional Well-being. Promotes Eye Health. Pregnancy, Infant Brain/Eye Development & Less Incidence of Childhood Disorders. Promotes Optimal Fat Metabolism. Lowers Risk of Prostate, Breast & Colorectal Cancer; Diabetes. I am going to take us through each of these "benefits" and offer another look into the research. =============================================// Promotes Cardiovascular Health & Protects Against Heart Attack and Stroke. Daily treatment for 5 years with n3 fatty acids did not reduce cardiovascular mortality and morbidity. N Engl J Med 2013; 368:1800-1808 May 9, 2013 DOI: 10.1056/NEJMoa1205409 n3 Fatty Acids in Patients with Multiple Cardiovascular Risk Factors. Of the 12,513 patients enrolled, 6244 were randomly assigned to n3 fatty acids and 6269 to placebo. With a median of 5 years of follow-up, the primary end point occurred in 1478 of 12,505 patients included in the analysis (11.8%), of whom 733 of 6239 (11.7%) had received n3 fatty acids and 745 of 6266 (11.9%) had received placebo (adjusted hazard ratio with n3 fatty acids, 0.97; 95% confidence interval, 0.88 to 1.08; P=0.58). The same null results were observed for all the secondary end points. In a large general-practice cohort of patients with multiple cardiovascular risk factors, daily treatment with n3 fatty acids did not reduce cardiovascular mortality and morbidity. Consumption of excess polyunsaturated fatty acids likely underlie the persistent national burden of heart disease. Am J Cardiovasc Dis 2013;3(1):17-26. Interaction between sphingomyelin and oxysterols contributes to ath-erosclerosis and sudden death. Fred A Kummerow. By increasing the ratio of thromboxane to prostacyclin, these factors interact to interrupt blood flow, thereby contributing to heart attack and sudden death. Levels of oxysterols and OxLDL increase primarily as a result of three diet or lifestyle factors: the consumption of oxysterols from commercially fried foods such as fried chicken, fish, and french fries; oxidation of cholesterol in vivo driven by consumption of excess polyunsaturated fatty acids from vegetable oils; and cigarette smoking. Along with the consumption of trans fatty acids from partially hydrogenated vegetable oil, these diet and lifestyle factors likely underlie the persistent national burden of heart disease.
Fish Oil contributes to the highest amount of oxidative stress in heart mitochondria. Mitochondrion. 2011 Jan;11(1):97-103. Epub 2010 Aug 5. Dietary fatty acids and oxidative stress in the heart mitochondria. Lemieux H, Bulteau AL, Friguet B, Tardif JC, Blier PU. Our study compared the effects of different oils on oxidative stress in rat heart mitochondria, as well as on plasma parameters used as risk factors for cardiovascular disease. The rats were fed for 16 weeks with coconut, olive, or fish oil diet (saturated, monounsaturated, or polyunsaturated fatty acids, respectively). The cardiac mitochondria from rats fed with coconut oil showed the lowest concentration of oxidized proteins and peroxidized lipids. The fish oil diet leads to the highest oxidative stress in cardiac mitochondria, an effect that could be partly prevented by the antioxidant probucol. Total and LDL cholesterols decreased in plasma of rats fed fish oil, compared to olive and coconut oils fed rats. A diet enriched in saturated fatty acids offers strong advantages for the protection against oxidative stress in heart mitochondria. Reduced Physical Endurance by 50%. Lipids. 1997 Dec;32(12):1265-70. Dietary fatty acid profile affects endurance in rats. Ayre KJ, Hulbert AJ. "The diets comprised an essential fatty acid-deficient diet (containing mainly saturated fatty acids); a diet high in n-6 fatty acids, High n-6; and a diet enriched with n-3 fatty acids, High n-3. Submaximal endurance in rats fed the High n-3 diet was 44% less than in rats fed the High n-6 diet (P <

0.02). All rats were then fed a standard commercial laboratory diet for a 6-wk recovery period, and their performances were reevaluated. Although endurance in all groups was lower then at 9 wk, it was again significantly 50% lower in the High n-3 group than the High n-6 group (P < 0.005). Although n-3 fats are considered beneficial for cardiovascular health, they appear to reduce endurance times, and their side effects need to be further investigated."
Increase in Blood Glucose by 22%. Ann Intern Med. 1988 May;108(5):663-8. Adverse metabolic effect of omega-3 fatty acids in noninsulin-dependent diabetes mellitus. Glauber H, Wallace P, Griver K, Brechtel G. "Increased interest in using omega-3 fatty acids led us to examine their metabolic effects in six men with type II (non-insulindependent) diabetes mellitus. After 1 month of a diet supplemented with these fatty acids, the patients' fasting glucose rose from 13.1 +/- 1.3 to 15.3 +/- 1.3 mmol/L (P = 0.03) and glucose area during a mixed meal profile rose by 22% (P = 0.04). Basal hepatic glucose output rose from 97 +/- 9 to 122 +/- 8 mg/m2 . min (P = 0.004) but glucose disposal rates measured by euglycemic glucose clamp were unchanged. Fasting insulin levels were similar; peak insulin levels stimulated by meals or intravenous glucagon fell by 30% and 39%, respectively. Plasma and erythrocyte content of omega-3 fatty acid rose significantly. After omega-3 fatty acid withdrawal, fasting glucose returned to baseline. Omega-3 fatty acid treatment in type II diabetes leads to rapid but reversible metabolic deterioration, with elevated basal hepatic glucose output and impaired insulin secretion but unchanged glucose disposal rates. Caution should be used when recommending omega-3 fatty acids in type II diabetic persons."

