Omega-6 fatty acids: linoleic acid
The omega-6 fatty acid linoleic acid (LA) is the most abundant dietary polyunsaturated fatty acid (PUFA). The results of prospective cohort studies examining the relationships between PUFA intake and the risk of coronary heart disease (CHD) have been inconsistent (37). Some have found that higher PUFA and LA intakes are associated with significant reductions in CHD risk (38, 39, 40) or cardiovascular-related mortality (41). The largest prospective cohort study to examine the effects of dietary fat intake on CHD risk is the Nurses’ Health Study, which followed more than 78,000 women for 20 years. In that group, those with the highest intakes of total PUFA (7.4% of energy) and LA had a risk of CHD that was 25% lower than those with the lowest intakes of total PUFA (5% of energy) and LA (39). Although saturated fatty acid (SFA) intake was not associated with CHD risk, a higher ratio of PUFA to SFA intake was associated with lower CHD risk.
In controlled feeding trials, replacing dietary SFA with PUFA consistently lowers blood serum total and LDL cholesterol concentrations (42). In fact, LA has been shown to be the most potent fatty acid for lowering blood serum total and LDL cholesterol when substituted for dietary SFA (43).
Several dietary intervention trials have compared the effects of diets high in SFA (18–19% of energy) with diets low in SFA (8–9% of energy) and high in PUFA (14–21% of energy) on illness (‘morbidity’) and mortality from CHD (37). Although most of the increase in dietary PUFA was provided by LA, ALA intakes were also increased in these trials (44).
Other dietary intervention trials in men found that replacing dietary SFA with PUFA reduced morbidity or mortality from CHD (45, 46, 47, 48). However, two similar dietary intervention trials in women did not result in significant reductions in morbidity or mortality from CHD (49, 50).
The American Heart Association concluded that obtaining 5–10% of total caloric intake from omega-6 PUFAs is associated with a reduced risk of CHD (51). Increasing the consumption of LA above recommended levels does not appear to increase the levels of AA in adults consuming a Western diet (270).
Omega-3 fatty acids: alpha-linolenic acid
Several prospective cohort studies have examined the relationship between dietary alpha-linolenic acid (ALA) intake and coronary heart disease (CHD) risk: in a group of more than 45,000 U.S. men followed for 14 years, each 1 g/day increase in dietary ALA intake was associated with a 16% reduction in the risk of CHD (52). Moreover, in those who ate little or no seafood, each 1 g/day increase in dietary ALA intake was associated with a 47% reduction in the risk of CHD.
In a group of more than 76,000 U.S. women followed for ten years, those with the highest ALA intakes (about 1.4 g/day) had a risk of fatal CHD that was 45% lower than women with the lowest intakes (about 0.7 g/day) (53). In particular, women who consumed ALA from oil and vinegar salad dressing 5–6 times weekly had a risk of fatal CHD that was 54% lower than those who rarely consumed it.
In a smaller group of more than 6,000 U.S. men, those with the highest intakes of ALA had a risk of death from CHD over the next ten years that was 40% lower than those with the lowest intakes (54).
In contrast, two studies in Europe found no association between dietary ALA intake and CHD risk (55, 56). Additionally, in the Nurses' Health Study of 76,763 women who were followed for 18 years, dietary intake of ALA was not associated with death due to (‘fatal’) CHD or non-fatal myocardial infarction, but rather with a lower risk of sudden cardiac death (5, 6, 7). A systematic review of the evidence noted that ALA intake did not reduce the rate of overall mortality, cardiac, and sudden death, and possibly stroke (64).
Although not as consistent as the evidence supporting higher intakes of long-chain omega-3 fatty acids from seafood, the results of most prospective studies suggest that higher dietary ALA intakes (2–3 g/day) are associated with significant reductions in CHD risk, especially in populations with low levels of fish consumption (58).
Unlike omega-6 fatty acid LA, the heart-protecting effects of higher ALA intakes do not appear to be related to changes in blood serum lipid profiles. A meta-analysis of 14 randomized controlled trials concluded that ALA supplementation had no effect on total cholesterol or LDL cholesterol levels (59).
However, several controlled clinical trials found that increasing ALA intake decreased blood serum concentrations of 'C-reactive protein' (CRP), a marker of inflammation that is strongly associated with the risk of cardiovascular events, such as myocardial infarction and stroke (60, 61, 62).
