Controversies in omega-3 fatty acid research
Long chain omega-3 fatty acids play important roles in growth, development, optimal functioning, and maintenance of health and well-being right across the life course.
Optimizing vision throughout the lifespan is a public health priority worldwide, not only because of its central importance to quality of life, but also because of the health care costs associated with the loss of vision in an aging population. Oxidative stress is thought to be a key pathogenic mechanism of compromised vision, and the antioxidant properties of some nutrients show the capacity to modulate disease conditions linked to oxidative stress. Considerable evidence has accumulated showing that vitamins A, C, E, beta-carotene and zinc help support vision and may be protective against the development or progression of some common – especially age-related – eye diseases such as age-related macular degeneration and cataracts. In addition, increased intakes of the carotenoids lutein and zeaxanthin and the omega-3 fatty acid docosahexaenoic acid (DHA) – all concentrated in the eye – have been associated consistently with lower likelihood of sight-threatening conditions. There has also been some promising research with B vitamins in age-related eye diseases and with vitamin A and DHA in the rare disease retinitis pigmentosa (see also Key nutrients for healthy vision).
Many eye diseases have been found to be modifiable by nutrients: Cataracts – a clouding of the lens in the eye – have the highest prevalence among vision impairments and age-related eye diseases of adults worldwide. Glaucoma, which damages the optic nerve, is second only to cataracts as a leading cause of blindness. Age-related macular degeneration (AMD), which gradually destroys sharp, central vision, is the leading cause of blindness and visual impairment among people age 50 and older in the world. As a complication of diabetes, diabetic retinopathy, damaging the tiny blood vessels inside the retina, is a leading cause of blindness in many countries. Another common eye problem is dry eye syndrome, which occurs when the eye does not produce tears properly, making it difficult to use a computer or read for an extended period of time. A comparatively rare inherited eye disease, with first signs usually occurring in early childhood, is retinitis pigmentosa, in which the retina slowly and progressively degenerates.
Age-related macular degeneration
Age-related macular degeneration (AMD) is the leading cause of blindness and visual impairment among people aged 50 and older. Although AMD rarely affects those under age 50, prevalence increases dramatically thereafter, approximately doubling every decade after this age (1). Early macular changes (including lipid deposits and pigmentary changes) may progress into advanced AMD, with its two forms: dry and wet AMD. The latter is less frequently observed, but contributes to 90% of AMD-related vision loss. Symptoms of advanced AMD can include blurred vision and “holes” or spots in the center of the visual field. As the condition progresses, these blurred spots become bigger and darker, robbing the sufferer more and more of central vision. Dry AMD involves loss of the retinal pigment epithelial (RPE) cells and photoreceptors and can develop into wet AMD if abnormally proliferating blood vessels begin to grow into the macula (2). Blindness can ensue rapidly due to leakage of blood into the retina. When the retinal cells are lost, they do not regenerate; thus, vision loss from AMD is usually irreversible. AMD presently has no cure, and treatment options are limited. Besides non-modifiable risk factors for AMD (e.g., genetics, age and ethnicity), modifiable risk factors, such as diet, obesity, smoking and sun exposure, exist.
