“You are what you eat.” This old adage has been attributed to several historical figures and has been interpreted in many ways. At a molecular level, alterations of protein expression are influenced by nutrients obtained through dietary intake and supplementation. With vitamin and nutraceutical sales topping $23 billion annually in the U.S., the dietary supplement industry is a very big business.¹

The Dietary Supplement Health and Education Act (DSHEA) defines dietary supplements as “products aimed to provide nutrients not consumed in the diet.”² The quantity of vitamins and minerals necessary for healthy physiologic functioning is known as the dietary reference intake (DRI), which replaced the RDA (recommended dietary allowance) in 1997. The DRI is a set of dietary recommendations that appear as daily values (DV), and are based on age and sex.

Nutrients That Might Help Protect Against AMD • Trans-resveratrol • Epigallocatechin gallate (EGCG) • Coenzyme Q10 (CoQ10) • Vitamin D • Omega-3 fatty acid • Lutein • Zeaxanthin

Under the DSHEA, ocular nutritional supplements are regulated for safety and labeling by the manufacturer. Thus, the manufacturer is responsible for following “good manufacturing practices,” including product validation.² Many products are available over the counter and have the potential to cause undesirable side effects. So, it is crucial to properly educate your patients about which nutritional supplements are most applicable for them. For example, it is interesting to note that, in some cases, what was recommended in the past may be contraindicated today (e.g., beta carotene supplements for cigarette smokers). In addition, the interaction of nutrients obtained through diet with those from supplements is still being investigated.

Although conditions resulting from absolute vitamin deficiency, such as beriberi, pellagra and scurvy, are relatively rare in developed countries, malabsorption or poor nutritional habits may be extremely problematic. In fact, many Americans are currently vitamin deficient, based on the RDA or DRI.³ Also, neither the RDA nor the DRI is set at a level to combat degenerative diseases associated with free radical formation, such as macular degeneration. So, supplement intervention must be considered for patients who have such conditions.

AREDS    
Nutritional supplementation is a critical part of the overall management plan for AMD. To date, AREDS was the largest evidence-based medicine (EBM) study that documented the effectiveness of nutritional supplements for slowing the progression of moderate AMD.^4,5 AREDS had a long-term follow-up of nearly 4,000 subjects from 11 centers for a minimum of five years. The results showed that high intake levels of vitamin C, vitamin E, beta-carotene and zinc lowered the risk for disease progression by 25% in patients with intermediate or advanced AMD.^4,5 Moreover, these nutritional supplements reduced the overall risk of moderate vision loss by 19%.^4,5

Keep in mind, however, that the AREDS formula was found to be effective in slowing a patient’s risk for AMD progression, not for actually curing the disease. Also, up to 67% of AREDS subjects were also taking Centrum multivitamins (Pfizer), which could have significantly impacted the results.⁴

Remember, positive results from the AREDS formula were primarily apparent in cases of intermediate or advanced AMD. Due to the slow progressive nature of early AMD, however, these high levels of antioxidants are not typically recommended for early AMD patients. Today, the AREDS formula is available in a variety of supplements, and is commonly used in the management of AMD patients.

Moving Beyond AREDS
Although AREDS was a landmark research project that highlighted the benefits of nutritional supplementation for patients with AMD, the study still had a few limitations. For example, in recent years, zinc has been associated with increased risks of genitourinary complications.^4,5 Additionally, high levels of beta-carotene have been linked to lung carcinogenesis in smokers.^4,6 Of even greater significance, subsequent studies have shown that beta-carotene may be entirely ineffective in preventing early AMD.^7,8
The AREDS results were published nearly 10 years ago; researchers have since focused greater attention on the ocular health benefits of other nutrients, including trans-resveratrol, epigallocatechin gallate (EGCG), coenzyme Q10 (CoQ10), vitamin D, omega-3 fatty acid, lutein and zeaxanthin.

• Trans-resveratrol. Trans-resveratrol is a phytoalexin that is found in red grapes, red wine, peanuts and Japanese knotweed. It is well absorbed, but rapidly metabolized. Though trans-resveratrol has been shown to act as an antioxidant, its efficacy is relatively weaker than that of other well-known antioxidants, such as vitamins A, C and E.⁹ However, trans-resveratrol may also have other benefits, such as cardioprotective properties.^10,11 Trans-resveratrol’s protective effect against AMD may be complementary to its ability to lower LDL cholesterol.¹²

Several recent reviews have suggested that trans-resveratrol may also play a role in cancer prevention.^13-21 While this information should be interpreted with great caution, trans-resveratrol’s anti-apoptotic and anti-angiogenic properties may be extendable to macular degeneration as well. Trans-resveratrol also has been shown to possess anti-inflammatory properties. In human cell cultures, trans-resveratrol was found to have a protective effect on the retinal pigment epithelium (RPE).^22,23 At this time, a safe, scientifically supported, daily dose of trans-resveratrol has not yet been established. However, a daily intake of 10mg to 50mg of trans-resveratrol is probably acceptable, and maybe beneficial. Nonetheless, always use caution when making such supplementation recommendations to your patients.

