n-3 Omega PUFAs, inflammatory diseases, diseases in cholesterol, saturated fat and sugar origin (Fig. 2, Fig. 3)
The anti-inflammatory properties of n-3 omega PUFAs are used in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), eczema, psoriasis and rheumatoid arthritis (Cleland et al., 2003). Similarly, an increase in n-6 omega PUFAs and a decrease in n-3 omega PUFAs raises the rate of occurrence of Crohn’s disease (inflammation of colon). Inhibition of the proinflammatory cytokine (proteins, peptides or glycoproteins that are produced widely by cells throughout the body cells which are critical to the development and functioning of the immune response by activating immune cells to increase the systems response to the pathogen) synthesis by n-3 omega PUFAs can therefore be beneficially used in the treatment of Crohn’s disease (Griffiths, 1998). Treatment of such diseases with n-3 omega PUFAs also reduces mucosal damage caused by inflammation or by Crohn’s disease. Stenson et al. (1992) and Hawthorne et al. (1992) have treated ulcerative colitis with first 5.4 g and then 4.5 g of n-3 omega PUFAs (fish oil) and observed significant healing of the colon mucosa. The effects of leukotrienes which are proinflammatory mediators which can lead to post-traumatic immune dysregulation, can also be mediated by n-3 omega PUFA supplementation in the postoperative period. Thus, n-3 omega PUFAs are important anti-inflammatory agents in the postoperative periods (Köller et al., 2003). Additionally, n-3 omega PUFAs, DHA and EPA, were found as to have different in the effects on leucocyte functions such as phagocytosis, chemotactic response and cytokine production. For example, DHA has got an increasing effect in neutrophil proliferation and monocyte phogocytosis while EPA does not have got the same effect (Gorjao et al., 2009).
The supplementation of the standard diet with key nutrients which have immunomodulatory properties such as arginine, omega 3 fatty acids and glutamine (the most abundant non-essential amino acid in body) control the surgery-induced immunosuppression and hyperinflammation effectively (Gianotti et al., 2003). The administration of n-3 omega PUFAs ameliorates the host defence mechanisms, controlling the inflammatory response, not only in postoperative but also in the preoperative periods (Braga et al., 1998). Chen & Yeh (2003) reviewed the beneficial effects of administering by injection of omega 3, in the form of fish oil and indicated the importance of these effects. They showed that incorporation of the omega 3 into the cellular membranes of many cell populations can consequently influence the disease process, lead to a decrease in platelet aggregation and thrombosis or ameliorate the disease process in certain conditions and reduce accumulation of lipid peroxidation products in liver. Confirming these findings, DHA and EPA were found to serve as substrate for the production of the anti-inflammatory compounds such as resolvins and protectins while inhibiting the activation of nuclear factors that induce inflammation (nuclear factor kappa B and interleukins) (Goldberg & Katz, 2007). The meta-analysis made by them to examine the pain relieving effects of EPA/DHA in patients with rheumatoid arthritis or joint pain secondary to inflammatory bowel disease or dysmenorrhoea (severe uterine pain during menstruation) supports the premise that n-3 omega PUFAs (EPA and DHA) may decrease the pain experience in the patients.
Cardiovascular disease and n-3 omega PUFAs
Besides the anti-inflammatory effect of n-3 omega PUFAs, the other beneficial and protective effect of these fatty acids is on the cardiovascular system. Trans fatty acids, cholesterol and saturated fats are mainly responsible for atherosclerosis. On the contrary, n-3 omega PUFAs are beneficial in reducing cholesterol and thus the risk of myocardial infarction (Zyriax & Windler, 2000). Another cause of cardiovascular disease formation is the hypertriglyceridaemia, an increase in the serum triglyceride in blood serum level, can also be reduced by the addition of n-3 omega (fish oil) to the diet (Hau et al., 1996). The modern sciences of dietetics and nutrition studies the relationship between nutrition and health so that people can protect themselves from diseases or ameliorate the adverse effects of these diseases by means of appropriate diets (Table 1). The many close relationships between ‘a high selenium intake and a lower incidence rate of cancer’ (Borek, 2004; Diwadkar-Navsariwaka & Diamond, 2004; Jacobs et al., 2004; Charalabopoulos et al., 2006) despite conflicting evidence of no effect (Clark et al., 1996), ‘high carotenoid intakes and lower risk of cancer’ (Mannisto et al., 2004), ‘dietary fat, high