Permeability (Damage) to the Intestinal Epithelium (Bowel Capillaries) increased by 20 - 60%. Clin Nutr. 2001 Aug;20(4):351-9. Effect of eicosapentaenoic acid (EPA) on tight junction permeability in intestinal monolayer cells. Usami M, Muraki K, Iwamoto M, Ohata A, Matsushita E, Miki A. "Caco-2 cells formed polarized columnar epithelial cells with densely packed microvilli and well developed junctional complexes. Addition of EPA enhanced FS permeability to 3.0+/-1.6-fold and lowered TEER to 0.59+/-1.2-fold vs. control with concentration dependency without cell injury (P

=================================// Reduces Inflammation/Pain and Promotes Healthy Joints.

Lipid Peroxidation triggers Inflammation in Cell Membranes, Disrupting the Antioxidant System. J Nutr. 2000 Dec;130(12):3028-33. Polyunsaturated (n-3) fatty acids susceptible to peroxidation are increased in plasma and tissue lipids of rats fed docosahexaenoic acid-containing oils. Song JH, Fujimoto K, Miyazawa T. "Docosahexaenoic acid [DHA, 22:6(n-3)], a major component of membrane phospholipids in brain and retina, is profoundly susceptible to oxidative stress in vitro. The extent of this peroxidation in organs when DHA is ingested in mammals, however, is not well elucidated. We investigated the effect of dietary DHA-containing oils (DHA 7.0-7.1 mol/100 mol total fatty acids), in the form of triacylglycerols (TG), ethyl esters (EE) and phospholipids (PL), on tissue lipid metabolism and lipid peroxidation in rats. Groups of Sprague-Dawley rats were fed semipurified diets containing 15 g/100 g test oils and were compared with those fed 80% palm oil and 20% soybean oil as the control (unsupplemented group) for 3 wk. The DHA oil diets markedly increased (P: < 0.05) the levels of DHA in the plasma, liver and kidney, 1.5-1.9, 2.5-3.8 and 2.2-2.5 times the control values, respectively, whereas there was a concomitant reduction (P: < 0.05) in arachidonic acid. All forms of DHA oil caused lower TG concentrations in plasma (P: < 0.05) and liver (P: < 0.05), but had no effect in kidney. The DHA oil-fed rats had greater phospholipid hydroperoxide accumulations in plasma (191-192% of control rats), liver (170-230%) and kidney (250-340%), whereas the alpha-tocopherol level was reduced concomitantly (21-73% of control rats). Consistent with these results, rats fed DHA-containing oils had more thiobarbituric reactive substances in these organs than the controls. Thus, high incorporation of (n-3) fatty acids (mainly DHA) into plasma and tissue lipids due to DHA-containing oil ingestion may

