ABSTRACTOmega-3 [(n-3)] fatty acids have been linked to healthy aging
throughout life. Recently, fish-derived omega-3 fatty acids EPA and
DHA have been associated with fetal development, cardiovascular
function, and Alzheimer's disease. However, because our bodies do
not efficiently produce some omega-3 fatty acids from marine sources,
it is necessary to obtain adequate amounts through fish and fish-oil
products. Studies have shown that EPA and DHA are important for
proper fetal development, including neuronal, retinal, and immune
function. EPA and DHA may affect many aspects of cardiovascular
function including inflammation, peripheral artery disease, major
coronary events, and anticoagulation. EPA and DHA have been linked
to promising results in prevention, weight management, and cognitive
function in those with very mild Alzheimer's disease.
IntroductionOmega-3 [(n-3)] long-chain PUFA, including EPA and DHA, are dietary
fats with an array of health benefits. They are incorporated in many
parts of the body including cell membranes and play a role in anti-
inflammatory processes and in the viscosity of cell membranes. EPA
and DHA are essential for proper fetal development and healthy aging.
DHA is a key component of all cell membranes and is found in
abundance in the brain and retina. EPA and DHA are also the
precursors of several metabolites that are potent lipid mediators,
considered by many investigators to be beneficial in the prevention or
treatment of several diseases.
It can be challenging to get the appropriate intake of EPA and DHA
through diet alone, even though EPA and DHA are produced by water
plants such as algae and are prevalent in marine animals. A shorter
chain omega-3 fatty acid, α-linolenic acid (ALA), is a prominent
component of our diet as it is found in many land plants that are
commonly eaten, but it does not provide the health benefits seen with
EPA and DHA. Although it is possible for the body to convert ALA to
EPA and DHA by enlongase and desaturase enzymes, research
suggests that only a small amount can be synthesized in the body from
this process. For example, 1 study suggested that only ∼2 to 10% of
ALA is converted to EPA or DHA, and other studies found even less:
Goyens et al. found an ALA conversion of ∼7% for EPA, but only
0.013% for DHA; Hussein et al. found an ALA conversion of only 0.3%
for EPA and <0.01% for DHA.
The current American diet has changed over time to be high in SFA
and low in omega-3 fatty acids. This change in eating habits is
centered on fast food containing high amounts of saturated fat, which
has small amounts of essential omega-3 PUFA compared with food
prepared in the home. Seafood sources such as fish and fish-oil
supplements are the primary contributors of the 2 biologically
important dietary omega-3 fatty acids, EPA and DHA. This low intake
of dietary EPA and DHA is thought to be associated with increased
inflammatory processes as well as poor fetal development, general
cardiovascular health, and risk of the development of Alzheimer's
disease (AD).
This review focuses on the many benefits of EPA and DHA
supplementation throughout life, including use during pregnancy for
proper fetal development and full-term gestation, to reduce many
cardiovascular issues, and potential uses in AD.
Omega-3 fatty acids and fetal developmentMaternal nutrition guidelines have always stressed a diet including
sufficient caloric and protein requirements, but recently fatty acids
have also been deemed important. This is partially due to the fact that
EPA and DHA supplementation during pregnancy has been associated
with multiple benefits for the infant. During pregnancy, the placenta
transfers nutrients, including DHA, from the mother to the fetus. The
amount of omega-3 fatty acid in the fetus is correlated with the
amount ingested by the mother, so it is essential that the mother has
adequate nutrition. The 2010 U.S. Department of Health and Human
Services dietary guidelines recommend that women who are pregnant
or breastfeeding should “consume 8 to 12 ounces of seafood per week
from a variety of seafood types”. Ingesting 8–12 oz of seafood per
week, depending on the type of fish, is equivalent to ∼300–900 mg
EPA+DHA per day. Unfortunately, this amount is not being met by
most mothers in the United States and Canada, which means that
infants many not be receiving adequate amounts of these vital
nutrients in the womb.
Several studies confirmed the benefit of omega-3 supplementation
during pregnancy in terms of proper development of the brain and
retina. Of the 2 most important long-chain omega-3 fatty acids, EPA
and DHA, DHA is the more important for proper cell membrane
function and is vital to the development of the fetal brain and retina.
During the third trimester, vast amounts of DHA accumulate in fetal
tissue. The 2 most infiltrated fetal areas include the retina and brain,
which may correlate with normal eyesight and brain function. A study
by Judge et al. found that children whose mothers had taken DHA
supplementation during pregnancy (n = 29) had significantly better
problem-solving skills at 9 mo old (P = 0.017) than those whose
mothers had not taken DHA supplementation during pregnancy (n =
15). Another study provided a cognitive assessment of children 2.5 y
after maternal EPA+DHA supplementation during pregnancy from 20
wk of gestation until delivery (n = 33) compared with children in a
placebo group (n = 39). Children in the EPA + DHA–supplemented
group attained significantly higher scores for eye and hand
coordination [mean score, 114 (SD 10.2] than those in the placebo
group [mean score, 108 (SD 11.3)] (P = 0.021, adjusted P = 0.008).