Long-chain omega-3 fatty acids: eicosapentaenoic acid and docosahexaenoic acid
Evidence is accumulating that increasing intakes of long-chain omega-3 fatty acids (EPA and DHA) can decrease the risk of cardiovascular disease by
- preventing abnormal heart rhythms (‘arrhythmias’) that can lead to sudden cardiac death;
- decreasing the risk of blood clot formation (‘thrombosis’) that can lead to myocardial infarction or stroke;
- decreasing blood serum triglyceride levels;
- slowing the growth of atherosclerotic plaque;
- improving vascular endothelial function;
- lowering blood pressure;
- decreasing inflammation (63).
A review of randomized controlled trials found that consumption of EPA and DHA (but not ALA) from fish or fish oil supplements was associated with reductions in all-cause mortality, cardiac death, and sudden death (64).
Another review and meta-analysis of randomized controlled trials and prospective cohort studies concluded that long-chain omega-3 fatty acids do not significantly reduce the risk of total mortality or cardiovascular events (65). However, this study was limited by the small number of clinical studies that were included in the analysis.
Coronary heart disease
Several prospective cohort studies have found that men who eat fish at least once weekly have lower mortality from coronary heart disease (CHD) than men who do not eat fish (66, 67, 68).
One such study followed 1,822 men for 30 years and found that mortality from CHD was 38% lower in men who consumed an average of at least 35 g fish daily than in men who did not eat fish, while mortality from myocardial infarction was 67% lower in the group that ate fish (69).
A study in China that followed more than 18,000 men for ten years found that those who consumed more than 200 g fish or shellfish weekly had a risk of death due to myocardial infarction that was 59% lower than men who consumed less than 50 grams weekly (70).
Less information is available regarding the effects of higher omega-3 fatty acid and fish intakes in women: in the Nurses’ Health Study, which followed more than 84,000 women for 16 years, CHD mortality was 29–34% lower in those who ate fish at least once a week compared to women who ate fish less than once a month (71).
In a prospective study in 2,445 Finnish women, those with the highest intake of fish (greater or equal 41 g/day; mean of 70 g/day) had a 41% lower risk of CHD compared to those with the lowest intake (less or equal 8 g/day; mean of 4.2 g/day) (72).
A large prospective study of a group of 41,478 Japanese men and women found that higher intakes of fish are associated with further reductions in risk of CHD. In this study, those who consumed fish eight times weekly had a 57% lower risk of coronary events and a 56% lower risk of myocardial infarction compared to those who consumed fish only once weekly (73).
A smaller prospective study of 8,879 Japanese men and women found that consumption of fish twice daily did not lower risk of all-cause mortality or CHD mortality compared to eating fish 1–2 times weekly (74). However, it is estimated that consumption of 250 mg/day of DHA plus EPA from fish results in a 36% reduction in cardiovascular mortality risk (44).
Sudden cardiac death
Sudden cardiac death (SCD) is the result of a fatal abnormal heart rhythm of the lower heart chambers (‘ventricular arrhythmia’), which usually occurs in people with coronary heart disease (CHD).
The results of epidemiological studies suggest that regular fish consumption is associated with a decreased risk of sudden cardiac death (75).
In a large prospective cohort study that followed more than 20,000 men for 11 years, those who ate fish at least once a week had a risk of sudden cardiac death that was 52% lower than those who ate fish less than once a month (76, 77).
A prospective study that followed more than 45,000 men for 14 years found that the risk of sudden cardiac death was about 40–50% lower in those who consumed an average of at least 250 mg/day dietary EPA + DHA (the equivalent of 1–2 oily fish meals weekly) than those who consumed less than 250 mg/day (52). Dietary EPA + DHA intake was not related to the risk of non-fatal MI or total CHD events, suggesting the anti-arrhythmic effects of long-chain omega-3 fatty acids may be important at usual dietary intake levels.
It is not clear whether omega-3 supplementation reduces the risk of ventricular arrhythmias: a meta-analysis of three clinical trials (78, 79, 80) concluded that fish oil supplementation did not help prevent ventricular arrhythmias in patients with existing cardiac problems (81).
More research is needed to determine whether omega-3 fatty acid status influences the risk of ventricular arrhythmias (82).
Stroke
Strokes are the result of insufficient blood flow to an area of the brain, which may occur when an artery supplying the brain becomes occluded by a clot (‘ischemic strokes’). ‘Hemorrhagic strokes’ occur when a blood vessel ruptures and bleeds into the brain.
Some prospective studies that have examined the relationship between fish or omega-3 fatty acid intake and total stroke incidence have found increased fish intake to be beneficial (83, 84), while others have found no beneficial effect (85, 86, 87).
