The Biological Significance of DHA

Sue McGarrigle -  ND, DipION, CNHC  Registered,  MBANT

It has been estimated that the ratio of omega-6 to omega-3 fatty acids in the diet of early humans was 1:1; however we now know this all-important ratio has altered, leading to an overwhelming increase in Omega 6 in the Western diet. The need for arachidonic acid (ARA), which is utilized for eicosanoid synthesis and is a constituent of membrane phospholipids involved in signal transduction, is the main reason why the Omega 6 class of Polyunsaturated Fatty Acids (PUFA) is essential but ARA’s involvement is also in the metabolism of the pro-inflammatory series 2 prostaglandins. Professor Michael Crawford, Director of the Institute of Brain Chemistry and Human Nutrition, is convinced that the current ratio which varies up to 30:1 Omega 6 to Omega 3 in the diet is a major cause of many of the ‘diseases of civilisation’ and the cause of most inflammatory disease including  cardiovascular disorders. 

Over the years there has been extensive coverage in Omega-3 research of the role of eicosapentaenoic acid (EPA) particularly with respect to  inflammatory response. By implication, this has tended to downplay the essential role of docosahexaenoic acid (DHA). It is not the intention of this article to dismiss EPA but simply to redress the balance of understanding between DHA and EPA by explaining the functional essentiality of DHA. 
Although EPA also is a substrate for eicosanoid synthesis, DHA is an essential fatty acid universally needed in neurological tissues, for vascular tissue and is required for the maintenance of the central nervous system, the development of the brain and for visual function. However DHA and its metabolites have a number of newly recognised multifunctional roles to play in other vital biochemical functions beyond that of simply being the major structural  component in many biological membranes. DHA may have an integral role in modulating many vital intra-cellular activities. 

The brain is 60% fat, of which DHA is one of the most important components. DHA is essential for brain and eye function as it is highly concentrated in membranes of brain synapses in phospholipids and in the retina of the eye. The composition of the lipids critical for the signalling processes that  eventually led to the development of the human brain has hardly changed. Specifically DHA has been structurally and functionally fixed in photoreceptors and synapses since that time. DHA is a vital component of the photoreceptors responsible for receiving light photons and sending image messages to the brain and some 30%-50% of the retina is made from DHA.

While DHA which has remained unchanged for between 500 and 600 million years, ‘the conditions of existence’, to quote Charles Darwin, have changed constantly.  For as life forms have evolved they have done so within an environment which is itself evolving. Professor Crawford has argued that DHA and, more generally, membrane lipids (fats), can be seen as the masters of DNA. For we now know that DHA, which has always been rigidly entrenched in vision, neural transmission and cellular organisation, is also a regulator of selective gene expression by direct and indirect actions on nuclear factors. 

Cardiovascular disease has risen alongside Cancer. Obesity is now a major health issue. Western man has thus changed in shape, size and disease pattern in one century. In the evolutionary timescale this is the “blinking of an eye”. Professor Crawford and others believe that the changing lipid  composition of the diet has been a major contributor to this change in body shape and disease pattern. Despite many changes in DNA and in other aspects of cephalopods, fish, amphibia, reptiles, birds, mammals, primates and humans, the rigid, unchanging 600 million year track record of DHA suggests that it is the ‘selfish DHA’, not the ‘selfish gene’, that has been most powerful.

This, Crawford explained, is the meaning of the term epigenetic - the power of environmental pressures to change the behaviour (or expression) of DNA. Thus, although its structure remains unchanged, environmental pressures on the genome will cause it to produce more or less of specific proteins, thus causing generational change in different tissues and organs. 
We are still adapted for a wild food diet that differs enormously from modern food. There are fewer calories and less fat in the wild forms of currently farmed animals and fish and what fat there is consists of a much higher proportion of polyunsaturated fatty acids (PUFAs).  As we have moved from the wild to extensive animal husbandry, to selection for fast growth and intensively fed systems, the proportion of visible fat, and fat within the muscle tissue of the animals we eat, which is mostly saturated fat, has increased. Over this period the total proportion of calories derived from all fats has doubled to some 40%.

