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Introduction
With the focus on concepts such as the glycemic index, macronutrient ratios, and food groups, essential fatty acids (EFAs) are one of the most neglected aspects of nutrition in modern society. One can have a diet that is nutritious by most standards and still underconsume EFAs. Omega-3s are of particular importance in today's world. A deficiency of omega-3 EFAs in the diet, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may play a strong role in many of the widespread and interrelated conditions of today, such as cardiovascular disease, inflammatory conditions, and obesity. Although omega-3s are most commonly emphasized only when one of these conditions is present, ensuring adequate intake can play a very strong preventative role.
Our ancestral diet was very different than the diet of today. The diets of the Paleolithic era in which our genetic patterns were establishe consisted of an omega 6
mega 3 ratio of about 1:1 to 2:1 (with the estimate usually falling closer to 1:1) [1]. DHA may have played a particularly important role in the development of the hominid brain [2]. In contrast, the ratio in the typical Western diet is 10:1 to 25:1 with the average being around 16:1 [1, 3], and the importance of this difference cannot be underestimated.
Consuming fat sources rich in omega-3s, such as flax seed oil, may help to correct this imbalance. However, the omega-3 found in flax seed oil, alpha linolenic acid (ALA, not to be confused with alpha lipoic acid), has only limited conversion to the more important EPA and DHA, and the magnitude of its biological effects is much smaller [4]. Also, it only partially corrects the evolutionary imbalance, because a large portion of the omega-3s we consumed provided ample amounts of DHA [2]. For this reason, it is important to emphasize a diet that is high in both EPA and DHA, and one of the best ways to achieve this is supplementation with fish oil [4]. The EPA and DHA found in fish increases plasma concentrations more than from fish oil supplements, but in this case one has to eat a lot of fish on a regular basis [5], and an additional problem is that fish that are not caught in the wild tend to have lower concentrations of EPA/DHA. Fish oil supplements are also a more convenient and less expensive source of EFAs.
Body composition
One of the primary benefits of fish oil supplementation is improvement in body composition, as dietary fatty acid composition plays an important role in the accumulation of excessive body fat. A reduction in fat mass is to be expected, as well as fat being less likely to be distributed in the abdominal area. There are quite a few mechanisms of action, one of the most important being activation of peroxisome proliferator-activated receptor alpha (PPARalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma), which in turn increases the production of various enzymes that break down fat [6-8]. Fish oil also deactivates a number of lipogenic (fat forming) enzymes [7-9].
Many studies in rats have found a diet high in fish oil to significantly reduce fat accumulation [7, 8, 10-12]. This reduction is dose-dependant [8]. Also, fish oil causes less relative distribution of fat in the abominal area in rats gaining weight compared to saturated fat [13] and increases lipid mobilization in visceral adipose tissue [14]. Although this effect has not been confirmed in humans, fish oil has definite potential in the treatment of obesity [6], and the evidence for changes in gene expression and enzyme activity is quite strong, as well as the health benefits of fish oil supplementation which in many cases are interrelated with the antiobesity effects. Fish oil may be especially useful during a period of weight gain due to the fat redistribution, and also due to the fact that one study noted that changes in liver membrane fatty acids due to fish oil were not significant during a period of energy restriction and concluded that "the influence of dietary fat type on cellular structure and perhaps function becomes increasingly important with progressively positive energy balance" [15].
