OMEGA-3 FATTY ACIDS AND METABOLISM
The long chain omega (ω)-3 fatty acid docosahexaenoic acid (DHA, 22:6ω-3) is specifically enriched in brain gray matter and the rod and cone outer segment membranes of the retina, where it is acylated primarily in phosphatidylethanolamine, ethanolamine plasmalogen, and phosphatidylserine, which together comprise about 20% to 25% of brain lipid (1). Typically, DHA represents about 10% of total fatty acids in brain grey matter, with lower amounts in white matter (2). The rod and cone outer segments, on the other hand, are a highly specialized series of membrane disks in which DHA represents about 35% of the total fatty acids (3). Dietary deficiency of ω-3 fatty acids during development leads to decreased DHA in the brain and retina, and this is accompanied by alterations in electro-retinogram recordings, visual acuity, visual transduction pathways, and impaired performance on several maze-tasks of learning in animals (1,4,5). With the exception of cats, which are obligate carnivores (6), numerous studies in animals, including nonhuman primates, pigs, and rodents, have provided considerable evidence that when provided with a dietary source of the ω-3 fatty acid α-linolenic acid (18:3ω-3), these animals are able to synthesize and accumulate large amounts of DHA in the developing brain and retina (1,4,5,7). Whether or not humans have different needs for ω-3 fatty acids from most other animals, perhaps because of poor ability to form DHA from 18:3ω-3, imbalance or high concurrent intakes of ω-6 fatty acids, and the implications for brain and retina development and function are major areas of current importance in human lipid nutrition.
As introduced, although DHA is enriched in membrane lipids in the central nervous system (CNS), the ω-3 fatty acids are present in the diet in different forms, and in different amounts in different foods. All of the ω-3 fatty acids are characterized by a double bond at the third carbon from the methyl (ω) end of the fatty acid (Fig. 1), and all ω-3 fatty acids originate from synthesis in plants and algae. Once consumed, 18:3ω-3 can be further metabolized by Δ-6 and Δ-5 desaturase to form eicosapentaenoic acid (20:5ω-3) and DHA (22:6ω-3), with these reactions being most important in the liver (Fig. 2). Synthesis of DHA appears to be absent or low in the brain and other organs, including the heart (8,9). Transport of DHA derived from synthesis in the liver, or DHA provided in the diet are major sources of DHA for the brain (1,9–11).
The ω-6 fatty acids are a second series of essential fatty acids, which are defined by a double bond at the ω-6 position of the fatty acid (Fig. 1), and which animals are also unable to synthesize. The 18 carbon chain linoleic acid (18:2ω-6) is desaturated to form arachidonic acid (20:4ω-6) using the same Δ-6 and Δ-5 desaturases as used in the metabolism of 18:3ω-3 (Fig. 2). Further metabolism of 20:4ω-6 via 22:4ω-6 leads to synthesis of 22:5ω-6, following a similar pathway to that involved in synthesis of DHA (1). Circulating and tissue levels of 22:5ω-6, however, are generally low, but are increased in ω-3 fatty acid deficiency, or when a diet high in ω-6 fatty acids is fed (1,4,7,10).
Fatty acid metabolism is complex with the metabolism and functions of the ω-3 and ω-6 fatty acids interrelated on many levels. High intakes of 18:2ω-6 inhibit the metabolism of 18:3ω-3, with inhibition of 18:3ω-3 conversion to DHA, and decreased liver and brain DHA occurring at intakes of 18:2ω-6 above 3% energy (7,10). Modern human diets contain in excess of 3% energy 18:2ω-6 (11,12), leading to the argument that ω-6 fatty acid intakes are now so high as to flood the fatty acid metabolic pathway and suppress metabolism of the ω-3 fatty acids (13). An alternate view is that humans have a poor ability to form DHA from 18:3ω-3. Tracer studies have shown that the proportion of 18:3ω-3 converted to DHA in adults and infants is very low, less than 1% (14–17). Higher amounts of 18:3ω-3 in infant formula does not increase the infants' circulating lipid levels of DHA (18), and in pregnancy and lactation, providing more 18:3ω-3 does not increase maternal to fetal transfer of DHA, or the secretion of DHA in breast milk (19,20). On the other hand, higher intakes of DHA increase blood levels of DHA in infants, and higher intakes of DHA increase maternal-to-fetal transfer of DHA in pregnancy, and increase the secretion of DHA in breast milk during lactation (21–25). Dietary DHA is also readily taken up and incorporated into the developing brain (7,10,26).
