Historical perspectives on the impact of n3 and n6 nutrients on health
Historical perspectives on the impact of n3 and n6 nutrients on health
Year: 2014
Authors: Lands, B.
Publication Name: Prog Lipid Res
Publication Details: Volume 55C; Pages 17 – 29
Abstract:
Current public advice from the Food and Nutrition Board (FNB) about essential fatty acids (EFA) has limited quantitative details about three processes: (1) similar dynamics for n 3 linolenic and n 6 linoleic polyunsaturated fatty acids (PUFA) in maintaining 20 and 22 carbon n 3 and n 6 highly unsaturated fatty acids (HUFA) in tissues; (2) different dynamics for tissue n 3 and n 6 HUFA during formation and action of hormone like eicosanoids; (3) simultaneous formation of non esterified fatty acids (NEFA) and low density lipoprotein (LDL) from very low density lipoprotein (VLDL) formed from excess food energy and secreted by the liver. This report reviews evidence that public health may benefit from advice to eat less n 6 nutrients, more n 3 nutrients and fewer calories per meal. Explicit data for linoleic acid fit an Estimated Average Requirement (EAR) near 0.1 percent of daily food energy (en percent) meeting needs of half the individuals in a group, a Recommended Dietary Allowance (RDA) near 0.5 en percentmeeting needs of 97–98 percent of individuals, and a Tolerable Upper Intake Level (UL) near 2 en percent having no likely risk of adverse health effects. Quantitative tools help design and monitor explicit interventions that could beneficially replace imprecise advice on “healthy foods with explicit preventive nutrition. (Authors abstract)
The past 50 years brought recognition that dietary EFA accumulate as highly unsaturated fatty acids (HUFA) in tissues where they form hormone like eicosanoids that act on selective receptors influencing physiological processes in nearly every tissue of the body. Competing metabolism by n 3 EFA can moderate actions of the n 6 EFA. The relative intakes of n 6 and n 3 nutrients create tissue HUFA proportions that create a propensity or predilection for more or less vigorous eicosanoid actions, respectively. The wide scope of harmful n 6 eicosanoid actions now known to occur requires careful discrimination between associated and causal mediators when advising the public about “optimal” intakes of n 3 and n 6 nutrients. Rigorous logic can avoid evidence based misunderstandings.
In 1946, with no clear evidence for a lack of essential fatty acids in humans, Hansen and Burr suggested that a “required” level of intake for humans might be 1 per cent of the diet based on the assumption that humans and rats have similar metabolic responses to these nutrients. Their review concluded by noting that the greatest difficulty in studying quantitative requirements for humans was an inability to monitor accurately the status of essential fatty acids in blood and tissues. Evidence from infants show rates of growth were similar and satisfactory for almost all of the infants who received 1.3 percent, 2.8 percent and 7.3 percent of calories as linoleic acid; whereas progress was unsatisfactory for many, but not all, of the infants with linoleic acid intakes below 0.1 en percent. Signs of deficiency disappeared promptly whenever linoleic acid provided 1 percent or more of food energy.
Gas chromatographic measurements indicate that the borderline EFA deficiency likely occurs after the proportions of the n 9 acid is 50 percent or greater in blood HUFA for some weeks. The transition from EFA deficiency occurred when the percent n 6 in HUFA rose above 50 percent. This biomarker for a transition from EFA deficiency is obtained with dietary linoleate intakes between 0.1 and 0.5 en percent.
Instead of explaining how n 3 and n 6 nutrients prevent classical signs of EFA deficiency, research from 1964 to 2004 provided an expanded network of EFA based physiological and pathophysiological mediators that act on selective receptors that occur on nearly every cell and tissue in the human body. New research showed increasingly sophisticated signaling networks by which mediators derived from dietary PUFA and tissue HUFA regulate cytokines and chemokines and affect human health. Paradoxically, a principal goal for successful new drug development was to diminish excessive actions of the essential n 6 HUFA, arachidonate. n 3 HUFA are less active in forming prostaglandins, and they diminish arachidonate mediated processes in animal models of stroke and heart attack. This knowledge raised hope that a lowered intake of n 6 EFA precursors and increased intake of competing n 3 precursors might moderate excessive unwanted actions of linoleate based mediators in humans.
