AREDS Formulations and Other Multi-nutrient Combinations
The large Age-Related Eye Disease Study (AREDS) treated over 4000 subjects (aged 50-85 years) with a supplement containing the following daily nutrients: 15 mg (25 000 IU) β-carotene, 500 mg vitamin C, 400 IU vitamin E, 80 mg zinc, and 2 mg copper. The analysis of 3640 adults (age 55-80 years) who were followed for an average of 6.3 years reported that consumption of this AREDS supplement was associated with a 25% reduced risk of developing advanced macular degeneration compared to subjects receiving placebo (AREDS 2001). Recent research has suggested that supplementation with the carotenoids lutein and zeaxanthin may also be helpful in preventing macular degeneration and other eye diseases. A study of adults aged 50-85 years who were taking the AREDS daily supplement reported that the risk of developing late macular degeneration was reduced by 18% in subjects taking the AREDS supplement with 10 mg lutein and 2 mg zeaxanthin (Chew 2013).
Mixture of omega-3 fatty acids, carnitine, and coenzyme Q10. Carnitine and coenzyme Q10 (CoQ10) play a critical role in energy-producing mitochondrial reactions, whereas omega-3 fatty acids are important for health of blood vessels and cell membranes within the eye. One study treated adults (55-70 years) with early macular degeneration with either a mixture of 100 mg acetyl-L-carnitine, 530 mg omega-3 fatty acids, and 10 mg CoQ10 (48 subjects) or placebo (53 subjects) twice daily. After 12 months of treatment, vision worsened in only 2% (1 of 48) of the participants in the treatment group compared to 17% (9 of 53) of the participants in the placebo group (Feher 2005).
Multi-nutrient combination. A 2007 study treated older adults (average age 76) whom had macular degeneration with a daily mixture of the following nutrients: 10 000 IU vitamin A, 18 640 IU β-carotene, 452 mg vitamin C, 200 IU vitamin E, 70 mg zinc oxide, 400 mg taurine, 1.6 mg copper, 180 mg eicosapentaenoic acid (EPA), 120 mg docosahexaenoic acid (DHA), 8 mg lutein, and 0.4 mg zeaxanthin. The subjects were compared to a placebo group. After 6 months of treatment, visual acuity improved significantly in the adults treated with the multi-faceted supplement program, while visual acuity declined significantly in the subjects given placebo (Cangemi 2007).
Regular use of B-complex vitamin supplements may also help maintain eye health and prevent buildup of the toxic metabolite homocysteine. A study of 5442 women aged ≥40 years at baseline were treated with either a daily supplement containing 2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12 or placebo. After an average 7.3-year follow-up period, the risk of developing macular degeneration was 33% lower in the group taking the supplement compared to placebo (Christen 2009). Adequate folate consumption is also important for eye health. In some individuals, supplementation with 5-methyltetrahydrofolate (5-MTHF) may be more efficient than supplementation with folic acid. Folic acid is converted into the active form of folate, 5-MTHF, via an enzymatic metabolic pathway (Pietrzik 2010). However, several common genetic mutations interfere with the effective metabolism of folic acid into 5-MTHF (Pietrzik 2010; Kirke 2004). Studies with pregnant women and adults with coronary artery disease reported that supplementation with 5-MTHF was associated with significantly higher levels of the active 5-MTHF in both blood serum and red blood cells (Willems 2004; Lamers 2006). In some cases, 5-MTHF supplementation was up to 7 times more effective in increasing blood plasma levels than folic acid (Willems 2004).
Other B-vitamins also play an important role in preventing cataracts. In one review, five of 8 published studies reported that increased riboflavin (B2) use was associated with a significantly lower risk of cataracts (Chiu, Taylor 2007). A cross-sectional study examined the use of supplemental B-vitamins and incidence of cataracts in 2873 Australian adults aged 49-97 years. Compared to adults who did not use B-vitamin supplements, the risk of cataracts was 30% lower in those who consumed at least 4.4 mg supplemental thiamine (B1) daily, 30% lower in those who took ≥6.8 mg riboflavin (B2) daily, and 50% lower in those who took ≥8 µg vitamin B12 daily (Kuzniarz 2001).
Use of benfotiamine (a fat-soluble form of vitamin B1) has been able to prevent experimentally induced diabetic retinopathy in preclinical research. Benfotiamine was found to inhibit several mechanisms implicated in high blood sugar-induced vascular damage, including inhibition of advanced glycation end products (AGEs) (Hammes 2003).
