About 6 million years ago, our ancestors had experienced a tremendous brain growth, widely viewed as a “major adaptive shift” in human evolution. Half of human brain composition is fat and 20% of its dry weight is long‐chain polyunsaturated fatty acids (LCPUFA). Consequently, improvements in consumption of dietary fat were necessary condition for promoting encephalization. Dietary fat quantity and quality have been subjected to tremendous change over the past 10,000 years with the introduction of industrially produced trans fatty acids and reduced intakes of ω‐3 fatty acids. The absolute human brain size reached its peak of approximately 90,000 years ago and has decreased by 11% since 35,000 years ago, most of it (8%) coming in the last 10,000 years. The shortfall in consumption of animal foods since the late Paleolithic and mainly consequent shortfall in consumption of preformed LCPUFA would be the plausible hypothesis for the brain size decreasing. Genetically, we are still adapted to the East African ecosystem on which our genome evolved, with some adaptations since the Out‐of‐Africa Diaspora. Dietary fat quantity and quality change has caused a conflict with our slowly adapting genome and this mismatch is likely to be at the basis of “typically Western” diseases. Many recommendations for the intakes of EPA + DHA have been issued, notably for prevention. However, the ultimate goal might be to return to the fat quality of our ancient diet on which our genes have evolved during the past million years of evolution.
- human encephalization
- LCPUFA sources
- dietary transition
- LPUFA in health
- W‐3/W‐6 LCFA and modern diseases
- therapeutical W‐3 LCPUFA
The evolution of Homo erectus in Africa is widely viewed as a “major adaptive shift” in human evolution. Humans share a common ancestor with the chimpanzee and bonobo that probably lived in East Africa and, since some 6 million years ago our ancestors had experienced a tremendous brain growth and assumed an upright position .
Half of brain composition is fat, but the central nervous system contains almost a quarter of the unesterified cholesterol present in the whole human body and, long‐chain polyunsaturated fatty acids (LCPUFAs) make up to 20% of brain dry weight, including 6% for arachidonic acid (AA) and 8% for docosahexaenoic acid (DHA) .
2. Polyunsaturated fatty acids
LCPUFAs are building blocks of the membrane phospholipids of all cells. Nevertheless, LCPUFAs are not only important structural elements of membranes, together with their highly potent metabolites (prostaglandins, thromboxanes, leukotrienes, resolvins, and (neuro)protectins), LCPUFAs are involved in the functioning of membrane‐bound receptors, transporters, ion channels, and enzymes, and also in signal transduction and gene expression.
LCPUFAs are ligands of nuclear transcription factors (PPARS, SREBPs, NF‐kB, and others) [3–6] that coordinate expression and repression of key enzymes and proteins participating in intermediary metabolism in glycolysis and “
3. Effect of diet on brain development
Improvements in dietary quality and the increased consumption of dietary fat appear to have been a necessary condition for promoting encephalization in the human lineage .
Primitive humans with enlarging brains developed more sophisticated tool technology (including the fire cooking) and became more efficient hunter/gatherers and so gained greater access to more nutritious and easily digestible foods (e.g., fruits, nuts, and meat) .
Consequently, reductions of posterior tooth size (and grinding teeth) and, also the size of the face and so, no longer needed the large gastrointestinal tract. Key genetic mutations during later hominid evolution were critical to promoting the enhanced lipid metabolism necessary for subsisting on diets with greater levels of animal material .
In fact, associated with the evolution of our high‐quality diet, humans developed distinct molecular pathways for detecting and metabolizing high‐fat foods .
The ability to effectively detect, metabolize, and store fats likely provided tremendous selective advantages to our hominid ancestors, allowing them to expand into diverse ecosystems around the world .
Mammalian brain growth is dependent upon sufficient amounts of two LCPUFAs: DHA and AA .
It appears that mammals have a limited capacity to synthesize these fatty acids from dietary precursors. Because the composition of all mammalian brain tissue is similar with respect to these two fatty acids, species with higher levels of encephalization have greater requirements for DHA and AA. Consequently, dietary sources of DHA and AA were likely limiting nutrients that constrained the evolution of larger brain size in many mammalian lineages .
