Docosahexaenoic acid

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain and retina. In chemical structure, DHA is a carboxylic acid with a 22-carbon chain and six cis double bonds; the first double bond is located at the third carbon from the omega end. Its trivial name is cervonic acid, its systematic name is all-cis-docosa-4,7,10,13,16,19-hexa-enoic acid, and its shorthand name is 22:6(n-3) in the nomenclature of fatty acids.

Cold-water oceanic fish oils are rich in DHA. Most of the DHA in fish and complex organisms with access to cold-water oceanic foods originates in photosynthetic and heterotrophic microalgae, and becomes increasingly concentrated in organisms, as they move up the food chain. DHA is also commercially manufactured from microalgae; Crypthecodinium cohnii and another of the genus Schizochytrium. DHA manufactured using microalgae is vegetarian. Some animals with access to seafood make very little DHA through metabolism, but obtain it in the diet. However, in strict herbivores, and carnivores that do not eat seafood, DHA is manufactured internally from α-linolenic acid, a shorter omega-3 fatty acid manufactured by plants (and also occurring in animal products as obtained from plants). Although α-linolenic acid (ALA) does convert to DHA in humans, the process is inefficient and very limited even in healthy individuals. DHA is a major fatty acid in sperm and brain phospholipids and in the retina. Dietary DHA may reduce the risk of heart disease by reducing the level of blood triglycerides in humans. Below-normal levels of DHA have been associated with Alzheimer's disease.

Central nervous system constituent
DHA is the most abundant omega-3 fatty acid in the brain and retina. DHA comprises 40% of the polyunsaturated fatty acids (PUFAs) in the brain and 60% of the PUFAs in the retina. Fifty percent of the weight of a neuron's plasma membrane is composed of DHA.

DHA modulates the carrier-mediated transport of choline, glycine, and taurine, the function of delayed rectifier potassium channels, and the response of rhodopsin contained in the synaptic vesicles, among many other functions.

DHA deficiency is associated with cognitive decline. PS controls apoptosis, and low DHA levels lower neural cell PS and increase neural cell death. DHA are reduced in the brain tissue of severely depressed patients.

Metabolic synthesis
In humans, DHA is either obtained from the diet or synthesized from eicosapentaenoic acid (EPA, 20:5, ω-3) via docosapentaenoic acid (DPA, 22:5 ω-3) as an intermediate. This synthesis had been thought to occur through an elongation step followed by the action of Δ4-desaturase. It is now more likely that DHA is biosynthesized via a C24 intermediate followed by beta oxidation in peroxisomes. Thus, EPA is twice elongated, yielding 24:5 ω-3, then desaturated to 24:6 ω-3, then shortened to DHA (22:6 ω-3) via beta oxidation. This pathway is known as Sprecher's shunt.

Attention Deficit Hyperactivity Disorder (ADHD)
One study of pure DHA supplementation on children with ADHD found no behavioral improvements, while another study found fish oil containing both EPA and DHA did improve behavior.

Alzheimer's disease and decline of mental health
Preliminary studies indicated that DHA can slow the progression of Alzhiemer's disease in mice, sparking interest in additional research. However, the first large-scale human trials showed that DHA did not slow decline of mental function in elderly people with mild to moderate Alzheimer's disease. These trials were part of a large US National Institutes of Health (NIH) intervention study to evaluate DHA in Alzheimer's disease.

Researchers from the National Institute on Aging-supported Alzheimer's Disease Cooperative Study conducted a double-blind, randomized, placebo-controlled clinical trial comparing DHA and placebo over 18 months in 402 people (average age=76) diagnosed with mild to moderate Alzheimer's at 51 sites. According to this study, treatment with DHA increased blood levels of DHA, and appeared to increase brain DHA levels, based on a measured increase of DHA in study participants' cerebrospinal fluid.

However, DHA treatment did not slow the rate of change on tests of mental function, global dementia severity status, activities of daily living, or behavioral symptoms in the study population as a whole. Treatment effects did not differ between the mild and moderate Alzheimer's patients, leading study authors to conclude that the results do not support the routine use of DHA for patients with Alzheimer's.

Animal studies in the TG3 transgenic mouse model of Alzheimer's disease had linked dietary DHA to decreases in amyloid plaques and tau. Animal studies also showed, when DHA was combined with arachidonic acid (also present in fish oil), plaque formation was greater with the arachidonic acid compared to DHA alone.

DHA deficiency likely plays a role in decline of mental function in healthy adults, which is indicated in a study from 2010 conducted at 19 U.S. clinical sites on 485 subjects aged 55 and older who met criteria for age-associated memory impairment. The study found algal DHA taken for six months decreased heart rate and improved memory and learning in healthy, older adults with mild memory complaints. These findings indicate the importance of early DHA intervention and provided a statistically significant benefit to cognitive function in individuals over 50 years of age. Higher DHA levels in middle-aged adults is related to better performance on tests of nonverbal reasoning and mental flexibility, working memory, and vocabulary.

Cancer
DHA was found to inhibit growth of human colon carcinoma cells, more than other omega-3 PUFAs. The cytotoxic effect of DHA was not caused by increased lipid peroxidation or any other oxidative damage, but rather a decrease in cell growth regulators. However, different cancer lines handle PUFAs differently and display different sensitivities toward them. Such preliminary findings point to the need for further research, and are not proof DHA does or does not provide any benefit for intended treatment, cure, or mitigation of cancer. However, in 2008, DHA was shown to increase the efficacy of chemotherapy in prostate cancer cells, and in 2009, a chemoprotective effect in a mouse model was reported. One large clinical trial, the "Prostate Cancer Prevention Trial", found that DHA was correlated with an increase in high-grade prostate cancer.