More recently, two large prospective studies found that increased intake of fish (at least twice weekly) and omega-3 fatty acid was associated with significantly lower risks of ischemic stroke (43%–52%), but not hemorrhagic stroke (88, 89).
Although the effects of long-chain omega-3 fatty acid intake on the incidence of stroke have not been studied as thoroughly as that of coronary heart disease (CHD), a meta-analysis of available evidence suggests that increased fish intake may decrease the risk of ischemic stroke, but not hemorrhagic stroke (90). It is estimated from cohort studies that consumption of fish and fish oil reduces the risk of ischemic stroke by 30% (44).
Results of a more recent study indicate that high-dose EPA supplementation may be beneficial in preventing recurrent stroke in individuals with a prior history (‘secondary prevention of stroke’) (91). Ongoing studies include a secondary prevention trial that evaluates the combination of folate, B vitamins and omega-3 fatty acid supplementation on the incidence of fatal and non-fatal cardiovascular disease, including ischemic stroke (271).
Blood serum triglycerides
A meta-analysis of 17 prospective studies found high blood serum triglyceride levels (greater than 200 mg/dl) to be an independent risk factor for cardiovascular disease (92).
Numerous randomized controlled trials in humans have demonstrated that increasing intakes of EPA and DHA significantly lower blood serum triglyceride concentrations (93). Clinically meaningful reductions in blood serum triglyceride concentrations have been demonstrated at doses of 2 g/day EPA + DHA (2). DHA alone reduces serum TG levels as well as EPA+DHA (272).
Summary: omega-3 and omega-6 PUFA and cardiovascular disease prevention
The results of epidemiological studies and randomized controlled trials suggest that replacing dietary saturated fatty acids (SFA) with omega-6 and omega-3 polyunsaturated fatty acids (PUFAs), especially DHA and EPA, decreases the risk of cardiovascular disease and stroke. Decreasing SFA while increasing omega-6 and omega-3 fatty acid levels also contributes to improved cardiovascular status. The lowering effects of increased consumption of omega-6 and omega-3 fatty acids on serum LDL levels may also contribute to improved cardiovascular outcomes.
Additionally, there is strong evidence that increasing dietary omega-3 fatty acid intake is associated with significant reductions in cardiovascular disease risk through mechanisms other than lowering LDL cholesterol.
In particular, increasing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake from seafood has been associated with significant reductions in sudden cardiac death, suggesting that long-chain omega-3 fatty acids have anti-arrhythmic effects at intake levels equivalent to the amount in two small servings of oily fish per week. This amount of fish would provide about 400–500 mg/day EPA + DHA (94). Overall, consumption of EPA+DHA between 250 mg/day and 400-500 mg/day seems to be the appropriate amount needed for primary prevention when the diet is used as a means to obtain DHA and EPA.
Cancer
Breast cancer
The balance between omega-3 and omega-6 fatty acids appears to play an important role in the development and growth of breast cancer.
While further research is still needed to understand the effect that omega-3 fatty acids may have on prevention or treatment, several researchers speculate that omega-3 fatty acids in combination with other nutrients, such as vitamin C, vitamin E, beta-carotene, selenium, and coenzyme Q10 may be of particular value in the prevention and treatment of breast cancer (95).
Colon cancer
Significant dietary intake of omega-3 fatty acids may reduce the risk of colorectal cancer. Certain populations such as the Inuit, who have high-fat diets, but also consume significant quantities of fish rich in omega-3 fatty acids, have surprisingly low rates of colorectal cancer.
Animal studies have shown that the intake of omega-3 fatty acids can prevent the progression of colon cancer, while high levels of omega-6 fatty acids can actually promote the growth of those tumors (96).
Some studies have shown the slowing or reversing of the progression of colon cancer with daily consumption of DHA and EPA (97).
One animal study has shown that in rats with spreading (‘metastatic’) cancer, omega-3 fatty acids actually promoted the growth of cancer cells in the spleen (98). The reason for this is not clear and needs further investigation.
Prostate cancer
Both epidemiological studies as well as clinical studies suggest that omega-3 fatty acids may inhibit the growth of prostate cancer (99).
As with breast cancer, the balance of omega-3 to omega-6 fatty acids may play a role, while as with colon cancer studies, alpha-linolenic acid (ALA) has actually been seen in higher levels of individuals with prostate cancer in a study of 67 men with the condition (100).
