As the direct precursor to pro-inflammatory metabolites that drive inflammatory processes, modulators of the arachidonic acid (AA) cascade have been the focus of research for the treatment of inflammation and pain for several decades.  With our Western-style diets rich in omega-6, and AA accumulation at the heart of inflammatory driven conditions, there is an increasing need to seek out non-pharmacological approaches to manage inflammation and avoid many of the common side effects associated with standard drugs. We can identify an individual’s inflammatory risk quite simply by monitoring the AA to EPA (eicosapentaenoic acid) ratio and it is possible to reduce AA at the cellular level by direct EPA supplementation.
Unlike standard drugs, EPA has no side effects, acting as an effective anti-inflammatory, reducing AA accumulation and therefore its subsequent production of inflammatory eicosanoids. As a biomarker, the AA to EPA ratio gives us valuable information about our inflammatory status, but because diet has the capacity to influence the amount of polyunsaturated fats within our cell membranes we also need a structural biomarker of omega-3 status; combining the AA to EPA ratio with the actual amount of omega-3 within our cells (the amount of EPA + DHA within cell membranes calculated as a % of total fats is known as the omega-3 index) gives us a comprehensive overview of inflammatory health.
Using biomarkers for bespoke personalised nutrition
A low Omega-3 Index (≤4%) is well established as a cardiovascular risk factor. Arising from epidemiological studies that show an inverse relation between clinical events and intake of omega-3 fatty acids (EPA and DHA), the greatest protection has been observed at omega-3 levels ≥8%. In addition to the omega-3 index providing valuable information on cardiovascular health, increasing evidence is beginning to support its role as a reliable biomarker for mental health disorders. In addition, a high omega-3 index is not only associated with slowed “cellular aging” (as measured by the rate of telomere shortening),  but also associated with a healthier body composition,  particularly in women, suggesting there may be a role for intervention targeted at raising the omega-3 for managing metabolic issues related to obesity, and inflammation as a consequence of age related oxidative stress. Given that inflammation plays a role in driving most chronic diseases, and that the omega-3 index is related to the AA to EPA ratio (AA is the significant pro-inflammatory omega-6) which is itself an established indicator of inflammatory status,  the use of biomarker analysis to offer bespoke personalised nutrition plans holds promised for successful intervention.
Why fish oils fail: clarifying influential variables
Raising the omega-3 index as a therapeutic intervention for cardiovascular issues has been the focus of many large intervention studies. However, in contrast to the evidence provided by epidemiological studies, meta-analysis and reviews of intervention trials using omega-3 fatty acids have reported neutral findings on both total mortality and major adverse cardiac events. Such lack of evidence has, unsurprisingly, raised significant questions related to the benefits of omega-3 intervention for cardiovascular health. Before drawing negative conclusions on the role of omega-3 in cardiovascular disease, it is worth addressing the key influencers that can affect outcomes. In his recent review “omega-3 fatty acids in cardiovascular disease – an uphill battle”, Clemens von Schacky, a key developer of the omega-3 index, explains how bioavailability issues, inter-individual variability and failure to address EPA and DHA baseline levels can directly affect the outcomes of a study. Differences in bioavailability of different chemical forms of EPA+DHA supplements exist and it is well established that the bioavailability of EPA and DHA as ethyl-ester (the predominant forms used in many large intervention trials) is significantly improved by taking the supplement with a fatty meal. Yet in many of the large scale interventions, participants were advised to take their study capsules at breakfast time, which in many countries consists of a low fat meal. Thus, poor absorption could potentially contribute to reduced bioavailability of the supplement. In addition, and possibly the most significant of contributing factors, study participants are often recruited irrespective of their baseline omega-3 index and treated with fixed doses, ignoring the large inter-individual variability that exists in uptake of EPA and DHA.
The importance of reaching therapeutic levels
In terms of the omega-3 Index, the response to a given dose of omega-3 can vary up to a factor of 13 from individual to individual,  yet it has been suggested that whilst dietary intervention with fish oil results in the incorporating of EPA and DHA into cell membranes, the omega-3 index must reach that as suggested to be optimal (≥8% in the case of cardiovascular patients) to obtain clinical efficacy.  From a therapeutic stance, dietary intervention for clinical outcomes must therefore focus on ensuring an ‘ideal’ omega-3 index of ≥8% is achieved. If blood cell omega-3 content is to be used as a risk factor and a dietary target for intervention, then the factors that influence this marker need to be elucidated, thus highlighting the increasing importance of personalised nutrition. For example, in a 2005 study addressing factors that influence omega-3 levels, fish consumption, age, body mass index (BMI) and diabetes all affected omega-3 status. The index increased by 0.24% units with each additional monthly serving of tuna or non-fried fish, and by 0.5% units for each additional decade in age. Was 1.13% units lower in subjects with diabetes (possibly due to low desaturase activity) and decreased by 0.3% units with each 3-unit increase in BMI. Gender, smoking status and ethnicity had no effect.
Treatment associated changes are dependent on the initial omega-3 fatty acid status
In their 2014 study, Silva and colleages addressed the impact of disease states on omega-3 requirements. By analysing red blood cell fatty acid composition in healthy individuals and different health conditions including psoriasis, cancer and ICU-trauma patients at baseline, they were able to show how this affects the incorporation of omega-3 fatty acids via supplementation. Baseline red blood cell fatty acid profile (EPA, DHA & AA) proved to be different and dependent on the nature of the study population, with the healthy population showing the best omega-3 levels and most favourable omega-6 to omega-3 status. Moreover, they showed that for the ITC-trauma patients, the treatment associated changes were dependent on the initial omega-3 fatty acid status, concluding that fatty acid profiles should be evaluated and considered individually for each patient or groups before generalised supplementation schemes, further strengthening the concept of personalised medicine. 
