Oil for life to balance omega-3 polyunsaturated fatty acid in cell membrane phospholipids improving health condition and wellness.

Since the 1950¡¯s there has been a rapid global shift towards a diet linked to the chronic degenerative diseases such as Heart disease, Stroke, Cancer, Diabetes, Osteoporosis and Alzheimer, the major causes of ill health and death. There are many ways in which the modern diet triggers disease, but it appears likely that the most important mechanism is that it creates a pro-inflammatory climate within the body, enhanced by smoking, our low-energy lifestyle and obesity. Five out of six of 60-year-olds already have one or more of the chronic degenerative diseases. Most of these people will not yet know that they have the disease - because it has yet to become noticeable. Chronic degenerative diseases are slowly progressing conditions, a pre-illness growing little by little every day for years or decades until the clinical illness finally emerge, sometimes overnight.

 

 

Excessive and / or inappropriate oxidative and closely related inflammatory stressors are profoundly involved in tissue damage, the ageing process and most of the chronic degenerative diseases. Antioxidant and anti-inflammatory defence systems are required to maintain health, but the modern diet has increased our exposure to oxidative and inflammatory components, and simultaneously reduced the integrity and functionality of our defences against these stressors. Our body needs to have a strong anti-inflammatory / antioxidant defence system - in the same way as it needs a strong immune system. The main defence against free radical attack are antioxidant enzymes and antioxidant nutrients. Free radicals generated in cigarette smoke are known to deplete antioxidants, a mechanism by which cigarette smoking will promote vascular disease. Many plant foods contain antioxidants that survive cooking in a bio available form and are absorbed by the body. The olive fruit, being an important part of the Mediterranean diet, is a plant that has the potential of being a part of a strong antioxidant defences. Secoiridoids are a class of compounds found only in virgin olive oil that are strong antioxidants. One important molecule in this family is oleuropein, a bitter-tasting glycoside that is converted to p-hydroxyphenyl ethanol and 3,4-dihydroxy-phenyl ethanol. The mixture of these minor components works synergistic in their antioxidant defence as in Oil4Life Balance. The described biophenols are absorbed by our body and enter exclusively into lipoproteins containing cholesterol, protecting the lipoproteins from oxidation.

 

The polyunsaturated fatty acid linoleic acid (omega-6) and ¨¢-linolenic acid (short chain omega-3) from plant oils are essential to the human diet. Neither is synthesized endogenously and the omega-3/omega-6 families cannot be interconverted. ¨¢-linolenic acid may be convertred to the long chain marine omega-3 EPA and DHA in the body. However,

due to competition an omega-6 rich diet of plant oils may inhibit EPA and DHA production, leading to depleted levels of EPA and DHA in the plasma, although the minimum levels to prevent disease is obtained. Our early diet contained small, but approximately equal amounts of omega-6 and omega-3 fatty acids, whereas the modern Western diet today contains an excess of omega-6 due to high consumption of plant oils. This imbalance of omega-6 to omega-3 has been associated with increased risks of cardiovascular disease, neurodegenerative disorders and some cancers, including carcinoma of the breast. The observed increased risk of breast cancer in Japanese women over the past four decades correlates with an increased imbalance of dietary omega-6 to omega-3 ratio.

 

The membrane of our trillions of cells physically separates the intracellular components from the extracellular environment. The movement of water, nutrients and waste across the membrane can be either passive or active (energy required). The arrangement of hydrophilic heads and hydrophobic tails in the lipid bilayer allow the cell to control the movement of substances via transmembrane protein complexes such as pores and gates. The fatty acid present in membrane lipids come from the diet. Phospholipids are main components of cell membrane in our trillions of cells with a hydrophilic head and generally one saturated fatty acid and one polyunsaturated fatty acid (omega-6 or omega-3) as the hydrophobic tails. The length and the degree of unsaturation of fatty acids chains have a profound effect on membranes fluidity. Unsaturated lipids create a kink, preventing the fatty acids from packing tightly together, thus increasing the fluidity of the membrane and facilitating the exchanges of substances. Human cells constantly receive signals from other cells and from the environment, which they perceive, interpret and respond to with appropriate metabolic or physiological changes.

