Introduction 

Ancient hunter-gatherer populations subsisted on a diet much lower in saturated fatty acids than is today’s diet. The ancient diet contained small and roughly equal amounts of two types of polyunsaturated fatty acids (PUFAs) – linoleic acid (LA) and alpha-linolenic acid (ALA) with lower amounts of trans fatty acids. The current Western diet is very high in n-6 (Omega-6) fatty acids (ratio of n-6 to n-3 fatty acids is 20-30:1). Decrease in fish consumption coupled with industrial production of animal feeds rich in grains containing n-6 fatty acids is leading to production of meat rich in n-6 and poor in n-3 (Omega-3) fatty acids.

Even cultivated vegetables contain fewer n-3 fatty acids than do plants in the wild. Modern agriculture driven by the goal to produce is suggested to have decreased n-3 fatty acid content in many foods: green leafy vegetables, animal meats, eggs and even fish. These dietary composition alterations, deficiencies and other environmental changes are contributing to diet-related diseases like cardiovascular disease (CVD), brain disorders and other diseases.

Essential Fatty Acid Metabolism and Function 

Linoleic acid (LA) and alpha-linolenic acid (ALA), the parent essential fatty acids (EFA), cannot be synthesized in the human body and diet is the only source of them. After ingestion, both linoleic acid (LA) and alpha-linolenic acid (ALA) are converted into long-chain metabolites known as long-chain polyunsaturated fatty acids (LCP) through chain elongation, desaturation and chain-shortening. The most important long-chain polyunsaturated fatty acids of the (n-6) fatty acid series is arachidonic acid (AA). Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the major long-chain polyunsaturated fatty acids of the (n-3) fatty acid series. Long-chain polyunsaturated fatty acids may also be derived from diet – AA from meat and EPA and DHA from fish.

Brain and retina are rich in AA and DHA, which are important building blocks of structural lipids. Long-chain polyunsaturated fatty acids in phospholipids contribute to membrane properties like permeability, fluidity and flexibility. For instance, DHA in retina and postsynaptic membranes is crucial for adequate functioning of embedded proteins like rhodopsin for vision and postsynaptic receptors (protein molecules on the nerve cell membrane) for transmission of nerve impulses across the nerve cells. AA, EPA and dihomo-gamma-linolenic acid (DGLA of omega-6 series) give rise to highly potent regulatory hormones collectively known as eicosanoids. These short-lived chemicals play vital roles in inflammatory reactions, blood pressure control and platelet (a type of blood cell) aggregation. In recent years, polyunsaturated fatty acids (PUFA), long-chain polyunsaturated fatty acids and their derivatives are getting attention from researchers, as these chemicals are believed to modulate the expressions of genes.

Brain and Essential Fatty Acids

It is now well established that 60 percent of the non-water content of the human brain is fat. About 20 percent of the brain’s dry mass is made of four unsaturated fatty acids – EPA and DHA from the omega-3 series, and DGLA and AA from the omega-6 series. These fats have unique biological properties due to partly the number of double bonds in their long carbon chains. On the other hand, saturated fats have no such double bonds while monosaturated fats such as oleic acid, found in olive oil, have just one double bond.

AA and DHA are main constituents of neuronal membranes. AA and DHA make up 15-20 percent of brain’s dry mass and more than 30 percent of the retina. During prenatal development, adequate supply of highly unsaturated fatty acids (HUFA) is essential. Studies have shown that the placenta doubles the levels of highly unsaturated fatty acids in maternal plasma to meet the needs of the growing fetal brain.

Brain gray matter continues to expand till the age of 12. Adding DHA to diets of children under 12 may be a way to replenish this fatty acid in their brains, influencing cognitive function.

DHA is particularly concentrated in highly active sites such as synapses and photoreceptors. It is essential for normal visual and cognitive development. In early life, highly unsaturated fatty acids are essential in supporting further brain growth and maturation and are therefore found in breast milk. Studies comparing the effects of infant formula with and without pre-formed highly unsaturated fatty acids have shown clear advantages of adding highly unsaturated fatty acids for both visual and cognitive development of infants. 

Highly unsaturated fatty acids are essential for maintaining the fluidity or elasticity of neuronal membranes. This fluidity is key for the proper functioning of the membrane-bound and membrane-associated proteins that carry the chemical or electrical signals underlying all information processing in the brain. Certain highly unsaturated fatty acids – notably AA and EPA - also play key roles as ‘second messengers’ in chemical neurotransmitter systems, as well as contributing to many other aspects of cell signaling.

