Polyunsaturated Fatty Acid Intake and Brain Health: Balance is the Key

The brain consists of a diverse variety of lipids differing in fatty acid length, and saturation status of the hydrocarbon chain. Saturated and monounsaturated fatty acids can be synthesized de novo by the brain, but polyunsaturated fatty acids (PUFAs) are mainly obtained from the blood.¹ The PUFAs, α-linolenic acid (omega-3 fatty acid [ω3-FA]) and linoleic acid (omega-6 fatty acid [ω6-FA]) are considered essential as they cannot be completely synthesized in the human body and must be supplied by the diet. In this issue, Liu et al² investigated the association of dietary fat intake with cognitive outcomes using the National Health and Nutrition Examination Survey (NHANES) food intake data. The authors demonstrated that ω–3FAs and ω6-FAs were positively associated with cognition in older adults. Since aging is associated with an overt inflammatory phenotype, emerging evidence that ω3-FAs and ω6-FAs are precursors for bioactive molecules that play a role in self-limiting the acute inflammatory response lends credence to the results.³

Humans can convert linoleic acid to arachidonic acid (AA) which is an ω6-FA, and α-linolenic acid to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) which are ω3-FAs, but the conversion is inefficient.¹ EPA and DHA can be obtained in the form of fish oil supplements or through consumption of fatty fish such as mackerel, salmon, or trout. The consumption of cereal and grains prompted by the agricultural revolution, the development of the vegetable oil industry, and the emphasis on grain feeds for livestock have contributed to the increase in the consumption of ω6-FAs. The ratio of ω6-FAs to ω3-FAs was 1:1 in the diet that human beings have embraced for most of their existence, but approximates 15:1 in the present day Western diet.⁴

Brain tissue is highly susceptible to neural trauma, neurodegenerative diseases, and infections. Neuroinflammation, when appropriately activated and regulated is a protective mechanism that combats invading pathogens, removes damaged cells, and promotes repair and recovery. A variety of immune system modulators propagate and maintain neuroinflammation providing an environment in which lipid mediators such as AA-derived eicosanoids (prostaglandins and leukotrienes), cytokines, chemokines, and reactive oxygen and nitrogen species are generated. This process is turned off by neural cells to limit tissue injury.⁵

Resolution of the inflammatory process is an active coordinated program initiated within the first few hours following an inflammatory response. Crosstalk between cells can convert AA to mediators with anti-inflammatory, as well as tissue repair and healing properties. The switch of AA-derived prostaglandins and leukotrienes to lipoxins and their endogenous analogs initiates the termination of inflammation. The signal to end the acute inflammatory response coincides with biosynthesis of signaling molecules that have the potential to stimulate critical resolution events. These molecules include resolvins, protectins, and maresins derived from metabolism of ω3-FAs.⁵ Chronic neuroinflammation lingers as the immune system continues to attack at a cellular level. The molecular mechanisms modulating the dynamics of acute and chronic neuroinflammation and the contribution to secondary brain injury are unclear.³

Eicosapentaenoic acid and DHA have long been thought to have anti-inflammatory properties because they compete with AA and reduce the production of pro-inflammatory eicosanoids.⁵ However, AA supplementation does not adversely affect the inflammatory process and may improve cognitive function.⁶ DHA is enriched in the brain and plays a role in normal neurologic and cognitive function. The involvement of ω3-FAs as precursors to resolution-phase mediators and their functional importance is human health is an active area of research.⁵ The encouraging results from the use of dietary DHA and other ω3-FAs in neurologic disorders notwithstanding, the evidence to support the benefits of their supplementation on cognition, is equivocal. The results largely from studies with small sample sizes and of short duration suggest that the effects of ω3-FAs depend on the aspects of cognition assessed and the stage of cognitive decline.^5,6 However, in a recent large randomized controlled trial, ω3-FA supplementation for over five years increased the risk for depression and depressive symptoms.⁷

The NHANES food intake data is derived from 24 hour dietary recalls. By their reliance on participant memory, these recalls are inherently prone to mis-reporting. The positive association of ω6-FAs with cognition demonstrated by Liu et al contrasts with the common belief that increasing dietary intake of ω6-FAs enhances inflammation. The results are plausible in the light of the discovery of AA-derived pro-resolving mediators with their potential for promoting resolution of pathologic inflammation, and the conflicting reports of the effect of ω3-FA supplementation on mental health outcomes. However, the results warrant further investigation. Liu et al also observed an association of cognitive function in older adults with a decline in γ-glutamyl transpeptidase and an increase in uric acid, which are biomarkers of oxidative stress. The high content of easily oxidized PUFAs and high rate of oxygen consumption in the brain render it vulnerable to oxidative damage. Despite high-energy consumption pathways that scavenge and replace damaged PUFAs, the balance may be altered with age and neuroinflammation.⁶

Targeting brain fatty acid metabolism poses a challenge that arises from the myriad processes they regulate. Therefore, changing brain fatty acid levels may be accompanied by adverse side effects. Determining the underlying mechanisms that regulate the diverse features of inflammation and sorting out the processes that protect from neuronal damage and those that contribute towards it, is essential. The crux of the issue may lie in the balance of different mediators of inflammation. Collective evidence suggests that AA and DHA have complementary roles in neuroprotection. The pathway of AA synthesis from linoleic acid appears saturated from high intakes.⁶ Attaining a measure of balance rather than restoring the ratio of dietary ω3-FAs and ω6-FAs to levels customary in the ancient human diet may be a prudent approach. AA is found in foods of animal origins such as meats and eggs, which are central to our diets. Substituting some meat entrées with fatty fish and polyunsaturated vegetable oils with monounsaturated fats such as olive oil are small changes that are likely to garner adherence.

Abbreviations:

AA

Arachidonic acid

DHA

Docosahexaenoic acid

EPA

Eicosapentaenoic acid

PUFA

Polyunsaturated fatty acid