• EGCG. Like trans-resveratrol, EGCG might protect against cardiovascular disease, AMD and even glaucoma.^24,25 ECGC, the principal antioxidant found in green tea, has been shown to be beneficial to ganglion cells in rats following experimentally induced crush/reperfusion injury.²⁴ So, one of EGCG’s potential applications could be for glaucoma.
Regarding its anti-inflammatory and antiangiogenic properties, EGCG blocks the gene expression of tumor necrosis factor-alpha (TNF-α), a known inflammatory biomarker.²⁵ While in vitro, ECGC’s anti-angiogenetic properties have been shown to suppress endothelial cell growth/neovascularization stimulated by fibroblast growth factor-2 (FGF-2).^26,27
One cup of green tea contains about 400mg of EGCG.²⁸ Keep in mind, however, that patients should not ingest more than 800mg of EGCG per day. The long-term side effects of EGCG are not well established, but because ECGC is a water-soluble component of green tea, it is generally not associated with significant adverse effects.²⁸ Mild gastrointestinal discomfort has been reported. Also, it is best to recommend caffeine-free green tea to avoid any caffeine-related side effects.

• CoQ10. Co-enzyme Q10 has a widespread distribution in the body. It serves as an essential element in energy production in mitochondria.²⁹ Improvement of mitochondrial function is associated with enhanced metabolic activity. Researchers have evaluated CoQ10’s role in a number of degenerative conditions, such as Parkinson’s disease, heart disease and AMD.^30,31 CoQ10 may protect against AMD by reducing oxidative stress in the RPE. Also, there is evidence that both visual function and alteration in macular appearance may improve with increased intake of CoQ10 in addition to other antioxidants.30 In one study, patients with AMD were found to have lower plasma CoQ10 levels than patients in the control group.³¹ The AMD patients also showed a reduced capability to combat oxidative damage.

CoQ10 levels in the retina decline with advanced age, which likely increases the risk for macular degeneration and other degenerative processes.²⁹ So, it is especially important for elderly individuals to supplement with CoQ10. It is interesting to note that statins––commonly prescribed drugs for the treatment of hypercholesterolemia––are known to inhibit CoQ10 synthesis.

Today, physicians recommend 90mg to 150mg of CoQ10 per day. It is available as a supplement alone, or with multivitamin and mineral formulations. Wheat germ, fish and organ meat (e.g., liver or heart) are excellent dietary sources of CoQ10.

• Vitamin D. Vitamin D is a fat-soluble hormone that is essential for controlling inflammation as well as preventing certain types of cancer, skeletal disease and tooth decay. Vitamin D also has demonstrated anti-angiogeneic properties in a mouse model.³⁴ Accordingly, its anti-inflammatory and anti-angiogeneic properties may offer protection against AMD.^32,33

In 2007, a cross-sectional study of 7,000 people specifically evaluated the relationship between vitamin D and AMD. The results indicated that patients with the highest blood serum levels of vitamin D were least likely to show signs associated with early macular degeneration.³² Increased milk consumption was also associated with a reduction in the prevalence of early AMD. However, these results were not evident in patients with advanced AMD.³²

Fortified cow’s milk is a readily available source of vitamin D, and skin exposure to UV is required for vitamin D synthesis. Absorption rates, serum levels and daily requirements of vitamin D vary with diet, season, gender, race and sun exposure. For elderly individuals, the daily requirement of Vitamin D3 is 400IU to 600IU.^3,35 Because older individuals do not synthesize vitamin D as effectively, higher intake levels may be required to prevent chronic disease.³⁶ For example, many physicians recommend 700IU to 800IU of vitamin D3 per day to decrease an elderly patient’s risk for osteoporosis and associated complications.³⁷

At this time, however, there is no established daily vitamin D intake recommendation for AMD patients. Although increased levels may be beneficial, too much vitamin D can be toxic and can cause bone loss, kidney stones, and calcification of the heart and kidneys.^38,39 So, err on the safe side when recommending any nutritional supplement dosage.
• Omega-3 fatty acid. Omega-3 fatty acid is another nutritional supplement that offers anti-inflammatory and anti-angiogeneic properties. It is primarily found in cold-water fish (salmon, tuna and sardines) and nuts, and is readily available as a dietary supplement. While food sources of omega-3 are preferred, 1g to 2g of daily nutritional supplementation may be required (2:3 DHA:EPA ratio).