Pregnancy and lactation
DHA concentrations in breast milk range from 0.07% to greater than 1.0% of total fatty acids, with a mean of about 0.34%. DHA levels in breast milk are higher if a mother's diet is high in fish. The Food and Drug Administration has noted specific concerns for women who are pregnant or might become pregnant, nursing mothers, and young children regarding mercury levels in fish and shellfish.

DHA has recently gained attention as a supplement for pregnant women, noting studies of improved attention and visual acuity. Given the recently gained attention, the majority of pregnant women in the U.S. fail to get the recommended amount of DHA in their diets. One recent study indicated low levels of plasma and erythrocyte DHA were associated with poor retinal development, low visual acuity, and poor cognitive development. In that same study, alpha-linolenic acid was shown as a source of fetal DHA, but preformed DHA was more readily accredited. A working group from the International Society for the Study of Fatty Acids and Lipids recommended 300 mg/day of DHA for pregnant and lactating women, whereas the average consumption was between 45 mg and 115 mg per day of the women in the study. The March of Dimes recommends pregnant women consume at least 200 mg DHA per day. Other requirements are available from other sources.

Docosahexaenoic acid single-cell oil (DHASCO) has been an ingredient in several brands of premium infant formula sold in North America since 2001 after Mead Johnson, the first infant formula manufacturer to add DHASCO and arachidonic acid single-cell organism oil to its Enfamil Lipil product, received a "Generally Regarded As Safe" status by the Food and Drug Administration and Health Canada.

DHASCO does not make infant formulas more like human milk than "conventional" formula containing alpha-linolenic acid and linoleic acid, which are precursors to DHA. Formula sold in North America uses lipids from microorganisms grown in bioreactors as sources of DHA. No scientific review studies show DHA additives benefit brain development of term infants, as formula makers claim in their advertisements, which has led some public interest groups to file complaints with the Federal Trade Commission of the United States, alleging false and misleading advertising.

A study found that preterm infants fed baby formulas fortified with DHASCO provided better developmental outcomes than formulas not containing the supplement.

A study sponsored by March of Dimes and National Institutes of Health suggests that pregnant moms who take DHA supplements during pregnancy give their babies some degree of added protection against getting colds. The babies whose mothers had taken DHA supplements seemed to get over cold symptoms faster when they did get sick.

Current Research
Although most studies demonstrate positive effects of dietary DHA on human health, contrary results exist. For example, one study found that the use of DHA-rich fish oil capsules did not reduce postpartum depression in mothers or improve cognitive and language development in their offspring during early childhood.

Additional studies confirmed DHA benefits for other nervous system functions, cardiovascular health, and potentially other organs. In one study, men who took DHA supplements for 6–12 weeks decreased the concentrations of several inflammatory markers in their blood by approximately 20%. It has been shown that heart disease patients with higher intakes of DHA and EPA survived longer. 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. Preliminary studies showed that a high intake of DHA was associated with reduced risk for developing Alzheimer's disease, consistent with DHA being the most abundant omega-3 fatty acid in the brain. It is now considered so important to brain and eye development that DHA is included in most infant formulas. Lastly, in preliminary research, it was found that a diet rich in DHA might protect stroke victims from brain damage and disability and aid in a speedier recovery.

The Discovery of Algae-based DHA
In the early 1980s, NASA sponsored scientific research in search of a plant-based food source that could generate oxygen and nutrition on long-duration space flights. The researchers discovered that certain species of marine algae produced rich nutrients. This research led to the development of an algae-based, vegetable-like oil that contains contains two essential polyunsaturated fatty acids: DHA and ARA (arachidonic acid).

Use as a food additive
DHA is widely used as a food additive. It was first used primarily in infant formulas. In 2004, the US Food and Drug Administration endorsed qualified health claims for DHA, and by 2007 DHA-fortified dairy items (milk, yogurt, cooking oil) started to appear in grocery stores.

DHA is believed to be helpful to people with a history of heart disease, for premature infants, and to support healthy brain development especially in young children along with supporting retinal development. Some manufactured DHA is a vegetarian product extracted from algae, and it competes on the market with fish oil that contains DHA and other omega-3's such as EPA. Both fish oil and DHA are odorless and tasteless after processing as a food additive.

Studies of vegetarians and vegans
Vegetarian diets typically contain limited amounts of DHA, and vegan diets typically contain no DHA. Vegetarians and vegans have substantially lower levels of DHA in their bodies, and short-term supplemental ALA has been shown to increase EPA, but not DHA. However, supplemental preformed DHA, available in algae-derived oils or capsules, has been shown to increase DHA levels. While there is little evidence of adverse health or cognitive effects due to DHA deficiency in adult vegetarians or vegans, fetal and breast milk levels remain a concern.

DHA and EPA in fish oils
Fish oil is widely sold in gelatin capsules containing a mixture of omega-3 fatty acids including EPA and smaller quantities of DHA. 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. They note the brain normally contains DHA, but not EPA, though both DHA and EPA plasma concentrations increased significantly for participants.

Hypothesized role in evolution
An abundance of DHA in seafood has been suggested as being helpful in the development of a large brain, though other researchers claim a terrestrial diet could also have provided the necessary DHA.