Cardiovascular disease
Multiple large-scale, long-term epidemiologic studies have shown a significant association between consumption of fish and thrombotic stroke, sudden cardiac death, and other cardiovascular conditions [16- 18], with one study finding only 5.5 g per month of omega-3s from fish to be associated with a 50% lower risk of cardiac arrest [18]. A Japanese epidemiologic study also found consumption of omega-3s from fish to be associated with a decrease in all cause mortality among women [19]. Two large-scale clinical trials have confirmed these findings. The first was a two year study in men recovering from heart attacks. One group was counseled to consume at least two portions of fish weekly or fish oil capsules (900 mg of EPA/DHA daily), while the other received no counseling. The risk of death from ischemic heart disease was 33% lower in those that ate more fish and 62% lower in those that consumed fish oil supplements [16, 18]. Fish oil supplements also reduced all cause mortality by 57% in this group [16]. An additional study in 11,000 similar patients had similar results, finding that 850 mg per day of EPA/DHA reduced mortality risk by 41% in only three months [16]. The effect fish oil has on blood pressure has been extensively researched, with a recent meta-analysis of 90 trials finding that fish oil significantly reduced blood pressure, especially in the elderly and hypertensive [20]. Some of the mechanisms of action in the prevention and treatment of cardiovascular disease are antiarrhythmic properties, improved endothelial function, antiinflammatory properties, and reduction in serum triglycerides, with both EPA and DHA playing important roles [16].
Fish oil and the brain
When it comes to the brain, DHA is probably the most important fatty acid. DHA plays a very important role in brain development and the maintenance of normal brain function in adults [18]. The impact during development is significant enough that maternal supplementation with fish oil has been shown to increase the IQ of children at age four by an average of 4.1 points [21]. DHA is preferentially taken up by the brain compared to other fatty acids, where it then enhances membrane fluidity, which in turn changes the signaling properties of neurons and affects the function of the blood brain barrier [22]. In rats, DHA changes the expression of 23 genes in the hippocampus alone [23]. Epidemiological studies indicate that there is an association between high fish consumption and a reduced risk of cognitive decline [18, 22], while saturated fat is associated with an increase in dementia [22]. In animal models, fish oil supplementation improves learning and memory in both young and old rats [24, 25].
Fish oil also fights stress and depression. Multiple studies have found a direct association between depression and omega-3 content in various tissues of the body, including the content in adipose tissue, which is a marker of long-term dietary fat intake [26]. Supplementation with DHA increases levels of both serotonin and dopamine in rats without affecting norepinephrine [27]. Additionally, a trial with 42 college students taking 1.5-1.8 g of DHA daily vs. placebo over one college quarter found that DHA prevented the changes in various markers of stress during finals week, such as external aggression and changes in the plasma epinephrine:norepinephrine ratio [28]. Anti-stress effects of DHA have also been observed in mice [28]. In addition to anti-depressive and anti-stress properties, fish oil may be useful in the treatment of other conditions such as dyslexia and schizophrenia [29, 30].
Treatment and prevention of other conditions
Fish oil has many anti-inflammatory properties and for this reason has been explored in a number of inflammatory and autoimmune conditions. These include rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, lupus erythematosus, multiple sclerosis, migraine headaches, asthma, and cystic fibroris, and it usually has a significant beneficial effect [31-33]. Mechanisms of action include displacement of arachidonic acid (which is pro-inflammatory), suppression of proinflammatory cytokines, and changes in adhesion molecule expression [32].
N-3 PUFAs from fish oil also have a beneficial effect on insulin sensitivity. Animal studies show that fish oil increases insulin sensitivity, with a high fish oil diet being equivalent to a low fat diet in this regard [10]. Positive effects on bone metabolism have been observed in both rats and quails, indicating a possible benefit in the prevention or treatment of osteoporosis [34, 35]. Finally, epidemiologic, case-control, and animal studies respectively found that fish oil decreases the risk of lung, breast, and colon cancer [36-38].
Possible side effects
Fish oil consumption is generally safe and well tolerated, with less adverse effects than other dietary oils [12]. Doses equivalent to three times the FDA maximum safe dosage (which is 3 g EPA/DHA per day) appear to be safe in rats [39]. The primary reported side effect is "fish burps" or a "fishy taste in the mouth," although this can depend on the product, and it is also commonly reported to only be a problem for the first few weeks of fish oil consumption. However there are a few more serious side effects that may be seen with high dose fish oil consumption which may warrant caution.