 

An unbalanced ratio of mega-6 / omega-3 in cell membrane phospholipids may create a pro-inflammatory climate within the cells. Inflammations are a key cause of pain. Phospholipase A2 frees EPA (omega-3) and aracidonic acid (AA; omega-6) located in the 2^nd position of the phospholipid molecule. The released AA and EPA are further oxidized by specific enzyme to eicosanoids, signaling molecules called prostaglandins, leukotrienes, thromboxane and prostacyclins. These hormone-like compounds are involved in tissue damage, inflammation and pain. The enzymatic releases of arachidonic acid (AA - omega-6) from membrane phospholipids enhance the synthesis of eicosanoids of the 2 and 4 series. These eicosanoids are pro-inflammatory products that in turn create pain, which is recognised by pain receptors and transmitted to the brain. On contrary the release of eicosapentaenoic acid (EPA ¨C omega-3) from membrane phospholipids enhance the synthesis of eicosanoids of the 3 and 5 series being less inflammatory. The networks of controls that depend upon eicosanoids are among the most complex in the human body. They exert complex control over inflammation and immunity systems, and are messengers in the central nervous system.

 

Menstrual pain is the most common gynecological complaint among female adolescents and young women. The high intake of omega-6 fatty acids in the western diet is reflected in the cell membrane phospholipids. Due to progesterone withdrawal before menstruation arachidonic acid (omega-6) are released, and a cascade of eicosanoids is initiated in the uterus. The inflammatory response mediated by these eicosanoids produces both cramps and systemic symptoms such as nausea, vomiting, bloating and headaches, including ischemia, pain and systemic symptoms of dysmenorrhoea. EPA and DHA, as in Oli4Life Balance, compete with arachidonic acid for the production of eicosanoids. In the uterus, this competitive interaction between omega-3 and omega-6 fatty acids may result in the production of less potent eicosanoids and may lead to a reduction in the systemic symptoms of dysmenorrhea.

 

The arachidonic acid metabolism is also altered in psoriasis. Proinflammatory leukotrienes (LTB4) are markedly produced in the psoriatic lesions. Fish oil and omega-3 fatty acids are known to decrease the production of LTB4, a metabolite of arachidonic acid produced by activated neutrophils. Fish oil supplementationas in Oli4Life Balance offers an opportuinity in management of psoriasis and inflammatory skin disorders with negligible side effects.

 

The immune system must be ready to mount acute inflammatory reactions to kill invading micro-organisms, but it should not be so over-reactive as to create chronic inflammations which damage the host. Asthma is a chronic inflammation of the airways, which in many cases is considered to be due to an allergic reaction. The immune system learns to react to the allergen and starts the chronic inflammatory process. The rate of asthma increases as communities adopt western lifestyles and become urbanised. Diet is deeply implicated due to reduced intake of inflammation-damping elements like the flavonoids, sterols and omega 3 fatty acids, and the simultaneous increase in intakes of pro-inflammatory compounds. Potential therapeutic uses of prostaglandins include relief of asthma. A mixture of eicosanoids of the 4 series (LTC4, LTD4 and LTE4) is a potent constrictor of the bronchial airway musculature. They are also important regulators in many diseases involving inflammatory or immediate hypersensitivity reactions, such as asthma.

 

The analysis of fatty acid composition of phospholipids in red blood cell (RBC) membranes allows us to obtain relevant information about diet fatty acids deficiency, eicosanoids biosynthesis and eventual metabolic abnormalies. However, this marker analysis require a long lasting procedure. In our laboratory we have developed and tested a time saving and reliable method to determine AA/EPA and omega-6/omega-3 ratios in whole blood. Our method of AA/EPA ratio in whole blood demonstrate a good correlation with erythrocyte phospholipids composition and a significant correlation with the AA/EPA value of RBC membranes. This reliable biomarker method of dietary fat intake are at present being commercialised by the Itogha group under the brand name of Test4Life. The AA/EPA ratio may be considered a predictor of health status for risks of diseases such as cardiovascular disease (CVD), diabetes, chronic inflammation and depression, as well as an index of well-being. The Test4Life analysis can give information on cellular membrane fatty acid status and potential error in eicosanoid biosynthesis. Test4Life is a reliable and low-time consuming assays to establish a fatty acid balance for dietary advice and in the prevention and control of chronic diseases.