Of great clinical importance, EPA and DHA supplementation during
pregnancy has been associated with longer gestation and increased
concentrations of EPA and DHA in fetal tissues. In 2005, preterm
births accounted for 12.7% of all births in the United States,
increasing the likelihood of health complications. Carrying a baby to
term is very important because prematurity is the cause of various
infant diseases and can lead to death; preterm delivery is an
underlying factor for 85% of the deaths of normally formed infants.
One mechanism by which EPA and DHA may decrease the incidence of
preterm birth is by decreasing prostaglandin E 2 and prostaglandin
F 2α production, therefore reducing inflammation within the uterus,
which could be associated with preterm labor. Several studies
investigated EPA and DHA intake during pregnancy and its correlation
with longer gestation. Conclusions were that EPA+DHA
supplementation during pregnancy delayed the onset of delivery to
term or closer to term; however, supplementation did not delay
delivery to the point of being post-term. This supports the evidence
that EPA+DHA ingestion leads to optimal pregnancy length. EPA+DHA
supplementation reduced the HR of preterm delivery by 44% (95% CI:
14–64%) in those who consumed relatively low amounts of fish and
39% (95% CI: 16–56%) in those who consumed medium amounts of
fish; however, a level of statistical significance was not met (P = 0.10).
The Judge et al. study found that women who had DHA
supplementation from gestation week 24 until full-term delivery
carried their infants significantly (P = 0.019) longer than did the
women in the placebo group. One study found that DHA
supplementation after gestation week 21 led to fewer preterm births
(<34 wk of gestation) in the DHA group compared with the control
group (1.09% vs. 2.25%; adjusted RR, 0.49; 95% CI: 0.25–0.94; P =
0.03). Also, mean birth weight was 68 g heavier (95% CI: 23–114
g; P = 0.003) and fewer infants were of low birth weight in the DHA
group compared with the control group (3.41% vs. 5.27%; adjusted
RR, 0.65; 95% CI: 0.44–0.96; P = 0.03).
There is also evidence that mothers who use EPA and DHA
supplementation during pregnancy and breastfeeding may protect
their children against allergies. This may be due to the fact that fish-oil
supplementation has been associated with decreased levels of body
cells associated with inflammation and immune response. In a study
about food allergy and IgE-associated eczema, the period prevalence
of food allergy was lower in the maternal EPA+DHA supplementation
group compared to placebo (P < 0.05), and the incidence of IgE-
associated eczema was also lower in the maternal EPA+DHA
supplementation group compared to placebo (P < 0.05) .
Omega-3 fatty acids and cardiovascular diseaseCardiovascular disease is the cause of 38% of all deaths in the United
States, many of which are preventable. Chronic inflammation is
thought to be the cause of many chronic diseases, including
cardiovascular disease. EPA and DHA are thought to have
antiinflammatory effects and a role in oxidative stress and to improve
cellular function through changes in gene expression. In a study that
used human blood samples, EPA+DHA intake changed the expression
of 1040 genes and resulted in a decreased expression of genes
involved in inflammatory and atherogenesis-related pathways, such as
nuclear transcription factor κB signaling, eicosanoid synthesis,
scavenger receptor activity, adipogenesis, and hypoxia signaling.
Circulating markers of inflammation, such as C-reactive protein (CRP),
TNF α, and some ILs (IL-6, IL-1), correlate with an increased
probability of experiencing a cardiovascular event. Inflammatory
markers such as IL-6 trigger CRP to be synthesized by the liver, and
elevated levels of CRP are associated with an increased risk of the
development of cardiovascular disease. A study of 89 patients showed
that those treated with EPA+DHA had a significant reduction in high-
sensitivity CRP (66.7%, P < 0.01). The same study also showed a
significant reduction in heat shock protein 27 antibody titers
(57.69%, P < 0.05), which have been shown to be overexpressed in
heart muscle cells after a return of blood flow after a period of
ischemia (ischemia-reperfusion injury) and may potentially have a
cardio protective effect.