Epidemiologists have long known that ischemic heart disease was less prevalent for Mediterranean populations than for Americans while being more prevalent than for Japanese. Data on the EFA status of Arctic people eventually proved pivotal in alerting the public to important differences between n 3 and n 6 EFA actions in mediating cardiovascular disease. Tissue biomarkers for n 3 and n 6 EFA status are strongly associated with the severity of CHD in many diverse groups. People with more than 50 percent n 6 in tissue HUFA (and less than 50 percent n 3 in HUFA) have a greater risk for CHD mortality than those with less than 50 percent n 6 in HUFA. Values for tissue HUFA status of different ethnic groups world wide range from 32 percent to 87 percent n 6 in HUFA. Some populations unknowingly maintain a degree of primary prevention of chronic cardiovascular and immune inflammatory disorders by eating foods that balance the n 3 and n 6 HUFA in their tissues. Both n 6 linoleate and n 3 linolenate at 0.5 en percent (which fits the definition of their RDA and suppresses accumulation of n 7 and n 9 HUFA) would likely maintain both n 3 and n 6 HUFA at a level near 50 percent. A similar outcome is predicted when both acids are ingested together at higher levels of 1, 2, 4 or 7 en percent. However, continued intake of linoleate near 6.8 en percent with linolenate near 0.8 en percent predicts a imbalanced value near 79 percent n 6 in HUFA.
Meal induced vascular dysfunction and oxidative inflammatory conditions (measured by hydrogen peroxide and isoprostane levels) as well as released monocyte chemoattractant protein 1 were less when diets included fish oil n 3 HUFA. And leukocyte chemotaxis and adhesion are much greater when the mediator is n 6 LTB4 rather than n 3 LTB5. A significant increase in adhesion of monocytes to the endothelial monolayer occurred in the presence 20:4n 6, and it was decreased with 20:5n 3. Pro inflammatory mediators (intercellular adhesion molecule 1, vascular cell adhesion molecule 1, E Selectin, IL 6, and TNFα) are all significantly increased in endothelial cells incubated with 20:4n 6.
The author argues that evident risk from tissue HUFA imbalances with HRA values above 50 percent n 6 in HUFA opens the question of setting a Tolerable Upper Intake Level (UL) for linoleic acid intake. The currently recommended AI level for n 6 linoleate is far above the known level of 0.5 en percent at which EFA deficiency is prevented. One in three American deaths is due to cardiovascular disease that has not been prevented [74], and over 70 percent of Americans over 60 years have cardiovascular disease. With known harmful actions of n 6 mediators in CVD, the current USA median intake of n 6 linoleate near 7 en percent merits much more critical evaluation. The absence of a committee assigned tolerable upper limit is not evidence for the absence of a tolerable upper limit. Lowering the dietary supply of n 6 nutrients ensures that counter balancing n 3 HUFA can accumulate in tissues from which they form (often at slower rates) less aggressive mediators. One simple result of accumulating higher proportions of n 3 in tissue HUFA is that it lowers the proportion of n 6 in HUFA available for release by phospholipase A2, and it slows the formation and action of potent n6 bioactive lipids (as many pharmaceuticals are designed to do). Future research will apportion further the health benefits that may come from lessened actions of n 6 mediators compared to increased actions of n 3 bioactive lipids (such as resolvins, protectins, maresins and epoxides).
Measuring only n 3 status or n 6 status alone fails to keep the important context of balance between n 3 and n 6 nutrients and tissue HUFA balance that underlies health maintenance and disease prevention. In this regard, rather than elevating intakes of n 3 HUFA to 3.5 g per d to achieve an HRA status of 50 percent, the average American diet could be adjusted by lowering n 6 linoleate intake from its current level near 16.5 g per d (6.8 en percent) to a level near 2.5 g per d (1en percent). The diet tissue estimator shows that if intake of n 3 linolenate remained at 0.7 en percent, lowering n 6 linoleate intake to 1 en percent for Americans could meet an HRA goal near 50 percent n 6 in HUFA. If linolenate intake continued to be only 10 percent of the linoleate intake, then an additional 0.06 en percent n 3 HUFA could meet the HRA goal of 50 percent.