Greater consumption of animal foods would have increased total dietary fat consumption in early Homo, and markedly increased the levels of key fatty acids (AA and DHA) necessary for brain development. The available evidence seems to best support a mixed dietary strategy in early Homo that involved the consumption of larger amounts of animal foods than with the australopithecines. Brain tissue is a rich source of both AA and DHA, whereas liver and muscle tissues are good sources of AA and moderate sources of DHA .
Dietary fat quantity and quality have been subjected to tremendous change over the past 10,000 years. Important changes are the introduction of manufactured linoleic acid (LA), trans‐fatty acids, and reduced intakes of vegetal‐derived alpha‐linolenic acid (ALA) and fish‐derived eicosapentaenoic acid (EPA) and DHA, overall leading to a reduced supplying of omega‐3 fatty acids .
Analysis of changes in brain size in humans over the last 1.8 million years found that encephalization quotient (EQ) began reaching its peak with the first anatomically modern humans of approximately 90,000 years ago and has since remained fairly constant. Most surprisingly, however, absolute brain size has decreased by 11% since 35,000 years ago, with most of this decrease (8%) coming in just the last 10,000 years. Therefore, a genetic mutation is no more likely as an explanation for the decrease in absolute brain size. The most notorious dietary change in the last 10,000 years has been the decreased consumption of animal food (roughly from 50 to 10%) by the adventure of agriculture, followed by an increased consumption of grains. Hence, the most feasible biological hypothesis for the absolute decrease in brain size is the reduction of animal food intake with a consequent reduction of preformed long‐chain fatty acids. The brain is dependent on the DHA, docosatetraenoic acid (DTA), and AA to support its growth during the formative years. These are far more plentiful in animal foods than plant. It is possible that the levels of essential fatty acids (EFAs) provided in the prehistoric diets were sufficient to support the brain expansion and evolution from prehistoric times to the present, and the current low levels of EFA intake (provided by agricultural diets) may explain the recent smaller human brain size .
4. Transition of diet and the development of brain disease
Dietary fat quantity and quality change have, together with other man‐made changes in our environment, caused a conflict with our slowly adapting genome .
In fact, the EFA and other changes in our diet together with an energy intake that does not match with our current sedentary lifestyle have caused a conflict with our genome that is likely to be at the basis of typically “Western” diseases and their basis on the conflict (mismatch) caused by our current sedentary‐energy rich industrialized diet, way of life with our ancestrally molded genome. The dietary composition of our ancestors has also become clear from our current (patho)physiology: epidemiological data demonstrated a negative association of fish consumption with coronary artery disease (CAD) and (postpartum) depression, while landmark trials with ALA and fish oil in CAD, and with EPA in depression and schizophrenia supported the causality of these relations.
The similarity among diseases currently associated with dietary risk factors adds the notion that there is a common insult originated from our changed environment. These effects hit different organs and systems varying in genetic susceptibility and life stages, but extremely dependent on the doses and exposure time. Low‐grade inflammation might be a strong candidate for this common denominator. Low‐grade inflammation can be found in metabolic syndrome and its sequelae, some psychiatric and neurodegenerative diseases. The LCPUFA, AA, EPA, and DHA are intimately related to the initiation and resolution of inflammatory responses .
The current balance between AA and EPA + DHA is disturbed by the dominance of AA, which originates from the diet or synthesis from LA. Higher ratio of AA/EPA+DHA might led to a pro‐inflammatory condition that may precipitate a hyper‐inflammatory response (“systemic inflammatory response syndrome‐SIRS”) with collateral damage, scarring and fibrosis and the subsequent development of an immune paralysis (“compensatory anti‐inflammatory response syndrome‐CARS”) evidenced by debilitated host defense and secondary infection susceptibility [27, 28].
The chronic inflammation resulting from the unbalanced AA/EPA + DHA ratio might be central in the pathogenesis of the diseases of the metabolic syndrome and neurodegenerative disease, explain the relation between inflammation, depression, and dementia .
