A Balanced Approach to Omega-3 Benefits

Bill Lands, Fellow, American Society for Nutrition, College Park, MD, USA Email: wemlands@att.net; Website: http://efaeducation.org/ Similarities and differences between the omega-3 (n-3) and omega-6 (n-6) essential nutrients have moved in and out of discussions over the past 50 years as the biomedical community explored their diverse actions in human health. Evidence-based misunderstandings and apparent contradictions easily occur whenever a portion of the whole is discussed without a broader context to keep a balanced perspective (e.g., 1). Current paradoxes about benefits and harm from n-3 and n-6 nutrients prompt me to offer links to some recent open-access articles to give readers a convenient context that may help them review and resolve some apparent contradictions and lead to more constructive interpretations with positive outcomes for the use of omega-3 nutrients in human health.
  1. Balancing just enough and not too much
The pharmaceutical industry has provided much evidence of harmful actions of n-6 arachidonate derivatives, which became profitable targets for drug development and marketing. Hundreds of national and international meetings have discussed ways to decrease unwanted signaling by many n-6 derivatives and receptors in the arachidonic cascade (2; Figs. 1 and 2). The large number of successful drugs leaves no doubt that human harm comes from excessive n-6 eicosanoid actions, and the two figures show much less intense actions occur with some n-3 compared to n-6 derivatives. Health conditions made worse by excessive n-6 mediator actions include heart attacks, atherosclerosis, thrombosis, stroke, immune-inflammatory disorders, asthma, arthritis, cancer proliferation, obesity, psychiatric disorders, depression, suicide, homicide, oppositional behavior, unproductive workplace behaviors and length of stay in hospitals (see also 2; Table 1). In the course of developing drugs for treatments, dose-response studies showed the range of effective dose (therapeutic window) that had enough drug to decrease the “target process” without suppressing other desired n-6 functions. Aspirin-related non-steroidal anti-inflammatory drugs (NSAID) that inhibit cyclooxygenase-1 plus coxib drugs that inhibit cyclooxygenase-2 all give health benefits with a finite therapeutic window of efficacy (2; Fig. 1). Whenever a therapeutic window is narrow, the drug should be used at the lowest effective dose and reviewed regularly (3). This issue continues to disrupt NSAID and coxib marketing (4), and it has importance in section 3 below. While the pharmaceutical industry continues to focus on creating new patented materials that diminish n-6 arachidonate-based conditions, the extensive evidence they have provided about bioactive derivatives and receptors can be applied to designing nutrition strategies that decrease the need for such treatments.
  1. Food controls the accumulated balance of n-3 and n-6 highly unsaturated fatty acid (HUFA)
A nutrition-based approach to diminish unwanted actions of n-6 derivatives is to decrease the availability of the n-6 precursor of the “arachidonic cascade” by displacing it competitively with similar naturally occurring n-3 precursors (5; Figs. 1, 2 and 3). This approach expands awareness beyond n-6 arachidonate and its products to include the competing n-3 20- and 22-carbon n-3 highly unsaturated fatty acids (HUFA) that share space with n-6 HUFA in tissue lipids and compete for release by the phospholipase, cPLA2. Both types of HUFA influence each other and are released during tissue responses. HUFA balance is easily monitored from finger-tip blood-spot samples and described as proportions of competing n-3 and n-6 in the total HUFA as proposed at the 2004 ISSFAL Congress in Brighton, UK (6). Figure 3 in 5 shows that in apparently healthy people arachidonate (20:4n-6) can range from 30% to 70% of HUFA while the competing n-3 HUFA range from 65% to 15% of HUFA. People in Japan and Mediterranean countries have lower %n-6 in HUFA and lower risk for heart attack mortality than Americans and Northern Europeans (7; Fig. 1). The mortality rates for diverse groups closely associate (r2=0.99) with the observed proportions of n-6 in HUFA (8), indicating that blood HUFA balance is a useful health risk assessment biomarker.