Omega-3 Fatty Acids
Consumption of omega-3 fatty acids has been shown in several studies to reduce risk of macular degeneration (Weikel 2012). Omega-3 fatty acids are found in higher concentrations in fatty fish/fish oils, evening primrose oil, and flax/flax oil. Fish-based omega-3 fatty acids consist largely of DHA and EPA while plant-based omega-3 fatty acids are primarily ALA (alpha [α]-linolenic acid) (Koh 2013; Weikel 2012).
Studies have revealed that higher consumption of omega-3 fatty acids is associated with significantly lower rates of macular degeneration and a significantly lower risk of progression to late macular degeneration (Weikel 2012). Higher fish intake was associated with significantly less progression to early and/or late macular degeneration in 4 of 6 studies (Weikel 2013). A 12-year study of 72 489 adults over age 50 years reported the risk of developing macular degeneration was reduced 30% in the highest versus the lowest groups of DHA consumption (Cho 2001). A 5-year study of 2335 adults over 49 years of age reported that consumption of fish at least once a week was associated with a 40% reduction in early macular degeneration risk, and consuming fish 3 or more times per week was associated with a 75% lower risk for late macular degeneration compared to subjects consuming fish less than once per week (Chua 2006).
Several studies have also reported that omega-3 fatty acids or fish oil can significantly reduce the symptoms of dry eye syndrome. A large double-blind study treated 325 patients with dry eyes with either an omega-3 supplement containing 325 mg EPA and 175 mg DHA or placebo twice daily for 3 months. After 3 months, 65% of the subjects who received omega-3 supplements reported significant improvement in dry eye symptoms compared to 33% of the placebo subjects (Bhargava 2013). Another study of 64 adults (age 45-90 years) with dry eye symptoms treated participants with either 180 mg EPA and 120 mg DHA twice daily for 30 days or 2 medium chain triglyceride oil capsules for 1 month. Subjects given the EPA-DHA supplement had significantly fewer dry eye symptoms and significantly more tear secretion compared to subjects given the medium chain triglycerides (Kangari 2013). Another study reported significantly fewer dry eye symptoms in 152 subjects given fish oil capsules containing 1245 mg EPA and 540 DHA daily compared to 15 subjects given placebo (Kawakita 2013).
Carotenoids are phytochemicals found in a wide range of fruits and vegetables - especially those of dark green or yellow color. Higher carotenoid consumption has been linked to better eye health, including a lower risk of macular degeneration and cataracts. Lutein, zeaxanthin, and meso-zeaxanthin are considered to be especially helpful since they are the most common carotenoids found in the eye lens and retina (Ma 2013; Nolan 2013; Hammond 1997). Lutein, zeaxanthin, and meso-zeaxanthin absorb low wavelength light and minimize oxidative damage to the retina and other parts of the eye (Krinsky 2003). These carotenoids are found in especially high concentrations in the macula of the eye. Meso-zeaxanthin is the most common carotenoid in the center of the macula, zeaxanthin is the most common carotenoid in the middle periphery of the macula, and lutein is the most common carotenoid in the outer peripheral macula region. Meso-zeaxanthin is thought to be produced in the body from the phytochemical lutein (Nolan 2013). However, studies have reported that the ability to synthesize meso-zeaxanthin declines with age and macular levels of meso-zeaxanthin may fall considerably in older adults and smokers (Kirby 2010).
One study that included 3139 adults aged 60-79 years reported that those in the highest group of dietary consumption of lutein and zeaxanthin were 90% less likely to develop early changes associated with macular degeneration (eg, pigmentary abnormalities and age-related maculopathy) than those in the lowest consumption group (Mares-Perlman 2001). Several studies have reported that higher blood levels of lutein, zeaxanthin, or total carotenoids are associated with lower risk of cataracts (Weikel 2013). A study that included 1689 older adults (61 to 81 years old) reported that subjects with the highest blood lutein levels were 42% less likely to have nuclear cataracts (cataracts that affect the center of the lens) than those with the lowest levels. Subjects with the highest zeaxanthin blood levels had a 41% lower risk for nuclear cataracts (Karppi 2012). A comprehensive review of 6 studies involving close to 42 000 aging adults reported that higher dietary levels of lutein and zeaxanthin were associated with significantly lower rates of cataract formation (Ma 2013). The largest of these 6 studies involved 39 876 women with a follow-up period of 10 years. Women with the highest levels of lutein/zeaxanthin consumption (median daily intake of 6.7 mg) had an 18% lower risk of cataracts than those with the lowest levels of lutein/zeaxanthin consumption (median daily intake of 1.2 mg) (Christen 2008).