Reducing the linoleate content of the diet is easily achieved by replacing soybean oil (with an omega 3–6 balance score of −50) with an oil of low linoleate content and by eating other food with less negative Omega 3–6 Balance Scores. Canola oil (score, −11) has twice the content of linoleate as olive oil with some counterbalancing n 3 linolenate. Flaxseed oil (score of +48) has n 6 linoleate content similar to canola counterbalanced by 3 fold more n 3 linolenate.
Voluntary informed choices of foods that shift tissue HUFA balance and lower the average HRA status of employees from 77 percent n 6 in HUFA to 57 percent n 6 in HUFA might prevent more than $400 million financial losses annually for a self insured corporation with 100,000 employees and a typical health care plan. In the USA overall, there may be a trillion dollars of preventable annual financial loss that self insured corporations could recover and redirect to other priorities. The evidence examined in this review suggests that employees and employers in North America (and globally) have much to gain together from monitoring and preventing imbalances among n 3 and n 6 hormone precursors. (Editors comments)
The past 50 years brought recognition that dietary EFA accumulate as highly unsaturated fatty acids (HUFA) in tissues where they form hormone like eicosanoids that act on selective receptors influencing physiological processes in nearly every tissue of the body. Competing metabolism by n 3 EFA can moderate actions of the n 6 EFA. The relative intakes of n 6 and n 3 nutrients create tissue HUFA proportions that create a propensity or predilection for more or less vigorous eicosanoid actions, respectively. The wide scope of harmful n 6 eicosanoid actions now known to occur requires careful discrimination between associated and causal mediators when advising the public about “optimal” intakes of n 3 and n 6 nutrients. Rigorous logic can avoid evidence based misunderstandings.
In 1946, with no clear evidence for a lack of essential fatty acids in humans, Hansen and Burr suggested that a “required” level of intake for humans might be 1 per cent of the diet based on the assumption that humans and rats have similar metabolic responses to these nutrients. Their review concluded by noting that the greatest difficulty in studying quantitative requirements for humans was an inability to monitor accurately the status of essential fatty acids in blood and tissues. Evidence from infants show rates of growth were similar and satisfactory for almost all of the infants who received 1.3 percent, 2.8 percent and 7.3 percent of calories as linoleic acid; whereas progress was unsatisfactory for many, but not all, of the infants with linoleic acid intakes below 0.1 en percent. Signs of deficiency disappeared promptly whenever linoleic acid provided 1 percent or more of food energy.
Gas chromatographic measurements indicate that the borderline EFA deficiency likely occurs after the proportions of the n 9 acid is 50 percent or greater in blood HUFA for some weeks. The transition from EFA deficiency occurred when the percent n 6 in HUFA rose above 50 percent. This biomarker for a transition from EFA deficiency is obtained with dietary linoleate intakes between 0.1 and 0.5 en percent.
Instead of explaining how n 3 and n 6 nutrients prevent classical signs of EFA deficiency, research from 1964 to 2004 provided an expanded network of EFA based physiological and pathophysiological mediators that act on selective receptors that occur on nearly every cell and tissue in the human body. New research showed increasingly sophisticated signaling networks by which mediators derived from dietary PUFA and tissue HUFA regulate cytokines and chemokines and affect human health. Paradoxically, a principal goal for successful new drug development was to diminish excessive actions of the essential n 6 HUFA, arachidonate. n 3 HUFA are less active in forming prostaglandins, and they diminish arachidonate mediated processes in animal models of stroke and heart attack. This knowledge raised hope that a lowered intake of n 6 EFA precursors and increased intake of competing n 3 precursors might moderate excessive unwanted actions of linoleate based mediators in humans.
Epidemiologists have long known that ischemic heart disease was less prevalent for Mediterranean populations than for Americans while being more prevalent than for Japanese. Data on the EFA status of Arctic people eventually proved pivotal in alerting the public to important differences between n 3 and n 6 EFA actions in mediating cardiovascular disease. Tissue biomarkers for n 3 and n 6 EFA status are strongly associated with the severity of CHD in many diverse groups. People with more than 50 percent n 6 in tissue HUFA (and less than 50 percent n 3 in HUFA) have a greater risk for CHD mortality than those with less than 50 percent n 6 in HUFA. Values for tissue HUFA status of different ethnic groups world wide range from 32 percent to 87 percent n 6 in HUFA. Some populations unknowingly maintain a degree of primary prevention of chronic cardiovascular and immune inflammatory disorders by eating foods that balance the n 3 and n 6 HUFA in their tissues. Both n 6 linoleate and n 3 linolenate at 0.5 en percent (which fits the definition of their RDA and suppresses accumulation of n 7 and n 9 HUFA) would likely maintain both n 3 and n 6 HUFA at a level near 50 percent. A similar outcome is predicted when both acids are ingested together at higher levels of 1, 2, 4 or 7 en percent. However, continued intake of linoleate near 6.8 en percent with linolenate near 0.8 en percent predicts a imbalanced value near 79 percent n 6 in HUFA.