In summary, DHA is required for brain development and membrane turnover, and most brain DHA is derived by uptake from plasma. There is no doubt that humans lack Δ-15 and Δ-12 desaturases, and as a result can neither form ω-3 fatty acids nor interconvert them from ω-6 fatty acids; clearly ω-3 fatty acids meet the criteria of essential dietary nutrients. The following review considers the approaches used to develop dietary recommendations for essential nutrients, and the scientific information available from studies in humans to support the development of recommendations for ω-3 fatty acids focusing on neural development to 2 years of age.
DIETARY ESSENTIAL FATTY ACID RECOMMENDATIONS
Although different panels have approached the derivation of dietary recommendations differently, the underlying concept is that the term “recommendation” or “recommended intake” describes the intake of the nutrient that is sufficient or more than sufficient for practically all healthy individuals in a population, and not the average requirement of the group, or the required intake of an individual. Classically, the term “requirement” is considered as the intake of the nutrient to maintain normal function (absence of signs of deficiency) and prevent depletion of that nutrient (loss of body stores). The intake of 18:2ω-6 to prevent biochemical and clinical evidence of deficiency is 1% to 2% of energy (27,28), with recommendation for at least 1% energy from 18:2ω-6 plus18:3ω-3 in infant formulas in the United Kingdom in 1988, 4.5% energy from 18:2ω-6 and 0.5% energy from 18:3ω-3 in Europe in 1987, and 3% energy from essential fatty acids in infant formulas in the United States in 1976 (27,28). Recommendations for essential fatty acids, however, underwent a major change when they became inextricably linked to public health strategies to reduce elevated serum cholesterol by replacing dietary saturated fatty acids with 18:2ω-6, in which early dietary guidelines promoted 8–10% energy from 18:2ω-6 (29). In 2002, the US Dietary Reference Intakes (DRI) stated a lack of evidence for determining ω-3 or ω-6 fatty acid requirements, and instead reported the median ω-3 and ω-6 fatty acid intakes by life stage and gender derived from dietary surveys in the United States, and termed these “adequate intakes (AI)” (30). Recognition that these “AI” are descriptors of US population intakes and are not based on any health or biochemical endpoint is important.
In recent years, dietary recommendations have evolved from a focus on nutrient deficiency to consider the intakes of macronutrients, certain vitamins, minerals, and other dietary factors that minimize risk of adverse outcome for health endpoints, such as cardio-metabolic diseases, certain cancers and bone health, although neurological development or health has not yet been included. Although there is no doubt that DHA is critical for neural development and function, robust scientific evidence on which to base dietary requirements for this endpoint may not be a realistic goal. Clinical studies to address nutrient requirements need a rigorous scientific approach to determine the estimated average requirement (EAR, intake below which 50% of individuals are deficient) and an estimate of variance in the EAR from which to derive a recommended intake that covers the needs of all, or almost all individuals (usually the EAR+ 2 standard deviations). Studies to establish an EAR for ω-3 fatty acids for CNS development in pregnant women, infants and children are neither ethical nor practical. Furthermore, because neural development itself has distribution and a child's potential neural development is unknown, variance in requirements cannot be estimated by usual approaches. Alternatively, recommendations, typically termed AI, for ω-3 fatty acids that aim to minimize risk of poor CNS development to 2 years of age are more likely to be attainable, and are consistent with a philosophy of dietary recommendations that promote optimal child development and health.