Omega-3s inhibit nuclear factor kappaB (NF kappaB) signaling, which may reduce inflammatory responses of the retina and RPE in AMD patients.40-43 NF kappaB is up-regulated in response to oxidative stress, such as ultraviolet radiation exposure, that could lead to AMD or cardiovascular disease.⁴⁰ Additionally, omega-3s have been shown to help reduce chronic dry eye.⁴¹

Of the omega-3s, alpha-linolenic acid (ALA) is classified as an essential fatty acid because it is not synthesized by the body. Arachadonic acid (AA), a pro-inflammatory protein, can be synthesized from the long-chain omega-6 fatty acid, linoleic acid (LA). The long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can be synthesized from ALA; however, this metabolic process may yield insufficent EPA and DHA levels under certain conditions.⁴⁴ Any omega-3 fatty acid imbalance can promote inflammation throughout the body.⁴⁵ So, nutritional omega-3 supplementation should be recommended to patients who might be deficient in EPA and DHA. Deficiencies of moderate scale can affect a variety of groups.

• Lutein and zeaxanthin. Lutein and zeaxanthin are carotenoids––organic pigments that occur naturally in plants. They are exclusively derived from nutritional origin and are not synthesized in the body. Lutein and zeaxanthin selectively accumulate in ocular tissues, including the lens and macula.

In fact, the macular pigment contains higher concentrations of lutein and zeaxanthin than any other anatomical structure in the human body.⁴⁶ This is an important consideration because increased macular pigment has been shown to protect against AMD.47-49 Instruments such as the MacuScope (MacuChek) and QuantifyEye (ZeaVision) can measure macular pigment as well as help validate the need for lutein and zeaxanthin supplementation, and even track its benefits.

Compelling epidemiological evidence indicates that increased dietary intake of lutein and zeaxanthin can increase macular pigment levels and help to protect against AMD.49-53 Additionally, regular lutein and zeaxanthin intake has been associated with both functional and structural benefits. For example, increased consumption of lutein and zeaxanthin has been proven to decrease photophobia and glare, increase contrast sensitivity, and prevent inflammation and angiogenesis.^54,55

Dietary sources of lutein include leafy, green vegetables, such as kale and spinach. In fact, eating one cup of uncooked spinach, four times a day provides 6mg of lutein. Zeaxanthin primarily is found in yellow peppers, corn, egg yolk and goji berries.

Regrettably, Americans generally consume less than 2mg of lutein and zeaxanthin per day.^54,55 So, you may wish to recommend supplementation for patients who are unwilling or unable to obtain sufficient intake levels from dietary sources alone. Recommnedations are based on an “individual basis,” ranging from 2mg to 8mg of zeaxanthin and 6mg to 20mg of lutein.

Unlike other carotenoids, such as beta-carotene, lutein and zeaxanthin are water soluble and do not possess vitamin A activity. To date, there have been no reported adverse reactions associated with high levels of lutein or zeaxanthin intake. Also, both lutein and zeaxanthin are considered relatively safe by the FDA, and adequately meet its “no observed adverse effect level” (NOAEL) guidelines.

At this time, there are no RDA guidelines for daily intake of lutein or zeaxanthin. However, AREDS 2 will further examine their effect on AMD and will provide greater insight on appropriate daily intake levels.

AREDS 2
AREDS 2 is a phase III randomized clinical trial designed to assess the efficacy of a refined AREDS formula on AMD, cataracts and moderate vision loss. The AREDS 2 nutritional supplement formula includes 1,000mg of omega-3, 10mg of lutein, 2mg of zeaxanthin, as well as vitamin C, vitamin E and low levels of zinc. Unlike the original AREDS supplement, the AREDS 2 supplement will not contain beta-carotene.

Report 23 from the original AREDS study indicated that increased dietary intake of omega-3 fatty acid and lutein/zexanthin was inversely correlated with advanced AMD.56 These findings also have been demonstrated in several other trials, including the Blue Mountains Eye Study.⁵⁷

As previously mentioned, however, you must be careful when basing your dietary and supplementary recommendations on results from small subsets of patients. Still, these findings on dietary modification can offer hope and encouragement to patients who are at risk for AMD.

Final Considerations
We now know that certain substances, such as zinc, lutein, zeaxanthin and omega-3 fatty acid, can be beneficial to the retina as well as the cardiovascular system in small study groups. But, sweeping, generalized dietary recommendations are not yet possible, because findings from large, experimental animal models and epidemiological studies still need to be tested in human subjects. Prior to recommending any nutritional supplement, you must take complete systemic, pharmaceutical and dietary histories. Additionally, you must account for subjective dosing guidelines as well as potential contraindications, drug interactions and possible side effects. Finally, it is both sensible and responsible to inform the patient’s primary care physician of any nutritional supplement recommendations you make.

Nutrients play a vital role in physiological ocular function. Current evidence supports the hypothesis that nutritional supplements, dietary modifications and certain lifestyle alterations (cigarette smoking cessation) may become mainstream preventive management strategies for AMD. However, the next research frontier may help clarify the true role of nutritional supplements in helping to treat or prevent this devastating disease.

Dr. Semes is a professor at the University of Alabama School of Optometry in Birmingham, Ala. Dr. Shechtman is an associate professor at Nova Southeastern University College of Optometry in Ft. Lauderdale, Fla.

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