undesirably affect tissues by enhancing susceptibility of membranes to lipid peroxidation and by disrupting the antioxidant system." Kidney Inflammation increased by 85%. J Immunol. 1989 Nov 15;143(10):3192-9. The antiinflammatory effects of essential fatty acid deficiency in experimental glomerulonephritis. The modulation of macrophage migration and eicosanoid metabolism. Schreiner GF, Rovin B, Lefkowith JB. "Dietary polyunsaturated fatty acid modulation exerts a beneficial effect in immune-mediated glomerulonephritis. To elucidate the mechanisms underlying this phenomenon, the effects of essential fatty acid (EFA) deficiency on the heterologous phase of nephrotoxic nephritis in rats (induced by the injection of a rabbit antiglomerular basement membrane antibody) were studied. The heterologous phase of nephrotoxic nephritis was characterized by an invasion of leukocytes into the glomerulus. Polymorphonuclear neutrophils predominated early on (3 h), whereas macrophages predominated at 24 and 72 h. EFA deficiency selectively prevented the influx of macrophages into the glomerulus. The invasion of polymorphonuclear neutrophils, in contrast, was unaffected. The influx of leukocytes into the glomerulus during nephritis was accompanied by a marked enhancement (10- to 40-fold) in glomerular thromboxane and leukotriene B4 production. EFA deficiency largely attenuated this change. Renal dysfunction during the heterologous phase of nephritis was manifested as azotemia, polyuria, sodium retention, and proteinuria. With EFA deficiency, polyuria, azotemia, and sodium retention were not seen. Proteinuria was reduced by approximately 85%. To address whether the lack of macrophage migration into the glomerulus in the context of nephritis with EFA deficiency might be due to a functional defect in macrophage migration, the chemotactic responsiveness of EFA-deficient macrophages was examined. EFA-deficient macrophages displayed normal chemotactic migration toward activated C. In sum, EFA deficiency prevents the invasion of macrophages into the glomerulus in nephrotoxic nephritis and attenuates the accompanying metabolic and functional alterations, but does not affect macrophage chemotactic responsiveness. Alterations in macrophage elicitation and lipid mediator generation by inflamed glomeruli thus appear to be central to the salutary effect of dietary polyunsaturated fatty acid modification on glomerulonephritis." =======Combined due to overlapping research=======// Supports Mental Focus & Long-Term Cognitive Function & Supports Positive Mood & Emotional Well-being. No Beneficial Effects on Mood and Cognitive Function. Br J Nutr. 2008 Feb;99(2):421-31. Epub 2007 Oct 24. No effect of n-3 long-chain polyunsaturated fatty acid (EPA and DHA) supplementation on depressed mood and cognitive function: a randomised controlled trial. Rogers PJ, Appleton KM, Kessler D, Peters TJ, Gunnell D, Hayward RC, Heatherley SV, Christian LM, McNaughton SA, Ness AR. "Low dietary intakes of the n-3 long-chain PUFA (LCPUFA) EPA and DHA are thought to be associated with increased risk for a variety of adverse outcomes, including some psychiatric disorders. Evidence from observational and intervention studies for a role of n-3 LCPUFA in depression is mixed, with some support for a benefit of EPA and/or DHA in major depressive illness. The present study was a double-blind randomised controlled trial that evaluated the effects of EPA+DHA supplementation (1.5 g/d) on mood and cognitive function in mild to moderately depressed individuals. Of 218 participants who entered the trial, 190 completed the planned 12 weeks intervention. Compliance, confirmed by plasma fatty acid concentrations, was good, but there was no evidence of a difference between supplemented and placebo groups in the primary outcome namely, the depression subscale of the Depression Anxiety and Stress Scales at 12 weeks. Mean depression score was 8.4 for the EPA+DHA group and 9.6 for the placebo group, with an adjusted difference of - 1.0 (95 % CI - 2.8, 0.8; P = 0.27). Other measures of mood, mental health and cognitive function, including Beck Depression Inventory score and attentional bias toward threat words, were similarly little affected by the intervention. In conclusion, substantially increasing EPA+DHA intake for 3

months was found not to have beneficial or harmful effects on mood in mild to moderate depression. Adding the present result to a meta-analysis of previous relevant randomised controlled trial results confirmed an overall negligible benefit of n-3 LCPUFA supplementation for depressed mood."
No Increase in Cognitive Function; Placebo Proved more Beneficial. Exp Clin Psychopharmacol. 2012 Jan 16. Omega-3 polyunsaturated fatty acids and cognition in a college-aged population. Karr JE, Grindstaff TR, Alexander JE. "The cognitive influences of omega-3 polyunsaturated fatty acids (n-3 PUFA) remain unclear throughout the life span. Dietary n-3 PUFA appear cognitively beneficial prenatally and neuroprotective at later age; however, researchers using supplementation designs have reported disparate findings across age groups. Few studies have examined the cognitive impact of n-3 PUFA during young adulthood. This study assessed the cognitive effects of fish oil supplementation at college age, hypothesizing benefits on affect, executive control, inhibition, and verbal learning and memory. College-aged participants were assigned to active (n = 20, 5 men; xage = 19.9, sage = 1.8) or placebo (n = 21, 7 men; xage = 20.4, sage = 1.6) treatments, receiving fish oil (480 mg DHA/720 mg EPA), respectively. Both groups completed four weeks of supplementation. At baseline and posttreatment, the researchers administered the Rey Auditory Verbal Learning Test (RAVLT; Lezak, 1995), Stroop Color and Word Test (SCWT; Golden & Freshwater, 2002), Trail Making Test (TMT; Corrigan & Hinkeldey, 1987; Gaudino, Geisler, & Squires, 1995; Lezak, 1995), and Positive and Negative Affect Schedule (PANAS; Watson, Clark, & Tellegen, 1988). Repeated-measures ANOVAs indicated no benefits of fish oil on the SCWT, RAVLT Stages 1 to 5, or PANAS. An interaction occurred between condition and time of measurement (i.e., baseline and posttreatment) on RAVLT Stages 6 and 7, and placebo significantly improved TMT performance over fish oil. The benefits of n-3 PUFA on RAVLT performance derived more from depreciated placebo performance than improved performance due to fish oil. The placebo gain on TMT performance likely derived from a learning effect. Together, these results present limited cognitive benefits of n-3 PUFA at college age; however, the treatment may have been subtherapeutic, with a larger sample needed to generalize these results."