Fatty Acid Deficiency and Brain Disorders: From Fetus to Infancy to Aging

As essential fatty acids must be obtained from the diet, their deficiency is bound to disrupt major physiological activities. The worst affected organ because of their deficiency is brain. Brain needs a continuous supply of fatty acids throughout life. But the most critical stages when fatty acids are needed are infancy and aging. During infancy, essential fatty acids deficiency delays brain development. During aging, such deficiency speeds up the degeneration of brain cells. 

Several in vitro studies have shown that ALA (omega-3 fatty acid) aids in the differentiation and functioning of brain cells. It has been shown that ALA deficiency alters the course of brain development, disrupts the composition and physicochemical properties of brain cell membranes, neurons, oligodendrocytes, and astrocytes, bringing about minor cerebral dysfunctions. These deficiency symptoms have been observed in animals as well as human infants. The effects of these types of deficiencies are manifested in neurosensory and behavioral disorder.

Recent studies have shown that dietary ALA deficiency causes distinct abnormalities in certain brain regions. The frontal cortex and pituitary gland are severely affected, which could lead to behavioral disorders affecting certain tests (habituation, adaptation to new situations). The deficiency of ALA reduces the perception of pleasure, slackening the efficacy of sensory organs and affecting certain cerebral structures. Age-related impairment of hearing, vision and smell is linked to decreased efficacy of the brain parts of the brain and disorders of sensory receptors, particularly of the inner ear or retina. For example, a given level of perception of a sweet taste requires a larger quantity of sugar in subjects with ALA deficiency.

The organization of the neurons is almost complete several weeks before birth. Any disturbance to the neurons or any disruption of their connections or depleted reservoir of their constituents at any stage of life is known to accelerate aging. Brain lacks the ability to synthesize LA and ALA. AA and cervonic acid, which are derived from diet unless human liver synthesizes LA and ALA, are essential for the brain, The age-related reduction of hepatic desaturase activities (which participate in the synthesis of long chains, together with elongases) can impair turnover of cerebral membranes. In many structures, especially in the frontal cortex, a reduction of cervonic and AA is observed during aging.

Many studies have shown that (n-3) fatty acid deprivation during development results in decreased DHA in brain membrane phospholipids, reduced performance in learning tasks, altered activity of membrane receptors and proteins, and altered metabolism of several neurotransmitters, including dopamine. Low DHA status is also associated with poorer development of visual acuity and lower indices of neural development in human infants. It is also suggested that (n-3) fatty acid deficiency decreases the mean cell body size of neurons in the hippocampus, hypothalamus, and parietal cortex. Furthermore, higher DHA intakes during pregnancy and lactation increase measures of cognitive performance in infants.

Recent studies have suggested that pregnant women following Westernized diets consume less than the recommended intakes of (n-3) fatty acids.

Studies with rats have shown that fatty acid deficiency has long term effects on a developing brain. In a study with rats, the cerebral hemispheres of the (n-3) fatty acid deficient embryos were noticeably reduced compared with those of the control group (not fatty acid deficient). A decrease in size of the cortical plate, primordial hippocampus, and dentate gyrus was associated with n-3 fatty acid deficiency. In the primordial cerebral cortex, the mean thickness of the cortical plate was 25 percent lower in the fatty acid deficient embryos than in controls.

Some studies strongly show that fatty acid deficiency disrupts neurogenesis (the development of nervous tissue) in the embryonic brain. Deficiency at key stages of brain development can have lasting effects on neural function, regardless of later compensation with an adequate diet. In this regard, recent studies have provided evidence that maternal intakes of DHA during pregnancy are associated with higher scores on tests of cognition in infants and preschool. Similarly, it is suggested that there could be an association between in utero DHA deprivation and several neurologic birth defects. A study with embryonic rat brain showed altered neurogenesis in the dentate gyrus of the hippocampus, which is one of two regions that where growth of new neurons occurs throughout adult life. The rate of neurogenesis has been linked to aging-related cognitive decline in hippocampal-dependent learning tasks, such as spatial memory tasks. In addition, DHA deficiency has also been linked to aging-related cognitive decline.