However, more recent studies that were specifically designed to look for prostate cancer risk factors in humans as well as one systematic review found no such link (101). Two recent cohort studies of prostate cancer by the same investigators report conflicting results with respect to the consumption of fish oil (DHA+EPA) and the risk of prostate cancer. One study suggested an increased risk of having a high-grade tumor with higher DHA+EPA levels, while the second study showed no increased risk for developing prostate cancer with fish oil consumption (273).
Age-related macula degeneration
A questionnaire administered to more than 3,000 people over the age of 49 found that those who consumed more fish in their diet were less likely to have age-related macular degeneration, a serious eye condition that can progress to blindness, in comparison to those who consumed less fish (102).
Similarly, a clinical study comparing 350 people with macular degeneration to 500 people without the eye disease found that those with a healthy dietary balance of omega-3 and omega-6 fatty acids and higher intake of fish in their diets were less likely to have this particular eye disorder (103).
Another larger epidemiological study confirms that consuming EPA and DHA from fish four or more times per week may reduce the risk of developing macular degeneration. Notably, however, this same study suggests that ALA may actually increase the risk of this eye condition (104).
Alzheimer's disease and dementia
Alzheimer's disease, the most common cause of dementia in older adults, results in memory loss and confusion that worsens over time (105). Many epidemiological studies have associated high intake of fish or high DHA intake or plasma levels with decreased risk of impaired cognitive function (274), dementia (107, 113, 275), and Alzheimer's disease (107, 108, 111, 112). Docosahexaenoic acid (DHA), the major omega-3 fatty acid in the brain, may be protective against some sub-populations of Alzheimer's disease patients (276) and those with mild cognitive impairment (277) and age-related cognitive decline (278).
In the Framingham Heart Study, men and women with the highest concentration of blood plasma DHA and consumed an average of three servings of fish weekly (0.18 g/day DHA), had a 47% decreased risk of developing all-cause dementia and a 39% decreased risk of developing Alzheimer's disease when compared to those with lower concentrations (113). Thus, low DHA status may be a risk factor for Alzheimer's disease, other types of dementia, and age-related cognitive impairment.
A trial of 204 mild to moderate Alzheimer's disease patients showed no delay in rate of decline on the Alzheimer Disease Assessment Scale-Cognitive Examination (ADAS-Cog) with DHA+EPA (2-3 g/day) administration (276). However, in a sub-group of individuals with very mild Alzheimer's disease Mini-Mental State Examination (MMSE scores >27), there was a significant decrease in the MMSE rate of decline after supplementation for periods of six and 12 months. Similarly, a recent randomized controlled trial of 402 mild to moderate Alzheimer's disease patients supplemented with 2 g/day DHA or a placebo for 18 months demonstrated no decrease in the rate of cognitive or functional decline overall (279). However, a sub-group analysis by ApoE e4 allele (a significant risk factor for Alzheimer's disease) showed significantly less decline on the both the ADAS-Cog and MMSE score in ApoE4 negative individuals supplemented with DHA. These findings suggest that sub-populations of Alzheimer's disease patients, based on genotype and severity of disease, may benefit from DHA supplementation and that further clinical trials within these groups are needed.
DHA has also recently been shown as a beneficial supplement that supports cognitive health in older adults with mild memory complaints (278). A large, randomized, controlled trial of 485 healthy adults with age-related cognitive decline found that 900mg/day of DHA significantly improved visuospatial learning and memory skills after six months of supplementation. Improvements in verbal recognition memory were also demonstrated with DHA supplementation and the changes in memory scores were correlated with increases in plasma DHA levels. Additionally, DHA treatment over six months showed a significant decrease in heart rate in this older age group, demonstrating a cardiovascular benefit. Other studies conducted on healthy elderly people have not demonstrated cognitive benefits of fish oil supplementation (280, 281). Differences in study designs, especially baseline cognitive variability, baseline dietary omega-3 fatty acid intake, DHA dose, and sensitivity of cognitive measures, likely contributed to the null results in these studies. The long-term effects of DHA on cognitive decline rates or conversion rates to MCI have not been studied and remain a target for further clinical research.
In summary, the results of recent trials in Alzheimer's disease and cognitive decline indicate that treatments such as DHA may be most beneficial for cognitive aging and prevention of cognitive decline. Early detection of impairment, enabling early intervention, is critical. Clinical data suggest that sub-populations of Alzheimer's disease patients may benefit from DHA supplementation. However, more research to confirm these findings is needed.