  1. Choosing foods that give a healthy HUFA balance
HUFA balance is also a useful measure of average daily intakes of competing n-3 and n-6 nutrients in foods (9). An Omega 3-6 Balance Score uses data on 11 n-3 and n-6 acids in a food, expressing them as a single Score (10). People’s observed HUFA balances from 81% to 30% n-6 in HUFA correspond to average daily food scores from –7 to +2. Estimates of the impact of food items on tissue HUFA balance are made easy by free “apps” that can be downloaded from a wellness website to personal mobile devices and computers. Omega Foods shows omega 3-6 balance scores for over 5,000 food items, and Omega Meals helps people plan daily menu plans that will give a desired HUFA balance. The apps are useful in personal decisions for menu planning, food shopping or discussing food choices with friends.
  1. A narrow therapeutic window for dietary n-6 linoleate is widened by n-3 nutrients
We learned long ago that dietary n-6 linoleic acid is very effective in forming 20- and 22-carbon highly unsaturated fatty acids (HUFA) that accumulate in tissues and prevent deficient growth (11). In the absence of dietary n-3 nutrients, a dietary n-6 linoleic supply as low as 0.5% of food energy gives accumulated arachidonate more than 50% of HUFA (7). Knowing risk of heart attack is progressively greater for people with more than 50% n-6 in HUFA (8), we begin to see how benefits from eating omega-3 (n-3) nutrients come from widening the very narrow therapeutic window for dietary essential omega-6 (n-6) linoleic acid. Adding 2,000 mg of n-3 HUFA to typical daily USA intakes of n-3 and n-6 nutrients (which include 17,000 mg of n-6 linoleate; far above the lowest effective dose) can lower the HUFA balance from 80% to 45% n-6 in HUFA (12). Fortunately, supplemental intakes of the competing n-3 HUFA (EPA and DHA) at doses up to 5 g/day do not raise safety concerns (13). Importantly, the n-3 linolenic nutrient competes effectively with n-6 linoleic with similar dynamics during accumulation in tissue HUFA (14). Those similar dynamics were not readily apparent in a large meta-analysis of diet-tissue studies, which all had much more competing n-6 than n-3 nutrients (15). Rather, the study emphasized the greater efficacy of n-3 HUFA over n-3 linolenate in balancing HUFA accumulated in tissues when n-6 linoleate is far above its lowest effective dose. If typical daily USA intakes of n-6 linoleate were lowered from 17,000 mg to 4,000 mg (1.6 % of food energy), it would allow as little as 400 mg added n-3 HUFA to lower the HUFA balance from 80% to 45% (12). Clearly, typical USA daily intakes of n-6 linoleate greatly exceed their lowest effective dose and need to be reviewed (7).
  1. Viewing a biologically significant range of HUFA balance
Knowing of n-6-mediated pathophysiology and using biomarker values for %n-6 in HUFA, three apparent contradictions in the current biomedical literature were re-examined (5). For example, the lack of association of depression with %n-6 in HUFA in a large longitudinal study of American women (16) may appear to contradict the cross-national association of depression with low intakes of n-3 HUFA (17). However, estimates of the likely HUFA balance in the cross-national groups had a wide range from 30% to 80% n-6 in HUFA, whereas it ranged from only 69% to 73% n-6 in HUFA for the quintiles in the longitudinal study. Such small differences are not likely biologically significant. Similarly, a report of greater prostate cancer mortality with higher %n-3 in plasma in two clinical studies (18, 19) appeared to contradict the strong association of prostate cancer mortality rates with the % n-6 in HUFA for five different countries (20). Deaths from prostate cancer associated with estimates of likely HUFA balance ranging from 35% n-6 in HUFA for “traditional” Japanese and 50% n-6 in HUFA for “modern Japanese” compared to 60% n-6 in HUFA for Italy and about 70–80% n-6 in HUFA for UK and USA. In contrast, HUFA proportions in the clinical study were 77% n-6 in HUFA in controls compared to 76% in cases (18), and 72% n-6 in HUFA in controls compared to 71% in cases (19). Such a very narrow range of HUFA balance has little biological significance for interpreting omega-3 benefits. Finally, a 2001 study reported no benefit of n-3 HUFA on the number of pain attacks. However, a 2013 report (21) used concepts mentioned in Section 2 to design biologically significant lowering of the competing n-6 nutrients to allow increased intake of omega-3 nutrients to lower the %n-6 in HUFA from 77% to 61% and greatly reduce pain and the need for vasoactive medications, acute opioids, and non-steroidal anti-inflammatory drugs. Clearly, investigators should be cautious about over-interpreting negative results when their study examines only a small range of HUFA balance. The HUFA balance for individuals worldwide can range from 20% to 85% n-6 in HUFA depending on voluntary food choices. Scientific studies should plan to examine a much broader set of possibilities than the 75-80% n-6 in HUFA common in the USA.