The first of these is that high doses of fish oil may decrease immune function (in opposition to lower intakes, which may enhance it) [40-42]. While this is beneficial in some autoimmune diseases it is not always desirable. For example, high amounts of fish oil may impair bacterial resistance [43]. Modest doses, in the range of 1-2 g of EPA/DHA daily, do not appear to have a negative impact on immune function over 6 months [40]. This effect may also be avoided with supplemental vitamin E [42]. A second potential problem is increased lipid peroxidation, resulting in an increase in oxidative stress [44-47]. However, this effect can also be remedied with vitamin E [9, 48].
Another possible side effect is an increase in LDL cholesterol and a decrease in HDL cholesterol [49-50]. The first of these effects can be seen with doses as low as 3.6 g/day in humans [49]. However, LDL increase is generally less than 5% [16], and fish oil on balance has a very positive impact on the cardiovascular system. Since fish oil thins the blood, it may also increase the likelihood of bleeding, but it does not appear to do this at lower doses. 2-5 grams a day, even when combined with other blood thinners such as aspirin, do not appear to increase bleeding time, but intake over 20 grams a day will increase bleeding times [16]. Other possible side effects of high or very high dose fish oil consumption reported in animals are increased liver and spleen weight, adverse effects on iron metabolism, and red blood cell deformities [45, 46, 50], but it is doubtful that these are relevant in moderate doses.
What all of this amounts to is, fish oil consumption in a healthy individual should probably be kept within a reasonable range, and additional supplementation with vitamin E is also a good choice. The amount of fish oil one takes should be dependent on both goals and the amount of EPA/DHA present in the fish oil. The optimal range for both safety and effectiveness in most healthy individuals is 1-4 g of EPA/DHA daily, and this amount shouldn't be exceeded without medical supervision. Most fish oils are standardized to 30% EPA/DHA, so this would be about 3-12 one gram caps daily. If the fish oil is standardized to a different amount the dosage should be changed accordingly, for example 2-8 caps of a 50% EPA/DHA product. Most of the benefits (other than possibly the change in body composition, for which there is presently little functional data) can be seen with 1-2 grams of EPA/DHA daily. Most fish oil capsules also contain vitamin E, but if they don't, a vitamin E supplement should be taken also.
With the focus on concepts such as the glycemic index, macronutrient ratios, and food groups, essential fatty acids (EFAs) are one of the most neglected aspects of nutrition in modern society. One can have a diet that is nutritious by most standards and still underconsume EFAs. Omega-3s are of particular importance in today's world. A deficiency of omega-3 EFAs in the diet, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may play a strong role in many of the widespread and interrelated conditions of today, such as cardiovascular disease, inflammatory conditions, and obesity. Although omega-3s are most commonly emphasized only when one of these conditions is present, ensuring adequate intake can play a very strong preventative role.
Our ancestral diet was very different than the diet of today. The diets of the Paleolithic era in which our genetic patterns were establishe consisted of an omega 6
mega 3 ratio of about 1:1 to 2:1 (with the estimate usually falling closer to 1:1) [1]. DHA may have played a particularly important role in the development of the hominid brain [2]. In contrast, the ratio in the typical Western diet is 10:1 to 25:1 with the average being around 16:1 [1, 3], and the importance of this difference cannot be underestimated. Consuming fat sources rich in omega-3s, such as flax seed oil, may help to correct this imbalance. However, the omega-3 found in flax seed oil, alpha linolenic acid (ALA, not to be confused with alpha lipoic acid), has only limited conversion to the more important EPA and DHA, and the magnitude of its biological effects is much smaller [4]. Also, it only partially corrects the evolutionary imbalance, because a large portion of the omega-3s we consumed provided ample amounts of DHA [2]. For this reason, it is important to emphasize a diet that is high in both EPA and DHA, and one of the best ways to achieve this is supplementation with fish oil [4]. The EPA and DHA found in fish increases plasma concentrations more than from fish oil supplements, but in this case one has to eat a lot of fish on a regular basis [5], and an additional problem is that fish that are not caught in the wild tend to have lower concentrations of EPA/DHA. Fish oil supplements are also a more convenient and less expensive source of EFAs.