For centuries, fishing communities all over the world have used fish oil for various purposes and it has gained wide acceptance for its health benefits. In the second half of the last century the rapid increase in the prevalence of coronary heart disease and stroke occurring in the developed world stimulated epidemiological and laboratory based research which has greatly increased understanding of the underlying factors which promote or interfere with the healthy development of the cardiovascular system.  

In the early 1970’s a Danish study on Greenland Eskimos revealed that the rarity of ischemic heart disease and decreased thrombous tendency in this population could be linked to the ingestion of omega-3 fatty acids, the researchers concluded that the real reason for this was ironically, the high-fat but Omega 3 rich fish diet that the Eskimos consumed. Although fish oil has been widely used and widely recommended for its health benefits it is now being recognised that DHA is responsible for many of the benefits. 

DHA is present in every cell in your body, in the membrane of mitochondria that make energy and these are especially concentrated in heart muscle cells. The antiarrhythmic effect of dietary fish oil appears to depend more on the accumulation of DHA in myocardial cell membranes than EPA, indeed, even at low dietary intake, DHA but not EPA inhibits ischaemia-induced cardiac arrhythmias. Although fish oils often contain mainly EPA, the myocardium, including mitochondrial membranes, accumulates DHA as the principal n-3 PUFA, even after feeding purified EPA. Research has found that the DHA fraction of fish oil dramatically alters the mitochondria in the heart muscle increasing healthy heart energy production. Researchers found that DHA  activates the gene PPAR to help prevent the increasing incidence of heart failure and risk from a deadly heart attack.  

Many of the mechanisms that increase incidence of a heart attack also contribute to stroke risk.  DHA becomes incorporated into the cell wall structure where it stabilizes existing plaque, making it less likely to break off and cause a stroke. DHA has been shown to help blood flow more easily, increasing red blood cell membrane fluidity, lowering  the risk for clotting and appears more effective in lowering blood pressure than EPA.  DHA inhibits transcription factor NF−κB (reducing formation of pro-inflammatory cytokines). One study found fish oil higher in DHA than EPA lowered inflammatory cytokines, such as IL-6 and IL-1β, associated with neurodegenerative and autoimmune diseases. Both DHA and EPA plasma concentrations increased significantly for participants.

DHA decreases the concentrations of fasting and postprandial triglycerides, small dense LDL particles, remnant-like chylomicron particles, and  inflammatory markers and increases the concentrations of large HDL and LDL particles. In a study of hypertriglyceridemic men, it showed that DHA, in the absence of EPA, significantly reduced the number of circulating neutrophils and serum CRP and GM-CSF and increased the concentration of MMP-2. The maximum effect of DHA on the number of circulating granulocytes was attained within 45 days, whereas significant effects on serum CRP and  MMP-2 were found at 91 days. To determine the effect of DHA supplementation on the global gene expression pattern, researchers performed Affymetrix GeneChip microarray analysis of blood cells (treated with lipopolysaccharide (LPS) or vehicle) drawn before and after the supplementation of DHA from the hypertriglyceridemic men who participated in that study. Results provide supporting evidence for the anti-inflammatory effects of DHA  supplementation, and reveal previously unrecognized genes that are regulated by DHA, and are associated with risk factors of cardiovascular diseases.

DHA also provides protection in reducing the hazards of immune-suppression. EPA is physiologically important but at high levels of supplementation may exert a competitive inhibitory effect upon DHA metabolism in certain individuals. Incorporation of certain fatty acids into cell membranes affects second-messenger systems (molecular signalling systems within cells) that can modify gene expression. An experiment that studied the individual effects of EPA and DHA found that EPA reduced natural killer (NK) cell activity and cell-mediated immune response, but that DHA does not. This study concluded that the immune-suppressing effects of fish oil are mainly due to EPA, not DHA. DHA does play a vital role within the immune system influencing the activity of adhesion proteins on the lipid membrane environment, communication between leukocytes and the body, and the regulation of smooth muscle contraction.