amounts of animal, saturated and trans fat intakes and obesity’ (Bray & Popkin, 1998; Field et al., 2007), ‘high dietary sodium intake and increase in the risk of hypertension’ (de Wardener et al., 2004; Adrogue & Madias, 2007), ‘high alcohol intake and stroke risk’ (Reynolds, 2003) have been proven and similarly the close link between omega 3 PUFAs and cardiovascular disease is now widely accepted (Temple, 2002). According to Harris et al. (2003), of all known dietary factors, long-chain omega 3 fatty acids may be the most protective against death from coronary heart disease (CHD), by increasing the n-3 omega intake of an individual with coronary artery disease by approximately 1 g day−1 (Tables 2 and 3). The best prevention of cardiovascular diseases appears to be achieved by replacing saturated fats with n-3 omega PUFAs (Temple, 1996). Such replacement appears to have a direct effect on the intrinsic ability of a cardiac muscle fibre to contract at a given fibre length. These effects indicate to the beneficial and protective effects of omega 3 fatty acids in preventing sudden death following myocardial infection (Bhatnagar & Durrington, 2003). Eicosanoid synthesis from n-3 omega PUFAs minimises the production of PGE2 and thromboxane A2, IL-1, IL-2 and IL-6 (Fig. 1). Specifically, minimising the production of thromboxane A2 and IL-1, IL-2 and IL-6 by n-3 omega PUFAs protects the individual’s health by protecting cardiac tissue from clot formation, platelet aggregation and thrombosis risk (Arkhipenko & Sazantova, Arkhipenko & Sazontova, 1995; Wahlqvist, 1998). A further benefit for the cardiovascular system is the lowering of total cholesterol by n-3 omega PUFAs (Kusunoki et al., 2003). Indeed, daily supplementations of 3 g in men and EPA containing soy phospholipid at 10% level in rat can decrease total serum cholesterol and LDL (bad cholesterol, which sticks free cholesterol in blood onto the walls of blood vessels) whilst slightly increasing high density lipoprotein (Lox, 1990) (HDL: good cholesterol, which is claimed as protective against hypertension and calcification since it can take bound cholesterol from the walls of vessels and return it to blood stream). Supportive data is found in a study in rats in which a soybean oil containing 5% EPA showed a significant decrease in serum triglyceride (TG) levels (Dasgupta & Bhattacharyya, 2007).
Table 1. The list of PUFAs
|Name||Lipid name||Chemical name|
|α-Linolenic acid (α-LN)||18:3 (n-3)||all-cis-9,12,15-ortadacatrienoic acid|
|Stearidonic acid (STD)||18:4 (n-3)||all-cis-6,9,12,15-octadecatetraenoic acid|
|Eicosatrienoic acid (ETE)||20:3 (n-3)||all-cis-11,14,17-eicosatrienoic acid|
|Eicosatetraenoic acid (ETA)||20:4 (n-3)||all-cis-8,11,14,17-eicosatetraenoic acid|
|Eicosapentaenoic acid (EPA)||20:5 (n-3)||all-cis-5,8,11,14,17-eicosapentaenoic acid|
|Docosapentaenoic acid (DPA)||22:5 (n-3)||all-cis-7,10,13,16,19-docosapentaenoic acid|
|Docosahexaenoic acid (DHA)||22:6 (n-3)||all-cis-4,7,10,13,16,19-docosahexaenoic acid|
|Tetracosapentaenoic acid||24:5 (n-3)||all-cis-9,12,15,18,21-docosahexaenoic acid|
|Tetracosahexaenoic acid||24:6 (n-3)||all-cis-6,9,12,15,18,21-tetracosenoic acid|
Table 2. Amounts (g) of some foods which should be consumed to provide 1 g EPA and DHA
|Fish/sea food||Gram day−1 to provide 1 g EPA and DHA per day|
|Crab, Alaska King||255|
Table 3. Fat content/EPA + DHA (g 100 g−1) and fat content/α-linolenic acid (g 100 g−1) ratio of some various fish, marine products, vegetables and oils
| ||Fat content (g 100 g−1)||EPA + DHA (g 100 g−1)|| Fat content (EPA + DHA) (g 100 g−1) |
| ||Fat content (g 100 g−1)||α-LN (g 100 g−1)||Fat content/α-LN (g 100 g−1)|
Although most studies define n-3 omega PUFAs as lowering cholesterol and LDL as reducers, a few studies suggest that long term use of n-3 omega PUFAs results in increase in LDL. Schacky et al. (1999) found a 7% increase in LDL, following a period of 2 years during which subjects consumed 3 g of EPA and DHA daily. Similarly, 3 g 7 kg−1 7 day−1 use of EPA and DHA, was shown to lower the amount of VLDL (Very Low Density Lipoprotein, which is claimed as more harmful than LDL because of its greater ability to bind free cholesterol on to the walls of blood vessels), while enhancing the production rate of LDL. The decrease in VLDL and increase in LDL seem to be due to the conversion of VLDL to LDL by postheparin lipase, an enzyme of the hydrolase class which shows its activity in the endothelial surface in mammary, muscle and adipose tissues and is activated by n-3 omega PUFAs (Lu et al., 1999). However, despite this increase of LDL, Schacky et al. (1999) found a slight mitigation of the progress of atherosclerosis. The cholesterol reducing and HDL increasing