5. Therapy of modern diseases with polyunsaturated fatty acids
Dietary supplementation of LCFA, especially EPA and DHA, has been used during pregnancy or early postnatal life for improvement of fetal and newborn brain development, at primary and secondary CAD preventions and psychiatric diseases. Consensus has been reached that those in CAD and depression are positive but not in all others. LCPω3 supplements might especially be effective in prevention, as suggested by the outcomes of epidemiological studies on CAD and prospective studies on Alzheimer's disease, and also from the favorable effects of LCPω3 in early disease stages .
It takes 20 years before the human brain obtains its complex adult configuration but the most dramatic neurodevelopmental changes occur prenatally and early post‐natal, including a major transformation in cortical organization 3–4 months after term and, considerable evidence indicates that prenatal and neonatal LCPUFA status is associated with neurodevelopmental outcome. Therefore, maternal and neonatal concentrations of DHA and AA are associated with improved outcomes in early infancy, and concentrations of DHA are associated with favorable neurodevelopmental outcome beyond early infancy .
Given the fact that LCPUFA accretion is especially abundant during the third trimester of gestation, it suggests that preterm infants would particularly profit from LCPUFA supplementation. However, studies of LCPUFA supplementation in preterm infants have not shown evidence of a positive effect on neurodevelopmental outcome. On the other hand, studies in full‐term infants indicated that DHA supplementation promotes neurodevelopmental outcome in early infancy but no longer positive effects later on, being virtually absent at school age or later. Generally, the literature suggests that LCPUFA supplementation in term infants does not affect outcomes beyond the age of 4 months .
It is known that up to 45% of the fatty acids of synaptic membranes are EFAs .
There is a well‐established positive correlation between depression and coronary artery disease. In fact, epidemiological studies in various countries suggest that decreased ω‐3 fatty acid consumption correlates with increasing rates of depression and, adequate long‐chain polyunsaturated fatty acids, particularly DHA, may reduce the development of depression just as ω‐3 polyunsaturated fatty acids may reduce coronary artery disease .
Eight database trials that randomly assigned participants to receive ω‐3 PUFAs/fish, with measured depressed mood, using human participants, came to the conclusion that trial evidence of the effects of ω‐3 PUFAs on depressed mood has increased. However, the considerable heterogeneity of the studies made them difficult to summarize the results. Overall, the available evidence supports the benefit of ω‐3 PUFAs in individuals with diagnosed depressive illness but no evidence of any benefit in individuals without a diagnosis of depressive illness .
The association between fish and meat consumption and risk of dementia in populations in developing countries was investigated in low‐ and middle‐ income countries of China, India, Cuba, the Dominican Republic, Venezuela, Mexico, and Peru. The found associations of fish and meat consumption with dementia risk to populations were consistent with mechanistic data on the neuroprotective actions of ω‐3 PUFAs commonly found in fish. However, the inverse association between fish and prevalent dementia is unlikely to result from poorer dietary habits among demented individuals (reverse causality) because meat consumption was higher in those with a diagnosis of dementia. But anyway, the found beneficial effects of fish consumption on dementia provide preliminary evidence of the etiological significance of diet in dementia .
Given the fact that PUFAs are naturally occurring endogenous substances, present in almost all tissues and are essential components of all mammalian cells and can be taken safely for long periods of time (from few months to few years) we can conclude that PUFAs, especially ω‐3 fatty acids, are useful in the prevention and treatment of Alzheimer’ disease, schizophrenia, and depression .
The pioneering studies in Greenland Eskimos almost 30 years ago suggested that ingestion of
Since then, many interventions have been conducted with LCPUFA, especially EPA and DHA, aiming at primary and secondary CAD preventions. From that, in most of the prospective cohort studies,
By comparing people who never or ate fish less than once per month, a meta‐analysis of 11 prospective studies (11.8 years follow‐up of more than 220 thousand subjects) showed the odds ratio for CHD mortality as 0.85 for fish consumption once per week, 0.77 for 2– 4 times/week, and 0.62 for 5 times/week. The authors calculated that each 20 g/day increase in fish intake was associated with a 7% lower risk of coronary heart disease mortality .