Exposure to UV light produces oxidants capable of damaging DNA, chromatin and lipids in cell membranes. Therefore, nutrients with antioxidant actions have been investigated for possible protective roles in the eye, including vitamins C and E , beta-carotene and zinc . In a large randomized controlled trial – the first Age-Related Eye Disease Study (AREDS) – the efficacy of three supplement combinations in preventing the progression of AMD and age-related cataract was compared to placebo (3): 1) antioxidant supplements containing 500 mg vitamin C, 400 IU vitamin E and 15 mg beta-carotene; 2) 80 mg zinc and 2 mgcopper; 3) antioxidants plus zinc. The 3,640 participants were separated into four groups depending on the severity of their macular disorder and visual impairment at the beginning of the study. AREDS found that people at highest risk for developing advanced AMD – those with intermediate AMD and those with advanced AMD in one eye only – showed a reduced likelihood of developing advanced stages of AMD by about 25% when treated with the combination of antioxidants plus zinc. The combination of antioxidants plus zinc also reduced the risk of central vision loss by 19% in the same group. Participants at high risk for developing advanced AMD who were treated with zinc alone reduced their risk of developing advanced AMD by about 21% and their risk of vision loss by about 11%. Participants who were treated with antioxidants alone reduced their risk of developing advanced stages of AMD by about 17% and their risk of vision loss by about 10%. The investigators concluded that anyone older than 55 years with signs of intermediate AMD or advanced disease in one eye should consider taking a supplement of antioxidants plus zinc such as that used in the AREDS trial. In the decade following this trial, dietary supplements containing the AREDS formula came to be considered the standard of care for AMD. Long-term follow-up of participants in AREDS found that supplementation continued to reduce the risk of developing wet AMD and prevent vision loss five years after the trial had ended (4).
While AREDS was in progress, evidence was accumulating to suggest that lutein and zeaxanthin may be even more effective than the other antioxidants in reducing AMD risk, at least in most people. Both xanthophylls together with meso-zeaxanthin comprise the macular pigment, which has the capacity to function in reduction of oxidative stress and as a filter for damaging wavelengths of visible blue light. Reduction in photo- oxidative damage by the macular pigment is accompanied by a reduction in inflammation, another possible mechanism influencing AMD risk (5). Most of the clinical trials investigating the efficacy of lutein and zeaxanthin supplementation in AMD patients found either stabilization of the disease or improvements in measurements of visual acuity (6-9). The large AREDS2, using several variations on the AREDS formula, including the addition of lutein and zeaxanthin to the original formula and the replacement of beta-carotene with the two carotenoids, did not find these benefits (10). The trial evaluated whether and to what degree the various combinations of nutrients could slow progression of AMD in 4000 people at moderate to high risk for development of advanced AMD. Virtually everyone in the study continued to take variations of the AREDS supplement, so there was no true placebo (untreated) group. Based on the primary analyses, the study found that addition of the xanthophylls did not confer a statistically significant added benefit beyond that provided by the standard AREDS formula. A subgroup analysis revealed that lutein and zeaxanthin showed a significant 9% risk reduction for progression to advanced AMD as compared to participants not receiving lutein and zeaxanthin. This reduction in risk was most pronounced (26%) among persons with the lowest dietary intakes of the carotenoids at baseline, which is consistent with other findings, suggesting a saturation point for the xanthophylls in the macula. The researchers noted that the AREDS2 study population as a whole was well nourished as compared to the US population, and this may be one reason why lutein and zeaxanthin showed benefit only in the subgroups with low intakes before the study. Another possible reason cited was the competition for absorption between the carotenoids (beta-carotene vs. lutein and zeaxanthin). In a subgroup taking the original AREDS formulation with lutein and zeaxanthin but no beta-carotene, there was a significant 18% risk reduction for progression to advanced AMD, as compared to a subgroup taking the original AREDS formulation with beta-carotene. Of relevance to the basic vitamin/mineral combination, AREDS2 also found from secondary analyses that a dose of 25 mg zinc was just as effective as the original 80 mg level, and eliminating beta-carotene did not affect the ability of the supplement to slow progression of AMD.