No Beneficial Effect on Mental Well-being. Am J Clin Nutr. 2008 Sep;88(3):706-13. Effect of fish-oil supplementation on mental well-being in older subjects: a randomized, double-blind, placebo-controlled trial. van de Rest O, Geleijnse JM, Kok FJ, van Staveren WA, Hoefnagels WH, Beekman AT, de Groot LC. "Plasma concentrations of EPA+DHA increased by 238% in the high-dose and 51% in the low-dose fish-oil group compared with the placebo group, reflecting excellent compliance. Baseline CES-D scores ranged from 5.9 to 6.8 in the 3 groups and were not significantly different between groups. Mean changes in CES-D scores after 26 wk were -0.2, 0.2, and -0.4 (P = 0.87) in the high-dose fish oil, low-dose fish oil, and placebo groups, respectively. Treatment with neither 1800 mg nor 400 mg EPA+DHA differentially affected any of the measures of mental well-being after 13 or 26 wk of intervention compared with placebo. In this randomized, double-blind, placebo-controlled trial we observed no effect of EPA+DHA supplementation for 26 wk on mental well-being in the general older population studied. This trial was registered at as NCT00124852."
Increased Depressive Behavior; No Effect on Cognition and Mood. J Psychopharmacol. 2009 Sep;23(7):831-40. Epub 2008 Jun 26. Omega-3 fatty acids (fish-oil) and depression-related cognition in healthy volunteers. Antypa N, Van der Does AJ, Smelt AH, Rogers RD. "Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation may be beneficial in the treatment of several psychiatric disorders, including depression. A small number of studies have suggested that there may also be cognitive and mood effects in healthy samples. The purpose of the present study was to investigate the effects of n-3 PUFA on depression-relevant cognitive functioning in healthy individuals. Fifty-four healthy university students were randomized to receive either n-3 PUFA supplements or placebo for 4 weeks in a double-blind design. The test battery included measures of cognitive reactivity, attention, response inhibition, facial emotion recognition, memory and risky decision-making. Results

showed few effects of n-3 PUFAs on cognition and mood states. The n-3 PUFA group made fewer riskaverse decisions than the placebo group. This difference appeared only in non-normative trials of the decision-making test, and was not accompanied by increased impulsiveness. N-3 PUFAs improved scores on the control/perfectionism scale of the cognitive reactivity measure. No effects were found on the other cognitive tasks and no consistent effects on mood were observed. The present findings indicate that n-3 PUFA supplementation may have a selective effect on risky decision making in healthy volunteers, which is unrelated to impulsiveness."
No Beneficial Influence on the Quality of Life. J Am Geriatr Soc. 2009 Aug;57(8):1481-6. Epub 2009 Jun 22. Effect of fish oil supplementation on quality of life in a general population of older Dutch subjects: a randomized, double-blind, placebocontrolled trial. van de Rest O, Geleijnse JM, Kok FJ, van Staveren WA, Olderikkert MG, Beekman AT, de Groot LC. "Mean age of the participants was 70, and 55% were male. Plasma concentrations of EPADHA increased 238% in the high-dose and 51% in the low-dose EPA-DHA group, reflecting excellent adherence. Median baseline total WHOQOL scores ranged from 107 to 110 in the three groups and were not significantly different from each other. After 26 weeks, the mean difference from placebo was -1.42 (95% confidence interval (CI)=-3.40-0.57) for the high-dose and 0.02 (95% CI=-1.95-1.99) for the lowdose fish oil group. Treatment with 1,800 mg or 400 mg EPA-DHA did not affect total QOL or any of the separate domains after 13 or 26 weeks of intervention. Supplementation with high or low doses of fish oil for 26 weeks did not influence the QOL of healthy older individuals."

Brain Edema (Swelling). J Neurochem. 1980 Oct;35(4):1004-7. Transient formation of superoxide radicals in polyunsaturated fatty acid-induced brain swelling. Chan PH, Fishman RA. "The involvement of superoxide free radicals and lipid peroxidation in brain swelling induced by free fatty acids has been studied in brain slices and homogenates. The polyunsaturated fatty acids linoleic acid (18:2), linolenic acid (18:3), arachidonic acid (20:4), and docosahexaenoic acid (22:6) caused brain swelling concomitant with increases in superoxide and membrane lipid peroxidation. Palmitic acid (16:0) and oleic acid (18:1) had no such effect. Furthermore, superoxide formation was stimulated by NADPH and scavenged by the addition of exogenous superoxide dismutase in cortical slice homogenates. These in vitro data support the hypothesis that both superoxide radicals and lipid peroxidation are involved in the mechanism of polyunsaturated fatty acid-induced brain edema." Edema (Swelling) in Brain Cortex. Science. 1978 Jul 28;201(4353):358-60. Brain edema: induction in cortical slices by polyunsaturated fatty acids. Chan PH, Fishman RA. "The presence of polyunsaturated and saturated fatty acids in leukocytic membranes prompted study of their possible role in the induction of brain edema. Polyunsaturated fatty acids including sodium arachidonate, sodium linoleate, sodium linolenate, and docasahexaenoic acids induced edema in slices of rat brain cortex. This cellular edema was specific, since neither saturated fatty acids nor a fatty acid containing a single double bond had such effect."