Body composition
One of the primary benefits of fish oil supplementation is improvement in body composition, as dietary fatty acid composition plays an important role in the accumulation of excessive body fat. A reduction in fat mass is to be expected, as well as fat being less likely to be distributed in the abdominal area. There are quite a few mechanisms of action, one of the most important being activation of peroxisome proliferator-activated receptor alpha (PPARalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma), which in turn increases the production of various enzymes that break down fat [6-8]. Fish oil also deactivates a number of lipogenic (fat forming) enzymes [7-9].
Many studies in rats have found a diet high in fish oil to significantly reduce fat accumulation [7, 8, 10-12]. This reduction is dose-dependant [8]. Also, fish oil causes less relative distribution of fat in the abominal area in rats gaining weight compared to saturated fat [13] and increases lipid mobilization in visceral adipose tissue [14]. Although this effect has not been confirmed in humans, fish oil has definite potential in the treatment of obesity [6], and the evidence for changes in gene expression and enzyme activity is quite strong, as well as the health benefits of fish oil supplementation which in many cases are interrelated with the antiobesity effects. Fish oil may be especially useful during a period of weight gain due to the fat redistribution, and also due to the fact that one study noted that changes in liver membrane fatty acids due to fish oil were not significant during a period of energy restriction and concluded that "the influence of dietary fat type on cellular structure and perhaps function becomes increasingly important with progressively positive energy balance" [15].
Cardiovascular disease
Multiple large-scale, long-term epidemiologic studies have shown a significant association between consumption of fish and thrombotic stroke, sudden cardiac death, and other cardiovascular conditions [16- 18], with one study finding only 5.5 g per month of omega-3s from fish to be associated with a 50% lower risk of cardiac arrest [18]. A Japanese epidemiologic study also found consumption of omega-3s from fish to be associated with a decrease in all cause mortality among women [19]. Two large-scale clinical trials have confirmed these findings. The first was a two year study in men recovering from heart attacks. One group was counseled to consume at least two portions of fish weekly or fish oil capsules (900 mg of EPA/DHA daily), while the other received no counseling. The risk of death from ischemic heart disease was 33% lower in those that ate more fish and 62% lower in those that consumed fish oil supplements [16, 18]. Fish oil supplements also reduced all cause mortality by 57% in this group [16]. An additional study in 11,000 similar patients had similar results, finding that 850 mg per day of EPA/DHA reduced mortality risk by 41% in only three months [16]. The effect fish oil has on blood pressure has been extensively researched, with a recent meta-analysis of 90 trials finding that fish oil significantly reduced blood pressure, especially in the elderly and hypertensive [20]. Some of the mechanisms of action in the prevention and treatment of cardiovascular disease are antiarrhythmic properties, improved endothelial function, antiinflammatory properties, and reduction in serum triglycerides, with both EPA and DHA playing important roles [16].
Fish oil and the brain
When it comes to the brain, DHA is probably the most important fatty acid. DHA plays a very important role in brain development and the maintenance of normal brain function in adults [18]. The impact during development is significant enough that maternal supplementation with fish oil has been shown to increase the IQ of children at age four by an average of 4.1 points [21]. DHA is preferentially taken up by the brain compared to other fatty acids, where it then enhances membrane fluidity, which in turn changes the signaling properties of neurons and affects the function of the blood brain barrier [22]. In rats, DHA changes the expression of 23 genes in the hippocampus alone [23]. Epidemiological studies indicate that there is an association between high fish consumption and a reduced risk of cognitive decline [18, 22], while saturated fat is associated with an increase in dementia [22]. In animal models, fish oil supplementation improves learning and memory in both young and old rats [24, 25].
Fish oil also fights stress and depression. Multiple studies have found a direct association between depression and omega-3 content in various tissues of the body, including the content in adipose tissue, which is a marker of long-term dietary fat intake [26]. Supplementation with DHA increases levels of both serotonin and dopamine in rats without affecting norepinephrine [27]. Additionally, a trial with 42 college students taking 1.5-1.8 g of DHA daily vs. placebo over one college quarter found that DHA prevented the changes in various markers of stress during finals week, such as external aggression and changes in the plasma epinephrine:norepinephrine ratio [28]. Anti-stress effects of DHA have also been observed in mice [28]. In addition to anti-depressive and anti-stress properties, fish oil may be useful in the treatment of other conditions such as dyslexia and schizophrenia [29, 30].