Many international organizations have made recommendations to increase the intake of EPA plus DHA, and these are summarized by the International Society for the Study of Fatty Acids and Lipids . In general, these recommendations are for 200 mg/day of EPA plus DHA for all adults. The United States has also issued a Dietary Reference Intake for
The 2002 American Heart Association recommendations for dietary intake of
Several mechanisms have been proposed to explain how EPA plus DHA might beneficially influence cardiovascular disease. These include preventing arrhythmias, lowering plasma triacylglycerols, decreasing blood pressure, decreasing platelet aggregation, improving vascular reactivity, and decreasing inflammation. Overall, the therapeutic effect appears to be due to suppression of fatal arrhythmias rather than stabilization of atherosclerotic plaques [50–60].
Elevated plasma triacylglycerol concentrations have been associated with increased risk of coronary heart disease (CHD). Prospective evidence shows that nonfasting plasma triacylglycerol concentration is a strong and independent predictor of future myocardial infarction once elevated postprandial triacylglycerolemia leads to a series of metabolic reactions that reduce high‐density lipoprotein (HDL)‐cholesterol concentrations and promote the formation of small, dense low‐density lipoprotein (LDL) particles. Metabolism of plasma triacylglycerols also influences postprandial factor VII activation .
EPA and DHA are
Omega‐3 fatty acid supplementation provided additional benefits to Lifestyle Modification Program (LSMP) in the resolution of metabolic syndrome of free living adults. The fish oil group received 3 g of fish oil per day (360 mg of DHA and 540 mg of EPA) (G2,
A significant decrease of plasma oxidative‐stress markers in patients with ulcerative colitis was shown when fish oil ω‐3 fatty acids were used in combination with sulfasalazine .
Regarding type 2 diabetes mellitus (T2DM), a prospective cohort analysis of men and women showed that long‐term dietary intake of long‐chain omega 3 fatty acids does not decrease the risk of T2DM. Instead, a modestly but significantly higher incidence of T2DM was associated with higher fish and long‐chain omega 3 fatty acid consumption .
Doses 3 g/day, EPA plus DHA can improve cardiovascular disease risk factors, including decreasing plasma triacylglycerols, blood pressure, platelet aggregation, and inflammation, while improving vascular reactivity .
By the fact that EFAs and their long‐chain metabolites and other products prevent platelet aggregation, lower blood pressure, reduce LDL‐cholesterol, and ameliorate the adverse actions of homocysteine, the EFAs and their metabolites show all the actions expected of the “polypill” .
The concept of cardiovascular “polypill” was coined  by the fact that, when combined, the effects of statins, aspirin, and blood pressure lowering drugs reduced the all causes mortality in CHD patients.
In conclusion, it is evident that PUFAs, especially an optimal combination of EPA, DHA, and possibly, gamma‐linolenic acid (GLA), dihomo‐gamma‐linolenic acid (DGLA), and AA show all the qualities of the suggested “polypill”, viz., aspirin‐like action, inhibition of HMG‐CoA and angiotensin‐converting enzymes (ACEs), and possess diuretic, antihypertensive, and beta‐blocker‐like actions. Additionally, given the fact that PUFAs are naturally occurring endogenous substances, present in almost all tissues and are essential components of all mammalian cells and can be taken safely for long periods of time (from few months to few years), we can conclude that PUFAs, especially ω‐3 fatty acids, are useful in the prevention and treatment of Alzheimer’ disease, schizophrenia, and depression , suggesting that PUFAs have a much wider benefit compared to the “polypill” .
Thus, LCPω3 supplements might especially be effective in prevention, as suggested by the outcomes of epidemiological studies on CAD and prospective studies on Alzheimer's disease, and also from the favorable effects of LCPω3 in early disease stages . Consensus has been reached that those interventions in CAD and depression are positive but not in all others.