A double-blind study treated 36 adults (average age 51 years) with one of the following: lutein and zeaxanthin; lutein, zeaxanthin and meso-zeaxanthin; or placebo. At the end of the 6-month study, both visual acuity and contrast sensitivity (with and without glare) improved significantly only in the group given all 3 eye carotenoids (Loughman 2012). Another study of healthy adults reported that daily supplementation with meso-zeaxanthin, lutein, and zeaxanthin for 6 months resulted in significant increases in blood levels of lutein and zeaxanthin and an increase in the central macular pigment optical density compared to subjects given placebo (Connolly 2011).
Astaxanthin. Astaxanthin, another carotenoid, is a red-colored pigment produced by algae, bacteria, and fungi. It is present in algae-eating fish and shellfish and is found in especially high levels in red-colored seafood such as crab, lobster, krill, salmon, and shrimp. Astaxanthin has strong anti-inflammatory and anti-oxidative properties. Several Japanese studies reported that 6 mg daily of supplemental astaxanthin was associated with significantly better visual acuity and significantly less visual fatigue (Kidd 2011).
Vitamins A, C, E, and D
Some studies have reported that higher consumption of the antioxidant vitamins A, C, and E (in diet or supplements) is associated with a significantly lower risk of many eye problems, especially cataracts. Vitamin C is an important antioxidant found in the lens and aqueous humor of the eye at concentrations at least 50-fold greater than in the blood plasma (Weikel 2013). In one review, eight of 15 published studies reported that higher vitamin C intake, supplement use, or blood levels were associated with significantly lower rates of nuclear cataracts (Chiu, Taylor 2007). Researchers noted that consuming ≥135 mg of vitamin C daily (food and supplements) was associated with an approximately 40% decreased risk of cataracts (Weikel 2013). Studies also report that higher consumption of vitamin E is associated with a significantly lower risk of cataracts (Chiu, Taylor 2007).
Several studies have reported that higher intake or higher blood levels of retinol or vitamin A are associated with a significantly lower risk of cataracts (Weikel 2013). One study reported that risk of cataracts was 58% lower in people who used vitamin A supplements and 46% lower in those who used vitamin D supplements compared to supplement nonusers (Klein 2008).
Lipoic acid, a powerful antioxidant, is involved in many energy-producing reactions and may help control blood sugar in diabetics. In a double-blind study 38 adults with type-2 diabetes were randomly assigned to receive placebo or various doses of alpha-lipoic acid (300, 600, 900, and 1200 mg/day). After 6 months, all treatment groups showed significantly better blood sugar control compared to placebo: there was a dose-dependent decrease in fasting blood glucose levels (with maximal effect at 900 mg/day for blood glucose, but there was a further improvement in HbA1c for the 1200 mg dose). A similar dose response was seen for HbA1c with maximal effect at 1200 mg/day (Porasuphatana 2012). Supplemental lipoic acid significantly reduced both blood sugar levels and risk of cataracts in diabetic rats. The authors conclude, “Light-scattering measurements indicated that dietary LA [lipoic acid] is effective in delaying not only cataract development but also its progression. LA may be able to do this by preventing protein glycation and reducing oxidative stress…” (Kojima 2007). In a preclinical study, supplemental lipoic acid significantly increased tear production in a dry eye model (Andrade 2014). Human clinical trials involving lipoic acid supplementation and eye health are eagerly awaited.
Concentrations of zinc are high in the retina (Weikel 2012). Zinc is involved in many processes involving immunity, reproduction, and nerve development. Several studies found that higher zinc intake was associated with a lower risk of macular degeneration or vision loss (Weikel 2012; Mares-Perlman 1996; van Leeuwen 2005; VandenLangenberg 1998; Tan 2008). A large study of 4170 adults reported that higher zinc and vitamin E intake was associated with a lower rate of early macular degeneration. This study also found an above-median intake of β-carotene, vitamins C and E, and zinc was associated with a 35% reduced risk of AMD (van Leeuwen 2005). One study of 80 macular degeneration subjects reported that supplementation with 25 mg zinc twice daily was associated with significantly better vision (Newsome 2008).