 

The AA/EPA ratio found in healthy Italian subjects without omega-3 supplementation is high and comparable to data reported for the Western population, indicating an unbalanced omega-6/omega-3 fatty acid intake, leading to a subsequent imbalance in membrane composition and the eicosanoid biosynthesis. We have also observed that patients with allergic-, skin- and neurodegenerative diseases have higher values of the AA/EPA ratio than other pathological subjects.

 

About 7% of children between the ages of 5-11 years have been diagnosed with Attention Deficit Hyperactivity Disorder (ADHD). General consensus is that many genes are involved in the transmission of the disorder. Diet may be an ethiological risk factor for ADHD. Abnormalities in PUFA metabolism in red blood cell membranes has been reported in children with ADHD, having lower levels of long chain omega-3 fatty acids (EPA+DHA) in their blood due to lack of dietary intake in conjunction with a more rapid metabolism. Our studies have highlighted a deficiency of the long chain omega-3 fatty acids in the membrane phospholipids of patients affected with ADHD. The AA/EPA-ratio in phospholipids in blood and in RBC membranes was elevated, indicating an increased upstream inflammatory potential. In our study of 30 children with ADHD the diet were supplemented with 2.5 mg /10 kg/day of EPA+DHA 2:1 as in Oil4Life Balance. The supplementation of EPA and DHA in relatively high doses compared to body weight, verified that an improved AA/EPA balance in the cell membrane increased attention level and decrease both hyperactivity levels and impulsiveness. There was a correlation between the dose of long chain omega-3 fatty acids, the decrease of AA/EPA ratio and/or the entity of the clinical improvement. Our data are in agreement with the results obtained by different Authors.

 

Depletion of omega-3 fatty acid levels in red blood cell membranes of depressed patients has been reported. A significant positive relationship was observed between the severity of the illness and the AA/EPA ratio in serum phospholipids and in erythrocyte membranes. Preliminary results in our laboratory on depressed elderly patients demonstrated that counteracting and balancing high levels of AA with EPA+DHA 2:1, as in Oil4Life Balance, also decreased depression symptoms. Several authors have also reported lower concentrations of erythrocyte essential fatty acids among schizophrenic patients as compared with control. DHA is the major acid of neurological and retinal membranes. It makes up more than 30% of the structural lipids of the neuron. Low levels of circulating DHA may be a significant risk in the development of Alzheimer dementia. The inability to maintain a high level of DHA may be due to a reduced capacity to synthesise DHA late in life, as the result of a reduction in Ä-6-desaturase activity. Alterations in phospholipids, which are structural components of all cell membranes in the brain, may induce changes in membrane fluidity and, consequently, in various neurotransmitter systems that are believed to be related to the pathophysiology of major depression.

 

Executive Summary                                                                                                                                                                            Greenland Eskimos with a traditional diet consisting of substantial amounts of meat and fat (blubber) from seal and whales have reduced mortality due to CVD, in contrast to high frequency of cardiovascular and other inflammatory diseases in Western populations. Significant vascular benefits from modest fish consumption are also observed, both when consuming fatty fish with relatively high amounts of n-3 LC-PUFAs and lean fish with relatively small amounts of n-3 LC-PUFAs. Thus, it is likely that interactions of n-3 LC-PUFAs and other nutrients found in fish and mammalian animals play important roles in physiologic and biologic metabolisms related to cardiovascular function.

 

By mimicking parts of the traditional Eskimo diet we have since 1990 performed various studies of the effects of intake of fish, seal and whale oils and the n-3 LC-PUFAs, EPA and DHA, in healthy human volunteers. The endpoints of our studies have been measurements of serum fatty acids, lipids, lipoproteins and various parameters associated with cardiovascular/ thrombotic diseases.

