The omega-3 fatty acid deficiency syndrome.

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“Leave your drugs in the chemist’s pot if you can heal the patient with food.” Hippocrates - 450-380 B.C. Hippocrates, a founding father of modern medicine, can be credited as being among the first to appreciate the impact of nutritional deficiency on human health, and to promote nutrition as a first-line approach for the treatment and prevention of disease. Indeed, history has since taught us that diet-dependent nutrient deficiencies can cause a constellation of adverse symptoms (‘a syndrome’) that are treatable and preventable by replacing the nutrient in the diet. Some of the more recognizable examples include vitamin C and scurvy, vitamin A and night blindness, iron and anemia. Similarly, mammals are completely dependent on their diet to maintain optimal levels of omega-3 fatty acids in cellular membranes throughout the body. Over the past 70 years, omega-3 fatty acids have been among the most widely studied micronutrients in biomedical research and emerging evidence is revealing their importance for multiple aspects of human health and resilience to several common diseases. As background, omega-3 fatty acids are members of the polyunsaturated fatty acid family, and are comprised of the short-chain alpha-linolenic acid (ALA, 18:3n-3) and the long-chain omega-3 (LCn-3) fatty acids including eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). EPA and DHA are critical components of cellular membranes, regulating multiple signaling events that maintain cellular homeostasis, functional integrity, and ultimately resilience to dysregulation. The biosynthesis of EPA and DHA from dietary ALA is mediated by a series of desaturase and elongase enzymes. However, it has become clear that humans are very poor at converting ALAEPADHA, due in part to competition for desaturase enzymes by the more ubiquitous dietary omega-6 fatty acid linoleic acid (LA, 18:2n-6) as well as heritable variants in desaturase functional efficiency. Therefore, obtaining an adequate amount of EPA and DHA would require either a substantial increase in the dietary ALA/LA ratio or a relatively modest increase EPA and DHA intake. The latter is achievable through the regular intake of fish and seafood, fish oil capsules, as well as algal-derived (vegetarian) EPA and DHA. It has been estimated that LCn-3 fatty acid levels in typical western diets have declined over the last century, largely being replaced by omega-6 fatty acids. Individuals residing in western countries commonly exhibit tissue and breast milk EPA and DHA levels that are approximately one-half those observed in individuals residing in countries that regularly consume LCn-3 fatty acids (e.g., Japan). Cross-national epidemiological studies have observed an inverse correlation between per capita fish or seafood (sources of EPA+DHA) consumption and the lifetime prevalence rates of the two leading causes of disability in western countries, major depression and cardiovascular disease. Although peripheral tissues, including heart, liver, and immune cells, are vulnerable to more rapid cellular EPA+DHA reductions in response to dietary LCn-3 fatty acid insufficiency, the central nervous system is also vulnerable, particularly during early brain development. Because dietary LCn-3 fatty acid insufficiency would impact all tissues/organ systems, ensuing peripheral and central cellular dysregulation would be anticipated to give rise to a constellation of peripheral and central symptoms, herein termed the ‘omega-3 fatty acid deficiency syndrome’. This book, written by experts from around the world, describes the relationship between LCn-3 fatty acid status and different aspects of human physiology and disease. The first section of the book describes the gene-diet interactions that regulate LCn-3 fatty acid biosynthesis and tissue status, the potential role of the LCn-3 fatty acid DHA in human brain evolution, and how the decline of LCn-3 fatty acid status may have contributed to the relatively recent emergence of ‘western’ diseases. The second section is devoted to understanding associations between LCn-3 fatty acid status and resilience to different peripheral tissue diseases, including psoriasis, osteoporosis, sacrcopenia, diabetes, arthritis, cardiovascular disease, obesity, and cancer. The third section explores the relationship between LCn-3 fatty acid status and resilience to central nervous system diseases, including retinal diseases, attention deficit disorder, major depressive disorder, schizophrenia, and Alzheimer’s disease. Together, these polygenic and multifactorial diseases currently represent a major source of morbidity and mortality, as well as health care utilization, in western countries. The fourth section of the book focuses on the future development of standard practices for diagnosing, treating, and preventing LCn-3 fatty acid deficiency. The ultimate goal of this book is to raise awareness of current evidence implicating LCn-3 fatty acids in disease resilience in an effort to inform and evolve future research, clinical practice, and nutritional policies. While the eradication of LCn-3 fatty acid deficiency represents a complex challenge, history has demonstrated that public education, evolving policy, and ultimately fortification of commonly consumed foods will be required. To this end, evidence-based consensus recommendations by national organizations, including the American Heart Association and the American Psychiatric Association, have endorsed increasing LCn-3 fatty acid intake in an effort to reduce disease morbidity and mortality. Moreover, DHA-fortified prenatal vitamins, infant formula, and children’s vitamins have become available to consumers, as have commonly consumed foods fortified with DHA including milk and eggs. There has also been a recent emergence of laboratory facilities that diagnose blood EPA+DHA status, and ‘prescription’ LCn-3 fatty acids are now available to physicians. However, a Recommended Daily Allowance for LCn-3 fatty acids has not been established in the United States, leading to confusion about appropriate intake levels. Moreover, fears about environmental toxins in fish, including methyl mercury, confusion about good dietary sources of EPA+DHA, and a general lack of knowledge about the need to fortify the diet with LCn-3 fatty acids have hindered greater progress. Nevertheless, increasing evidence that LCn-3 fatty acid deficiency may increase resilience to many prevalent diseases should galvanize research and evolve nutritional policies and clinical practice. Research is now needed to evaluate whether LCn-3 fatty acid supplementation is an efficacious first-line treatment for diseases associated with LCn-3 fatty acid deficiency, and whether prior correction of LCn-3 fatty acid deficits can prevent or mitigate disease progression in at-risk individuals.

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