Carnosine Eye Drops
N-acetylcarnosine is a small molecule consisting of 2 amino acids. N-acetylcarnosine can be used topically as eye drops and easily reaches both the water soluble and fatty parts of the eye. (N-acetylcarnosine is metabolized to carnosine in the lipid area of the eye). Carnosine is a strong antioxidant and helps prevent glycation (glycation involves sugar binding to and damaging proteins in the body) of the eye tissue and other body tissues (Budzen 2013; Babizhayev 2009; Babizhayev 2012; Babizhayev 2010; Babizhayev, Khoroshilova-Maslova 2012).
Several studies have reported beneficial effects of N-acetylcarnosine eye drops. A study treated 96 adults with cataracts with 1 or 2 drops of eye drops containing N-acetylcarnosine in each eye 3 or 4 times daily for 3-6 months. At the end of the treatment, vision improvement was reported in all subjects with primary senile cataract and 80% of subjects with mature senile cataract (Wang 2000). A double-blind study treated 147 adults that had cataracts and/or refractive errors with either eye drops containing 1% N-acetylcarnosine or placebo twice daily in each eye for 9 months. After 9 months, significantly better visual acuity and significantly lower glare problems were noted in the adults who received the N-acetylcarnosine eye drops compared to placebo. No significant side effects were seen in the N-acetylcarnosine treatment group (Babizhayev 2009).
Resveratrol is an anti-inflammatory phytochemical found in grapes (especially dark-colored grapes), cranberries, other berries, Japanese knotweed, and peanuts (Baur 2006). Studies with cultured human cells have reported that resveratrol is protective against oxidative damage (Sheu 2013). Evidence from a small case series showed that 3 adults aged 75-88 years whom had severe visual loss from macular degeneration benefited from treatment with 100 mg of oral trans-resveratrol daily. All 3 subjects had been taking standard eye health supplements containing 15 mg β-carotene (a form of vitamin A), 500 mg vitamin C, 400 IU vitamin E, 80 mg zinc, and 2 mg copper. After 2-6 weeks of treatment with 100 mg trans-resveratrol daily, vision improved significantly in all 3 subjects (Richer 2013). Larger studies are needed to examine the potential beneficial effects of resveratrol supplementation on elderly people with macular degeneration.
Anthocyanins and C3G
Anthocyanins are water-soluble plant pigments found in dark-colored fruits and vegetables. Some of the richest sources of anthocyanins include chokecherries, black currants, wild blueberries, bilberries, blackberries, and red or purple grapes (Hosseinian 2007; Anisimoviene 2013; Flamini 2013; Wu 2006; Nile 2014; Mazza 2007; Jaakola 2010). During World War II, British pilots ate bilberry jam several hours before night missions to improve their night vision. Research findings on the night vision effects of bilberry or bilberry extracts have been mostly positive. Subjects in these studies generally received bilberry or bilberry extracts containing 12-40 mg of anthocyanins daily (Canter 2004). A 2-year study reported that 50 mg daily consumption of black currant anthocyanins was associated with a significant drop in eye pressure in patients with open-angle glaucoma compared to 19 people given placebo (Ohguro 2012). An experimental in vivo animal model revealed that the daily consumption of 1 mL of blueberry juice was protective against light-induced retinal damage (Tremblay 2013).
An anthocyanin of particular interest is cyanidin-3-glucoside or C3G. C3G has a wide range of health benefits including antioxidant, anti-inflammatory, and DNA-protecting effects (Ding 2006). C3G has been shown to selectively upregulate expression of genes that protect aging tissue, while downregulating genes that cause damage (such as pro-inflammatory cytokines) (Tsuda 2006; Sasaki 2007; Tsuda 2005). C3G helps protect the retina by several mechanisms and stimulates production of a retinal pigment called rhodopsin (Liu 2012; Matsumoto 2003; Tirupula 2009). Rhodopsin is a critical pigment for seeing in dim light. C3G also serves to protect retinal cells from harmful oxidation and free radical protection in the light (Jang 2005).