================= Promotes Eye Health.

Increased Microvascular Retina Damage by 75%. Diabetologia. 1996 Mar;39(3):251-5. Acceleration of experimental diabetic retinopathy in the rat by omega-3 fatty acids. Hammes HP, Weiss A, Fhrer D, Krmer HJ, Papavassilis C, Grimminger F. "Omega-3 fatty acids exert several important biological effects on factors that may predispose to diabetic retinopathy. Potential pathogenetic mechanisms include platelet dysfunction, altered eicosanoid production, increased blood viscosity in association with impaired cell deformability and pathologic

leucocyte/endothelium interaction. Therefore, we tested whether a 6-month administration of fish oil (750 mg Maxepa, 5 times per week), containing 14% eicosapentaenoic acid (EPA) and 10% docosahexaenic acid, could inhibit the development of experimental retinopathy of the streptozotocin-diabetic rat. The efficiency of fish oil supplementation was evaluated by measuring EPA concentrations in total, plasma and membrane fatty acids and by measuring the generation of lipid mediators (leukotrienes and thromboxanes). Retinal digest preparations were quantitatively analysed for pericyte loss, and the formation of acellular capillaries. Omega-3 fatty acid administration to diabetic rats resulted in a twofold increase of EPA 20:5 in total fatty acids, and a reduction of the thromboxane ratio from 600 (untreated diabetic rats) to 50 (treated diabetic rats). Despite these biochemical changes, diabetes-associated pericyte loss remained unaffected and the formation of acellular, occluded capillaries was increased by 75% in the fish oil treated diabetic group (115.1 +/- 26.8; untreated diabetic 65.2 +/- 15.0 acellular capillary segments/mm2 of retinal area). We conclude from this study that dietary fish oil supplementation may be harmful for the diabetic microvasculature in the retina." ===================================================// Pregnancy, Infant Brain/Eye Development & Less Incidence of Childhood Disorders.
Increased Risk of Atopy (Immediate Allergy) in Breastfed Infants. Clin Exp Allergy. 2004 Feb;34(2):194-200. Maternal breast milk long-chain n-3 fatty acids are associated with increased risk of atopy in breastfed infants. Stoney RM, Woods RK, Hosking CS, Hill DJ, Abramson MJ, Thien FC. "For infants sensitized to foods at 6 months (n=29), the total n-3 FA level in the colostrum was significantly higher (P=0.004) as were levels of individual long-chain n-3 FAs, docosoapentaenoic acid (DPA, C22:5, P=0.001) and docosahexaenoic acid (DHA, C22:6, P=0.002) than in non-sensitized infants. Infants with aero-allergen sensitization at 24 months (n=30) had higher levels of the n-3 FA, DPA (P=0.002) and DHA (P=0.007), and similarly higher total n-3 FA (P=0.009) in maternal colostrum than those infants who were not sensitized. Higher n-3 FA levels in the colostrum do not appear to confer protection against, but may be a risk factor for, the eventual development of atopy in high-risk breastfed infants." Increased Spleen and Liver Toxicity due, with No effect on Brain Development. J Anim Sci. 1984 Apr;58(4):971-8. Essential fatty acid status and characteristics associated with colostrum-deprived gnotobiotic and conventional lambs. Growth, organ development, cell membrane integrity and factors associated with lower bowel function. Bruckner G, Grunewald KK, Tucker RE, Mitchell GE Jr. "A factorial experiment involving gnotobiotic (GN) and conventional (CV) colostrum-deprived lambs and diets formulated to be adequate or deficient in linoleic acid was conducted to determine the effect(s) of the intestinal microflora on the essential fatty acid (EFA) status of the host and subsequent physiological consequences, i.e., growth, organ development, cell membrane integrity and lower bowel function. Lambs were obtained by sterile surgical procedures and housed in sterile isolators or in conventional metabolism stalls for 60 d. Skimmed cow's milk with 6% hydrogenated coconut oil and vitamins A, D and E added with and without .32% of the total calories as linoleic acid was homogenized, bottled and autoclaved, then fed to appetite three to four times daily. The GN lambs supplemented with linoleic acid gained significantly faster between 13 and 41 d of age and more efficiently between 27 and 41 d than the other treatment groups. The absence of dietary linoleic acid decreased liver and spleen weights and, in general, suppressed development of organs except the brain. Red blood cell hemolysis was not affected by treatment. Although showing signs of chronic mild diarrhea, the GN neonatal ruminant differed in Cl- concentration and dry matter percentage of its lower bowel contents from the "classic rodent model." The results indicate that neonatal colostrum-deprived lambs have an EFA requirement, as evidenced by decreased growth and performance characteristics in the GN linoleic deficient vs GN supplemented group, and suggests that the required level is in excess of .32% of the total caloric intake as linoleic acid."

