Omega-3 Fatty Acids and Brain Health
Omega-3 Fatty Acids
Omega-3 fatty acids are a type of polyunsaturated fatty acid (PUFA). Polyunsaturated fatty acids contain more than one double bond, compared to monounsaturated fatty acids with one double bond, and saturated fats which have no double bonds. While this all seems highly technical, the presence, or absence, of double bonds confer important properties to fatty acids. Two of the most commonly studied PUFAs are omega-3 and omega-6 fatty acids. Omega-6 fatty acids are found in high amounts in the Standard American Diet, from foods including animal meat, soybeans, and corn oil. Conversely, omega-3 fatty acids are enriched in diets similar to the Mediterranean Diet, which emphasizes fish and nutrient-rich foods such as flaxseed. Lipids are critical to brain function through their role as components of the brain. The lipid composition of the brain is unique and when composition, metabolism, or signaling are altered, many neurological issues can arise.1
The relative intake of omega-3 to omega-6 fatty acids dictates many physiological effects in the body. Omega-3 fatty acids exert an anti-inflammatory effect, while omega-6 fatty acids tend to be pro-inflammatory. Any change in diet that replaces omega-3 fatty acids with omega-6 fatty acids, can be detrimental to health, but replacing omega-6 with omega-3 fatty acids can be very beneficial. The ideal ratio of omega-6:omega-3 is 1:1-4:1, but currently that ratio is closer to 20:1 for the Standard American Diet.2 This has many implications to human health and diseases, including increasing risk of obesity, cardiovascular disease, neurological issues, and pre-mature death. When comparing circulating levels of omega-3 fatty acids, those with the highest levels compared to lowest had a significantly reduced risk of dying, including from cardiovascular disease and cancer.3
EPA and DHA: Benefits and Mechanisms of Action
Two omega-3 fatty acids are especially important for brain health- eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Humans cannot make EPA and DHA so they must be obtained from the diet or converted from alpha-linolenic acid (ALA), although conversion is generally inefficient.4 EPA and DHA modulate the immune response, support healthy inflammation resolution by influencing gene expression, and alter cell membrane composition.5 They also are extremely important for neurodevelopment and brain function.5
Additionally, omega-3 fatty acids have several beneficial effects on the body, including:6,7
- Lowering plasma triglycerides
- Increasing beta-oxidation
- Lowering heart rate and blood pressure
- Improving endothelial function
- Anti-thrombotic properties
- Reducing oxidative stress
- Promoting healthy neuron and synaptic formation
- Increasing gut barrier integrity
Omega-3 fatty acids have a significant effect throughout the body due to their anti-inflammatory effects and their role in membranes. Omega-3 fatty acids can replace arachidonic acid, a precursor to pro-inflammatory omega-6 fatty acids. Increasing omega-3 fatty acids helps decrease arachidonic acid concentration which helps reduce inflammation.6 Mediators produced from omega-3 fatty acids, such as maresins, protectins, and resolvins, help resolve inflammation in the cardiovascular and central nervous systems through modulation of NF-κB, the major regulator of inflammation.6 Omega-3 and omega-6 fatty acids also compete for several of the same enzymes so an increase in omega-3 fatty acids helps decrease levels of omega-6 fatty acids and therefore reduces the number of pro-inflammatory molecules. In fact, supplementation with EPA and DHA reduced pro-inflammatory cytokine levels in patients with chronic systemic inflammation.8
EPA, DHA, and Brain Development
During pregnancy, omega-3 fatty acids help build and support the developing brain. DHA is especially important for infants- it makes up more than 90 percent of the omega PUFAs found in the brain, and it comprises about 10-20 percent of the total brain content.9,.10 Brain development processes including cell migration and proliferation, differentiation, neurogenesis, and myelinization and synaptogenesis are all regulated by PUFAs.11
The third trimester is a time of immense incorporation of DHA into the brain, as is the first 18 months after birth.4,9 Estrogen helps pregnant women mobilize stored DHA and increase synthesis by up to ten percent.4 Because omega-3 fatty acids accumulate in the developing brain in the third semester, babies that are born premature are at an especially high risk of being low in essential fatty acids, which can cause inadequate brain formation.4