Information Used to Set Requirements and Recommendations
The information used to provide estimates of requirements have been described in different editions of dietary recommendations from different nations over the last 60 years, and a general summary of concepts is in Table 1. The infant before birth and during the first 6 months of exclusive breast-feeding is entirely dependent on the mother for transfer of ω-3 fatty acids (20,21). Consideration of ω-3 fatty acids to 6 months of age thus focuses on the need for ω-3 fatty acids by the pregnant and lactating woman to meet her needs and those of her infant. With the introduction of weaning foods, the dietary demands for ω-3 fatty acids for continued neural development shift gradually from a sole dependence on the mother to complete dependence on the diet of the infant. Recommendations are, therefore, considered for the 3 stages of pregnancy, lactation including human milk substitutes, and weaning. Risks of nutrient deficiency decrease with the increase in the intake of the nutrient (Fig. 3). Thus, information from observation and intervention studies that relate ω-3 fatty intake, blood, and tissue ω-3 fatty acids to measures of neural development may, therefore, be considered to derive a consensus on those ω-3 fatty acid intakes that minimize risk of deficiency.
EVIDENCE FOR ω-3 FATTY ACID RECOMMENDATIONS
Biochemical Measures of Circulating Lipid Fatty Acids
A large and consistent body of information has shown that circulating levels of DHA increase with increasing DHA intake, but not with increasing intakes of 18:3ω-3, and this occurs in gestation and in infants fed different human milks (20,21). Circulating lipid levels of DHA decrease, whereas 22:5ω-6, which is a biochemical marker of ω-3 fatty acid deficiency, increase during pregnancy (31,32). This suggests that ω-3 fatty acid intakes among some pregnant women following their usual diet may be limiting in ω-3 fatty acids. The mean intake of DHA for groups of pregnant women in different countries is 80 to 300 mg/day, but the standard deviation of intake often exceeds the mean (33–38). However, although mean intakes are often reported, the distribution of DHA intakes is skewed, with a lower median than mean intake (31), which is important because risk of deficiency increases with decreasing nutrient intake (Fig. 3). Autopsy analysis has estimated that the fetus accumulates about 60 mg/day DHA during the last trimester of gestation (39), a minimum that must be provided by ω-3 fatty acids in the mother's diet each day. Data on DHA accumulated in the placenta, other pregnancy associated tissues, or losses in turnover are not available, and this precludes a balanced approach to extrapolate the needs for DHA in gestation.
After birth, breast-milk provides ω-3 fatty acids to support the infant's development, often continuing as a major source of essential fatty acids through much of the first year when cereals, fruits, and vegetables are added to infants' diets. Like plasma, human milk DHA varies widely among and within populations, from about 0.1% to 1.0% milk fatty acids (20,40,41). The secretion of DHA in human milk is readily increased by increasing the lactating mother's intake of DHA from fish, or other sources (20,24,25). Accordingly, plasma and erythrocyte lipid levels of DHA also vary widely among breast-fed infants, and increase with increasing amounts of DHA in the mother's milk (24,25,42). Plasma and erythrocyte levels of DHA in infants breast-fed by women with <0.1% DHA in their milk are low and overlap with the levels in infants fed formula with no DHA (43). Assuming the fully breast-fed infant consumes 780 mL/day breast milk with 3.7 g/dL fat, then it can be estimated that the mother will loose 29, 101, or 202 mg/day DHA when secreting milk with 0.1%, 0.35%, or 0.7% DHA, respectively, which again would need to be replaced by diet, or from DHA stored in maternal tissues. Using an average amount of 0.35% DHA in human milk (41), then the average lactating woman will need to consume about 100 mg/day DHA to balance the losses of DHA in milk. If provided as 18:3ω-3, much higher amounts would be needed to account for losses of 18:3ω-3 in β-oxidation, and the relatively low estimated conversion of <1% dietary 18:3ω-3 converted to DHA (14–17).