Decreased Immune System Activation. Am J Clin Nutr. 2004 Apr;79(4):674-81. Effects of oils rich in eicosapentaenoic and docosahexaenoic acids on immune cell composition and function in healthy humans. Kew S, Mesa MD, Tricon S, Buckley R, Minihane AM, Yaqoob P. "The fatty acid composition of plasma phospholipids and neutrophils was dramatically altered by supplementation with EPA or DHA, and the effects of EPA differed notably from those of DHA. DHA supplementation decreased T lymphocyte activation, as assessed by expression of CD69, whereas EPA supplementation had no significant effect. Neither the EPA-rich oil nor the DHA-rich oil had any significant effect on monocyte or neutrophil phagocytosis or on cytokine production or adhesion molecule expression by peripheral blood mononuclear cells. Supplementation with DHA, but not with EPA, suppresses T lymphocyte activation, as assessed by expression of CD69. EPA alone does not, therefore, influence CD69 expression. No other marker of immune function assessed in this study was significantly affected by either EPA or DHA." Transport of Diabetic Lipid and Triglyceride Tissue to Fetus increased by 200%. Biol Neonate. 1985;47(6):343-9. Increased maternal-fetal transport of fat in diabetes assessed by polyunsaturated fatty acid content in fetal lipids. Goldstein R, Levy E, Shafrir E. "The distribution of fatty acids was determined by gas-liquid chromatography in total lipid and triglyceride fraction of extracts of several tissues of streptozotocin-diabetic rats and their fetuses on day 20 of pregnancy. In maternal rats, diabetes did not significantly affect fatty acid distribution apart from small changes in the relative content of linoleate in adipose tissue and liver. In the placenta, the fetal carcass and the fetal liver the triglyceride content increased approximately 2-fold as a result of maternal diabetes, in association with the elevation in triglycerides and free fatty acids in the maternal circulation. A pronounced increase in the relative content of linoleate was recorded in the total lipid and triglyceride extracts of placenta (35 and 59%), fetal carcass (56 and 66%) and fetal liver (100 and 205%). Small increases in arachidonate proportion were also seen in some fetal tissues. The large increase in fetal hepatic linoleate indicates that this tissue is an important uptake target of maternal lipids transported in excess into the fetus. The results confirm the previous observations on increased transplacental fat passage in diabetes by demonstrating that the increment in the essential fatty acid, linoleate, parallels the diabetes-induced triglyceride accumulation in the fetoplacental unit."

=====================// Promotes Optimal Fat Metabolism.

Carbohydrate Oxidation (Metabolism) Decreased by 26%. Br J Nutr. 2003 Oct;90(4):777-86. Fish-oil supplementation reduces stimulation of plasma glucose fluxes during exercise in untrained males. Delarue J, Labarthe F, Cohen R. "The present study examined the effects of a 3-week fish-oil supplementation (6 g/d) on the rate of plasma glucose disappearance (Rd glucose), hepatic glucose production (HGP), carbohydrate oxidation and lipid oxidation during exercise. Six untrained males (23+/-1 years; 67.6+/-2.7 kg) performed two 90 min cycling exercise sessions at 60 % of maximal O2 output separated by 20 d. During the 20 d before the first test, they ingested 6 g olive oil/d, then 6 g fish oil/d during the 20 d before the second test. Plasma glucose fluxes and lipolysis were traced using 6,6-[(2)H2]glucose and 1,1,2,3,3-[(2)H5]glycerol respectively. Substrates oxidation was obtained from indirect calorimetry. At rest HGP and the Rd glucose were similar after olive oil and fish oil (1.83 (SE 0.05) v. 1.67 (SE 0.11) mg/kg per min). During exercise, fish oil reduced the stimulation of both the Rd glucose (5.06 (SE 0.23) v. 6.37 (SE 0.12) mg/kg per min; Pand HGP (4.88 (SE 0.24) v. 5.91 (SE 0.21) mg/kg per min; PCarbohydrate oxidation tended to be less stimulated by exercise after fish oil than after olive oil (12.09 (SE 0.60) v. 13.86 (se 1.11) mg/kg per min; NS). Lipid oxidation tended to be more stimulated by exercise after fish oil (7.34 (SE 0.45) v. 6.85 (SE 0.17) mg/kg per min; NS). Glycaemia, lactataemia, insulinaemia and glucagonaemia were

