NC1039: N-3 polyunsaturated fatty acids and human health and disease
Statement of Issues and Justification
The need as indicated by the stakeholders: Dietary recommendations have been made for n-3 fatty acids as a part of Dietary Reference Intakes (DRIs) by the Institute of Medicine of the National Academy of Sciences (NAS) (1,2). The Adequate Intake (AI) for n-3 fatty acids has been set, based on the observed median n-3 intakes in the US, at 1.6 g/day alpha linolenic acid (ALA) for men and 1.1 g/day ALA for women (1). While the NAS acknowledges that up to ten percent of the ALA recommendation can be met from long chain n-3 fatty acids such as eicosapentaenoic and docosahexaenoic acids (EPA and DHA), the committee chose to base n-3 recommendations on current n-3 intakes of ALA. In contrast to this approach, the American Heart Association (AHA) Diet and Lifestyle Recommendations Revision 2006 has reemphasized the importance of EPA and DHA consumption by recommending the consumption of fish, especially oily fish, at least twice weekly (3). Furthermore, for the first time the AHA has recommended increased EPA and DHA consumption either from fish or fish oil supplements - for those with established cardiovascular disease and obesity-induced hyperlipidemia (3). The problem: Not only are Americans unlikely to achieve the enhanced AHA recommendation for long-chain polyunsaturated (PUFA) n-3 fatty acid intakes by increasing fish consumption, but Americans are likely to be confused by the competing recommendations from the NAS and the AHA. Basing n-3 recommendations on ALA, the NAS approach, suggests to consumers that the benefits of ALA consumption are equal to those from long-chain n-3 sources such as EPA and DHA and alternative agricultural sources of n-3 fatty acids. Members of the NC-1167 Committee have been at the forefront in showing that the benefits of long-chain n-3 PUFA are quite unique and distinct from those of the parent fatty acid, ALA. Because of concerns regarding the sustainability of fish stocks and the contamination of fish by both mercury and pesticides agricultural-based sources of n-3 PUFA must be investigated as an alternative means of achieving equivalent health promotion and disease prevention benefits. N-3 PUFA comprise a heterogeneous group of fatty acid with diverse and unique health benefits. The overall goal of this application is to determine the effectiveness of both agricultural-based n-3 PUFA and marine-based n-3 PUFA, and to determine both the form and the amount of n-3 PUFA, necessary to promote health and prevent disease.This project addresses the goals of the ESCOP Science Roadmap Challenge 7: We can ensure improved food safety and health through agricultural and food systems, by improving the nutritional value of foods and discovering better educational methods to help individuals make informed food choices. The project also addresses CSREES/GPRA Goal 3, Healthy, well-nourished children, youth and families by: 1. reduced disease prevalence and enhanced quality of life by defining the relationship between diet and the risk of chronic disease; 2. improving the scientific basis for more effective Federal food assistance programs by better defining nutrient requirements &.. and analyzing the effects of nutrition information on food choices and diets; 3. generate a more nutritious food supply through research to modify the health-promoting properties of plant and animal foods and 4. enhance public understanding of diets role in lifelong health through nutrition education. This project addresses three Food and Nutrition Crosscutting Research Areas and Objectives of the NCRA identified in Appendix A1 of the NCRA Manual. The three crosscutting objectives to be addressed by NC-1167 are: Research Objective 1: Expand our understanding of the relationship between diet, health and disease prevention with particular focus on dietary lipids Research Objective 2: Elucidate the health benefits associated with the functional or phytochemical properties of food constituents. Dietary guidelines for fat intakes were originally based on the formulae that predicted the impact of polyunsaturated fatty acids (PUFA), saturated fatty acids (SFA) and monounsaturated fatty acid (MUFA) on serum cholesterol levels as the cardinal biomarker of cardiovascular disease (CVD) risk. There has been an evolution in the dietary guidelines over the 1996-2006 period, which recognizes