There have been conflicting results reported about EPA and DHA and
their use with regard to major coronary events and their use after
myocardial infarction. EPA+DHA has been associated with a reduced
risk of recurrent coronary artery events and sudden cardiac death
after an acute myocardial infarction (RR, 0.47; 95% CI: 0.219–0.995)
and a reduction in heart failure events (adjusted HR: 0.92; 99% CI:
0.849–0.999). A study using EPA supplementation in combination
with a statin, compared with statin therapy alone, found that, after 5 y,
the patients in the EPA group (n = 262) who had a history of coronary
artery disease had a 19% relative reduction in major coronary events
(P = 0.011). However, in patients with no history of coronary artery
disease (n = 104), major coronary events were reduced by 18%, but
this finding was not significant. This Japanese population already has a
high relative intake of fish compared with other nations, and, thus,
these data suggest that supplementation has cardiovascular benefits
in those who already have sufficient baseline EPA+DHA levels.
Another study compared patients with impaired glucose metabolism
(n = 4565) with normoglycemic patients (n = 14,080). Impaired
glucose metabolism patients had a significantly higher coronary artery
disease HR (1.71 in the non-EPA group and 1.63 in the EPA group).
The primary endpoint was any major coronary event including
sudden cardiac death, myocardial infarction, and other nonfatal
events. Treatment of impaired glucose metabolism patients with EPA
showed a significantly lower major coronary event HR of 0.78
compared with the non–EPA-treated impaired glucose metabolism
patients (95% CI: 0.60–0.998; P = 0.048), which demonstrates that
EPA significantly suppresses major coronary events. When looking at
the use of EPA+DHA and cardiovascular events after myocardial
infarction, of 4837 patients, a major cardiovascular event occurred in
671 patients (13.9%). A post hoc analysis of the data from these
diabetic patients showed that rates of fatal coronary heart disease and
arrhythmia-related events were lower among patients in the
EPA+DHA group than among the placebo group (HR for fatal coronary
heart disease: 0.51; 95% CI: 0.27–0.97; HR for arrhythmia-related
events: 0.51; 95% CI: 0.24–1.11, not statistically significant). Another
study found that there was no significant difference in sudden cardiac
death or total mortality between an EPA+DHA supplementation group
and a control group in those patients treated after myocardial
infarction. Although these last 2 studies appear to be negative in their
results, it is possible that the more aggressive treatment with
medications in these more recent studies could attribute to this.
Omega-3 fatty acids have been found to play a role in atherosclerosis
and peripheral arterial disease (PAD). It is thought that both EPA and
DHA improve plaque stability, decrease endothelial activation, and
improve vascular permeability, thereby decreasing the chance of
experiencing a cardiovascular event. It was found that EPA
supplementation is associated with significantly higher amounts of
EPA in the carotid plaque than placebo (P < 0.0001), which may lead
to decreased plaque inflammation and increased stability. PAD, a
manifestation of atherosclerosis, is characterized by buildup of plaque
in the arteries of the leg and can eventually lead to complete blockage
of the arteries. EPA+DHA supplementation has been shown to
improve endothelial function in patients with PAD by decreasing
plasma levels of soluble thrombomodulin from a median value of 33.0
μg/L to 17.0 μg/L (P = 0.04) and improve brachial artery
flow–mediated dilation from 6.7% to 10.0% (P = 0.02). Patients who
had PAD and were supplemented with EPA experienced a significantly
lower major coronary event HR than those who did not take EPA (HR:
0.44; 95% CI: 0.19–0.97; P = 0.041).
Omega-3 fatty acids have been shown to increase platelet
responsiveness to sub therapeutic anticoagulation therapies,
including aspirin. Recently, it was noted that patient response to
aspirin for anticoagulation therapy is widely variable, and, thus, the
number of patients with a low response to aspirin or aspirin
resistance is estimated to range from <1% to 45%, depending on
many variables. However, in patients with stable coronary artery
disease taking low-dose aspirin, EPA+DHA supplementation has been
proven to be as effective as aspirin dose escalation to 325 mg/d for
anticoagulation benefits. The antiplatelet drug clopidogrel has also
been associated with hypo responsiveness in some patients. This
could be attributed to poor patient compliance, differences in genes
and platelet reactivity, variability of drug metabolism, and drug
interactions. More importantly, in 1 study, patients receiving standard
dual antiplatelet therapy (aspirin 75 mg/d and clopidogrel 600-mg
loading dose followed by 75 mg/d) were assigned to either EPA+DHA
supplementation or placebo. After 1 mo of treatment, the
P2Y 12 receptor reactivity index (an indicator of clopidogrel resistance)
was significantly lower, by 22%, for patients taking EPA+DHA
compared with patients taking placebo (P = 0.020) .