similarly affected by exercise after fish oil and olive oil. Lipolysis at rest was similar after fish oil and olive oil (2.92 (SE 0.42) v. 2.94 (SE 0.28) micromol/kg per min) and similarly stimulated by exercise (6.42 (SE 0.75) v. 6.77 (SE 0.72) micromol/kg per min). It is concluded that fish oil reduced the Rd glucose by 26 % by reducing glucose metabolic clearance rate, possibly by facilitating fat oxidation, and reduced HGP by 21%, possibly by a feedback mechanism."
Inhibited Break Down of Cortisol by Lymphocytes. Metabolism. 1989 Mar;38(3):278-81. The effect of fatty acids on the vulnerability of lymphocytes to cortisol. Klein A, Bruser B, Malkin A. "We have shown previously that cortisol-sensitive lymphocytes (thymocytes) have a much lower capacity than cortisol-resistant cells to catabolize cortisol and that linoleic acid inhibits the catabolism of cortisol by lymphocytes and modulates the sensitivity of lymphocytes to cortisol. In the present study, we attempted to see whether other fatty acids are inhibitory and if inhibition of cortisol catabolism by lymphocytes indicates a change in resistance of the cells to cortisol. Measuring the effect of fatty acids on cortisol catabolism by lymphocytes indicated that the polyunsaturated fatty acids, linoleate, arachidonate, and eicosapentaenoic, inhibit cortisol catabolism by lymphocytes. Using prostaglandin PGE2 and indomethacin as a blocker of prostaglandin formation, we observed that the effect of the polyunsaturated fatty acids was not due to the formation of prostaglandins. Examining the effect of fatty acids on the vulnerability of lymphocytes to cortisol, we noted that saturated fatty acids had no significant effect, whereas the aforementioned polyunsaturated fatty acids make lymphocytes more sensitive to cortisol."

Oxidation Consumes Energy, which Lowers Cellular ATP. Arch Biochem Biophys. 1986 May 1;246(2):820-8. Effect of growth hormone on fatty acid oxidation: growth hormone increases the activity of 2,4-dienoyl-CoA reductase in mitochondria. Clejan S, Schulz H. "The effect of growth hormone on the beta-oxidation of saturated and unsaturated fatty acids was studied with mitochondria isolated from control rats, hypophysectomized rats, and hypophysectomized rats treated with growth hormone. Rates of respiration supported by polyunsaturated fatty acylcarnitines, in contrast to rates observed with palmitoylcarnitine or oleoylcarnitine, were slightly lower in hypophysectomized rats than in normal rats, but were higher in hypophysectomized rats treated with growth hormone. The effects were most pronounced with docosahexaenoylcarnitine, the substrate with the highest degree of unsaturation. Since uncoupling of mitochondria with 2,4-dinitrophenol resulted in lower rates of docosahexaenoylcarnitine-supported respiration, while substitution of ATP for ADP yielded higher rates, it appears that energy is required for the effective oxidation of polyunsaturated fatty acids. Growth hormone treatment of hypophysectomized rats caused a threefold increase in the activity of 2,4-dienoyl-CoA reductase or 4-enoyl-CoA reductase (EC in mitochondria, but not in peroxisomes. The activities of other beta-oxidation enzymes remained virtually unchanged. Rates of acetoacetate formation from linolenoylcarnitine, but not from palmitoylcarnitine, were stimulated by glutamate in mitochondria from hypophysectomized rats and hypophysectomized rats treated with growth hormone. All data together lead to the conclusion that the mitochondrial oxidation of highly polyunsaturated fatty acids is limited by the availability of NADPH and the activity of 2,4-dienoyl-CoA reductase which is induced by growth hormone treatment."

================================// Lowers Risk of Prostate, Breast & Colorectal Cancer; Diabetes. Promotes Colon Cancer Metastasis in the Liver. Cancer Res. 1998 Aug 1;58(15):3312-9. Dietary omega-3 polyunsaturated fatty acids promote colon carcinoma metastasis in rat liver. Griffini P, Fehres O, Klieverik L, Vogels IM, Tigchelaar W, Smorenburg SM, Van Noorden CJ. "The effects of omega-3 polyunsaturated fatty acids (PUFAs) and omega-6 PUFAs on the development of experimentally induced colon carcinoma metastasis in rat liver

