Omega-3 PUFAs: Who Could Have Predicted?
The physiological effects of n-3 LC-PUFAs—lower resting heart rate, blood pressure and plasma triglycerides; improved endothelial function; lower inflammatory markers; enhanced cardiac function; and the molecular effects on membrane structure and function, modification of ion channels, signaling proteins and gene expression—all point to more favorable cardiovascular outcomes. In spite of recent studies suggesting that supplemental n-3 LC-PUFAs in heart disease patients with state-of-the-art medical care provide no further reduction in cardiovascular mortality and morbidity, others reported as much as a 35% lower risk of CVD mortality in healthy older adults with the highest levels of plasma phospholipid n-3 LC-PUFAs. The n-3 LC-PUFAs may be most effective in deterring CVD in healthy adults, in those at high risk of sudden cardiac death and in secondary prevention. How they function in specific types of CVD remains to be clearly elucidated, but the evidence supports the conclusion of Wu and Mozaffarian that “moderate dietary intake of fatty fish should be one cornerstone of a heart-healthy diet.”
In maternal and infant health, DHA is now recognized as “conditionally essential,” while alpha-linolenic acid, its plant-based precursor, is insufficiently converted to DHA in humans to meet the needs of the developing fetus and infant. We now have international recommendations for pregnant and lactating women to consume at least 200 mg of DHA daily. Given the importance of DHA in the structure and function of the developing brain and the low intakes of n-3 LC-PUFAs in many Western countries, especially among vegetarians, clear recognition of DHA as a vital nutrient for women in the child-bearing years is an important step forward.
However, it has been difficult to demonstrate clear benefits of maternal DHA or n-3 LC-PUFA supplementation on childhood outcomes. Most large controlled trials have not found statistically significant or meaningful differences in the growth or birthweight of term infants whose mothers consumed n-3 LC-PUFA supplements in pregnancy, but there are exceptions. In contrast, preterm infants may experience improved growth and global neurodevelopmental scores. Similarly, evidence of improved cognitive and visual development in the infants of supplemented mothers remains inconclusive. Some have reported significant developmental benefits with maternal n-3 LC-PUFA supplementation, but questions about the suitability of global tests of cognition or individual neurodevelopmental tests at particular ages have been inadequately addressed.
The most widely reported benefits of DHA supplementation in pregnancy are greater gestational age, fewer very early preterm births (<33 weeks’ gestation) and a lower rate of preterm birth. However, the evidence is insufficient to warrant their deliberate use to avoid preterm deliveries.
A potentially promising area where the increased consumption of n-3 LC-PUFAs or fatty fish in pregnancy may be beneficial is reducing the risk of allergies, particularly in infants at high risk for them. Data remain inconsistent, with some studies reporting no reduction in the risk of allergic disease in children whose mothers consumed n-3 LC-PUFAs during pregnancy or even a higher risk associated with higher LC-PUFAs in cord serum phospholipids.
Eating fish 2 to 3 times a week during pregnancy was associated with a lower risk of asthma in the offspring, a significantly lower risk of eczema at one year of age and less atopic wheeze and house dust mite sensitization at age six. Regular fish consumption in infancy was also associated with significantly less allergic disease up to 12 years of age and with a lower risk of eczema at age 2 years. Relatively consistent data indicate that maternal n-3 LC-PUFA supplementation during pregnancy is linked to less atopic eczema in early childhood.
One of the most riveting developments in n-3 LC-PUFA research has been the progressive identification, characterization and functional investigation of EPA- and DHA-derived mediators that stop inflammation and promote resolution. These include resolvins and their cousins, protectins and maresins. Rapid advances in this field have expanded the view of inflammation to include the cessation of inflammatory responses and the promotion of proresolving activities. This category of substances, now called specialized proresolving mediators, suggests promising clinical applications to more rapidly stop inflammation, hasten healing and return to homeostasis.
Although not yet commercially available for human treatments, resolvins led to significant clinical improvements in animal models of periodontitis, asthma and lung injury. Interestingly, an observational study from Japan reported that periodontal patients with low intakes of DHA had significantly more periodontal disease events compared with those having high DHA consumption. Similarly, DHA-derived neuroprotectins reportedly conferred neuroprotection in experimental stroke and retinal pigment epithelial cells, and reduced infarct volume in permanent ischemic stroke. Neuroprotectin D1 was also shown to promote corneal nerve regeneration and increase nerve sensitivity following surgery in animals, suggesting an adjunct treatment in corneal surgery.