DHA only, is significantly associated with tumour response in breast cancer and was shown to be an independent predictor to chemo-sensitivity, suggesting that DHA may increase breast tumour response to cytotoxic drugs. A new study found that higher intake of DHA was associated with slower rates of telomere shortening, which is a basic DNA-level marker of aging. Most DHA comes from our diet. Fish are the major food source of EPA and DHA. All fish contain EPA and DHA; notwithstanding the issues involving contaminated fish which has influenced our choices, the quantities do vary among species and within a species according to environmental variables such as diet and whether fish are wild or farm-raised. The brain cannot synthesize enough DHA from a-LNA to maintain a normal DHA composition, but must be provided by dietary DHA or DHA that has been converted from a-LNA by the liver, to maintain its normal DHA concentration.

Very small amounts of DHA may be made in the body from ALA, but the amount made is probably low due to a number of factors. There are some individuals who are more efficient at converting ALA ultimately to DHA (e.g. some vegetarians and vegans) but the majority of Westerners are poor converters and adults and children alike who follow a low fat, low fish diet often miss out on beneficial Long Chain PUFA’s. Factors include a lack of the vitamins (B3, B6, C) and minerals (zinc, magnesium) which are necessary for conversion, a  lack of enzymes through competition; Linoleic acid (LA )and Alpha Linolenic Acid (ALA) compete for the same elongase and desaturase enzymes in the synthesis of longer polyunsaturated fatty acids, such as ARA and EPA. Although ALA is the preferred substrate of the delta-6 desaturase enzyme, the excess of dietary LA compared to ALA results in greater net formation of ARA (20:4n-6) than EPA (20:5n-3), and this can also happen in ageing.  

In addition the better conversion efficiency of young women compared to men appears to be related to the effects of oestrogen. Many behavioural disorders, such as ADHD, dyslexia, dyspraxia and autism are more common in males than females. Although ALA is considered the essential omega-3 fatty acid because it cannot be synthesized by humans, evidence that human conversion of EPA and, particularly, DHA is relatively inefficient suggests that EPA and DHA may also be essential under some conditions. Other nutritional factors and toxic influences have a negative role and there is evidence that high carbohydrate diets slow down conversion, whereas diets higher in proteins enhance conversion. Impaired liver function where DHA synthesis occurs, impaired metabolic pathways due to viral and bacterial infection/damage also contribute to the conversion reduction/blockage.

A practical way to significantly increase DHA levels is to take a supplement that delivers higher levels of DHA. ALA to EPA to DHA is minimal when you consider the requirement during pregnancy for example. Hormones during pregnancy increase conversion, something that evolved out of necessity as DHA is vital for foetal brain development and immune health. Sperm are also DHA rich particularly in the tail. The Department of Food Science and  Human Nutrition at the University of Illinois recently reported from a 2011 study that DHA is necessary to construct the arch that turns a round, immature sperm cell into a pointy-headed super swimmer with an extra-long tail. “Normal sperm cells contain an arc-like structure called the acrosome that is critical in fertilization because it houses, organizes, and concentrates a variety of enzymes that sperm use to penetrate an egg," said Manabu Nakamura, an Associate Professor of Biochemical and Molecular Nutrition.

The study shows for the first time that DHA is essential in fusing the building blocks of the acrosome together. "Without DHA, this vital structure doesn't form and sperm cells don't work," said Timothy Abbott, a doctoral student who co-authored the study. The scientists became intrigued with DHA's role in creating healthy sperm when they experimented with "knockout" mice that lack a gene essential to its synthesis.  "We looked at sperm count, shape, and motility, and tested the breeding success rate. The male mice that lacked DHA were basically infer-tile," Nakamura said. “But when DHA was introduced into the mice's diet, fertility was completely restored. It was very striking. When we fed the mice DHA, all these abnormalities were prevented," he said.