that while PUFA are associated with a reduction in serum cholesterol and CVD risk, not all PUFA are created equal with regards to their beneficial effects and excessive consumption of n-6 PUFA is not without detrimental effects. The 2006 Revision of the American Heart Association (AHA) dietary guidelines (3) has highlighted the abandonment of the nutrient-based PUFA recommendation in favor of food-based recommendations of unsaturated fat consumption from fish, vegetables, legumes and nuts. The 2006 AHA revision is the first guideline to recommend enhanced long-chain n-3 consumption in the form of EPA and DHA, either from fish or fish-oil supplements, for those with heart disease and hypertriglyceridemia. These new guidelines emphasize that n-3 PUFA confer benefits over and above those attributable to improved serum lipid profiles- for example in reducing cardiac arrhythmias and sudden cardiac death (3). Despite this, consumers are unaware as to how much n-3 PUFA should be consumed, either in terms of absolute amounts, the forms of dietary n-3 PUFA, or the importance of the dietary n-3/n-6 ratio. Furthermore, consumers are unaware that different forms of dietary PUFA have differing health benefits based on their ability to impact the functional tissue long chain n-3 PUFAs, EPA and DHA. In addition, the approach of the National Academy of Sciences in setting an AI for n-3 fatty acids based on current US consumption of ALA and the absence of deficiency symptoms does little to emphasize the importance of dietary long-chain n-3 fatty acid such as EPA and DHA in cardiovascular health, cancer, gestational health, obesity induced inflammatory-mediated CVD, arthritis, bone health, and fertility. Members of the NC-1167 Committee are strongly convinced that the approach of the NAS in setting n-3 recommendations based on current ALA intakes contributes to confusion at the level of the consumer as to what forms and amounts of n-3 fatty acids confer health protection and disease prevention benefits, and also promotes the impression that all forms of n-3 fatty acids are metabolically equal. Research Objective 3: Design effective nutrition education programs and delivery methods that modify human behavior such that individuals including those most at risk choose healthier diets. Members of the NC-1167 Committee (CO, KS, NJ, NB) have developed a questionnaire that shows over 80% of dieticians in these four states indicated a need for more education and knowledge about n-3 fatty acid and the different effects of both n-3 forms and amounts. These results show that practicing dieticians need the scientific information on the effectiveness of n-3 PUFA forms and intakes in order to devise effective, theory-driven, education programs and intervention strategies such that targeted nutrition education will result in improved n-3 intakes and consumer health.
Importance of the work: As part of the Dietary Reference Intakes (DRI) for macronutrients, recommendations for n-3 intakes were made by the National Academy of Sciences (NAS) in 2002 (1,2). These recommendations were based on current US n-3 fatty acid intakes and the absence of deficiency symptoms. An Adequate Intake (AI) was set for ALA at 1.6 g/day for men and 1.1 g/day for women in the 19-50 year age group. In making these recommendations the NAS recognized that up to ten percent of the AI for ALA can be met from EPA and DHA (1,2). The NAS also recognized that a dietary requirement for n-3 fatty acids could not be set due to insufficient data for establishing an Estimated Average Requirement (EAR) which is the basis for determining a Recommended Dietary Allowance (RDA). While the DRI report noted that intakes of n-3 fatty acids above the AI confer additional health benefits, recommendations emphasizing greater intakes of both specific forms and amounts of n-3 fatty acids were not made because of a paucity of robust data at the time of the report. NC-1167 proposes to address this lack of data such that a clear picture of specific n-3 fatty acid forms and amounts consistent with health promotion and disease prevention can form the basis for modification of the NAS n-3 fatty acid recommendations. Members of NC-1167 will focus their efforts on identifying both the dietary n-3 forms and amounts that confer health promotion/disease prevention benefits rather than the NAS approach of focusing on the prevention of deficiency symptoms (1,2).