Supplementation with DHA throughout pregnancy can help women reach optimal levels of omega-3 fatty acids in their blood and breastmilk. PUFA content in the breastmilk is inversely associated with production of inflammatory factors in infants, meaning the higher PUFA content, the lower inflammatory molecules.11 Additionally, supplementation has been related to various positive effects both in the mothers and children as they age, including improving perinatal depression in the mother and measures of IQ in the child up to four years after birth.4,11 Supplementation has also produced beneficial effects in children with autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD).11
Because the brain is still developing throughout childhood, maintaining adequate omega-3 levels is crucial to brain development and brain health. DHA accumulates in the brain throughout childhood, although at a slower rate than infancy.9 Maintaining healthy levels of omega-3 fatty acids has many downstream effects in children including cognition, behavioral development, and social function. Low levels of EPA and DHA have been found in children with autism spectrum disorder, ADHD and depression, with supplementation yielding overall beneficial effects.4
EPA and DHA Throughout the Lifespan
Omega-3 fatty acids are required throughout life to maintain the health and function of the brain. Levels of EPA and DHA, as measured through the Omega-3 index, have been associated with complex cognitive functions including problem solving, executive functioning, and memory from age four into mid-eighties.4 Cross-sectional studies have demonstrated that increased consumption of both DHA and EPA is associated with better cognitive function through the lifespan.12
Brain function depends on several elements, including brain structure, brain perfusion, and a healthy inflammatory state.4 DHA is critical in the developing baby but, because the brain is constantly turning over cells, DHA is required throughout the entire lifespan to support brain structure.4 Brain perfusion is also critical as the brain requires a constantly supply of nutrients- about 20 percent of the blood pumped by the heart is utilized by the brain.4 EPA and DHA are important regulators of brain perfusion and higher levels have been related to higher blood flow in the brain.4 Finally, omega-3 fatty acids can regulate inflammatory processes in the brain through the role of omega-3 derived mediators in resolving and maintaining healthy inflammation.4 The ability of omega-3 fatty acids to outcompete omega-6 fatty acids for enzymes is critically important in preventing neuroinflammation.13
Omega-3 fatty acids are known for modulating inflammation, but they also promote health through other pathways. They help alleviate oxidative stress by enhancing the activity of antioxidant enzymes, which lowers oxidative stress.14 High omega-3 intake has also been associated with increased integrity of the blood brain barrier.13 Maintaining blood brain barrier integrity is very important in preventing cognitive decline and Alzheimer’s disease.13 Supplementation may also have benefits for sleep, which helps support brain health and function.15
As cells age, they become senescent, meaning they cannot proliferate and instead enter a stable state of cell cycle arrest.14 However, senescent cells still have an effect on the body through secretion of pro-inflammatory factors, which may lead to a chronic inflammatory state through activation of immune cells.14 This is commonly referred to as “inflammaging”, and it plays a role in aging, cognitive and physical decline, and development of age-related diseases.14 However, omega-3 fatty acids can help prevent inflammaging and slow cognitive decline.14
Dietary and Supplement Options
Pregnant women, vegans and vegetarians, and athletes may require higher intake of omega-3 fatty acids due to fetal demand, low dietary intake, and higher breakdown of nutrients, respectively.4 Additionally, the omega-3 content of fish has declined in the past decade, resulting in lower intake.16 As a result, supplementation should be considered an effective option to obtain EPA and DHA and the associated health benefits. The FDA considers up to three grams per day of EPA and DHA safe and tolerable.4
Omega-3 fatty acids provide many benefits to the body, including helping resolve inflammation and supporting brain structure and function. Adequate intake is especially important in the third trimester of pregnancy to support the developing brain, but adequate intake or supplementation throughout the entire lifecycle can provide many benefits to the body including improving cognitive health and preventing onset of serious diseases.