6. Future directions
Genetically, we are for the greater part still adapted to the East African ecosystem on which our genome evolved, with some adaptations since the Out‐of‐Africa Diaspora. Dietary fat quantity and quality change have, together with other man‐made changes in our environment, caused a conflict with our slowly adapting genome that is implicated in “typically Western” diseases. Fortunately, the majority of Western diseases occur typically after reproductive age. Rather than reducing our life expectancy, these diseases notably diminish our number of years in health.
Many recommendations for the intakes of saturated fat,
White T.D., Asfaw B., DeGusta D., Gilbert H., Richards G.D., Suwa G., et al. Pleistocene Homo sapiens from middle awash, Ethiopia. Nature. 2003;423:742–747. DOI: 10.1038/nature01669
Burini R.C., Nunes C.N.M., Kano H.T., Nakagaki M.S. Epygenetics of Plasma Cholesterol Variation: From an Evolutionary Genome and Environmental‐Induced Frugality to Contemporary Diseases‐Basis for Primary Care with Lifestyle Modifications. In: Advances in Dyslipidemia. Publisher: Avid Science. Location: Telangana, India. 2016. pp. 2–35.
Clarke S.D. The multi‐dimensional regulation of gene expression by fatty acids: Polyunsaturated fats as nutrient sensors. Current Opinion in Lipidology. 2004;15:13–18. DOI: 10.1097/01.mol.0000113205.97033.22
Duplus E., Forest C. Is there a single mechanism for fatty acid regulation of gene transcription? Biochemical Pharmacology. 2002;64:893–901. DOI: 10.1016/S0006‐2952(02)01157‐7
Jump D.B. Fatty acid regulation of gene transcription. Critical Reviews in Clinical Laboratory Sciences. 2004;41:41–78. DOI: 10.1080/10408360490278341
Lapillonne A., Clarke S.D., Heird W.C. Polyunsaturated fatty acids and gene. Current Opinion in Clinical Nutrition & Metabolism Care. 2004;7:151–156. DOI: 10.1097/01.mco.0000120004.58274.9e
Auwerx J. PPARgamma, the ultimate thrifty gene. Diabetologia. 1999;42(9):1033–1049. DOI: 10.1007/s001250051268
Jump D.B. N‐3 polyunsaturated fatty acid regulation of hepatic gene. Current Opinion in Lipidology. 2008;19:242–247. DOI: 10.1097/MOL.0b013e3282ffaf6a
Nakamura M.T., Nara T.Y. Essential fatty acid synthesis and its regulation in. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2003;68:145–150. DOI: 10.1016/S0952‐3278(02)00264‐8
Calder P.C. N‐3 polyunsaturated fatty acids, inflammation, and inflammatory. American Journal of Clinical Nutrition. 206;83:1505S–1519S.
Muskiet F.A.J. Pathophysiology and Evolutionary Aspects of Dietary Fats and Long‐Chain Polyunsaturated Fatty Acids across the Life Cycle. In: Montmayeur J.P., le Coutre J., editors. Fat Detection: Taste, Texture, and Post Ingestive Effects. Boca Raton, FL: CRC Press/Taylor & Francis. 2010. Chapter 2.
Antón S.C. A natural history of Homo erectus. Yearbook of Physical Anthropology. 2003;46:126–170. DOI: 10.1002/ajpa.10399
Leonard W.R., Robertson M.L., Snodgrass J.J., Kuzawa C.W. Metabolic correlates of hominid brain evolution. Comparative Biochemistry and Physiology. 2003;136:5–15. DOI: 10.1016/S1095‐6433(03)00132‐6
Milton K. The critical role played by animal source foods in human (Homo) evolution. The Journal of Nutrition. 2003;133:3886S–3892S.
Cordain L., Brand‐Miller J., Eaton S.B., Mann N., Holt S.H.A., Speth J.D. Plant to animal subsistence ratios and macronutrient energy estimations in worldwide hunter‐gatherer diets. The American Journal of Clinical Nutrition. 2010;71:682–692.
Aiello L.C., Wheeler P. The expensive‐tissue hypothesis: The brain and the digestive system in human and primate evolution. Current Anthropology. 1995;36:199–221. DOI: 10.1086/204350
Finch C.E., Stanford C.B. Meat‐adaptive genes and the evolution of slower aging in humans. The Quarterly Review of Biology. 2004;79:3–50.
