Advanced cognitive functioning is uniquely human, and cognition can change throughout the lifespan matching the brain’s development, maturation, aging, and health status. A substantial amount of literature identifies nutrition’s importance on brain health and cognition, with particular focus being placed on dietary fats.
According to the evidence, the proper functioning of the brain has significant dependence on maintaining optimal lipid composition. Over half of the brain’s dry weight is comprised of lipids, and the high amounts of omega-3 fatty acids suggest these nutrients play a crucial role in brain health and function.
What Are Omega-3 Fatty Acids?
Polyunsaturated fatty acids (PUFAs) are unique nutrients that play essential roles in human health. Omega-3 fatty acids are a type of PUFA that has garnered attention in recent years due to their associations with several aspects of health, from cardiovascular disease to prenatal health to cognition. Omega-3s play important structural roles in cellular membranes, act as precursors for several signaling molecules, and can activate numerous gene transcription factors.
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The three main types of omega-3 fatty acids include alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ALA is found in plant oils such as flaxseed, soybean, and canola oils. Common dietary sources of EPA and DHA typically include oils from microalgae and fatty fish. ALA, DHA, and EPA are considered “essential” fatty acids because the body cannot make them in sufficient quantities; therefore, we must obtain them from our diet.
Some may argue that DHA can be made from ALA, which is true in theory, but conversion rates are too low to be considered adequate. Therefore, DHA is still considered “essential” due to the inefficiencies of the enzymes required for its biosynthesis. Likewise, researchers have concluded that DHA consumption is necessary for reaching and maintaining ideal DHA concentrations, particularly in the brain.
Omega-3 Affects Cognition Across the Lifecycle
Long-chain PUFAs, like omega-3s, are essential for early brain development. DHA, in particular, is transferred in substantial quantities to the fetus via the placenta and after birth through breast milk or enriched formulas. Increasing evidence from epidemiological and intervention studies indicates that DHA supplementation during pregnancy and lactation plays important roles in infant and childhood neurodevelopment.
In fact, several studies outlined in a 2010 review of human evidence demonstrated positive associations between blood DHA levels and improvements in cognitive and visual tests and childhood psychiatric disorders. Furthermore, without adequate levels of DHA, central nervous system (CNS)-related conditions, including learning and memory deficits, dyspraxia, and dyslexia, can occur.
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While the evidence is clear that maintaining optimal DHA levels is vital during the development and maturation of the child’s brain, it is also critical for the successful aging of the adult brain.
According to a 2013 review investigating the effects of omega-3 fatty acids on the prevention of cognitive decline in humans, longitudinal observational studies demonstrate an inverse relationship between fish intake or serum DHA concentrations and cognitive impairment. Furthermore, while intervention studies of EPA and DHA supplementation in (1) cognitively healthy older individuals and (2) individuals with established Alzheimer’s Disease have not reported benefits, studies that include adults with mild or age-related cognitive impairment have reported positive outcomes. Furthermore, evidence demonstrates that DHA supplementation can improve memory and reaction time in healthy young adults whose diets were initially low in DHA.
DHA accretion in the brain begins during development, accelerates during the middle of gestation, slows down during infancy, and plateaus in early adulthood. The brain metabolizes approximately 4mg of DHA daily, and adults accrue DHA in the brain at a much slower rate than infants.
According to the literature, adults with red blood cell DHA concentrations on par with the average American (~4% of total fatty acids) require 4-6 months of oral DHA supplementation to reach a steady state concentration depending on dose (8% for 1000mg/day; 6% for 200mg/day). The ability of DHA to reach and incorporate into the brain may determine the difference between an aging person’s golden years or dark age.
Omega-3s’ Incorporation into the Brain
Quantitatively, DHA is the brain’s most significant omega-3 fatty acid, making up over 90% of the omega-3s in the brain and 10-20% of the total lipids. Enriched in membrane structures found at synaptic terminals, mitochondria, and endoplasmic reticulum, DHA can affect cellular characteristics and physiological processes, including membrane fluidity, lipid raft function, neurotransmitter release, transmembrane receptor function, gene expression, signal transduction, myelination, neuroinflammation, and neuronal differentiation and growth.
