Brain Health across the Lifespan: A Systematic Review on the Role of Omega-3 Fatty Acid Supplements

The brain is the most significant and complex organ of the human body. Increasingly, we are becoming aware that certain nutrients may help to safeguard brain health. An expanse of research has investigated the effects of omega fatty acids in relation to brain health but effects across the lifespan have not been widely evaluated. The present systematic review collated evidence from 25 randomized controlled trials (n = 3633) published since 2013. Compared with control groups, omega-3 supplementation generally correlated with improvements in blood biomarkers. Subsequently, these appear to benefit those with lower baseline fatty acid levels, who are breastfeeding or who have neuropsychiatric conditions. Whilst multiple studies indicate that omega fatty acids can protect against neurodegeneration in older adults, more work is needed in the years preceding the diagnosis of such medical conditions. Bearing in mind the scale of ageing populations and rising healthcare costs linked to poor brain health, omega supplementation could be a useful strategy for helping to augment dietary intakes and support brain health across the lifespan. Ongoing research is now needed using harmonious methodologies, supplement dosages, ratios and intervention periods to help formulate congruent conclusions.


Introduction
The brain is one of the body's most complex organs and indeed one of its most crucial organs. Throughout the lifespan, the brain helps to make sense of the world, oversee daily operations and life itself [1]. Brain health is a multi-dimensional concept but, overall, refers to the ability to concentrate, remember, learn, play and maintain a clear and active mind [1]. The US Centers for Disease Control and Prevention defines a healthy brain as: "One that can perform all the mental processes that are collectively known as cognition, including the ability to learn new things, intuition, judgment, language, and remembering" [2].
We now recognize that a healthy brain is needed to live a fuller and longer life. Brain health supports human thoughts, planned actions and emotional connections [3]. Together these can influence the daily lives and indeed "quality" of lives of individuals, families and communities [3]. Maintaining brain health across the course of a lifetime can also help to optimize levels of independence [3]. Preserving brain health is also important in the mission to curtail heavy healthcare and economic costs that poor brain health can bring [3]. Over time, poor brain health can manifest in several different ways but characteristically as cognitive impairment or dementia [4]. A host of underlying cellular and molecular changes within the brain including oxidative damage, mitochondrial impairment, and alterations in glucose-energy metabolism and nerve inflammation have been purported to contribute to cognitive decline and brain ageing [5]. Table 1. Extended roles of omega-3 fatty acids on brain health and beyond.

Potential Extended Roles:
Anticoagulation Cardio-protective effects Cognitive function Fetal development Immune function Improved insulin sensitivity in Asians Neuronal function Reduced risk of breast cancer (women) Reduced risk of colorectal cancer (men) Reduced risk of ischemic stroke (men and women) Reduced total stroke risk (women) Retinal function Weight management

Methods
A comprehensive literature search was conducted to identify randomized controlled trials (RCTs) examining the relationship between omega-3 fatty acid supplements and aspects of brain health. The US Centers for Disease Control and Prevention definition of a healthy brain formed the basis of the search terms used [2]. A PubMed search was undertaken to identify relevant RCTs using the selection filter. Filters were applied to identify English-language human trials published in the last 5 years (between January 2013 and May 2018). Search terms applied were: "omega" fatty acids AND "brain health", "mindfulness", "cognitive function", "learning", "judging", "remembering", "memory/memorizing" and "language use".
Studies were organized according to the seven ages of the brain: (1) Pregnancy, (2) Infancy, (3) School age, (4) Teenage, (5) Young adults, (6) Middle age, (7) Older age/Dotage (Table 2). Studies focusing on school age or teenage subjects were merged in Tables Tables1 Tables2 due to overlapping age ranges. RCTs were included if the following criteria were met: (1) the trial was randomized and involved human subjects; (2) the trial was a controlled intervention using omega-3/6 supplements; (3) the trial clearly specified the dose and form of fatty acids; (4) the trial length was reported; (5) the trial was not a pilot study; (6) the trial did not use multi-domain interventions. Included participants did not have any severe, long-term medical conditions. Studies including participants with attention deficit hyperactivity disorder (ADHD), autism, depression and/or mild cognitive impairment (MCI) were included. When full texts were not available, these were purchased where sites permitted. Infants in the placebo group were at increased risk of lower language development assessed as words understood and produced at 14 months and words understood and sentences produced at 18 months.  Reading, spelling and non-verbal cognitive development The treatment group showed improvements in Draw-A-Person compared with the placebo during Phase 1 (p = 0.029). The placebo group showed significant within-group improvements after switching to treatment (p < 0.001). Cognitive performance and functional brain activation.
Following EPA-rich supplementation, participants' brains worked 'less hard' and achieved a better cognitive performance than prior to supplementation.
1.16 g DHA or a placebo. Cognitive performance.
DHA supplementation improved memory and the reaction time of memory in healthy, young adults whose habitual diets were low in DHA. The response was modulated by sex.  Four 1000-mg n-3 FA supplements (containing EPA 1200 mg plus DHA 800 mg) or placebo.
In vivo glutathione concentration.
Compared with the group given the n-3 FA supplements, the placebo group had greater change in the glutathione-to-creatine ratio in the thalamus (p = 0.049). 12-week randomized, DB, parallel-group comparative study.
2 weeks of treatment with: medium-chain triglycerides as placebo; krill oil, which is rich in n-3 PUFAs incorporated in phosphatidylcholine; or sardine oil, which is abundant in n-3 PUFAs incorporated in triglycerides.