effect of n-3 omega PUFAs makes them one of the most effective substances in the prevention of atherosclerosis, comparable to niacin, statins, and fibres (Barbeau et al., 1997; Rader, 2003). n-3 Omega PUFA supplementation of the diet has also been seen to lower the blood pressure in rats (Yahia et al., 2003). Similarly, n-3 omega rich rapeseed oil supplementation also has a reducing effect on cholesterol and the ratio of LDL to HDL (Eder & Brandsch, 2002). Li (2003) has supported these findings by confirming the beneficial effects of these fatty acids on systolic and diastolic blood pressure and stroke. This beneficial effect of n-3 omega PUFAs has attracted the attention of humanity in this new millennium and appropriately, the aeronautical industry is employing PUFAs to protect the cardiovascular systems of astronauts against the abnormal and extraordinary oxidative stress of space (Turner et al., 2002).
The protective effect of n-3 omega PUFAs on the cardiovascular system, can easily be increased by niacin, bile acid, resins, sport and exercise, which highlights the importance of life style and nutrition on health. Similarly, increased intakes of marine n-3 omega PUFAs can result in decreased triglycerides, fibrinogen and platelet aggregation, which are considered to be beneficial for cardiovascular diseases (Wijendran & Hayes, 2004). It was found in a study by Sweeney et al. (1999) that Japanese students who had relocated to USA showed higher serum triglyceride, cholesterol levels and a high risk of cardiovascular diseases when compared with the general population of Japan. The apparent explanation of this difference is that the native Japanese diet is high in n 3-omega PUFAs whilst the American diet is not. The fact that higher serum triglyceride, cholesterol levels and high risk of cardiovascular diseases found in Japanese students, following their moving to the USA, can be compared with the lower triglyceride and cholesterol levels of the general population of Japan, is a clear example, showing the significance of n-3 omega fatty acids as cardio protectors (Sweeney et al., 1999). Liu et al. (2001) added n-3 omega PUFAs to bread, as one of the most commonly consumed food products and this enrichment lowered serum triglyceride level and also total serum cholesterol by increasing HDL. Russo (2009) recommends the intake of 1 g day−1 of EPA and DHA for treatment of post Myocardial Infarction (MI) and prevention of sudden cardiac death and other cardiovascular dysfunctions. n-3 Omega PUFAs also inhibit protein kinase C and increase in nitrous oxide (NO) release, which inhibits platelet adherence to the collagen and thus eases blood circulation (Schoene, 2001; El-seweidy et al., 2002). Thus, supplementation of the diet with n-3 omega PUFAs is very effective and protective against cardiovascular diseases, such as hypertension and atherosclerosis (Shoda et al., 1996; Temple, 2002) and even in the reduction of the incidence of sudden cardiac death (Villa et al., 2002). n-3 Omega supplementation of the diet of rats, decreased the mortality rate, caused by myocardial infarction (MI) while decreasing creatine phosphokinase as the indicator for MI. In contrast, an increased mortality rate was observed when the rat diets were supplemented by saturated fat from coconut oil (Nageswari et al., 1999). Mente et al. (2009) conducted a systematic search of Medline for cohort studies on randomised trials investigating dietary exposures in relation to CHD. They pointed to the moderate evidence of associations that exists for intake of fish, marine n-3 omega PUFAs (Table 2), folate, whole grains, dietary vitamins E and C, beta carotene, alcohol, fruit and fibre.
Although there is important evidence relating to the protective effects of n-3 omega PUFAs on cardiovascular health, very surprisingly, these fatty acids may accelerate heart beat, cause adverse effects and even be life threatening according to the findings of Raitt et al. (2005). In their randomised controlled trial involving 200 patients, 1.8 g daily fish oil supplementation caused significantly important accelerations of the heart beat in patients with ventricular tachycardia (VT), an accelerated heart beat initiated within the ventricules that may prevent heart from pumping enough blood and ventricular fibrillation (VF), a heart failure due to sudden cardiac death. The findings are seriously important since it indicates that patients with VF and VT should rather avoid n-3 omega PUFAs. When 37.393 deaths in only USA in 2002 with 1.6% of all deaths that year with $2.2 billion payment to medicare beneficiaries for cardiac dysrhythmias concerned, findings are seriously important and needs further studies for definiteness.