After ingesting omega-3 fatty acids, they must cross the blood-brain barrier to reach the brain. A review by Lacombe et al. noted that following entry into the brain, DHA is esterified into and recycled amongst membrane phospholipids contributing to the distribution of DHA throughout the brain. They also suggest that during neurotransmission and following brain injury, DHA is released from membrane phospholipids and converted into mediators, which regulate aspects of neural function and recovery, such as synaptogenesis, cell survival, and neuroinflammation. Given that the capacity of the brain to synthesize DHA locally is low, the uptake of DHA from circulating lipid pools and the translocation across the blood-brain barrier is essential for cognitive and CNS development and maintenance.
Challenges in Understanding Omega-3 Transport
While it has been well established that omega-3 fatty acids must pass through the blood-brain barrier to take action on the brain and CNS, the mechanism by which they could do so has not been entirely understood. As it turns out, omega-3 transport across the blood-brain barrier is no simple feat.
Scientists have previously identified that DHA is delivered to the brain via selective transport through endothelial cells. Yet, to cross the membrane bilayer, specialized transporters must flip the lipids, translocating and inverting a charged headgroup across a hydrophobic region to realign with the opposite leaflet, all while maintaining the integrity of the cellular membrane. Lipid flipping, as you can imagine, is energetically costly and requires specialized transport proteins to accomplish. The major facilitator superfamily (MFS) is the class of membrane proteins responsible for lipid flipping. Specifically, the MFS domain-containing protein-2a (Mfsda2a) is the primary DHA specialized transporter across the blood-brain barrier.
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Mechanistic studies have shown that Mfsd2a is selective toward long-chain, unsaturated fatty acids, including DHA, ALA, and oleic acids. Moreover, it’s apparent that Mfsd2a is required for the formation, development, and function of both the blood-brain barrier and the CNS, and defects in the protein disrupt brain development and function.
However, molecular details of how Mfsd2a performs lipid-flipping and transport across the lipid bilayer remain unclear… until now. New findings published in Nature Communications in May 2023 have excited the nutrition and pharmaceutical communities by reporting an improved understanding of lipid transport across the blood-brain barrier, providing a better foundation for neurological conditions and motor dysfunctions linked to membrane transport defects.
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New Evidence Reveals How the Brain Acquires Omega-3 Fatty Acids
In a recent publication, Nguyen et al. studied and described five structures of Mfsd2a transport proteins more thoroughly than ever before. Using single-particle cryo-electron microscopy, the researchers were able to model the mechanism allowing for a clearer step-by-step lipid transport and flipping mechanism. Unlike previous studies that suggested a linear substrate tunnel, the proposed model revealed three distinct compartments, each comprising a separate hydrophobic pocket and a charged cavity, allowing for a step-wise rotation of the charged fatty acid.
The researchers explain in more detail how the fatty acid, now flipped by Mfsd2a, is translocated toward and integrated into the cytoplasmic side of the membrane. Finally, the researchers identified and mapped residues that, when mutated, (1) disrupt lipid transport and (2) are associated with known Mfsd2a-related diseases.
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These new findings could improve understanding of lipid transport across the blood-brain barrier and neurological conditions associated with lipid disruptions. Furthermore, the model may also enable researchers to design nutraceuticals and drugs that can directly reach the brain and potentially help reduce neuro-degenerative conditions.
Summary
Optimal DHA intake leads to overall better development, maintenance, and aging of the brain and CNS, supporting peak cognition throughout the lifespan. These benefits likely require a sustained supply of DHA across a person’s lifetime, either through omega-3-rich foods or dietary supplements. Inadequate omega-3 intake or abnormalities in fatty acid metabolism and utilization may contribute to different neurodevelopmental disorders, and targeting the brain with omega-3s might provide effective therapy against several neurodegenerative diseases.
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Until recently, the mechanism through which omega-3 fatty acids cross the blood-brain barrier to take action in the brain has been unclear. Yet, a new publication further expanded the understanding of lipid transport across the blood-brain barrier. With a better understanding of DHA translocation across the blood-brain barrier and incorporation into the brain and CNS tissue, targeted drug or nutraceutical treatment for cerebral and CNS diseases are more possible.
