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.