Inuit peoples have a substantially lower rate of acute myocardial infarction, commonly known as a heart attack which occurs when blood supply to heart is interrupted causing some heart cells to die, when compared with Western people despite having a diet high in fats. Studies (Bang et al., 1971; Kromann & Green, 1980) have shown that the diet is high in omega-3 polyunsaturated fats (PUFAs) from sea mammals and fish has a protective effect. In one study, which obtained information on deaths from different diseases for 2005 from US National Center for Health Statistics, Danaei et al. (2009) examined lifestyle and metabolic risk factors in death and determined a deficiency of n-3 omega PUFAs as the eighth highest killer in death for people living in USA. Deficiency of n-3 omega PUFAs with 84 000 death year−1 even beat out nutrition rich in trans fat with 82 000 deaths annually as a causative factor. The same study findings also suggested that the huge number of annual deaths (84 000 year−1) in USA is mainly depended on deficiency of n-3 Omega PUFAs, EPA/DHA, which can also be prevented by omega 3 supplementation and a change in nutrition style to a diet rich in n-3 omega PUFAs. Thus, the study indicates to the importance of increasing consumer awareness of the dangers of about the drastic deficiency of n-3 omega PUFAs. A recent meta-analysis of randomised controlled studies of omega-3 fatty acid supplementation of the diet by Preiss & Sattar (2009) confirmed that this treatment had a cardiovascular benefit but suggested that more data would be needed to support use in clinical practice. With our present data mentioned above, we can note this cardio protective effect of n-3 omega PUFAs. However according to Lee & Lip (2003), the use of n-3 omega PUFAs should be considered as a part of comprehensive secondary prevention strategy in patients following myocardial infarction. It has also been proposed that ischemia-induced arrhythmias may be prevented by n-3 PUFA supplementation (Leaf et al., 2003). In spite of many studies, indicating the protective effect of n-3 omega PUFAs on cardiovascular system, the minimum dose which shows this effect, was not established until the studies by Weber & Raederstorff (2000). They stated that, 1 g day−1 n-3 omega (in the form of fish oil) is sufficient to show this serum triglyceride and LDL lowering effect whilst a daily intake of 3 g of EPA and DHA is regarded as safe by Food and Drug Administration (O’Keefe & Harris, 2000). Similarly, Retterstol et al. (1996) claimed the serum triglyceride and LDL lowering effect of n-3 omega, but as combined with drugs to treat hypercholesterolemia. On the other hand, an insufficiency of n-3 omega PUFAs and high amounts of n-6 omega PUFAs may also increase the atherogenic effects of environmental chemicals such as polychlorinated biphenyls (PCB), leading to dysfunction of the vascular endothelium. In spite of the cardiovascular protective effects of n-3 omega PUFAs, n-6 omega PUFAs do not appear to be correlated with cardiovascular benefits even though they lower LDL and cholesterol (Lecerf, 2009). The effects of LA or PCB are contrary to those of n-3 omega PUFAs, disrupting the endothelial barrier function. Cellular enrichment with LA can amplify PCB induced endothelial cell dysfunction, which brings about a cardio toxic effect (Slim et al., 2001). These findings underline the importance of n-3 omega PUFAs supplementation in daily nutrition in the prevention of diseases associated with high cholesterol levels.
There appears to be significant evidence that n-3 omega PUFAs have a protective effect on the cardiovascular system and evidence of an inhibitory effect on inflammation. This evidence made n-3 omega rich foods, especially fish meat, as the most popular meat option when compared with other meats. Among red meat options, beef cut (round) may be advised with a higher α-LN content (32 mg 100 g−1) (as the indicator of n-3 omega PUFAs) and lower palmitic acid content (958 mg 100 g−1) followed by beef cut (leg) with 22 mg 100 g−1α-LN content and 2804 mg 100 g−1 palmitic acid content and dark chicken meat with 25 mg 100 mg−1α-LN content and 1097 mg 100 g−1 palmitic acid content (Almeida et al., 2006). Linseed oil with 55% LN content may be considered as the optimum plant oil being the richest among others although it is often neglected by the media.