Commercial infant formulas were first prepared from cows' milk modified to decrease the energy from protein, with addition of some minerals and vitamins. Later, the fat was replaced with vegetable oils, or oil blends. Beginning in the 1980s, several studies reported lower plasma and erythrocyte levels of DHA in infants fed formula containing 18:2ω-6 and 18:3ω-3 as the only polyunsaturated fatty acids than in breast-fed infants (18,44,45). Higher amounts of 18:3ω-3, or lower ratios of 18:2ω-6 to 18:3ω-3 in the formula did not increase plasma or erythrocyte levels of DHA in infants fed formula to the levels found in infants breast-fed by mothers following mixed diets (18,46). Including a source of DHA in formula, however, increases blood lipid levels of DHA in formula-fed infants to the same levels as that in infants receiving a similar amount of DHA from human milk (22,23,45).
With weaning, part of the infants' milk or formula intake is replaced, typically with foods low in fat, and often lacking DHA. Little information is available on circulating levels of DHA following weaning, although weaning from breast milk to formula with no DHA leads to a decrease in circulating DHA (47). Blood levels of DHA in children ages 18 to 60 months are low, similar to those in infants fed formulas with no DHA (48).
Biochemical Measures of Tissue Saturation
Although extensive data are available on the effects of dietary ω-3 fatty acids on brain and retina DHA in animals, only limited data are available for infants. Human brain growth and development is complex, with crucial stages of neurogenesis and neurite outgrowth beginning in gestation, and rapid brain growth with structural reorganization and the development of neural circuitry continuing through the first 2 years after birth (49,50). For example, synapses that are rich in DHA, form at remarkable rates of about 30,000 synapses/sec/cm2 of cortex in the first few years of life, with peak synapse formation occuring from 34-week gestation to 24-month postnatal. Autopsy analyses have shown that brain cortex DHA was lower in formula-fed infants than in breast-fed infants (51,52), showing that diet can modify the fatty acid composition of the developing human brain. At that time, formulas had no DHA, and some had low amounts of 18:3ω-3 with high proportions of 18:2ω-6 relative to 18:3ω-3. The lower frontal cortex 22:6ω-3 in infants fed formula was accompanied by increased 22:4ω-6 and 22:5ω-6 (51), showing metabolic capacity for fatty acid desaturation and elongation, but changes in brain fatty acids consistent with ω-3 fatty acid deficiency (1,4). Although the explanation, such as too much 18:2ω-6, too little 18:3ω-3, or no DHA, or other problems is uncertain, it is clear that those formula lacking in DHA did not achieve similar DHA in the infant brain as that in breast-fed infants.
Epidemiological Observations Relating Intake and Status
Studies in different countries have linked low intakes of fish (the major dietary source of DHA) in pregnant women, low blood levels of DHA in pregnancy or in infants at birth, and low breast milk DHA to lower scores on tests of mental, motor and visual system development in infants, with the effects extending into later childhood (42,53–58). Although other dietary or family variables associated with dietary patterns rich in fish and seafoods could be involved, the number of different studies and countries in which this association has been found is remarkable. The Avon Longitudinal Study of Parents and Children in England collected information on fish intake for 11,875 pregnant women (53). A best-fit curve of verbal IQ showed a curvilinear relation in which children whose mothers consumed <0.1% energy from 20:5n-3 plus DHA were at increased risk of poor verbal IQ. Assuming a diet providing 2,000 kcal/day, this is equivalent to about 222 mg/day of 20:5ω-3 plus DHA. However, in the same cohort, dietary patterns among the children that included “junk food” had a negative effect on the child's school performance attainment (59), emphasizing the complexity of studies relating diet and dietary components to child neural development. In the United States, visual recognition memory at 6 month of age was highest in infants whose mothers consumed 2 or more servings of fish/week (55), and among Inuit infants in Artic Quebec, multiple regressions analyses showed novelty preference, and mental and motor skill development at 11 months of age were positively related to the infant cord DHA, although not breast milk DHA (54). Other studies have shown an association between human milk DHA, cord blood DHA and maternal blood lipid DHA in pregnancy and later measures of infant visual acuity, attention, and motor skill development (42,56–58). Term infants fed mothers' milks with <0.17% had lower measures of visual acuity than infants of mothers providing milk with >0.31% DHA (42), which would be equivalent to an intake of 90 mg/day DHA or more for the average breast-fed infant. The possibility that other factors in breast milk, or attributes of breast-fed infants and their families, or differences among women who do and do not consume fish, contribute to differences in infant development is clear. However, the information from different countries and in different settings appears sufficiently robust to consider that consuming 1 to 2 meals/week of fish during pregnancy and lactation, chosen to avoid fish with high contaminant burdens is associated with reduced risk of poor infant and neural child development (60,61).