- Bazinet, R.P., Layé, S. (2014). Polyunsaturated Fatty Acids and Their Metabolites in Brain Function and Disease. Nat Rev Neurosci, 15:771.
- Simopoulos, A.P. (2016). An Increase in the Omega-6/Omega-3 Fatty Acid Ratio Increase the Risk for Obesity. Nutrients, 8(3):128.
- Harris, W.S., et al. (2021). Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies. Nat Commun, 12(1):2329.
- von Schacky, C. (2021). Importance of EPA and DHA Blood Levels in Brain Structure and Function. Nutrients, 13:1074.
- Custers, E.M.E., Kiliaan, J.A. (2022). Dietary lipids from body to brain. Prog Lipid Res, 85:101144.
- Zirpoli, H., Chang, C.L., Carpentier, Y.A., Michael-Titus, A.T., Ten, V.S., Deckelbaum, R.J. (2020). Novel Approaches for Omega-3 Fatty Acid Therapeutics: Chronic Versus Acute Administration to Protect Heart, Brain, and Spinal Cord. Annu Rev Nutr, 40:161.
- Bellenger, J., Bellenger, S., Escoula, Q., Bidu, C., Narce, M. (2019). N-3 polyunsaturated fatty acids: An innovative strategy against obesity and related metabolic disorders, intestinal alteration and gut microbiota dybiosis. Biochimie, 159:66.
- Tan, A., Sullenbarger, B., Prakash, R., McDaniel, J.C. (2018). Supplementation with eicosapentaenoic acid and docosahexaenoic acid reduces high levels of circulating proinflammatory cytokines in aging adults: a randomized, controlled study. Prostaglandins Luekot Essent Fatty Acids, 132:23.
- Basak, S., Mallick, R., Banerjee, A., Pathak, S., Duttaroy, A.K. (2021). Maternal Supply of Both Arachidonic and Docosahexaenoic Acids Is Required for Optimal Neurodevelopment. Nutrients, 13(6):2061.
- Herrmann, M., Simstich, S., Fauler, G., Hofer, E., Fritz-Petrin, E., Herrmann, W., Schmidt, R. (2021). The relationship between plasma free fatty acids, cognitive function and structural integrity of the brain in middle-aged healthy humans. Aging, 13(18):22078.
- Martinat, M., Rossitto, M., Di Miceli, M., Layé, S. (2021). Perinatal Dietary Polyunsaturated Fatty Acids in Brain Development, Role in Neurodevelopmental Disorders. Nutrients, 13:1185.
- Patan, M.J., Kennedy, D.O., Husberg, C., Hustvedt, S.O., Calder, P.C., Khan, J., Forster, J., Jackson, P.A. (2021). Supplementation with oil rich in eicosapentaenoic acid, but not in docosahexaenoic acid, improves global cognitive function in healthy, young adults: results from randomized controlled trials. Am J Clin Nutr, 114:914.
- Barnes, S., Chowdhury, S., Gatto, N.M., Fraser, G.E., Lee, G.J. (2021). Omega-3 fatty acids are associated with blood-brain barrier integrity in a healthy aging population. Brain Behav, 11(8):e2273.
- Mora, I., Arola, L., Caimari, A., Escoté, X., Puiggròs, F. (2022). Structured Long-Chain Omega-3 Fatty Acids for Improvement of Cognitive Function during Aging. Int J Mol Sci, 23:3472.
- Patan, M.J., Kennedy, D.O., Husberg, C., Hustvedt, S.O., Calder, P.C., Middleton, B., Khan, J., Forster, J., Jackson, P.A. (2021). Differential Effects of DHA- and EPA-Rich Oils on Sleep in Healthy Young Adults: A Randomized Controlled Trial. Nutrients, 13:248.
- Sprague, M., Dick, J.R., Tocher, D.R. (2016). Impact of sustainable feeds on omega-3 long-chain fatty acid levels in farmed Atlantic Salmon, 2006-2015. Sci Rep, 6:21892.