The scientists then used confocal laser scanning (3D) microscopy to look at thin slices of tissue in progressive stages of a sperm cell's development. By labelling enzymes with fluorescence, they could track their location in a cell. "We could see that the acrosome is constructed when small vesicles containing enzymes fuse together in an arc. But that fusion doesn't happen without DHA," Nakamura said.  “In the absence of DHA, the vesicles are formed but they don't come together to make the arch that is so important in sperm cell structure”, he noted. Nakamura finds the role this omega-3 fatty acid plays in membrane fusion particularly exciting. Because DHA is abundant in specific tissues, including the brain and the retina as well as the testes, the scientists believe their research findings could also impact research relating to brain function and vision. " It's logical to hypothesize that DHA is involved in vesicle fusion elsewhere in the body, and because the brain contains so much of it, we wonder if deficien-cies could play a role, for example, in the development of dementia.

Any communication between neurons in the brain involves vesicle fusion," he noted. The Illinois scientists will continue to study sperm; meanwhile, Nakamura has sent some of his DHA-deficient knockout mice to other laboratories where scientists are studying DHA function in the brain and the retina.  Nakamura also stated that if DHA-synthesizing enzyme is defective, it could lead to problems with infertility. Low blood levels of DHA have been linked to decreased fertility in the past; some groups may have a decreased ability to synthesize DHA and in these cases dietary supplements may help. The greatest dependence on dietary DHA occurs in the foetus during the last third of pregnancy and (to a lesser extent) in the infant during the first 3 months after birth. It is during this period that brain synapses are forming most rapidly, and an infant's demand for DHA exceeds the capacity of the en-zymes to synthesize it. The additional requirements are fulfilled by mechanisms believed to concentrate DHA absorption from the mother's placenta.  

At the Food and Behaviour Expert Research workshop 2007 held under the aegis of the McCarrison Society and FAB Research, an extract from a more detailed report by the editor of the McCarrison Society Journal, David Marsh reveals the following: Dr Joseph Hibbeln, chief of the Outpatient Clinic at the National Institute on Alcohol Abuse and Alcoholism in Maryland, USA, detailed the work he has done on the Avon Longitudinal  Study of Parents and Children (ALSPAC) survey findings in relation to the consumption of seafood by pregnant mothers. From 1991, the ALSPAC team, under Jean Golding, has followed some 8,000 children, recording, amongst much other data, omega 3 fatty acid consumption, particularly DHA from fish.  The early 1990s saw the outbreak of bovine spongiform encephalitis (BSE) and foot and mouth disease followed by warnings about the degree of pollution in fish. Fish we were advised were laden with methyl mercury, PCBs and other chemicals.

Warnings were flashed across the media: pregnant mums could not eat more than two portions of fish a week without risking foetal damage. The then Ministry of Agriculture, Fisheries and Food repeated the advice which had come, initially from the US Federal Drugs Administration. It is likely that those women who heeded the advice may have suspected, as a result, that there was something bad about fish, so they may well not have eaten any at all. In February this year Dr Hibbeln published his analysis of maternal diet compared with the children’s learning and behavioural characteristics at the age of eight. The results were extraordinary. The study makes it clear that those mothers who followed government advice and consumed two portions of fish a week or less had children whose test scores were low and who suffered from problems with verbal IQ, fine motor skills and social development. Mothers who ignored the advice and ate ‘normal’ amounts of fish had children who scored highly and had a significantly lower incidence of developmental problems. The advice had been based on the assumption that increased intakes of fish would lead to increased intakes of methyl mercury. Yet there was no attempt to balance the increase in methyl mercury with benefit. Moreover, the evidence of harm had come from the use of mercury as a fungicide for seeds - not from its consumption in fish. There is evidence that lower DHA levels are associated with a shorter gestation length and a greater risk of preterm delivery. The lower the birth-weight the greater is the risk of brain disorders.

In a double-blind, randomized placebo-controlled trial, children born to mothers who were supplemented with fish oil (2.2 g DHA and 1.1 g EPA) during pregnancy (20 weeks' gestation until delivery) displayed higher scores of eye and hand coordination at 2 1⁄2 years of age compared to children whose mothers were supplemented with olive oil. Research from Paediatrics 2011 reported that a sample of 1094 pregnant women in Mexico was assigned to daily supplementation of DHA capsules (400 mg/day) or placebo capsules from 18 to 22 weeks gestation to childbirth. Mothers or caregivers completed 15-day recall questionnaires on common illness symptoms experienced by the infants at one, three, and six months of age. Birth outcomes, rates of exclusive breastfeeding, and rates of infant death were similar in both groups, but occurrence and duration of illness symptoms were at times markedly different.