It is possible that the cardioprotective effect of n-3 omega PUFAs is dependent on the anti-inflammatory properties. The anti-inflammatory properties are due to the incorporation of EPA and DHA into cell membranes. NADPH oxidase, the main producer of cell membranes, is also activated by n-3 omega PUFAs. Only after this activation, does the enzyme regulate the cell membrane production and make it more durable and cells become more resistant to extrinsic and intrinsic destructive factors, especially inflammatory agents. This protection against inflammation is of course the same for the cells of blood vessels and the heart (Heine et al., 1999). On the other hand, when omega 3 fatty acids are provided, there is partial replacement of AA in cell membranes by EPA as one of the important members of n-3 omega PUFAs which results in strengthening of the cell (Calder, 2003a,b).
The anti-inflammatory and cardioprotective functions of n-3 omega PUFAs improve the immune system. This improvement which is very important for immune system diseases such as HIV/AIDS, requires nutrients to power the immune system and support maximum cellular protection and function for long term survival. It can be clearly stated that, n-3 omega PUFAs have potential as an immune system defenders and enhancers in immune system deficiencies (Zimmerman, 1997).
PUFAs and cancer
As with cardiovascular diseases, one initial predisposing factor for cancer appears to be the fat composition of the diet. Whereas an increased ratio of saturated fatty acids in the diet leads to cancer, many researchers have determined the protective effect of dietary eicosanopentaenoic acid in diet against cancer in gastrointestinal origin. Increased concentrations of long chain fatty acids and eicosanopentaenoic acid (as the main constituents of n-3 omega PUFAs) protect against colorectal cancer (Nkondjock et al., 2003). Dietary supplementation with n-3 omega PUFAs has been shown to produce beneficial effects in patients with pancreatic cancer, by decreasing tumour formation (Gogos et al., 1998) and reducing weight-loss (Barber et al., 1999). Fish oil alone or soy bean and fish oil combined dietary supplementations produced an increase in body weight in a study on rats, indicating their potential for weight gain in cancer (Gavia et al., 2003). n-3 Omega fatty acid supplementation is very effective, not only as an antitumour agent but also in mediating the effects of nutritional interventions by prolonging life span, suppressing autoimmune diseases, decreasing tumourigenesis (Troyer & Fernandes, 1996) and tumour necrosis factor (TNF; a protein which is detected in high concentrations in various types of cancer which increases T suppressor cells) (Simopoulos et al., 1991).
Unlike the significant protective and suppressing effects of n-3 omega PUFAs in cancer and autoimmune diseases, n-6 omega PUFAs increase the risk of tumour promotion, indicating the advantages of olive and canola oils, which are low in n-6 omega (Wood et al., 1996). A 3 g daily supplement of flaxseed, which is a rich source of lignan and n-3 omega PUFAs, when combined with dietary fat restriction, results in decreased prostate specific antigen levels and proliferation rate in prostate cancer (Demark-Wahnefried et al., 2001). According to Moyad (2003), one of the initial causes of death in prostate cancer patients is cardiovascular disease rather than cancer. Thus, these patients with prostate cancer should increase their consumption of omega 3 fatty acids as well as maintaining a healthy weight and getting physical activity. The data relating to the protective effect of n-3 omega PUFAs against cancer is mainly determined by the following factors: the type of the cancer, metabolism, genes, sex, age and diet. Whereas n-3 omega PUFAs show their protective effect against cancer on metabolism by acting on the metabolism, high dietary LA (e.g. n-6 omega PUFAs) intake can elevate oestrogen levels in pregnancy, altering mammary gland morphology and expression of fat-and/or oestrogen-regulated genes and increasing breast cancer risk (Clarke et al., 1999). Theodoratou et al. (2007) found a significantly important association between n-3 omega PUFAs and colorectal cancer in a large scale meta-analysis, involving data from 1455 patients studied between 1999 and 2006 that, n-3 omega PUFAs decreased the risk of colorectal cancer whilst saturated fatty acids, namely palmitic, stearic and oleic acid increased the risk. Similarly, supplementing the diet of tumour-bearing mice with n-3 omega PUFAs was claimed to slow the growth of cancers including lung, colon, mammary and prostate, according to Hardman (2004). The author also indicates the importance of n-3 omega PUFAs as a complementary medicine which can improve the efficacy of cancer chemotherapy drugs such as doxorubicin, epirubicin, 5-fluorouracil, tamoxifen and of radiation therapy. Geelen et al. (2007), in their meta-analysis, involving fourteen studies, relating to colorectal cancer, suggested an evidence that n-3 omega PUFAs inhibited colorectal carcinogenesis but the authors also concluded that there is insufficient data available to definitively confirm this association.