A strong scientific rationale exists for a role for the omega-3 long-chain polyunsaturated fatty acids in reducing risk of AMD. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) may reduce or repair the damage of environmental exposures such as chronic light exposure and oxidative stress (11). In addition, there is experimental evidence showing that omega-3 fatty acids are capable of modulating processes involved in the development of AMD, including neovascularization, inflammation and programmed cell death (12). DHA likely works synergistically with the antioxidants, since it is highly vulnerable to oxidation and needs their protection. It is likely that AMD is influenced by interactions among multiple dietary, environmental and genetic factors, making it difficult to assess the relative importance of omega-3 fatty acids. Results from clinical trials of combinations of nutrients have generally shown some benefit in AMD patients (13, 14). The AREDS formulation did not contain EPA and DHA. However, in three follow-up reports, the investigators consistently found that higher intakes of omega-3 fatty acids were associated with a decreased risk for developing advanced forms of AMD (15–17). Based on this and other promising epidemiological and biochemical evidence, omega-3 fatty acids were evaluated in the AREDS2 clinical trial along with lutein and zeaxanthin. However, the results showed no statistically significant main effects for reduction in progression to advanced AMD (10). The authors commented that the amount of DHA in the supplement and the duration of treatment may have been inadequate. The study population was well nourished as a whole, with intakes of DHA and EPA twice as high as the AREDS cohort, so there was no true low-intake group for comparison. Further, the level of DHA in the AREDS2 supplement was only 350 mg per day, whereas much higher levels (e.g., 840 mg per day) have been indicated in studies showing a beneficial effect (18).
A number of scientific reports suggest that AMD and cardiovascular disease share a common risk profile, including elevated levels of homocysteine. Because of the roles of folic acid , vitamin B6 and vitamin B12 in homocysteine metabolism, scientists have theorized that supplementation with these vitamins might help reduce the risk of AMD in people with elevated CVD risk. A randomized controlled trial was conducted in more than 5000 women at high risk for CVD. After more than seven years of treatment and follow-up, the study showed that daily supplementation with the B vitamins reduced the risk of mild AMD by about 40% (19).
Despite their apparent effectiveness in reducing progression of intermediate and advanced AMD, the question remains as to whether nutrients have a role in primary prevention. Two reviews have concluded that there is insufficient evidence to support the use of vitamin and mineral supplements for the primary prevention of early AMD (20, 21). One of the challenges in designing primary prevention trials is that early AMD does not always progress to sight-threatening forms.
Age-related cataracts are the leading cause of blindness worldwide (22). Like AMD, the prevalence and risk of cataracts increase with age. Cataracts develop when the lens of the eye becomes cloudy or opaque. The two most common types of age-related cataracts are nuclear (observed in the center of the lens) and cortical (observed in the periphery of the lens). Less commonly, cataracts develop in the back of the lens, sometimes due to aging, but also often as a result of trauma to the eye, intraocular surgery or use of medications such as corticosteroids. Risk factors for cataracts include oxidative stress, genetics, male gender, diabetes, smoking, possibly inflammation, and dietary intakes of carbohydrates and fats (23).
The concentrations of vitamin C in the lens and aqueous humor are 20 times higher than those found in plasma, suggesting a role for the vitamin in protecting these areas against reactive molecular species. Many studies have attempted to explore the association between nutrients with antioxidant properties (vitamin C, vitamin E and beta-carotene) and nutrients acting as cofactors to enzymes with antioxidant properties (zinc, vitamin B2) with occurrence or progression of cataracts, with mixed results. Some studies that have found a significant protective effect of vitamin C have been conducted in poorly nourished populations, suggesting that very low plasma levels or dietary intakes of vitamin C place one at increased cataract risk (24, 25). In studies that failed to find relationships of nutrients with cataract, it is possible that nutrient intakes were not high or low enough to alter vitamin concentrations in the lens. Surprisingly, two studies found that long-term intake of very high-dose vitamin C supplements (1000 mg) was associated with an increased risk of cataract (26, 27). In the Nurses’ Health Study the prevalence of nuclear cataracts was significantly lower in women who used a vitamin C supplement for 10 years or more, compared to women who never used vitamin C supplements (28). This is consistent with earlier findings from this study showing that women who took supplemental vitamin E for five years had reduced likelihood of cataract progression (29). Subjects in the Beaver Dam Eye Study who used multivitamins or any supplement containing vitamin C or E for more than 10 years had a 60% reduced likelihood of developing cataract across a 5 year period (30). Long-term use of vitamin E supplements was associated with decreased risk of cataracts in a study of more than 35,000 US female health professionals (31). A reason for inconsistent results from observational studies is that different nutrients may influence the process of lens opacification at different stages. The studies that found a protective effect of vitamin C tended to be those investigating early stages of cataract development, whereas protective vitamin E and riboflavin associations existed for advanced forms of cataract (29).