Leonard W.R., Snodgrass J.J., Robertson M.L. Evolutionary perspectives on fat ingestion and metabolism in humans. In: Montmayeur J.P., le Coutre J, editors. Fat Detection: Taste, Texture, and Post Ingestive Effects. Boca Raton, FL: CRC Press/Taylor & Francis. 2010. Chapter 1.
Crawford M.A., Bloom M., Broadhurst C.L., Schmidt W.F., Cunnane S.C., Galli C., et al. Evidence for unique function of docosahexaenoic acid during the evolution of the modern human brain. Lipids. 1999;34:S39–S47.
Popovich D.G., Jenkins D.J.A., Kendall C.W.C., Dierenfeld E.S., Carroll R.W., Tariq N., et al. The western lowland gorilla diet has implications for the health of humans and other hominoids. The Journal of Nutrition. 1997;127:2000–2005.
Cordain L, Watkins BA, Mann NJ. Fatty acid composition and energy density of foods available to African hominids. World Review of Nutrition and Dietetics. 2001;90:144–161.
Bobe R., Behrensmeyer A.K. Faunal change, environmental variability and late Pliocene hominin evolution. Journal of Human Evolution. 2002;42:475–497. DOI: 10.1006/jhev.2001.0535
de Menocal P.B. African climate change and faunal evolution during the Pliocene–Pleistocene. Earth and Planetary Science Letters. 2004;220:3–24. DOI: 10.1016/S0012‐821X(04)00003‐2
Wynn J.G. Influence of Plio‐Pleistocene aridification on human evolution: Evidence from paleosols from the Turkana Basin, Kenya. American Journal of Physical Anthropology. 2004;123:106–118. DOI: 10.1002/ajpa.10317
Reed K. Early hominid evolution and ecological change through the African Plio‐Pleistocene. Journal of Human Evolution. 1997;32:289–322. DOI: 10.1006/jhev.1996.0106
Eaton S.B. The ancestral human diet: What was it and should it be a paradigm for contemporary nutrition? Proceedings of the Nutrition Society. 2006;65(1):1–6. DOI: 10.1079/PNS2005471
Innis S.M. Dietary lipids in early development: Relevance to obesity, immune and inflammatory disorders. Current Opinion in Endocrinology, Diabetes and Obesity. 2007;14:359–364. DOI: 10.1097/MED.0b013e3282be90b9
Mayer K., Seeger W. Fish oil in critical illness. Current Opinion in Clinical Nutrition & Metabolic Care. 2008;11:121–127. DOI: 10.1097/MCO.0b013e3282f4cdc6
Leonard B.E. Inflammation, depression and dementia: Are they connected? Neurochemical Research. 2007;32:1749–1756. DOI: 10.1007/s11064‐007‐9385‐y
Bourre J.M. Dietary omega‐3 fatty acids and psychiatry: Mood, behaviour, stress, depression, dementia and aging. The Journal of Nutrition Health & Aging. 2005;9:31–38.
Hadders‐Algra M. Prenatal and early postnatal supplementation with long‐chain polyunsaturated fatty acids: Neurodevelopmental considerations. American Journal of Clinical Nutrition. 2011;94(suppl):1874S–1879S. DOI: 10.3945/ajcn.110.001065
Sun G.Y., Sun A.Y. Effect of chronic ethanol administration on phospholipid acyl groups of synaptic plasma membrane fraction isolated from guinea pig brain. Research Communications in Chemical Pathology & Pharmacology. 1979;24:405–408. DOI: 10.1111/j.1530‐0277.2001.tb02131.x
Hibbeln J.R., Salem N. Jr. Dietary polyunsaturated fatty acids and depression: When the cholesterol does not satisfy. American Journal of Clinical Nutrition. 1995;62:1–9.