A number of lab animal and cell culture studies have reported that Ginkgo biloba extracts have strong antioxidant as well as anti-inflammatory properties and provide protection against oxidative damage to retina cells and mitochondria in cells (Huynh 2013). A Korean study examined the effects of Ginkgo biloba extract in 30 adults with normal tension glaucoma (a form of glaucoma in which damage to the retina and optic nerve occur even in the presence of normal internal eye pressure). Subjects who received 80 mg of Ginkgo biloba extract twice daily for 4 weeks had significantly better retinal blood flow compared to subjects who received placebo (Park 2011). Two small human studies reported that supplementation with 80 mg twice daily or 240 mg once daily of Ginkgo biloba led to modest improvement in vision of individuals with macular degeneration (Evans 2013).
Curcumin is a major phytochemical constituent of the common Indian herb turmeric. Several studies reported that curcumin has many anti-inflammatory and anti-cancer properties (Huynh 2013). Preclinical studies have reported that curcumin supplements can slow progression of diabetic retinopathy and cataracts and help prevent formation of new blood vessels (neovascularization) in animal models of macular degeneration (Pescosolido 2013; Xie 2012). One clinical study treated adults with diabetic retinopathy with either 200 mg curcumin twice daily (39 subjects) or placebo (39 subjects). After 4 weeks of treatment, the subjects receiving curcumin had significantly less eye swelling (edema) and improved blood flow in the retina and other parts of the eye (Steigerwalt 2012).
Pycnogenol®, a bark extract from the French Maritime Pine Pinus pinaster, has been shown to protect cells from oxidative damage (Bartlett 2008). In one study, subjects with diabetic or hypertensive retinopathy were treated with either 50 mg of Pycnogenol® or placebo three times daily for 60 days. Visual acuity improved significantly and retinopathy did not increase in subjects treated with Pycnogenol®. Visual acuity and retinopathy worsened in those receiving placebo. Eye blood vessel studies (fluorangiography) showed significant improvement in retinal blood vessels and reduction in eye membrane leakage in the Pycnogenol® but not the placebo group. This suggests that Pycnogenol® may support the structural integrity of delicate blood vessels in the eye (Spadea 2001). Another study of diabetic adults with moderate diabetic retinopathy reported that treatment with 50 mg Pycnogenol® three times daily (24 subjects) for 2 months showed significant improvement in visual acuity, eye blood flow, and reduced retinal edema (swelling) compared to placebo (22 subjects) (Steigerwalt 2009). Yet another study reported that treating people who had asymptomatic elevated eye pressure with 40 mg Pycnogenol® and 80 mg standard bilberry extract twice daily for 6 months significantly reduced eye pressure in 95% of subjects. A decrease in eye pressure was reported in only 5.5% of the placebo group (Steigerwalt 2008).
Taurine is an amino acid that comprises almost half of the free amino acid content of the retina. Animal and tissue culture studies have reported that taurine supplements provide significant protection against retinal cell degeneration (Froger 2012). Supplemental taurine was found to be protective against retinal damage in experimental animal models with the taurine-depleting seizure medication vigabatrin (Sabril®) (Jammoul 2009).
Integrative Interventions for Retinitis Pigmentosa and Leber’s Hereditary Optic Neuropathy
Vitamin A and omega-3 fatty acids appear to be potentially beneficial for individuals with retinitis pigmentosa. A study enrolled 601 adults (aged 18-49 years) with retinitis pigmentosa into one of 4 groups to receive the following daily: 15 000 IU vitamin A; 400 IU vitamin E; both supplements; or neither supplement. The subjects receiving vitamin A had a 32% decreased risk of their visual acuity declining by half in a given year compared to those not receiving vitamin A (Berson 1993). Another analysis reported that among 357 adults with retinitis pigmentosa who received 15 000 IU vitamin A daily for 4-6 years, rates of vision decline were 41% slower per year in subjects receiving at least 200 mg omega-3 fatty acids daily (Berson 2012).
A human study treated 62 retinitis pigmentosa subjects with either a daily supplement of 1 g taurine, 400 mg vitamin E, and 30 mg of diltiazem (Cardizem®) (a drug used to treat high blood pressure) or placebo for 3 years. The retinitis pigmentosa subjects who received the taurine, vitamin E, and diltiazem had significantly better changes in vision compared to placebo subjects. Over the 3-year study, peripheral (outer) visual acuity declined significantly in 69% of the placebo subjects but declined only 6% in the treated subjects (Pasantes-Morales 2002).
Supplemental CoQ10, L-carnitine, B-vitamins, and the amino acids creatine and arginine have been useful for some people with mitochondrial disorders. These nutrients present a potential treatment for Leber’s hereditary optic neuropathy and other vision diseases linked to mitochondrial genes (Parikh 2009).