According to Rose & Connolly (1999), a common feature of most of the mentioned cancer preventive activity of n-3 omega PUFAs is related to the inhibition of eicosanoid production caused by n-6 omega PUFAs. Another suggested effect mechanism of the cancer preventive effect is claimed as the inhibition of transactivation of transcription activator protein 1 (AP-1), a protein responsible from gene expressions that cause cell proliferation and tumour formation in cancer (Liu et al., 2001).
An important finding which conflicts with findings that claim n-3 omega PUFAs are significantly effective in reducing cancer risk belongs to MacLean et al. (2006). In their review, a total of thirty-eight articles with prospective cohort study design and different levels of exposure in the cohort were included. Interestingly, in their review, a large body of literature, spanning cohorts from many countries, did not provide evidence to suggest a significant association between n-3 omega PUFAs and cancer incidence. According to this meta-analysis in the review, dietary supplementation with n-3 omega PUFAs, as conflicting with many others, is unlikely to prevent cancer.
E. PUFAs, brain health and neurological disorders
Phospholipids make up 60% of the dry weight of the brain. An increase in phospholipid concentration of brain cell membranes has a significantly beneficial effect on the treatment of schizophrenia (Horrobin et al., 2002). New pharmacological mechanisms for the treatment of schizophrenia have included omega 3 fatty acids as well as partial dopamine D2-receptor agonism, glutamatergic agents and oestrogen (Fleischhacker, 2003). Phospholipids are also essential for neurone function, especially for synaptic structure and play a key role in the signal transduction responses to dopamine, serotonin, glutamate and acetyl choline. n-3 Omega PUFAs, by controlling the over-activity of T-cells and antiphospholipid antibodies may be effective in decreasing the severity of major depression events (Maes et al., 1993). The same relationship between low numbers of major depression incidents and high levels of omega 3 supplementation has been reviewed by Colin et al. (2003). On the other hand, these inflammatory processes mentioned above, may influence the levels of neurotransmitters, especially by decreasing serotonin levels. n-3 Omega PUFAs, by enhancing the production rate of serotonin, can also reduce the severity of depression (Maes et al., 2007; Song et al., 1998). In cases of depression, there are abnormally low levels of omega 3 PUFAs and EPA whilst excessive amounts of omega 6 PUFAs are seen. The unsaturated fatty acid components of phospholipids are abnormally low in depression, with deficits of eicosapentaenoic acid and other n-3 omega PUFAs and excesses of the n-6 omega PUFA (AA).Despite this, n-3 omega PUFAs can not be administered to the patients as an effective monothreapy to treat depression. However, adjuvant application of folic acid, S-adenosyl-methionine, n-3 omega PUFAs and l-tryptophan with antidepressants may be beneficial, particularly in people with both depression and dietary deficiency (Sarris, 2009). Hamazaki et al. (2005) examined the effect of n-3 omega PUFAs on catecholamines (adrenaline and noradrenaline). In a randomised, placebo controlled double blind study, daily doses of 762 mg EPA + DHA lowered the noradrenaline concentration in blood. Noradrenaline is an important catecholamine which closes vessels and increases blood pressure in many cases of stress and depression. This randomised, placebo controlled, double blind study is the only study, presently, as related to n-3 omega PUFAs and catecholamines. Hallahan et al. (2007) found significantly greater improvements in depression, suicidality and daily stresses by 1.2 g EPA or 0.9 g DHA supplementation as combined with psychiatric care for 12 weeks. Laure & Marc (2006) observed a progressive decline in anxiety as compared with placebo in patients who were given 3 g of EPA and DHA for 3 months as compared with patients receiving a placebo. Similarly, Yehuda et al. (2005) observed reduction of high cortisol levels back to normal values and remediation of sleep disturbances and anxiety during ‘test anxiety’(an anxiety which may be defined as incapacitating academic syndrome) in students supplied with 225 mg n-3 and n-6 omega PUFAs. Nemets et al. (2006) claimed highly significant therapeutic effects of 1 g day−1 supplementation of n-3 omega PUFAs for 16 weeks in children with childhood depression, between the ages of 6–12 years. Similarly, the same dose, 1 g EPA supplementation in twenty-four patients with depression, was claimed as beneficially effective in another double blind, randomised, placebo-controlled study (Frangou et al., 2006). According to a meta-analysis among randomised controlled trials by Freeman et al. (2006), although there is less evidence of benefit in schizophrenia, EPA and DHA may have some potential benefit in major and bipolar depressive disorder but the authors conclude that results remain inconclusive (Freeman et al., 2006).