At one month of age, the DHA group experienced reduced cold occurrence and shorter durations of cough, phlegm, and wheezing. The DHA group also experienced fewer illnesses overall at one and three months of age. At 3 months of age, infants in the DHA group spent 14% less time ill than children in the placebo group, and at six months of age, infants in the DHA group experienced shorter duration of nasal secretion, difficulty breathing, fever, and rash. Exceptions to DHA improving illness factors included longer duration of rash at one month of age and longer duration of vomiting at six months of age.

Tuna is a good source of preformed DHA and the ratio of the Omega 3's is DHA/EPA, which is interesting as Tuna consumption by the Japanese is very high and they have population per head higher IQ's than us in the Western World. According to the World Health Organisation the Japanese and Icelanders are the two nations with best birth weights and longevities. The approximately equal presence of omega-3 and omega-6 fatty acids in the brain has led to the view among some researchers that dietary intake of the two should ideally also be balanced equally and a number of scientists working in the field of nutrition believe this ‘imbalance’ has important consequences for our mental health. Studies over the last three decades have provided evidence that depletion of DHA from the developing retina and brain leads to abnormalities in electroretinogram and visual evoked potential (VEP) responses and learning behaviours.

DHA plays an important role in the regeneration of the visual pigment rhodopsin, which plays a critical role in the visual transduction system that converts light hitting the retina to visual images in the brain. Changes in DHA content of neuronal cell membranes could alter the function of ion channels or membrane-associated receptors, as well as the availability of  neurotransmitters. Ion channels are present in the membranes that surround all biological cells, ion channels are key components in a wide variety of biological processes that involve rapid changes in cells, such as cardiac, skeletal, and smooth muscle contraction, epithelial transport of nutrients and ions, T-cell activation and pancreatic beta-cell insulin release. When DHA is in short supply, other fatty acids - especially saturated fats - are incorporated into the nerve cell membranes instead. As these are more rigid, however, nerve cell membranes become less flexible and less efficient in passing on electrical and chemical messages.

As a result, the speed of communication between one brain cell and another is slowed. Dopamine concentration and receptors are diminished. Deficits in DHA abundance are associated with cognitive decline during ageing and homeostatic regulation of brain cell survival and repair. One candidate mechanism by which brain DHA deficiency may increase risk for major depression, impulsive behaviour and suicide is by altering central 5-HT neurotransmission and CSF 5-HIAA levels. Male and female patients with Major Depressive Disorder and Bipolar Disorder exhibit selective erythrocyte DHA deficits relative to healthy controls.

Depression is also a common clinical symptom of hypocalcaemia and one of the common findings in depressed patients is an increase in intracellular calcium. DHA has been shown to lower stimulated increases in intracellular calcium and further, calcium channel blockers have been found to be  effective in certain mental disorders. This is possibly due to their masking the negative effects of membrane DHA depletion on calcium metabolism.  DHA metabolites of CYP450 are known to be the most potent vascular BKCa channel activators and vasodilators thus far recognized. Findings indicate that the vasorelaxation effects of DHA on vascular smooth muscle cells are mainly due to its activation of BKCa channels.

Tissue and behavioural responses to induced tissue brain injury (TBI) have been compared between groups of treated animals. The tissue damage caused by TBI was significantly reduced in rats taking the highest dose of DHA: 40 milligrams per kilogram of body weight. Results raise the possibility of preventive treatment with DHA in groups at high risk of TBI, such as military personnel and athletes in contact sports - including football players. Cellular findings included a significant reduction in expression of a protein (beta amyloid protein) that has been implicated in the development of Alzheimer's  disease.

DHA has been shown to induce a 10-fold increase in transcription of the amyloid-ß-scavenger transthyretin. DHA supplementation has a significant role in the prevention of neurological and chronic diseases. However that does not mean that it would not be required once a disease process is established. DHA is required for general cell membrane function, so therefore is essential regardless of what stage it is used, from birth into old age.

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