Appleton K.M., Rogers P.J., Ness A.R. Updated systematic review and meta‐analysis of the effects of n23 long‐chain polyunsaturated fatty acids on depressed mood. American Journal of Clinical Nutrition. 2010;91:757–770. DOI: 10.3945/ajcn.2009.28313.
Albanese E., Dangour A.D., Uauy R., Acosta D., Guerra M., Guerra S.S. et al. Dietary fish and meat intake and dementia in Latin America, China, and India: A 10/66 Dementia Research Group population‐based study. American Journal of Clinical Nutrition. 2009;90:392–400. DOI: 10.3945/ajcn.2009.27580
Das U.N. Essential fatty acids: Biochemistry, physiology, and pathology. Biotechnology Journal. 2006;1:420–439. DOI: 10.1002/biot.200600012
Bang H.O, Dyerberg J., Hjoorne N. The composition of food consumed by Greenland Eskimos. Journal of Internal Medicine. 1976;200:69–73. DOI: 10.1111/j.0954‐6820.1976.tb08198.x
Rissanen T., Voutilainen S., Nyyssonen K., Lakka T.A., Salonen J.T. Fish oil‐derived fatty acids, docosahexaenoic acid and docosapentaenoic acid, and the risk of acute coronary events: The Kuopio Ischaemic heart disease risk factor study. Circulation. 2000;102:2677–2679. DOI: 10.1161/01.CIR.102.22.2677
Oomen C.M., Feskens E.J., Räsänen L., Fidanza F., Nissinen A.M., Menotti A. Fish consumption and coronary heart disease mortality in Finland, Italy, and The Netherlands. American Journal of Epidemiology. 2000;151:999–1006.
Gillum R.F., Mussolino M., Madans J.H. The relation between fish consumption, death from all causes, and incidence of coronary heart disease. The NHANES I Epidemiologic Follow‐up Study. Journal of Clinical Epidemiology. 2000;53:237–244. DOI: 10.1016/S0895‐4356(99)00149‐3
Yuan J.M., Ross R.K., Gao Y.T., Yu M.C. Fish and shellfish consumption in relation to death from myocardial infarction among men in Shanghai, China. American Journal of Epidemiology. 2001;154:809–816. DOI: 10.1093/aje/154.9.809
Hu F.B., Bronner L., Willett W.C., Stampfer M.J., Rexrode K.M., Albert C.M. Fish and omega‐3 fatty acid intake and risk of coronary heart disease in women. JAMA. 2002;287:1815–1821. DOI: 10.1001/jama.287.14.1815
Mozaffarian D., Lemaitre R.N., Kuller L.H., Burke G.L., Tracy R.P., Siscovick D.S. Cardiac benefits of fish consumption may depend on the type of fish meal consumed: The cardiovascular health study. Circulation. 2003;107:1372–1377. DOI: 10.1161/01.CIR.0000055315.79177.16
Ascherio A., Rimm E.B., Stampfer M.J., Giovannucci E.L., Willett W.C. Dietary intake of marine n3 fatty acids, fish intake, and the risk of coronary disease among men. The New England Journal of Medicine. 1995;332:977–982. DOI: 10.1056/NEJM199504133321501
Osler M., Andreasen A.H., Hoidrup S. No inverse association between fish consumption and risk of death from all‐causes, and incidence of coronary heart disease in middle‐aged, Danish adults. Journal Clinical of Epidemiology. 2003;56:274–279. DOI: 10.1016/S0895‐4356(02)00600‐5
He K., Song Y., Daviglus M.L., Liu K., Van Horn L., Dyer A.R., et al. Accumulated evidence on fish consumption and coronary heart disease mortality: A meta‐analysis of cohort studies. Circulation. 2004;109:2705–2711. DOI: 10.1161/01.CIR.0000132503.19410.6B
The International Society for the Study of Fatty Acids and Lipids. ISSFAL Board, 2009. Available from: http://www.issfal.org.uk/Recommendations.htm
Institute of Medicine. 2005. Available from: http://www.iom.edu/Object.File/Master/7/300/0.pdf
Kris‐Etherton P.M., Harris W.S., Appel L.J. Fish consumption, fish oil, omega‐3 fatty acids, and cardiovascular disease. Circulation. 2002;106:2747–2757. DOI: 10.1161/01.CIR.0000038493.65177.94
Breslow J.L. N‐3 Fatty acids and cardiovascular diseases. American Journal of Clinical Nutrition. 2006;83(suppl):1477S–1482S.