Frasure-Smith et al. (2004) examined the relationship between depression and omega 3 and 6 serum levels in patients at the age of 54 years and older in the recovery period from acute coronary syndromes in a case control study. Depressed patients had significantly lower concentrations of total n-3 omega PUFAs and higher ratios of AA to DHA and AA to EPA. They also concluded that their study was a case control study and should have been supplied by both prospective studies and randomised trials.
Antalis et al. (2006) point out that lower levels of long-chain PUFAs, particularly n-3 omega PUFAs in blood have repeatedly been associated with a variety of behavioural disorders including attention-deficit/hyperactivity disorder (ADHD). They reported in their meta-analysis that one small randomised controlled trial with n-3 omega PUFA supplementation in depression in children found a small beneficial effect over placebo. Four placebo controlled trials showed uncertain benefits of n-3 omega PUFAs for children with ADHD while a single placebo controlled trials showed no benefit in autism or bipolar disorder. Reviewers also concluded an absence of studies examining the benefits for first-episode psychosis or schizophrenia in children and adolescents (Clayton et al., 2007). A very high dose, 10 g day−1 of EPA was claimed to ameliorate the symptoms of schizophrenia while AA had no similar effect (Peet et al., 1997). Unfortunately, this study was a small scale study so that two out of the five patients had been taken out of the study due to clinical deterioration. In one of very few studies related to the association of n-3 omega PUFAs and schizophrenia, Fenton et al. (2001) administered 3 g day−1 of EPA for 16 week in their double blind, controlled trials, involving eighty-seven patients, but found no difference in improvement in symptoms of schizophrenia and cognitive impairment. Joy et al. (2006) reviewed research findings related to the effects of PUFAs for people with schizophrenia between 1998 and 2002. Limited evidence supports a hypothesis suggesting that schizophrenic symptoms may be the result of altered neuronal membrane and metabolism and neuronal membrane structure and metabolism which are closely dependent on blood plasma levels of n-3 omega PUFAs and their metabolites. The authors of the meta-analysis indicate to the necessity of further large well designed, conducted and reported studies since the results in the field remain inconclusive with very little useful data.
According to Hibbeln (1998), the prevalence of depression is inversely related to the amount of fish consumed. Similarly, other groups have reported a decrease in the ratio of n-3 omega fatty acids to n-6 omega fatty acids in the plasma and erythrocytes of patients with major depression and a decreased n-3 omega fatty acid concentration in erythrocytes with an increased severity of depression (Edwards et al., 1998; Peet et al., 1998). Also, a lower DHA content in mothers milk and lower seafood consumption are associated with higher rates of postpartum depression while omega 3 PUFAs supplementation of the mothers diet improves psychomotor development, cognitive development and birth weight without the risk of negative nitrogen balance which is always caused by n-6 omega PUFAs (Morley, 1998; Hayashi et al., 1999; Woltil et al., 1999; Hibbeln, 2002). Unlike n-3 omega PUFAs, which decrease cytokine production and depression, n-6 omega PUFAs increase cytokine production and therefore, may also directly stimulate depression. However, indirect effects such as the metabolic disorders including cardiovascular diseases, immunological activation, cancer, diabetic complications and osteoporosis may lead to depression or be associated with depression. By protecting against cardiovascular diseases, inflammation, cancer and diabetes, n-3 omega supplementation appears to have the function of reducing the risk and severity of depression both directly and by alleviation of these disorders (Horrobin, 2001). Also, Dyall & Michael-Titus (2008) indicates that increased intake of long chain n-3 omega PUFAs, EPA and DHA may confer benefits in a variety of psychiatric and neurological disorders in neurodegenerative conditions, although the mechanisms underlying these beneficial effects are still poorly understood.