Intervention Studies to Cure or Prevent Signs of Deficiency
Information from intervention studies to increase DHA intakes among pregnant and lactating women, and from clinical studies with infants fed with formula with and without DHA contribute more specific evidence to suggest inadequate ω-3 fatty acid nutrition does occur. In intervention studies, only those individuals in the group who are deficient can show physiological benefit from intervention to improve ω-3 fatty acid status. However, because increased dietary intake in individuals consuming adequate diets can have no benefit, a linear relationship between dietary intake or plasma DHA and neural function is expected only in groups where all, or almost all individuals are deficient. Adding complexity, CNS development and abilities do not have one value, rather it varies widely among infants. This means that large sample sizes are needed to detect differences in mean developmental test scores between control and intervention groups, particularly in studies that involve heterogeneous groups of infants, or when variance is increased in multicenter settings.
In a randomized study, children of pregnant women given cod liver oil to provide 1183 mg eicosapentaenoic acid plus 803 mg DHA/day had higher mental processing at 4 years of age, and sequential processing at 7 years of age than in children of women given a placebo (62,63). Other studies have reported that supplementation with DHA from fish oil or functional foods in gestation improved problem-solving skills at 9 months of age (64) and hand–eye coordination at 2.5 years of age (65), while intervention with 400 mg/day DHA during gestation decreased risk of lower visual acuity scores in infants at 2 months of age (31). In other reports, mean scores on tests of neural development were not different between infants of mothers assigned to supplemental DHA or a placebo (37,66,67), although regression analyses showed maternal DHA was positively related to measures of infant CNS development (37,66). Supplementation of lactating women with 200 mg/day DHA from single cell oil increased DHA in breast milk from 0.2% to 0.35% fatty acids, and this was associated with better scores on tests of psychomotor development in the infants at 30 months of age (68). These studies suggest that milk providing 0.35% rather than 0.2% DHA decreases the risk of lower scores on standardized tests of infant development. However, these studies can neither be used to infer how much DHA is required, nor to estimate an EAR for DHA, or any other ω-3 fatty acid. Regardless, published studies to show that interventions with fish oil or DHA during gestation and lactation can in some settings improve measures of infant and child neural development suggest recommendations are needed to minimize risk of dietary patterns that may limit optimal maternal to infant transfer of DHA in gestation and during breast-feeding.
Considerable investment has been made in assessing whether or not addition of DHA, often with 20:4ω-6, increases early visual, mental and motor skill development in formula-fed infants, and recent reviews are available (69–71). Birch et al (72,73) have reported several studies to show that inclusion of 0.36% DHA in formula increases visual acuity maturation in the first year of life, with benefit also found when formula with DHA was fed after initial breast-feeding (47). Other studies, including multicentre studies, have not found differences in visual, mental or motor skill development between breast-fed infants and infants fed formula without DHA, or as a result of including DHA in formula (74–76). The problem is complex. Although randomization may avoid group bias, differences in DHA status at birth, and heterogeneity among infants, as well as developmental testing after weaning to other foods has occurred all contribute variability, making it difficult to detect effects of postnatal fatty acid nutrition on the developing neural system; alternatively, dietary DHA in some cases may be without benefit. Again, scientific data to conclude DHA is required, or to establish an EAR for DHA or other ω-3 fatty acids is lacking. Although some data show that DHA, often with 20:4ω-6, at levels of about 0.35% milk or formula fatty acids prevents low visual acuity development, confirmatory evidence derived from different settings will provide more compelling evidence that any benefits are specific to infant nutrition with DHA, and not correction of maternal nutritional deficiency in pregnancy, or other dietary factors that impose metabolic constraints in the ability to synthesize or utilize DHA.