The levels of n-3 fatty acids in brain and other organs also influence the biosynthesis and accumulation of phosphatidylserine (PS) in brain. Dietary depletion of n-3 fatty acids during prenatal and postnatal development decreases the brain n-3 content by more than 80 percent with an increase in 6-n fatty acids in all tissues. Under these conditions, an approximately 30-35 percent reduction in total phosphatidylserine in rat brain cortex, brain mitochondria, and olfactory bulb was observed, while phosphatidylserine levels in liver and adrenal were unchanged. These data have implications in neuronal signaling events where phosphatidylserine is believed to play an important role. 

Fatty Acid Deficiency, Neuro-muscular Disorders and Effects on Nerve Cells 

Dyspraxia, also referred to as developmental coordination disorder, is the inability to make controlled movements and gestures due to impairment in motor coordination. Scientific evidence indicates that dyspraxia is often associated with fatty acid deficiency. The movement disorders of elderly people have been linked to highly unsaturated fatty acids (HUFA) deficiencies in a population based study. This is also true for movement abnormalities in Huntington’s disease and those that can result from antipsychotic drug treatment in schizophrenia. Studies show that treatment with fatty acids may be beneficial in both these conditions. Recent research shows that DHA, a key omega-3 fatty acid, is concentrated in brain regions involved in motor control.

Deficiencies of highly unsaturated fatty acids could give rise to developmental difficulties in visual processing that are characteristic in dyspraxia. Omega-3 fatty acids play vital role in proper functioning of visual processing. DHA makes up 30-50 percent of the retina. When DHA is deficient in diet and is replaced by omega-6 fatty acids, the signal transduction in the retina – the very first stage of visual information processing, drops. There is a growing evidence that indicates the role of omega-3 fatty acids for other aspects of visual development and function. 

DHA is found in high concentration in brain membrane phospholipids and is important for brain development and function through its influence on neurite outgrowth and neurotransmitter secretion. DHA plays vital role in transmitting impulses across nerve cells. Fusion of intracellular vesicles with the plasma membrane involving SNARE [soluble N-ethylmaleimide-sensitive fusion (NSF) protein attachment protein receptor] protein assembly, membrane fusion, and then disassembly are events common in membrane extension and neurotransmitter release. 

Studies with mice have shown that feeding an omega-3 fatty acid-deficient diet, known to reduce brain phospholipid DHA, alters SNARE protein and SNARE complex expression or protein nitrosylation in the hippocampus (seat of the memory) of rats. Hippocampus phospholipid DHA was lower and DPA (docosapentaenoic acid) was higher in the omega-3 fatty acid-deficient rats compared with the control group. These studies suggest that altered SNARE complex binding or disassembly could be important in explaining the diverse cellular events associated with altered tissue DHA.

Attention Deficit Hyperactivity Disorder (ADHD) and Fatty Acid Deficiency 

Growing body of evidence shows a possible link between attention deficit hyperactivity disorder (ADHD) and fatty acid deficiency. First evidence came in the early eighties when mild physical signs consistent with fatty acid deficiency were found among ADHD-afflicted patients. ADHD is associated with symptoms such as excessive thirst, frequent urination, rough, dull or dry skin, dandruff, soft or brittle nails, and follicular keratosis (a build-up of hard skin around the hair follicles that gives the skin a ‘bumpy’ appearance and feel). Animal studies have demonstrated fatty acid deficiency’s role in ADHD. Recently, several biochemical studies have also reported reduced concentrations of highly unsaturated fatty acids (HUFA) in the blood of ADHD children compared to controls. 

In one study comparing a sample of ADHD boys and controls revealed that regardless of clinical diagnosis, highly unsaturated fatty acids (HUFA) deficiency was correlated with a host of behavioral, learning and health problems. The interesting thing is that low levels of omega-6 fatty acids were related to some physical health measures (dry skin and hair, frequency of colds, and antibiotic use). Low omega-3 fatty acid status, on the other hand, was associated not only with physical signs of fatty acid deficiency (excessive thirst, frequent urination and dry skin) but also with behavioral problems (conduct disorder, hyperactivity-impulsivity, anxiety, temper tantrums and sleep problems) as well as learning difficulties in children.

Some studies have tried to uncover a possible mechanism how fatty acid deficiencies could lead to ADHD. Research has shown that omega-3 deficiency is associated with reduced levels of dopamine (and its binding to D2 receptors) in frontal cortex, a brain region. It is well known that dopamine is the main neurotransmitter boosted by the stimulant medications used to treat ADHD. Detailed studies indicated that the reduced availability of dopamine in these regions of brain due to omega-3 deficiency may be insufficient to maintain the high release needed during ‘stimulated cognitive processes’ such as sustained attention to a demanding task.