were investigated quantitatively in vivo. Rats were kept on either a low-fat diet or on a fish oil (omega-3 PUFAs) or safflower oil (omega-6 PUFAs) diet for 3 weeks before the administration of colon cancer cells to the portal vein, until they were sacrificed at 1 or 3 weeks after tumor transplantation. At 1 week after transplantation, the fish oil diet had induced 7-fold more metastases (in terms of number and size) than had the low-fat diet, whereas the safflower oil diet had not affected the number and total volume of metastases. At 3 weeks after tumor transplantation, the fish oil diet and the safflower oil diet had induced, respectively, 10- and 4-fold more metastases (number) and over 1000- and 500-fold more metastases (size) than were found in the livers of rats on the low-fat diet. These differences were sex independent. Immunohistochemical analysis revealed that the immune system in the liver (Kupffer cells, pit cells, T cells, newly recruited macrophages, and the activation state of macrophages) did not play a significant role in this diet-dependent outgrowth of tumors. In conclusion, omega-3 and omega-6 PUFAs promote colon cancer metastasis in the liver without down-regulating the immune system. This finding has serious implications for the treatment of cancer patients with fish oil diet to fight cachexia."
Primary Driver of Invasive Cancer Growth. Clin Exp Metastasis 2000;18(5):371-7. Promotion of colon cancer metastases in rat liver by fish oil diet is not due to reduced stroma formation. Klieveri L, Fehres O, Griffini P, Van Noorden CJ, Frederiks WM. "Recently, it was demonstrated that dietary omega-3 polyunsaturated fatty acids (PUFAs) induce 10-fold more metastases in number and 1000-fold in volume in an animal model of colon cancer metastasis in rat liver. It was observed that tumors of rats on a fish oil diet lacked peritumoral stroma unlike tumors in livers of rats on a low fat diet or a diet containing omega-6 PUFAs. In the present study, only one-third of the tumors in livers of rats on omega-3 PUFA diet contained peritumoral stroma, whereas peritumoral stroma was present in 87% of the tumors in livers of rats on low fat diet. To explain these findings, we tested the hypothesis that fish oil exerts a direct inhibiting effect on the formation of extracellular matrix in tumor stroma as a consequence of blocking transformation of fat storing cells into myofibroblasts. It was found with immunohistochemical analysis of desmin as marker for fat storing cells and alpha-smooth muscle actin as marker for myofibroblasts that numbers of myofibroblasts were higher in tumors containing intratumoral stroma only than in tumors containing both peritumoral and intratumoral stroma. As most of the tumors in fish oil-treated rats contained intratumoral stroma only, this suggests that transformation of fat storing cells into myofibroblasts was highest in tumor stroma of fish oil-treated rats. Therefore, it is unlikely that the lack of stroma around tumors in fish oil-treated rats is due to inhibition of transformation of fat storing cells into myofibroblasts, but lack of peritumoral stroma is rather a consequence of rapid development of tumors in livers of fish oil-treated rats." Negative Effects of Glucose Metabolism, Especially in Diabetic Subjects. Diabetes. 1989 Oct;38(10):1314-9. Effects of fish oil supplementation on glucose and lipid metabolism in NIDDM. Borkman M, Chisholm DJ, Furler SM, Storlien LH, Kraegen EW, Simons LA, Chesterman CN. Garvan Institute of Medical Research St. Vincent's Hospital, Sydney New South Wales, Australia. Fish oils, containing omega-3 fatty acids (omega 3FAs), favorably influence plasma lipoproteins in nondiabetic humans and prevent the development of insulin resistance induced by fat feeding in rats. We studied the effects of fish oils in 10 subjects (aged 42-65 yr) with mild non-insulindependent diabetes mellitus (NIDDM). Subjects were fed a standard diabetic diet plus 1) no supplementation (baseline), 2) 10 g fish oil concentrate (30% omega 3FAs) daily, and 3) 10 g safflower oil daily over separate 3-wk periods, the latter two supplements being given in radom order by use of a double-blind crossover design. At the end of each diet period, fasting blood glucose (FBG), insulin, and lipids were measured, and insulin sensitivity was assessed with a hyperinsulinemic-euglycemic clamp performed with [3-3H]glucose. FBG increased 14% during fish oil and 11% during safflower oil supplementation compared with baseline (P less than .05), whereas body weight, fasting serum insulin levels, and insulin sensitivity were unchanged. The absolute increase in FBG during each supplementation period correlated with the baseline FBG (fish oil, r = .83, P less than .005); safflower oil, r = .75, P = .012). Fasting plasma triglyceride levels decreased during fish oil supplementation in the 4

subjects with baseline hypertriglyceridemia (greater than 2 mM) but were not significantly reduced overall. There was no significant change in fasting plasma total, high-density lipoprotein, and low-density lipoprotein cholesterol levels. In summary, dietary fish oil supplementation adversely affected glycemic control in NIDDM subjects without producing significant beneficial effects on plasma lipids. The effect of safflower oil supplementation was not significantly different from fish oil, suggesting that the negative effects on glucose metabolism may be related to the extra energy or fat intake.