Connor W.E. Importance of n‐3 fatty acids in health and disease. American Journal of Clinical Nutrition. 2000;71(suppl):171S–175S.
Leaf A, Kang JX, Xiao YF, Billman GE. Clinical prevention of sudden cardiac death by n‐3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n3 fish oils. Circulation. 2003;107:2646–2652. DOI: 10.1161/01.CIR.0000069566.78305.33
Harris W.S. N‐3 Fatty acids and serum lipoproteins: Human studies. American Journal of Clinical Nutrition. 1997;65(suppl):1645S–1654S.
Sacks F.M, Katan M. Randomized clinical trials on the effects of dietary fat and carbohydrate on plasma lipoproteins and cardiovascular disease. The American Journal of Medicine. 2002;113(suppl):13S–24S. DOI: 10.1016/S0002‐9343(01)00987‐1
Geleijnse J.M., Giltay E.J., Grobbee D.E., Donders A.R., Kok F.J. Blood pressure response to fish oil supplementation: Meta‐regression analysis of randomized trials. Journal of Hypertension. 2002;20:1493–1499.
Knapp H.R. Dietary fatty acids in human thrombosis and hemostasis. American Journal of Clinical Nutrition. 1997;65(suppl):1687S–1698S.
Hornstra G. Influence of dietary fatty on arterial thrombosis tendency. The Journal of Nutrition Health and Aging. 2001;5:160–166.
Harris W.S., Rambjor G.S., Windsor S.L., Diederich D. n‐3 Fatty acids and urinary excretion of nitric oxide metabolites in humans. American Journal of Clinical Nutrition. 1997;65:459–464.
Goodfellow J, Bellamy M.F, Ramsey M.W, Jones C.J, Lewis M.J. Dietary supplementation with marine omega‐3 fatty acids improve systemic large artery endothelial function in subjects with hypercholesterolemia. Journal of the American College of Cardiology. 2000;35:265–270. DOI: 10.1016/S0735‐1097(99)00548‐3
Calder P.C. Grimble R.F. Polyunsaturated fatty acids, inflammation, and immunity. Lipids. 2001;36:1007–1024. DOI: 10.1038/sj.ejcn.1601478
Roche H.M., Gibney M.J. Effect of long‐chain n‐3 polyunsaturated fatty acids on fasting. American Journal of Clinical Nutrition. 2000;71(suppl):232S–237S.
Talon L.C., Oliveira E.P., Moreto F., McLellan K.C.P., Burini R.C. Omega‐3 fatty acids supplementation decreases metabolic syndrome. Journal of Functional Foods. 2015;19:922–928. DOI: 10.1016/j.jff.2015.01.022
Barbosa D.S., Cecchini R., El Kadri M.Z., Rodríguez M.A., Burini R.C., Dichi I. Decreased oxidative stress in patients with ulcerative colitis supplemented with fish oil omega‐3 fatty acid. Nutrition. 2003;19:837–842. DOI: 10.1016/S0899‐9007(03)00162‐X
Kaushik M., Mozaffarian D., Spiegelman D., Manson J.E., Willett W.C., Hu F.B. Long‐chain omega‐3 fatty acids, fish intake, and the risk of type 2 diabetes mellitus. American Journal of Clinical Nutrition. 2009;90:613–620. DOI: 10.3945/ajcn.2008.27424.
Undurti N. Das. Do polyunsaturated fatty acids behave like an endogenous “polypill? Medical Hypotheses. 2008;70:430–434. DOI: 10.1016/j.mehy.2007.05.023
Hippisley‐Cox J, Coupland C. Effects of combinations of drugs on all mortality in patients with disease: Nested case‐control analysis. British Medical Journal. 2005;330:1059–1063. DOI: 10.1136/bmj.330.7499.1059