Data Extraction
The present systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [28]. Publications were excluded if PRISMA benchmarks were not included in the trial publication but instead covered elsewhere. As shown in Figure 1, abstracts and papers were evaluated for relevance. Once identified, all eligible RCT had relevant data extracted, including: author, year, location, life stage, sample size, age, gender, baseline health status, study design, form of intervention, aspect(s) of brain health studied and outcomes measured. Relevant data extracted from the studies included the dose and composition of fatty acid supplements, the randomization method, and withdrawal rates. The Jaded scale and criteria was then used to develop quality scores for each RCT [27]. Quality scores were graded between 1 and 5 with higher scores being indicative of higher quality (Table 3).

Data Extraction
The present systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [28]. Publications were excluded if PRISMA benchmarks were not included in the trial publication but instead covered elsewhere. As shown in Figure 1, abstracts and papers were evaluated for relevance. Once identified, all eligible RCT had relevant data extracted, including: author, year, location, life stage, sample size, age, gender, baseline health status, study design, form of intervention, aspect(s) of brain health studied and outcomes measured. Relevant data extracted from the studies included the dose and composition of fatty acid supplements, the randomization method, and withdrawal rates. The Jaded scale and criteria was then used to develop quality scores for each RCT [27]. Quality scores were graded between 1 and 5 with higher scores being indicative of higher quality (Table 3).     Total quality assessment score for which scores range between 1 and 5: with 1 being the lowest quality and 5 being the highest quality. 3 = above average quality.

Results
The PubMed search identified 134 RCT papers after an adjustment for replica papers. Of these, 109 papers were discarded after reviewing the abstracts and article content as they did not meet the inclusion criteria. This left 25 RCT articles for general review. The algorithm of qualifying publications is shown in Figure 1. Of these, six studies were conducted in the United States or Canada, 11 in Europe or the United Kingdom, two in Asia and seven in Australasia.

Pregnancy and Infancy
Five RCTs considered the effects of omega supplementation during pregnancy or infancy in relation to neurodevelopment. The earliest trial began from 16 weeks of pregnancy until delivery allocating mothers to take 400 mg DHA/day [32]. When followed up at 14 to 18 months after delivery, scientists found that omega supplementation was associated with a reduced risk of poor language development compared with the placebo [32].
Other trials had less conclusive results. One study from 20 weeks of pregnancy using a higher 800 mg/day dose of DHA until birth did not observe any effects on infants' attention or working memory [33]. Similarly, 400 mg EPA/DHA provided from the 28th week of pregnancy until the cessation of breastfeeding was not found to affect infant neurodevelopment although the DHA profile and levels of nervonic acid (nerve cell myelin fatty acids) improved [34].
In the postpartum and infancy period, one trial allocating 89 lactating women to 200 or 400 mg DHA daily over 6 weeks observed that maternal plasma and breast milk DHA levels increased which improved the ratio of fatty acids available to infants for infant brain development [36]. Other work forming part of the Childhood Asthma Prevention Study [30] found that consuming tuna fish oil daily (high in omega-3 fatty acids) for the first 5 years of life correlated with plasma omega-3 levels, literacy and numeracy performance at age 8 [30].