Meal induced vascular dysfunction and oxidative inflammatory conditions (measured by hydrogen peroxide and isoprostane levels) as well as released monocyte chemoattractant protein 1 were less when diets included fish oil n 3 HUFA. And leukocyte chemotaxis and adhesion are much greater when the mediator is n 6 LTB4 rather than n 3 LTB5. A significant increase in adhesion of monocytes to the endothelial monolayer occurred in the presence 20:4n 6, and it was decreased with 20:5n 3. Pro inflammatory mediators (intercellular adhesion molecule 1, vascular cell adhesion molecule 1, E Selectin, IL 6, and TNFα) are all significantly increased in endothelial cells incubated with 20:4n 6.
The author argues that evident risk from tissue HUFA imbalances with HRA values above 50 percent n 6 in HUFA opens the question of setting a Tolerable Upper Intake Level (UL) for linoleic acid intake. The currently recommended AI level for n 6 linoleate is far above the known level of 0.5 en percent at which EFA deficiency is prevented. One in three American deaths is due to cardiovascular disease that has not been prevented [74], and over 70 percent of Americans over 60 years have cardiovascular disease. With known harmful actions of n 6 mediators in CVD, the current USA median intake of n 6 linoleate near 7 en percent merits much more critical evaluation. The absence of a committee assigned tolerable upper limit is not evidence for the absence of a tolerable upper limit. Lowering the dietary supply of n 6 nutrients ensures that counter balancing n 3 HUFA can accumulate in tissues from which they form (often at slower rates) less aggressive mediators. One simple result of accumulating higher proportions of n 3 in tissue HUFA is that it lowers the proportion of n 6 in HUFA available for release by phospholipase A2, and it slows the formation and action of potent n6 bioactive lipids (as many pharmaceuticals are designed to do). Future research will apportion further the health benefits that may come from lessened actions of n 6 mediators compared to increased actions of n 3 bioactive lipids (such as resolvins, protectins, maresins and epoxides).
Measuring only n 3 status or n 6 status alone fails to keep the important context of balance between n 3 and n 6 nutrients and tissue HUFA balance that underlies health maintenance and disease prevention. In this regard, rather than elevating intakes of n 3 HUFA to 3.5 g per d to achieve an HRA status of 50 percent, the average American diet could be adjusted by lowering n 6 linoleate intake from its current level near 16.5 g per d (6.8 en percent) to a level near 2.5 g per d (1en percent). The diet tissue estimator shows that if intake of n 3 linolenate remained at 0.7 en percent, lowering n 6 linoleate intake to 1 en percent for Americans could meet an HRA goal near 50 percent n 6 in HUFA. If linolenate intake continued to be only 10 percent of the linoleate intake, then an additional 0.06 en percent n 3 HUFA could meet the HRA goal of 50 percent.
Reducing the linoleate content of the diet is easily achieved by replacing soybean oil (with an omega 3–6 balance score of −50) with an oil of low linoleate content and by eating other food with less negative Omega 3–6 Balance Scores. Canola oil (score, −11) has twice the content of linoleate as olive oil with some counterbalancing n 3 linolenate. Flaxseed oil (score of +48) has n 6 linoleate content similar to canola counterbalanced by 3 fold more n 3 linolenate.
Voluntary informed choices of foods that shift tissue HUFA balance and lower the average HRA status of employees from 77 percent n 6 in HUFA to 57 percent n 6 in HUFA might prevent more than $400 million financial losses annually for a self insured corporation with 100,000 employees and a typical health care plan. In the USA overall, there may be a trillion dollars of preventable annual financial loss that self insured corporations could recover and redirect to other priorities. The evidence examined in this review suggests that employees and employers in North America (and globally) have much to gain together from monitoring and preventing imbalances among n 3 and n 6 hormone precursors. (Editors comments)