In the second year of life, brain growth and structural reorganization continues rapidly (50). Although information on which to base dietary recommendations for ω-3 fatty acids in this age group are lacking, including fish as part of the infants' weaning diet is consistent with the transition to a healthy adult diet that includes 1 to 2 servings/week of fish (60,61). Dietary recommendations are set to cover the needs of almost all healthy individuals by life stage and gender, and do not usually include clinical groups such as preterm infants whose nutritional needs are known to differ from that of healthy term infants. However, several clinical studies have provided evidence that preterm infants fed with formulas do benefit from inclusion of DHA in their formula feeds (70). More recent studies have reported that supplementation of human milk or formula that contains 20:4ω-6 to increase DHA to 1% fatty acids led to higher visual acuity in preterm infants at 4 months of age than in infants fed milk or formula with 0.3% DHA (77). Similarly, 9 weeks feeding with human milk supplemented with 32 mg DHA and 31 mg 20:4ω-6 per 100 mL was associated with higher problem solving and recognition memory scores than among infants fed unsupplemented milk (78). These studies provide amounts of DHA in milk at about 1% fatty acids, which is an amount predicted to approximate the intake needed to achieve in utero rates of DHA accretion (49). Some early studies in preterm infants raised the possibility of adverse effects of feeding oils sources of DHA without 20:4ω-6 (79,80), and animal studies also show that supplemental DHA from fish oil in an unbalanced diet can have long-term effects on neurological development and growth, may worsen endothelial dysfunction, and in addition to decreasing blood pressure and vascular wall thickness, may increase the risk of hemorrhagic stroke (81–84). These latter studies emphasize the need to consider potential adverse effects of individual nutrients, and the importance of information to define safe upper limits (UL) addressing relevant physiological endpoints, when recommending intakes of nutrients outside the context of their usual forms in foods such as human milk, fish, and other animal tissues.
While there is no doubt that DHA is critical for the developing brain, western diets poor in ω-3 fatty acids and rich in ω-6 fatty acids are becoming increasingly implicated in contributing to risk of poor neural development and function. Information has accumulated from observation and intervention studies with pregnant and lactating women, and with infants fed formula to show that under some circumstances, higher dietary intakes of DHA decrease risk of poor scores on tests of visual and neural development, with the effects lasting into childhood. Whether the benefits of fish or fish oils, for which DHA is a marker of intake, is explained solely by DHA is incompletely resolved. Similarly, whether or not the intake of ω-3 fatty acids that meets the needs of the CNS for DHA also best supports the needs of other tissues and cells, such as the developing immune system, is unclear. The ω-3 fatty acids are clearly essential nutrients, suggesting that dietary recommendations, such as AI, to minimize risk of poor CNS development can be justified, and are consistent with a philosophy of dietary guidance that promotes optimal child development and health. However, because dietary recommendations often promulgate changes in the food supply and supplement use, affecting the diet and health of the population at large, premature recommendations based on incomplete science that focus on individual nutrients rather than dietary practices such as breast-feeding and foods such as fish rich in DHA are not necessarily in the best public interest.
Research in the author's laboratory is supported by grants from the Canadian Institutes of Health Research (CIHR). A Freedom-to-Discover Award from the Bristol-Myers Squibb Foundation is also acknowledged.
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