  1. Overview:
A balanced view of benefits from omega-3 (n-3) nutrients is that dietary n-6 linoleic acid has a very narrow therapeutic window, which is widened by n-3 nutrients (7). Whenever a therapeutic window is narrow, the material should be ingested at the lowest effective dose. Eating fewer n-6 nutrients allows n-3 nutrients to be more effective in improving HUFA balance and preventing unwanted health conditions. A HUFA balance above 60% n-6 in HUFA is associated with higher risk for unwanted health conditions. Eating more n-3 nutrients keeps the HUFA balance low and broadens the window of safety for n-6 nutrients. A simple wellness program can use “apps” with over 5,000 different Omega 3–6 Balance Scores plus semi-annual monitoring of personal HUFA balance values from finger-tip blood-spot assays to effectively decrease health conditions made worse by HUFA balances above 50% n-6 in HUFA.   References:
  1. Whoriskey, P., 2015 http://www.washingtonpost.com/business/economy/claims-that-fish-oil-boosts-health-linger-despite-science-saying-the-opposite/2015/07/08/db7567d2-1848-11e5-bd7f-4611a60dd8e5_story.html
  2. Lands, B. 2015. Omega-3 PUFAs lower the propensity for arachidonic acid cascade overreactions. Hindawi Publishing Corporation, http://www.hindawi.com/journals/bmri/aa/285135/
  3. Mehta, P., Mason, J.C. 2010. NSAIDs and coxibs: the stomach, the heart and the brain. Arthritis Research, UK. http://www.arthritisresearchuk.org/health-professionals-and-students/reports/topical-reviews/topical-reviews-spring-2010.aspx
  4. FDA Drug Safety Communication. 2015. FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm
  5. Bibus D, Lands B. Balancing proportions of competing omega-3 and omega-6 highly unsaturated fatty acids (HUFA) in tissue lipids. Prostagl. Leukot. Essent. Fatty Acids 99 (2015) 19–23.   http://www.plefa.com/article/S0952-3278(15)00087-3/pdf
  6. Marangoni, F., Colombo, C., Martiello, A., Negri, E., Galli, C. 2007. The fatty acid profiles in a drop of blood from a finger tip correlate with physiological, dietary and lifestyle parameters in volunteers. Prostagl. Leukot. Essent. Fatty Acids 76 (2) 87–92, PubMedPMID:17208424.