The potential of vitamins with antioxidant properties to slow the progression of age-related cataract has been tested in more than a dozen clinical trials, but in most cases the results have not fulfilled the promise of epidemiological studies. Only six trials found protective effects, and within these, the effects were limited to specific supplements among subjects from specific subgroups (32–36). The largest trials conducted in healthy people in the USA –the Physicians’ Health Study (37) and AREDS (38) – found neither harm nor benefit from long-term antioxidant supplementation.
A relationship between high vitamin B2 (riboflavin) intakes or status and a reduced risk for nuclear cataracts was reported in the Beaver Dam Study (39), the Lens Opacities Case-Control Study (40), the Blue Mountains Eye Study (41) and the Nutrition and Vision Project (28). Some of these studies also reported associations of opacity with vitamin B3 (niacin) and vitamin B1 (thiamin), but because these nutrients are found in the same foods and vitamin supplements, independent effects could not be determined. A niacin/riboflavin supplement reduced cataract risk in a large clinical trial in China (42).
The presence of lutein and zeaxanthin in the lens suggests that they may act with vitamins and enzymes with antioxidant properties to reduce harmful effects of ultraviolet radiation and oxygen free radicals. A study in human lens epithelial cells found that lutein and zeaxanthin protect lens proteins, lipids and DNA from oxidative damage comparably to vitamin E (43). Higher intake of foods rich in lutein and zeaxanthin has been associated with a lower likelihood of having or developing cataract in several epidemiological studies (44, 45). In the Physicians’ and Nurses’ Health studies, only those in the highest quintile of dietary lutein and zeaxanthin intakes (6.8 mg/day among men, 11.7 mg/day among women) had statistically significant reduction in cataract risk (19% for men and 22% for women) (46, 47). The addition of lutein and zeaxanthin to the standard AREDS supplement was evaluated in AREDS2: While progression of the eye disease to cataract surgery was not significantly different in the lutein and zeaxanthin group as compared to the group that did not take the carotenoids over five years of treatment, a subgroup analysis indicated that in participants with the lowest lutein and zeaxanthin intake (a median of 0.7 mg) per day supplemental lutein and zeaxanthin showed a 36% reduction in risk for severe cataracts (48).
Even though observational data suggest that higher intakes of fish and omega-3 fatty acids modestly reduced the risk of cataract in women participating in the Nurses’ Health Study (49) there have been very few clinical trials studying omega-3 fatty acids and cataract risk. One small study tested docosahexaenoic acid (DHA) supplementation in a group of 15 elderly subjects with cataracts and/or glaucoma and found improved visual acuity in 10 of the subjects after the first month of DHA supplementation (50).
Diabetic retinopathy is a disorder of the blood vessels in the retina characterized by aneurysms, hemorrhages, and cellular degeneration that can cause visual impairment and blindness. As a chronic complication of diabetes, diabetic retinopathy is a leading cause of visual impairment and blindness in the USA; moreover, it is significantly associated with the likelihood of cardiovascular events (51). As a primary prevention strategy, intensive glycemic control and management of blood lipids has been shown to slow the progression of the eye disease. In theory, antioxidants might be beneficial in diabetic retinopathy by retarding oxidative damage to the retina and/or blood lipids. The evidence regarding an association between nutrients and diabetic retinopathy is suggestive but mixed. A cross-sectional study that evaluated plasma carotenoids in participants with type 2 diabetes found that levels of antioxidant non-provitamin A carotenoids ( lycopene , lutein and zeaxanthin ) were significantly lower in the retinopathy group than pro-vitamin A carotenoids (alpha-carotene, beta-carotene and beta-cryptoxanthin) (52). The authors suggested that synergies among antioxidant carotenoids are implicated in diabetic retinopathy, independent of other risk factors. In a clinical trial with type 1 and 2 diabetes patients of both sexes over age 45 who received insulin treatment, an additional supplementation with vitamin E significantly improved the patients’ retinopathy after 24 months (53). A potential preventive mechanism for omega-3 fatty acids may be reduction of the proliferation of new blood vessels in the retina, which may be relevant to diabetic retinopathy (54). Because of the possible anti-inflammatory and anti-angiogenic properties of vitamin D , some investigators have begun to explore a possible link with diabetic retinopathy (55).