Omega-3 fatty acids and ADAD is a devastating disease for which there are limited treatment
options and no cure. Memory loss is an early indicator of the disease,
which is progressive, and leads to the inability of the patient to care
for him- or herself and eventually to death. Currently, the number of
individuals with AD is estimated to be 26.6 million and is expected to
increase to 106.2 million by 2050. There have been many studies
conducted regarding the use of omega-3 fatty acid supplementation
and AD. DHA is present in large amounts in neuron membrane
phospholipids, where it is involved in proper function of the nervous
system, which is why it is thought to play a role in AD. A case-control
study consisting of 148 patients with cognitive impairment [Mini-
Mental State Examination (MMSE) score <24] and 45 control patients
(MMSE score ≥24) showed that serum cholesteryl ester-EPA and -DHA
levels were significantly lower (P < 0.05 and P < 0.001, respectively) in
all MMSE score quartiles of patients with AD compared with control
values. Another study found that a diet characterized by higher
intakes of foods high in omega-3 fatty acids (salad dressing, nuts, fish,
tomatoes, poultry, cruciferous vegetables, fruits, dark and green leafy
vegetables), and a lower intake of foods low in omega-3 fatty acids
(high-fat dairy products, red meat, organ meat, butter) was strongly
associated with a lower AD risk. Image analysis of brain sections of an
aged AD mouse model showed that overall plaque burden was
significantly reduced by 40.3% in mice with a diet enriched with DHA
(P < 0.05) compared with placebo. The largest reductions (40–50%)
were seen in brain regions that are thought to be involved with AD,
the hippocampus and parietal cortex. A central event in AD is thought
to be the activation of multiple inflammatory cells in the brain. Release
of IL-1B, IL-6, and TNF α from microglia cells may lead to dysfunction
of the neurons in the brain .In 1 study, AD patients treated with
EPA+DHA supplementation increased their plasma concentrations of
EPA and DHA, which were associated with reduced release of
inflammatory factors IL-1B, IL-6, and granulocyte colony–stimulating
factor from peripheral blood mononuclear cells.Unintended weight loss is a problem that many patients with AD may
face, and EPA+DHA supplementation has had a positive effect on
weight gain in patients with AD. In a study using EPA+DHA
supplementation, patients' weight significantly increased by 0.7 kg in
the EPA+DHA treatment group at 6 mo (P = 0.02) and by 1.4 kg at 12
mo (P < 0.001) and was observed mainly in patients with a BMI <23 at
the study start (54). This means that those patients with a lower BMI
preferentially gained weight compared with those patients already
with a higher BMI.
Although results from studies regarding the disease processes of AD
seem to be promising, there are conflicting data regarding the use of
omega-3 fatty acids in terms of cognitive function. Neuropsychiatric
symptoms accompany AD from early stages and tend to increase with
the progression of the disease (55). An analysis of 174 patients
randomized to a placebo group or to a group with mild to moderate
AD (MMSE score ≥15) treated with daily DHA (1.7 g) and EPA (0.6 g)
found that at 6 mo, the decline in cognitive function did not differ
between the groups. Yet, in a subgroup with very mild cognitive
dysfunction (n = 32, MMSE score >27), they observed a significant
reduction in the MMSE decline rate in the DHA+EPA-supplemented
group compared with the placebo group (47). Another study that
looked at DHA supplementation in individuals with mild to moderate
AD used the Alzheimer's disease Assessment Scale–Cognitive subscale,
which evaluates cognitive function on a 70-point scale in terms of
memory, attention, language, orientation, and praxis. This study found
that DHA supplementation had no beneficial effect on cognition during
the 18-mo trial period for the DHA group vs. placebo
ConclusionThe omega-3 PUFA EPA and DHA are important throughout life and
are a dietary necessity found predominantly in fish and fish-oil
supplements. The omega-3 fatty acids EPA and DHA are essential for
proper fetal development, and supplementation during pregnancy has
also been linked to decreased immune responses in infants including
decreased incidence of allergies in infants. Omega-3 fatty acid
consumption has been associated with improved cardiovascular
function in terms of anti-inflammatory properties, PAD, reduced
major coronary events, and improved antiplatelet effects in the face of
aspirin resistance or clopidogrel hypo responsiveness. Patients with
AD have been shown to be deficient in DHA, and supplementing them
with EPA+DHA not only reverses this deficiency, but may also
improve cognitive functioning in patients with very mild AD. With
increasing rates of paediatric allergies, cardiovascular disease, and AD
in the United States, EPA and DHA may be a safe and inexpensive link
to a healthier life. Further research should be conducted in humans to
assess a variety of clinical outcomes including quality of life and
mental status. In addition, because potent lipid mediator metabolites
of EPA and DHA are of great interest currently, their influence on
these important outcomes should be assessed because current
evidence suggests that their anti-inflammatory and tissue-protective
effects are nearly 1000 times greater than those of EPA and DHA.