Treatment and prevention of other conditions
Fish oil has many anti-inflammatory properties and for this reason has been explored in a number of inflammatory and autoimmune conditions. These include rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, lupus erythematosus, multiple sclerosis, migraine headaches, asthma, and cystic fibroris, and it usually has a significant beneficial effect [31-33]. Mechanisms of action include displacement of arachidonic acid (which is pro-inflammatory), suppression of proinflammatory cytokines, and changes in adhesion molecule expression [32].
N-3 PUFAs from fish oil also have a beneficial effect on insulin sensitivity. Animal studies show that fish oil increases insulin sensitivity, with a high fish oil diet being equivalent to a low fat diet in this regard [10]. Positive effects on bone metabolism have been observed in both rats and quails, indicating a possible benefit in the prevention or treatment of osteoporosis [34, 35]. Finally, epidemiologic, case-control, and animal studies respectively found that fish oil decreases the risk of lung, breast, and colon cancer [36-38].
Possible side effects
Fish oil consumption is generally safe and well tolerated, with less adverse effects than other dietary oils [12]. Doses equivalent to three times the FDA maximum safe dosage (which is 3 g EPA/DHA per day) appear to be safe in rats [39]. The primary reported side effect is "fish burps" or a "fishy taste in the mouth," although this can depend on the product, and it is also commonly reported to only be a problem for the first few weeks of fish oil consumption. However there are a few more serious side effects that may be seen with high dose fish oil consumption which may warrant caution.
The first of these is that high doses of fish oil may decrease immune function (in opposition to lower intakes, which may enhance it) [40-42]. While this is beneficial in some autoimmune diseases it is not always desirable. For example, high amounts of fish oil may impair bacterial resistance [43]. Modest doses, in the range of 1-2 g of EPA/DHA daily, do not appear to have a negative impact on immune function over 6 months [40]. This effect may also be avoided with supplemental vitamin E [42]. A second potential problem is increased lipid peroxidation, resulting in an increase in oxidative stress [44-47]. However, this effect can also be remedied with vitamin E [9, 48].
Another possible side effect is an increase in LDL cholesterol and a decrease in HDL cholesterol [49-50]. The first of these effects can be seen with doses as low as 3.6 g/day in humans [49]. However, LDL increase is generally less than 5% [16], and fish oil on balance has a very positive impact on the cardiovascular system. Since fish oil thins the blood, it may also increase the likelihood of bleeding, but it does not appear to do this at lower doses. 2-5 grams a day, even when combined with other blood thinners such as aspirin, do not appear to increase bleeding time, but intake over 20 grams a day will increase bleeding times [16]. Other possible side effects of high or very high dose fish oil consumption reported in animals are increased liver and spleen weight, adverse effects on iron metabolism, and red blood cell deformities [45, 46, 50], but it is doubtful that these are relevant in moderate doses.
What all of this amounts to is, fish oil consumption in a healthy individual should probably be kept within a reasonable range, and additional supplementation with vitamin E is also a good choice. The amount of fish oil one takes should be dependent on both goals and the amount of EPA/DHA present in the fish oil. The optimal range for both safety and effectiveness in most healthy individuals is 1-4 g of EPA/DHA daily, and this amount shouldn't be exceeded without medical supervision. Most fish oils are standardized to 30% EPA/DHA, so this would be about 3-12 one gram caps daily. If the fish oil is standardized to a different amount the dosage should be changed accordingly, for example 2-8 caps of a 50% EPA/DHA product. Most of the benefits (other than possibly the change in body composition, for which there is presently little functional data) can be seen with 1-2 grams of EPA/DHA daily. Most fish oil capsules also contain vitamin E, but if they don't, a vitamin E supplement should be taken also.
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