Dyslexia and Fatty Acid Deficiency

Recent research has also found a link between fatty acid deficiency symptoms and dyslexia (inability to read, spell and write words despite having ability to see and recognize letters). Ratings of fatty acid deficiency symptoms were significantly higher in dyslexic than non-dyslexic adults. In dyslexic group, these symptoms were associated with visual symptoms when reading, other visual problems, auditory and language confusions and motor problems. Their occurrence and severity was also found to correlate with the severity of difficulties with reading, spelling and working memory in dyslexic children.

Autism and Fatty Acid Deficiency 

Epidemiological studies show that cases of autism are on the rise across the developed countries. The diagnosis of autism has increased dramatically over the past ten years. According to UK’s Medical Research Council, there is one autistic child in 166 of the UK population while the UK National Autistic Society suggests the rate may be even higher.

Studies have shown that autistic children harbor higher levels of phospholipase enzyme, which removes highly unsaturated fatty acids (HUFA) from the membrane phospholipids. Researchers believe that higher levels of the enzyme phospholipase, seen in preliminary studies on blood samples from autistic children, may metabolise fatty acids in these children more quickly than in those without the condition. They say increased metabolism affects all fatty acids. But adding more omega-3 through diet or supplementation could compensate fatty acid deficiency arising out of metabolic anomalies. In a study where children were given fatty acid EPA supplements, the children exhibited better sleeping patterns, cognition, eye contact and sociability.

Cardiovascular, Immune and Metabolic Disorders and Omega-3 Fatty Acid Deficiency

ALA, an essential fatty acid, given in the early development period can affect blood pressure later in life. In a study with Sprague-Dawley rats, a species with predisposition for high blood pressure, omega-3 fatty acid deficiency in perinatal period resulted in raised blood pressure later in life, even when the animals were subsequently provided with these fatty acids.

Contemporary Western diet is rich in omega-6 fatty acids and deficient in omega-3 fatty acids. This tilted balance may be in favor of diseases. Research shows that the higher the ratio of omega-6 fatty acids to omega-3 fatty acids in platelet phospholipids, the higher is the death rate from cardiovascular disease. Due to increased intake of omega-6 fatty acids, eicosanoid metabolic products from AA, specifically prostaglandins, thromoxanes, leukotrienes, hydroxy fatty acids, and lipoxins, are formed in larger quantities than those from omega-3 fatty acids. If eicosanoids are formed in large amounts, they lead to the formation of thrombi and atheromas: the development of allergic and inflammatory disorders, particularly in susceptible people.

 
Studies have also shown that deficiency of omega-3 fatty acids brings about metabolic disorders. It is indicated that as the ratio of omega-6 fatty acids to omega-3 fatty acids increases, the prevalence of type 2 diabetes also increases.

Causes of Fatty Acid Deficiency 

 a)       Inadequate dietary intake of essential fatty acids

 Oily fish and seafood are rich source of omega-3 fatty acids (EPA and DHA) that the brain needs. ALA, the parent essential fatty acid of omega-3 series, is found in dark green leafy vegetables and certain nuts and seeds, but levels of both ALA and the more important omega-3 highly unsaturated fatty acids (HUFA) tends to be very low in many modern diets.

b)       Difficulties in conversion of essential fatty acids to highly unsaturated fatty acids (HUFA)

 Various enzymes and hormones play role in balancing the reservoir of fatty acids. Studies have shown that males are particularly vulnerable to highly unsaturated fatty acids (HUFA) deficiency. This also explains why males are largely affected by dyspraxia and other related disorders. In females, oestrogen helps to conserve to highly unsaturated fatty acids (HUFA) under conditions of dietary deprivation, while in males testosterone can inhibit highly unsaturated fatty acids (HUFA) synthesis. 

c)       Difficulties in recycling highly unsaturated fatty acids (HUFA) 

Highly unsaturated fatty acids (HUFA) deficiency can also be caused by inefficiency of the enzymes responsible for recycling them. Highly unsaturated fatty acids (HUFA) are replaced and recycled during remodeling of cell membranes and in the chemical cascades triggered by normal cell signaling processes. Enzymes from a group known as phospholipase A2 (PLA2) help remove highly unsaturated fatty acids (HUFA) from membrane phospholipids creating free fatty acids, which are vulnerable to destruction by oxidation. There is scientific evidence for both excessive highly unsaturated fatty acids (HUFA) breakdown and recycling problems in disorders such as dyspraxia.