NC-1167 maintains its focus in delineating the impact of dietary PUFA in the maintenance of health and the prevention of disease in the US population, with an emphasis on identifying the health benefits of various dietary forms and amounts of n-3 PUFA. NC-1167 members have been amongst the first to show differing effects of n-3 fatty acid forms and amounts in a variety of health problems. NC-1167 scientists have shown that high n-6 PUFA (linoleic acid) inhibits bone formation and mineralization (CO, IN) and that long chain n-3 such as EPA and DHA blunts bone resorption and favors bone mineralization. The NC-1167 group was among the first group of scientists to demonstrate that high n-6 PUFA diets promote tumor growth (TN) and that n-3 PUFA such as EPA and DHA inhibited tumor growth (TN). Members of the NC-1167 group were amongst the first to show that modest supplementation of pregnant women with DHA increased gestational duration and infant growth rates (CO) and that high maternal tissue n-6 PUFA was associated with premature delivery (CO). Other members of NC-1167 have shown that the long-chain n-3 PUFA EPA and stearidonic acid (SDA, a vegetable oil based n-3 PUFA that enhances EPA levels) inhibit adipose tissue release of inflammatory mediators that contribute to obesity-associated cardiovascular disease (MI). Infertility is also associated with nigh n-6 PUFA diets (WY) and n-3 PUFA consumption increases egg release to the oviduct.
Human diets in the US provide 6% to 7% of calories as LA and only 0.7 % of calories from n-3 PUFA, with 90% of this provided by ALA (4). Several studies indicate that humans are not efficient in converting ALA to the functional long-chain n-3 PUFA such as DHA and EPA, regardless of the n-6/n-3 dietary ratio (5). The reasons for this inefficient conversion may be competition between the n-6 (LA) and n-3 (ALA) fatty acids for the -5 and -6 desaturase enzyme conversions (5), or the suppression of -5 and -6 expression by high PUFA diets (6). Work by NC-1167 scientists has shown that there are threshold levels of n-6 PUFA with increased risks for coronary thrombosis, cancer proliferation, immunosuppression, bone loss, infertility, premature delivery and perinatal health, and modest supplements of long-chain n-3 PUFA can reverse many of the detrimental effects of elevated n-6 PUFA consumption, even without reductions in the dietary n-6 PUFA content. Work by members of the NC-1167 committee has shown that increasing ALA consumption dramatically does not increase tissue phospholipid DHA, the functional form of n-3 PUFA (TN, CO), and only modestly increases the low levels of phospholipid EPA (TN). Modest supplements of DHA, provided at the current US intake of ALA and without reduction in the LA content of the diet, significantly increase tissue phospholipid DHA levels (CO). These results indicate that ALA consumption is not an effective way to optimize tissue phospholipid EPA and, especially, DHA concentrations this can only be achieved by modest amounts of dietary EPA or DHA (TN, CO). These findings indicate that ALA cannot support tissue EPA and DHA levels at which health outcomes are improved. The Food and Drug Administration has recently cautioned consumers to limit fish consumption because of concern with environmental heavy metal and pesticide contamination. Thus, the investigation of agricultural-based sources of dietary n-3 PUFA in addition to marine based n-3 PUFA for achieving health promotion and disease prevention benefits in the US population is crucial. While no single station has the expertise to investigate all the n-3 PUFA linked wellness outcomes, the expertise of the NC-1167 Committee ensures that our search for an appropriate dietary n-3 PUFA intake, both form, amount, and useful consumer information will focus on major health outcomes such as CVD, cancer, bone diseases, prematurity and perinatal health, emphasized in the Health People 2010 Report (7).