Finally, in the case of AD, various genetic, medical and environmental factors appear to be causative. The risk of AD increases, when one of these factors leads to a decreased cerebral perfusion, which causes an insufficient flow of blood to the brain. Thus, the beneficial effects of n-3 omega PUFAs can decrease the risk of AD by easing the flow of blood in the brain and central nervous system (Heininger, 2000).
n-3 Omega PUFAs and eye health
One of the fields which needs further investigation and evidence as related to the effects of n-3 omega PUFAs is on eye health. One disease of the eye which has been most studied is age related macular degeneration (ARMD), an illness that progressively degenerates the back of the eye (macula). There is also insufficient evidence with few prospective studies and no randomised clinical trials to support n-3 omega PUFAs routine consumption for ARMD prevention (Chong et al., 2008). However, Chiu et al. (2009) claim in their study that weekly consumption of two or three portions of fatty fish can be beneficial for ARMD patients. The claim is based on an 8-year study of 3000 patients who were given n-3 omega supplements and monitored for the possible development of macular degeneration. Findings determined ARMD 25% less likely among participants consuming a diet rich in omega 3 fatty acids, EPA and DHA. The authors concluded that the combined consumption of a diet rich in omega 3 with low glycemic index carbohydrates such as whole bread products rather than processed may diminish the risk of progression of the disease to the advanced state. Deficiency of n-3 omega PUFAs was also shown to be adversely effective especially on visual and neural function in preterm infants which may need to be supported by n-3 omega formulas since n-3 omega PUFAs rich formula supports for visual and cortical function significantly in such infants (Hoffman et al., 1993).
Causes of ARMD have still not been identified although any arterial plaque may also affect the delicate blood vessels in the eye. Because of such possibility, it is commonly believed that a low-fat diet, but rich in n-3 omega PUFAs could help to guard against ARMD. In one of the studies, testing this theory, 90 000 participants over the age of 50 years, were monitored over a 12-year period. Findings of the research claimed that high intakes of LA (n-6 omega PUFA), exist in beef, pork and lamb and high amounts and trans fat in margarine appeared to increase the risk of ARMD, while the participants who consumed n-3 omega PUFAs rich foods such as tuna were about 35% less likely to develop ARMD (Cho et al., 2001). Ouchi et al. (2002) evaluated the relationship between fatty acids and ARMD by comparing the fatty acid fractions within the red blood cell membrane and plasma of 11 ARMD patients and ten healthy individuals (controls). They determined that there was a higher AA and DHA in the controls than in the ARMD patients which indicates that PUFAs, vulnerable to free radicals and reactive oxygen species, easily peroxidised, may be related to ARMD induction. Another study that claims the beneficial effects of n-3 omega PUFAs on eye health was conducted by Seddon et al. (2001). In the case study with 349 individuals at the age of 55–80 years, a higher intake of vegetable, monounsaturated and polyunsaturated fats and linoleic acid (n-6 omega PUFA) in 8 years was claimed to be associated with a greater risk for advanced ARMD while diets high in n-3 omega PUFAs and fish were inversely associated with risk for ARMD when intake of LA was low. Opposite to the findings of mentioned studies which indicates to the beneficial effects of n-3 omega PUFAs on ARMD, any significant relationship between age-related maculopathy and dietary fat including n-3 omega was not detected in a large cross-sectional survey of 7883 participants aged between 40 to 79 (Heuberger et al., 2001). Confirming this, oral n-3 omega PUFA supplementation as 1000 mg day−1 did not make any effect on improving visual activity recovery time. The authors underlined the importance of combined use of n-3 omega PUFAs with photodynamic therapy for ARMD in order to improve retinal metabolic function only under this combined use up to an extent (Scorolli et al., 2002). Since n-3 omega PUFAs exert important effects on eicosanoid metabolism, membrane properties and gene expression, it is reasonable to hypothesise that maternal n-3 fatty acid intakes might have significant effects on infant visual function and neurodevelopmental status. There is also very limited data as related to the effects of n-3 omega rich nutrition and supplementation during postpartum period on visual acuity of infants. In one of these studies, 1.3 g n-3 omega PUFAs supplementation of lactating women for the first 4 months of postpartum also did not effect visual acuity of infants (Lauritzen et al., 2004). Similarly, DHA in algae origin, but with a lower dose (200 mg daily), was given to lactating women during the first 4 months of postpartum. It had no effect on either neurodevelopmental progress of the infants at 12 months of age 4 years or the visual function at 4 or 8 months of age (Jensen et al., 2005). Confirming these earlier findings, Gibson et al. (1997) claimed that, 200, 90 and 130 mg day−1 DHA supplementation of breast feeding women during the first 12 week of postpartum period did not effect visual acuity of the infants. No clear consensus exists in studies as related to the effects of n-3 omega PUFAs on infant visual function and neurodevelopmental status of infants while only a few available data suggest a modest effect (Jensen, 2006).
Findings clearly indicate that a definite effect of n-3 omega PUFAs on eye health can not be claimed because some of the findings, especially those based on findings of meta-analysis are conflicted while some of the researches needs further evidence of more prospective studies and randomised clinical trials in ‘n-3 omega and eye health relation’.