 

The studies have revealed that there are other beneficial components of relevance for cardiovascular diseases in marine oils in addition to n-3 fatty acids. Non-refined marine oil have additional positive effects on parameters related to development of CHD despite a lower content of n-3 LC-fatty acids. Non-refined whale oil gave for instance, compared to refined marine oils, an increase of high density lipoprotein (HDL) cholesterol of 11%, a reduced concentration of prothrombin fragment 1 + 2 of 25%, a reduction of tumor necrosis factor (TNF) generation in lipopolysaccharide (LPS)-stimulated blood of 30%. The LPS-induced tissue factor (TF) activity in monocytes was reduced by 35%, and the most dramatic change was in thromboxane B₂ in LPS-stimulated blood with a 44% reduction. The supplementation of a regular diet with non-refined marine oils, especially with non-refined whale oil, have beneficial effects on several products associated with cardiovascular and thrombotic diseases. The content of n-3 LC-PUFAs in non-refined whale oil is less than halve compared to fish oil, while the content of monounsaturated (18:1 and 20:1 n-9) fatty acids are comparably enhanced.

 

The effect of protective substances of CHD in seafood and marine oils disappears when these products are subjected to rough processing conditions such as cooking or refining. Removal of molecules to improve sensory attributes or safety of the oil destroy potent antioxidants and remove components with potential beneficial effects. This supports our hypothesis that n-3 fatty acids are not the only products of the traditional Eskimo diet preventing cardiovascular diseases.

 

The health benefits of Mediterranean diets are a synergism of phytochemicals and fatty acids, providing a significant decrease in inflammatory markers after extra virgin olive oil consumption. Particularly the minor phenolic compounds are documented to contribute to the health benefits. Phenolic compounds of olive oil are dose dependently absorbed to modulate the LDL phenolic content, and the oxidative stress after food consumption. The phenolic metabolites are able to bind to LDL and to act as in vivo antioxidants. Preventing the oxidation of omega-6 and omega-3 fatty acids, which are also incorporated in LDL-particles, may prevent foam cell formation in the intima, the early event in atherogenesis. These antioxidants are also important in the downregulation of eicosanoid-metabolism. The lipoxygenase pathway leading to e.g. leukotriene B4, is well known to be inhibited by antioxidants with the resultant reduction in LTB4 production. Inhibition of the LTB4 receptor in transgenic mice predisposed for atherosclerosis reduce lesion formation by 70 % (Østerud et al., 2007 unpublished results). 

 

During the development of OliVita, a special extra virgin olive oil containing vast amounts of monounsaturated fatty acids, antioxidants and anti-inflammatory agents was discovered. A combination of refined seal oil (fish oil) and our special extra virgin olive oil may be regarded as an ¡°artificial ¡° or blended non-refined whale oil. The combination of fatty acids resembles the whale oil and the special extra virgin olive oil deliver the antioxidants and anti-inflammatory agents lost during refining of marine oils. In the OliVita study we compared the most promising combination of oils (seal and our special extra virgin olive oil) with marine oils such as refined cod liver oil (CLO) and refined seal oil (SO).

 

During the OliVita study the oils were consumed as liquid (15 ml/day) as a supplement to regular diet. Blood samples were analyzed for a series of test parameters like fatty acids and lipids in serum, some coagulation test parameters as prothrombin fragment 1+2 (thombin generator indicator), adhesion molecules and inflammatory products as monocyte chemotactic protein-1 (MCP-1), hypersensitive CRP (hsCRP) and lipopolysaccharide (LPS)-induced cytokines. The major results are that in contrast to refined CLO, intake of OliVita give a significant reduction in hsCRP and MCP-1, which imply that the inflammatory reactions in the subjects are altered in a very positive way. Furthermore, HDL-cholesterol, the good cholesterol, is increased by about 8 percent in groups consuming OliVita. This confirms our earlier observation that marine oils from blubber of mammalian animals have a very good effect on HDL-cholesterol. Production of thromboxane B2 and leukotriene B4 are reduced by both CLO and OliVita. The major difference between fish oil in combination with our special extra virgin olive oil (Oil4Life), as compared to OliVita, is a significantly higher rise in the good HDL-cholesterol when consuming OliVita.

 In conclusion, we have documented that a combination of a marine oil and our special extra virgin olive oil are superior to refined marine oils, even if the content of omega-3 fatty acids are halved. Thus, we have partly been able to mimic a non-refined whale oil, which was an important part of the traditional Eskimo diet.