Resolvins and protectins reduce inflammation, promote cell survival and limit tissue damage in an increasing range of pathologies including infectious disease, acute lung injury, neuropathic pain after nerve trauma, inflammatory pain, acute kidney injury, possibly multiple sclerosis and other inflammatory clinical conditions. Several clinical trials of these substances have been or are currently being conducted, a necessary prelude to their therapeutic approval.
In experimental traumatic brain, spinal cord and nerve injury, Adina Michael-Titus and others have clearly demonstrated the therapeutic potential of DHA, EPA and their derivatives. The provision of DHA immediately after brain or spinal cord injury in animals was associated with significantly reduced lesion size, neuronal and oligodendrocyte loss and apoptotic cell death. As a result, the treated animals experienced improved functional outcomes, increased neuronal cell survival and reduced macrophage and inflammatory responses. Dietary provision of these fatty acids also reversed the decline of several nuclear receptors and increased neurogenesis associated with age-related memory loss. In cell culture studies n-3 LC-PUFAs promoted neurite growth in the sensory neurons of young and aged animals. Interestingly, depletion of brain DHA prior to injury exacerbated the damage following brain trauma, impeded recovery and contributed to poorer sensorimotor outcomes. These and other studies have laid the foundations for clinical trials in humans. At least two clinical trials have been approved to study DHA or n-3 LC-PUFAs in individuals with sports-related concussion and three in individuals with spinal cord injuries. Two favorable case reports described the use of large doses of n-3 LC-PUFAs along with other treatments in the partial recovery of a patient who suffered traumatic brain injury and in the survivor of a mine explosion. These reports have been quite dramatic.
Another topic moving forward quickly, if not yet decisively, is the effect of DHA and n-3 LC-PUFAs in age-related cognitive decline and Alzheimer’s disease (AD). The pathology of AD begins decades before the occurrence of clinical symptoms, and signs of neurodegeneration have been reported prior to the development of abnormal beta-amyloid proteins in cognitively normal adults. An expanding literature has described many interactions between DHA or n-3 LC-PUFAs in AD patients, but dietary studies reported no improvements once the condition is established. However, higher blood levels of EPA and DHA were linked to the preservation of brain and hippocampal volumes and changes in gray and white matter, decreases in which are associated with the early stages of cognitive decline.
Observational studies have largely reported an inverse relationship between fish consumption or higher serum concentrations of DHA and impaired cognition, while interventions with n-3 LC-PUFAs in healthy older adults showed little or no benefit. Some studies with n-3 LC-PUFA supplementation in patients with mildly impaired cognition reported improvements in short-term and working memory, but others found no effects. This literature was reviewed in detail recently. A more extensive literature than this overview can mention suggests that these fatty acids are likely involved in many aspects of cognitive function and related pathologies.
Finally, the translation of research knowledge into clinical and public health applications is proceeding rapidly. N-3 LC-PUFAs are involved in cell differentiation and proliferation in stem cells, adipocytes and mesenchymal stromal cells with implications for guiding tissue development more favorably. In CVD, n-3 LC-PUFAs significantly lower high triglyceride levels and reduce arterial stiffness. Their use in surgical patients, either preoperatively or in postoperative care is associated with reduced inflammation and improved recovery, although not all surgical applications have reported beneficial effects. Data on the presurgical treatment with n-3 LC-PUFAs of cardiac patients at risk of atrial fibrillation are mixed, although benefits have been reported. N-3 LC-PUFAs appear to reduce the occurrence and severity of postoperative depressive symptoms in certain patients and cognitive decline in others.
In neuropsychiatry, n-3 LC-PUFAs are finding more widespread applications and are being investigated for their potential to reduce the risk of childhood behavioral difficulties and adult suicide, although the interpretation of conflicting data is difficult. Studies often use widely varying doses for different treatment periods and include several interventions. In other research, animal studies have suggested beneficial outcomes related to n-3 LC-PUFA treatments in bone, intestinal tract, corneal surgery, in dry eye syndrome and chronic kidney disease. These PUFAs have also shown promise in total parenteral nutrition, palliative cancer treatment, slowing the progression of prostate cancer, nonalcoholic liver disease, periodontitis and chronic headache pain. There is every reason to think this list will soon be many times longer.