  7. Lands, B., 2014. Historical perspectives on the impact of n-3 and n-6 nutrients on health. Prog. Lipid. Res. 55: 17–29. http://www.sciencedirect.com/science/article/pii/S0163782714000253
  8. Lands, W.E.M. 2003. Diets could prevent many diseases. Lipids 38(4):317–321. http://www.ncbi.nlm.nih.gov/pubmed/12848276
  9. Lands, B. 2015. Choosing foods to balance competing n-3 and n-6 HUFA and their actions. Oilseeds and fat Crops and Lipids, Published by EDP Sciences.  http://www.ocl-journal.org/articles/ocl/pdf/first/ocl150008.pdf
  10. Lands, B., Lamoreaux, E. 2012. Describing essential fatty acid balance as 3–6 differences rather than 3/6 ratios. Nutr. Metab. 9: 46–54.  http://www.nutritionandmetabolism.com/content/pdf/1743-7075-9-46.pdf
  11. Mohrhauer, H., Holman, R.T. 1963. The effect of dose level of essential fatty acids upon fatty acid composition of the rat liver. J. Lipid Res. 4: 51–159. http://www.ncbi.nlm.nih.gov/pubmed/14168145
  12. Calculator. 2002. http://efaeducation.org/?p=124
  13. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). 2012. Scientific Opinion related to the Tolerable Upper Intake Level of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). EFSA J. 10(7):2815. http://www.efsa.europa.eu/en/efsajournal/pub/2815.htm
  14. Mohrhauer, H., Holman, R.T. 1963. Effect of linolenic acid upon the metabolism of linoleic acid. J. Nutr. 81: 67–74. http://www.ncbi.nlm.nih.gov/pubmed/14061405
  15. Brenna, J.T., Salem Jr., N., Sinclair, A.J., Cunnane, S.C. 2009. “?-Linolenic acid supplementation and conversion to n-3 long chain polyunsaturated fatty acids in humans,” Prostagl. Leukot. Essent. Fatty Acids. 80(2-3):85–91. http://www.ncbi.nlm.nih.gov/pubmed/19269799
  16. Lucas, M., Mirzaei, F., O’Reilly, E.J., Pan, A., Willett, W.C., Kawachi, I., Koenen, K., Ascherio, A. 2011. Dietary intake of n-3 and n-6 fatty acids and the risk of clinical depression in women: a 10-year prospective follow-up study Internet. Am. J. Clin. Nutr. 93:1337–1343 http://www.ncbi.nlm.nih.gov/pubmed/21471279
  17. Hibbeln, J.R., Nieminen, L.R., Blasbalg, T.L., Riggs, J.A., Lands, W.E.M. 2006. Healthy intakes of n-3 and n-6 fatty acids: estimations considering world wide diversity. Am. J. Clin. Nutr. 83(6Suppl);1483S–1493S http://www.ncbi.nlm.nih.gov/pubmed/16841858
  18. Brasky TM, Till C, White E, Neuhouser ML, Song X, Goodman P, Thompson IM, King IB, Albanes D, Kristal AR. 2011. Serum phospholipid fatty acids and prostate cancer risk: results from the prostate cancer prevention trial. Am. J. Epidemiol. 173(12):1429-39. http://aje.oxfordjournals.org/content/173/12/1429.full.pdf+html
  19. Brasky TM, Darke AK, Song X, Tangen CM, Goodman PJ, Thompson IM, Meyskens FL Jr, Goodman GE, Minasian LM, Parnes HL, Klein EA, Kristal AR. 2013. Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial. J. Natl. Cancer Inst. 105(15):1132-41. http://jnci.oxfordjournals.org/content/105/15/1132.full.pdf+html
  20. Marugame, T., Mizuno,S. 2005. Comparison of prostate cancer mortality in five countries: France, Italy, Japan, UK and USA from the WHO mortality database (1960–2000). Jpn. J. Clin. Oncol. 35(11):690–691. http://jjco.oxfordjournals.org/content/35/11/690.full.pdf+html
  21. Ramsden CE, Faurot KR, Zamora D, Suchindran CM, Macintosh BA, Gaylord S, Ringel A, Hibbeln JR, Feldstein AE, Mori TA, Barden A, Lynch C, Coble R, Mas E, Palsson O, Barrow DA, Mann JD. 2013. Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial. Pain 154: 2441–2451. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3850757/pdf/nihms514426.pdf