School Age and Teenage
A growing body of evidence has explored inter-relationships between omegas and brain health at this life stage. Nine RCTs met the inclusion criteria with four of these concentrating on children with Autistic Spectrum Disorder (ASD) or Attention Deficit Hyperactivity Disorder (ADHD) [29,31,35,49]. One trial included 7-to 14-year-olds with depression and/or bipolar [37] with the remainder recruiting healthy mainstream or children underperforming at school [38][39][40][41].
One trial replicating previous research on mainstream children (aged 7-9 years) underperforming in reading found that 600 mg/day of algal oil DHA over 16 weeks showed some minor differences in behavioral aspects but effects on learning were less apparent [38]. Authors concluded that findings may have been dissimilar to earlier research due to national curriculum changes, a larger recruitment area, and an underpowered sample size [38]. Other work on mainstream children at school has observed benefits. For example, a 3-month trial providing 9-to 10-year-olds with three Omega 3/6 capsules (Equazen®) twice daily (corresponding to a daily dose of 558 mg EPA, 174 mg DHA, and 60 mg gamma-linoleic acid) observed improvements in reading ability-particularly clinically relevant "phonologic decoding time" and "visual analysis time" compared with the placebo, with this being most evident in children with attention problems [39].
Five trials focused on children with mood or neuropsychiatric conditions. Amongst children aged 7 to 14 years with mood disorders, 2 g/day of omega fatty acids (1400 mg EPA and 200 mg DHA) over 12 weeks improved EPA levels by sevenfold and DHA levels by half [37]. EPA, in particular, correlated positively with mood responses and inversely with body weight indicating that smaller children could be more responsive to omega supplementation [37]. Amongst children and teenagers (n = 60) with ASD, omega-3 fatty acids (962 mg or 1155 mg daily) over 8 weeks improved the fatty acid composition of biological membranes and some markers of behavior although longer periods of follow up were needed to observe clinical changes [29]. A longer 16-week trial conducted on 40 boys (8-14 years) with and without ADHD found that 650 mg EPA/DHA provided via the ingestion of 10 g margarine daily enhanced parent-rated attention [31]. Improvements in spelling, attention, hyperactivity, cognitive problems and reduced oppositional behavior have also been observed in 6-to 13-year-olds with ADHD supplementing with omega fatty acids for up to 1 year [35]. Other work on 6to 12-year-olds with ADHD showed that two daily capsules providing 720 mg omega-3 (600 mg EPA, 120 mg DHA) improved working memory function [49].
Amongst malnourished children, a 3-month Mexican trial found that three daily capsules of omega fatty acids (60 mg DHA and 90 mg EPA per capsule) taken by 8-to 12-year-olds improved 11 of 18 neuropsychological variables including processing speed, visual-motor coordination, perceptual integration, attention and executive function in more than 70% of the omega-3 supplemented children [40]. Similarly, amongst Australian children aged 3 to 13 years fish oil capsules (Equazen ® ) providing EPA (93 mg), DHA (29 mg) and GLA (10 mg) taken daily for up to 40 weeks improved measures of cognitive development after 20 weeks, particularly amongst 7-to 12-year-old indigenous children [43].

Young Adults
Three RCTs examined the role of omega fatty acids on brain health in young adults. A double-blind trial comprised of 72 healthy young adults (mean age 20 years) observed that 2800 mg/day fish oil (1680 mg EPA and 1120 mg DHA) over 35 days kept feelings of anger and confusion stable compared to increases in the placebo group [42]. A similar length 30-day trial where of 20-to 34-year-olds provided with varying ratios of EPA to DHA confirmed that EPA-rich supplementation enhanced neurocognitive function -implying that the brain worked less hard yet had better cognitive performance [46]. Other work using DHA specifically (1.16 g daily) over 6 months (mean age 33 years) observed that DHA significantly improved episodic memory in young women and reaction times of working memory in men, indicating benefits for those whose diets were habitually low in DHA [45].

Middle Age
Three RCTs were identified for this life stage. One 26-week trial providing 2200 mg/day omega-3 fatty acids to 50-to 75-year-olds (mean age 62 years) found that this dose significantly improved the recollection of object locations, implying positive effects on memory function [44]. Other research recruiting adults of a similar age range and time frame showed that 2200 mg/day omega-3 fatty acids improved brain structure, namely via white matter microstructural integrity and the volume of grey matter [48]. One trial focusing on adults with loneliness-related memory problems (mean age 51 years) discovered that omega-3 supplementation (1250 or 2500 mg/day) over 4 months attenuated verbal episodic memory declines that were linked to loneliness [47].

Older Age/Dotage
Five RCTs have focused on brain health in later life. One RCT focusing on adults over the age of 70 years showed that 800 mg DHA and 225 mg EPA over 36 months helped to maintain executive function amongst those at risk of dementia with a low omega-3 index [50]. Amongst Chinese elderly people of a similar age (mean 71 years) with Mild Cognitive Impairment, 480 mg DHA and 720 mg EPA taken daily over 6-months significantly improved cognitive aptitude scores and working memory [51] compared with the olive oil placebo. A similar length trial conducted on older adults with subjective memory impairment showed that 2400 mg EPA + DHA significantly improved omega-3 red blood cell levels, working memory performance and brain signals during working memory challenges, indicating that neuronal response was heightened [52]. Some work with krill oil showed that omega-3 fatty acids may activate cognitive function in older adults which was determined by changes in cerebral cortex ox hemoglobin levels over 12 weeks [53]. Older adults provided with 800 mg DHA and a higher ratio of EPA-1200 mg had attenuated levels of oxidative stress -a risk factor thought to be implicated in the pathophysiology of depression and prevention of depressive symptoms [54].