Glaucoma is second only to cataracts as a leading cause of blindness. Glaucoma, which produces peripheral vision loss that may progress to central vision loss, can occur at any age, but risk increases with advancing age. The eye disease involves damage to the optic nerve from increased eye pressure, which may occur when proper drainage of the aqueous humor is obstructed. Treatments that lower intraocular pressure can retard progression but cannot reverse any damage to the optic nerve that has already occurred. Research of the role of nutrients in glaucoma is still very preliminary. Some researchers suggest that oxidative stress may play a role in glaucoma (56), but the evidence is mixed in the few studies that have looked at antioxidant intake. A review of these studies found that reduced risk for glaucoma has been variously correlated with higher intakes of vitamin E , vitamin A and vitamin B2 (riboflavin) (57). While one study based on US intake survey data failed to find an association of glaucoma with either supplemental intakes or serum levels of vitamins C , E or A (58), another one reported about a 33% risk reduction among those participants with the highest intake of vitamin E (59). A small study of docosahexaenoic acid (DHA) supplementation in the elderly found improvements in visual acuity in some subjects with cataract and glaucoma (50).
Other eye diseases
Dry eye syndrome is a common eye problem, especially among postmenopausal women, which does not usually have serious consequences on vision (60). It is characterized by a low production of tears and causes the eyes to feel itchy, scratchy or stingy. It appears to be linked to inflammation and is generally treated either with lubricating eye drops or anti-inflammatory agents (61). Increasing omega-3 fatty acid intake has been suggested as a possible strategy to ameliorate dry eye syndrome due to its anti-inflammatory actions. A review of eight human studies, including six randomized controlled trials, found that all the studies confirmed a relationship between increased intakes of essential fatty acids and improvement in dry eye syndrome; however, these results are considered preliminary due to limitations in the research reported (62). Another review paper summarizing the existing evidence concluded that supplementation with omega-3 fatty acids may be beneficial in the treatment and prevention of dry eye syndrome (63).
Retinitis pigmentosa (RP) describes a cluster of inherited retinal diseases that can begin at any time from infancy through late middle age (64). RP is characterized by the progressive loss of rod and cone cells. As the condition progresses, peripheral vision may be lost in young adulthood and finally central vision is lost later in life. At least 45 genes are associated with RP, and research efforts to unravel the genetic complexity of the condition continue. Oxidative stress is believed to play an important role in the degeneration of photoreceptors as reactive species produced in this stress have the capacity to damage DNA, chromatin (proteins associated with DNA), and membrane lipids. Although there is no cure for RP yet, there are some means of slowing its progression. A large clinical trial reported that daily supplementation with 15,000 IU of vitamin A palmitate significantly slowed the decline of retinal function in RP patients (65). The same researchers subsequently looked at a combination of vitamin A and docosahexaenoic acid (DHA) supplementation because of the suggestive evidence on the protective role of DHA in the rods and cones. Over a four-year period they found no added benefit of DHA in a group that was already taking vitamin A before the trial started, but in subgroup analyses they did find a stronger protective effect among subjects who just started taking both supplements upon entry to the trial (66, 67). In a subsequent clinical trial by this research group, the results indicated that if a typical RP patient on vitamin A and an oily fish diet were to begin taking 12 mg daily of lutein by age 40, he or she would retain mid-peripheral visual field sensitivity 3 to 10 years longer than a patient not taking lutein (68).
Long chain omega-3 fatty acids play important roles in growth, development, optimal functioning, and maintenance of health and well-being right across the life course.