Can Dietary Supplementation Compensate Fatty Acid Deficiency and Alleviate Disorders 

Fatty acid deficiencies and their related diseases have raised the possibility that dietary supplementation with highly unsaturated fatty acids (HUFA) might be of some benefit. ForADHD, several controlled trials have shown mixed results. Such studies provided supplementation with evening primrose oil containing omega-6 fatty acid GLA (Gamma-linolenic Acid) and indicated only marginal, if any clear, benefits. Recent research shows that omega-3 fatty acids are likely to be more important than omega-6 in their effects on behavior and learning.

In another randomized trial of fatty acid treatment for ADHD children, a supplement of fish oil and evening primrose oil was used. This supplement mainly contained omega-3 fatty acids (EPA and DHA) and a little omega-6 (AA and GLA). This study indicated blood fatty acid changes in the treated children were associated with reduced ADHD symptoms. But, supplementation with DHA alone was ineffective in treating ADHD. This is consistent with other evidence from other studies that reported EPA, not DHA, is more important omega-3 fatty acid for improving attention and mood and reducing perceptual or cognitive difficulties. 

In a small study with dyslexic children, results showed that compared with placebo treatment, highly unsaturated fatty acids (HUFA) supplementation for three months significantly reduced anxiety and disruptive behavior. When the placebo group was given highly unsaturated fatty acids (HUFA) (without the children or their parents and teachers being aware of the switch) they showed noticeable reductions in ADHD-related symptoms over the next three months. In a separate larger study with dyslexic children, highly unsaturated fatty acids (HUFA) treatment has been shown to improve reading skills.

A study with dyspraxic children, which used supplementation with both omega-3 and omega-6 highly unsaturated fatty acids (HUFA) for three months from a combination of fish oil and evening primrose oil, showed reductions in motor difficulties and ADHD symptoms.

Recent researches have also found roles of fatty acids in adult psychiatric conditions. The omega-3 fatty acids appear to be a very promising new line of treatment for psychiatric conditions. The benefits of omega-3 supplementation have been shown in various studies. Such supplementation has been helpful in treating schizophrenia in controlled trials, bipolar (manic depressive) disorder, and most recently, treatment-resistant depression.

Biochemical and behavioral abnormalities could partially be alleviated by a dietary phospholipid supplement, especially omega-3-rich egg yolk extracts or pig brain. A study has shown that animal phospholipids are more effective than plant phospholipids to make up the ALA deficiency, partly because they provide very long preformed chains. Dietary omega-3 fatty acids play a role in the prevention of some disorders including depression, as well as in dementia, particularly Alzheimer's disease. In studies involving dietary intake of omega-3 fatty acids, it has been shown that the nature of polyunsaturated fatty acids (in particular omega-3) present in formula milks for infants (both premature and term) determines the visual, cerebral, and intellectual abilities.

In a recent study, a US research team has shown that DHA may slow the growth of two brain lesions that are hallmarks of Alzheimer’s disease. This study with genetically modified mice is first to show that DHA can slow the accumulation of tau, a protein that leads to the development of neurofribillary tangles. Such tangles are one of two signature brain lesions of Alzheimer’s disease. DHA also was found to reduce levels of the protein beta amyloid, which can clump in the brain and form plaques, the other Alzheimer’s lesion.

Encouraging results from animal studies have led researchers to undertake clinical trial with DHA. A nationwide trial will be conducted by the Alzheimer’s Disease Cooperative Study (ADCS), a consortium of leading researchers supported by National Institute on Aging and coordinated by the University of California, San Diego. The trial will take place at 51 sites across the US and seeks 400 participants over the age of 50 with mild to moderate Alzheimer’s disease. Researcher will primarily evaluate whether DHA, taken over months, slows the progression of both cognitive and functional decline in people with mild to moderate Alzheimer’s.

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2)   Omega-3s Are Important for More Than Just Heart Health

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15)    Fatty Acid Deficiency linked to Autism 

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17)    Omega-6 fatty acids

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19)    Can an Omega-3 Fatty Acid Slow the Progression of Alzheimer’s Disease?
NIH-Supported Researchers Launch Nationwide Trial