If blood cell omega-3 content is to be used as a risk factor, then the factors that influence this marker need to be elucidated. Consequently, knowledge of baseline levels will guide the practitioner recommendations—not surprisingly, low baseline values may require a larger dose than a high baseline value. Therefore, the Omega-3 Index may be useful for assessing both baseline risk and a change in risk as a function of intake, because the treatment associated changes that are derived from intervention are dependent on the initial omega-3 fatty acid status. The next barrier faced by the practitioner is how to raise the omega-3 index in terms of efficiency and affordability. Unlike pharmaceutical omega-3 supplements that offer high strength omega-3 as EPA and DHA (Omacor) or pure EPA (Vascepa-USA), huge diversity exists in their neutraceutical alternatives in both molecular structure and concentration/purity. For example, standard fish body oil offers around 30% omega-3 as triglyceride (TG), krill oil as little as 24% as phospholipid (PL), whereas concentrated fish oils can contain as much as 90% omega-3 as ethyl-ester (EE) or re-esterified triglyceride (rTG).
In a recent (2014) review of the bioavailability of different forms of omega-3 long-chain polyunsaturated fatty acids including EE, free fatty acids (FFAs), TAG, rTAG and PL, the consensus appears to that bioavailability is highest for FFA and rTG and lowest for the EE form. It is likely, however, that if subjects are advised to take EE supplements with a fatty meal that the incorporation into red blood cells would be similar if not equal to that of rTG. Interestingly, whilst marketing of krill oil focuses on its apparent superior bioavailability based on animal studies, no similar conclusion has been drawn for TAG versus PL from human data.  Whilst bioavailability is obviously a key factor to consider when choosing a health supplement (whether a practitioner or general fish oil consumer), it is the impact the dose taken has on the omega-3 index that is undoubtedly the factor that will influence outcomes and therefore should be the rationale behind supplementing. When looking at ‘like for like’ bioavailability studies, the practicalities of supplementing can become clouded. For example, of the studies that have reported superior uptake EPA and DHA from krill oil, the doses required for clinical effect have been, in some cases, 20x higher if not more, than the manufacturers’ recommended dose.
Bioavailability and dose: why some fish oils will not deliver therapeutically
On further examination, when we look at dosing guidelines set by fish oil manufacturers’ we can begin to deconstruct and expose some of the potential barriers that exists between supplementation and clinical effects. Indeed, this was the exact focus of Laidlaw’s 2014 paper, “A randomized clinical trial to determine the efficacy of manufacturers’ recommended doses of omega-3 fatty acids from different sources in facilitating cardiovascular disease risk reduction.”  The trial objective was to compare the increases in blood levels of omega-3 fatty acids after consumption of four different omega-3 supplements (rTG & EE fish oils, PL krill oil and TG salmon oil), and to assess potential changes in cardiovascular disease risk (as defined by the omega-3 index) following supplementation. At the prescribed dosage, the statistical ranking of the four products in terms of increase in whole blood omega-3 fatty acid levels was concentrated rTG fish oil > EE fish oil > triglyceride TG salmon oil > PL krill oil. Whilst these results would be expected given the varying content of omega-3 between the products, the significance to the consumer is that both krill oil and standard fish oil used at the manufactures recommendations failed to have a significant impact on either the omega-3 index or the AA to EPA ratio. Interestingly, whilst a dose of 1.1g rTG oil for 28 days raised the omega-3 index from 4.1% (high risk) to 6.8% (lower risk) it failed to reach the desirable target value for the omega-3 index set at ≥8% because they did not take into account body weight, a key factor that should be taken into account when dosing. Indeed, for a 77kg individual (the average weight of participants within this study), to raise their omega-3 index from 4.1% to 8% they would need a daily dose 16mg/kg omega-3 (equivalent to 1.25g) rather than the 14mg/kg dose provided by the rTG supplement. Given that the krill oil only provided 3mg/kg and the salmon oil 5mg/kg, it is not surprising that, used at the manufactures recommendations, these oils failed to have a significant impact on the omega-3 index. Indeed, to achieve the ‘correct’ dose, the consumer would have to take 5x the manufacturers’ recommended dose (10 capsules rather than 2), increasing the approximate daily price from 94p a day to just under £5. The daily price for a comparable dose of rTG Pharmepa RESTORE is £1.50.
We are metabolically unique individuals with high intra-variability in our response to omega-3 supplementation. With factors such as age, gender, physical activity, health state and baseline levels of omega-3 affecting our response to supplementation, we need to move away from the current concept of a ‘one size fits all’ dosing regimen to adopt one that is more personalised to individual requirements. It is important to understand that, from a therapeutic stance, dietary intervention for clinical outcomes must focus on ensuring ‘ideal’ levels of omega-3 are reached and that the AA to EPA ratio lies between 1.5 and 3. To enable this, the choice of product must be one clinically proven to raise the omega-3 index effectively. The Opti-O-3 fatty acid biomarker test identifies baseline levels of EPA and DHA and calculates the dose required to raise the omega-3 index to the predetermined level suggested to be optimal to obtain clinical efficacy. For example, a recent case study using Pharmepa RESTORE at 1.5g/daily raised the client’s omega-3 index from 3.5% (high risk) to 5.98% (lower risk) with a corresponding reduction in the AA to EPA ratio of 8.52 (suboptimal range) to 3.54 (acceptable range) in just 4 months.
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