Discussion
There is a strong body of evidence signifying that omega-3 fatty acids from dietary sources are under consumed. For example, systematic evidence from 53 studies across 17 different European countries shows that mean intakes of EPA and DHA are only consumed as recommended in 26% of countries, indicating that intakes are largely suboptimal [55]. Evidence from the US National Health and Nutrition Examination Survey (NHANES) survey similarly shows that childbearing aged women are eating seafood in amounts significantly lower than the Dietary Guidelines for Americans contributing to low habitual intakes of EPA and DHA [56].
Along with concerns over inadequate EPA and DHA intakes, interest in the "preservation" of brain health is emerging [3,55]. The American Heart Association/American Stroke Association has identified the risks of poor brain health as being similar and closely associated to those of cardiovascular disease [3]. Within their practical considerations, seven key ideal health behaviors are identified which include: not smoking, physical activity, a healthy body mass index (BMI), blood pressure, blood glucose, cholesterol levels and diet aligned with current healthy eating guidelines [3]. Increasingly, mindfulness is also being seen as a useful adjunctive therapy amongst those with ADHD [57,58] with this strategy also appearing to help reduce stress amongst older adults with memory complaints [59].
From a dietary perspective, findings from RCTs showed that omega fatty acid supplementation could help to reinforce habitual intakes by raising blood levels. For example, improvements in lipid profiles were observed in at least seven studies [30,34,36,37,49,52,53]. Certain subgroups such as those with lower baseline blood fatty acids levels [40,45,50], who are breastfeeding infants [34,36] or who have neuropsychiatric conditions such as ADHD, ASD or depression, also appear to benefit more strongly from omega use [29,31,35,39,54].
In the case of older adults, a number of studies alluded that omega fatty acids could help to protect against neurodegeneration and the chances of developing cognitive impairment [44,48,[50][51][52][53]. Similar conclusions have been formulated in other reviews, reflecting the current strength of the evidence base [60,61]. Whilst some research has looked into markers of brain health in the middle years of life, outcomes studied varied and findings were not strong enough to warrant any firm conclusions.

Limitations and Future Research
When comparing and contrasting study findings, it is important to consider methodological differences. For example, the dosage, length of supplementation and appropriate selection of assessment tools (erythrocyte analysis, where possible) should all be deliberated, especially in varying cultural populations with sufficient statistical power behind studies to allow for investigating interactions between gender and age [43]. Indeed, the present publication only evaluated RCTs which ideally should be at least 16 weeks in duration and measure outcomes of focus immediately during or after supplementation rather than a number of years post-intervention [45]. It is also worth mentioning at this point that movement away from the omega-6 to 3 ratio may now be required in order to fully decipher what an "optimal" omega fatty acid status is [62]. Instead metrics focusing on the shortfalls of EPA and DHA in Western diets should be used as a modern assessor, such as the Omega-3 index [62]. It is also evident that brain-imaging technologies should be used alongside measures such as 'speed of cognitive performance' [45].
Future studies should investigate the role of other nutrients such as B vitamins which may interact with omega-3 fatty acids and have a joint role in preventing brain atrophy [63]. Some work conducted with Canadian Inuit's identified a potential link between low iron intakes (higher serum ferritin levels) and reduced omega-3 fatty acid biosynthesis, indicating that iron deficiency could impact on fatty acid status [64]. Failure to confound or control for factors such as these could be why some trials looking at omega-3 fatty acids and cognition have been unsuccessful [63]. The complex interplay between factors such as apolipoprotein E genotype, gender breakdown, vegetarianism and veganism should also be further studied [45]. Clearly, more work is needed across the middle years of life as we now know that changes in the brain occur before any signs of poor brain health manifest [65]. Dotage, is another life phase worthy of continued exploration given that the number of octogenarians is presently around 15% of the elderly population with numbers projected to exceed the number of children by 2047 [66]. Finally, work looking at the dual effects of omega fatty acid alongside mindfulness strategies could be worthy of exploration given growing interest in this field [67].

Conclusions
The present article shows that omega-3 supplementation appears to be effective at improving EPA and DHA status. This in turn may have a role to play in maintaining and augmenting brain health, particularly amongst those with low baseline levels or fatty acids or with increased demands such as lactating mothers or those with diagnosed neuropsychiatric conditions. Certainly, given that ageing populations, mental health conditions, and cognitive decline are currently showing no signs of subsiding, it makes good sense to ensure that omega fatty acid levels are optimal across the lifespan be it through dietary or supplement sources.
Author Contributions: E.D. was responsible for the independent planning, analysis and the write-up of the publication.

Funding:
The author received funding from Equazen.