Consequences if not done: Without this research, the scientific rationale supporting the levels and types of dietary n-3 PUFA needed to reduce risk of chronic diseases, such as cancer inflammatory and cardiovascular diseases, will remain a matter of interpretation. This is important because of the prevalence of these diseases in the American population and their serious impact on the healthcare economy. It is imperative that we not lump all the n-3 fatty acids together with the assumption that they have similar biological properties. Equally, it is a mistake to assume that it is sufficient to recommend more fish in the diet with little hope that these recommendations are achievable. The most effective methods to implement dietary behavior change are being rigorously studied, particularly in relation to reducing total fat intake. However, these educational theories have not been applied to the area of n-3 fatty acid intake and without this data success is questionable. In addition, education to increase intake of n-3 fatty acids is further complicated because it contradicts previous nutrition communications recommending dietary fat reduction.
Therefore, without these studies, n-3 PUFA as a tool for health promotion and disease prevention will remain an interesting curiosity to the biomedical community. There is a need to determine how much and what type will result in a predictable outcomes and how to educate and motivate the public to achieve these desired outcomes.
Technical feasibility of the research: The scientists that make up the technical committee on NC-1167 are the leading authorities in their respective disciplines as it relates to the biological impact of dietary n-3 fatty acids. A review of annual reports and their publication record provides the basis for this statement. The methods outlined in this proposal are standard procedures developed and perfected by each of the investigators. As a result, each member provides a unique perspective to the problem, when seamlessly blended, will result in definitive answers. This applies to the natural as well as the social science portions of the proposal. For example, regarding the nutrition education component, this project is feasible because information will be sought from nutrition professionals who are highly organized into state and local districts. They meet on a regular basis and seek continuing education opportunities to maintain credentials. Specialized practice among nutrition professionals is common, thereby enabling us to identify practices specific to the diseases of interest. Development of an educational intervention is possible because members of the NC-1167 regional project possess n-3 fatty acid expertise and nutrition education experience, assuring scientific validity for both content and delivery components.
Advantages for doing the work as a multistate effort: The NC-1167 Research Project addresses the role of dietary n-3 PUFA in the promotion of health. No single station has the expertise or resources to investigate all the components needed to establish health driven guidelines for n-3 intakes. We will leverage our collective results into an integrative recommendation outlining the types and levels of n-3 fatty acids and their potential health outcomes. We will use this information in conjunction with the nutrition education component as a means to increase n-3 PUFA consumption by Americans and to insure that the amount and types of n-3 PUFA are biologically meaningful. To accomplish this, data have to be generated using different levels and types of n-3 PUFA under a variety of experimental conditions with multiple clinical and biochemical endpoints involving conditions such as cancer (TN, ), inflammation (MI, MO), diabetes (MI), reproductive issues and gestational/perinatal health (CO, WY), and Alzheimers disease (MO). Similarly, a multistate effort (directed by KS) makes it more technically feasible to have a large enough sample size of nutrition professionals for the nutrition education component. Intake of foods containing n-3 PUFA may vary by geographic locations, cultural background and demographic characteristics. A multistate effort provides the opportunity to address issues related to demographics, geography and ethnic diversity. Another advantage is the availability of a broad scope of technical and educational expertise for use in designing the intervention. A multistate effort will result in a larger sample size for the intervention. This will mean greater feedback on the nutrition education intervention practices and the ability to make statistically relevant group comparisons. This vigorous feedback increases the likelihood that nutrition education programs designed to increase n-3 PUFA intake will be efficacious.
Likely impacts from successful completion of the work: Health outcomes and biomarkers will be identified thereby enabling successful educational interventions to be documented. Effective educational programs that increase nutrition practitioner n-3 PUFA counseling will increase consumption of food-based sources of n-3 fatty acids to improve the quality of life and help reduce diseases, such as heart disease and cancer. The resulting economic impacts include decreasing healthcare costs and those related to an increased need for production of agriculture-based n-3 fatty acid sources, such as flaxseed, stearidonic (SDA)-containing vegetable oils and n-3 enriched animal products. The potential for negative health and economic consequences of excessive and unsafe n-3 supplementation practices will be reduced.
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