• Research Summaries - AREDS
• Research Summaries - Lutein

• MacularProtect Plus Monograph

Vitamin A (5,000 IU)
MacularProtect Plus provides 100% of the recommended Daily Value of vitamin A; half as pre-formed retinyl palmitate and half as beta-carotene, which is converted to vitamin A only as required by the body.

Vitamin A as Retinyl Palmitate (50%; 2,500 IU)
Vitamin A (also known as pre-formed A or retinyl palmitate) is essential for proper eye health. It protects night vision and is vital for the health of the eye’s cornea. It also works with zinc to support the proper function of various eye structures. vitamin A serves an important role in interactions with zinc and the amino acid taurine within the photoreceptors of the retina.

Vitamin A as Beta-Carotene (50%; 2,500 IU)
Beta-carotene functions primarily as an antioxidant and is converted to itamin A only as needed by the body. MacularProtect Plus contains one-tenth the level of beta-carotene administered to AREDS participants. High doses of beta-carotene are linked to increased health risks in smokers; therefore, levels of supplemental beta-carotene similar to the amount utilized in AREDS may not be advisable for current or recent former smokers. It is important to note that since AREDS began in 1991, new science has emerged suggesting that lutein and zeaxanthin are the carotenoid antioxidants more positively associated with macular health.

Vitamin C (1,000 mg)
Vitamin C is a water-soluble antioxidant that is concentrated in ocular tissues where it inactivates free radicals. Free radicals are the highly reactive compounds produced through the body’s use of oxygen, and generated by outside sources such as UV light. As an integral component of the body’s antioxidant defenses, vitamin C also aids in the recycling of other antioxidants such as vitamin E. Evidence indicates that the requirements for both vitamin C and E are higher in those who smoke. MacularProtect Plus supplies the form and level of vitamin C administered in the AREDS clinical trial, plus an additional 500 mg.

Vitamin E (400 IU)
Fat soluble vitamin E is the major chain-breaking antioxidant present in retinal and macular membranes. As a first line of defense against fatty acid peroxidation, vitamin E helps protect cell membranes against free radical attack. MacularProtect Plus provides the natural source rather than synthetic vitamin E, as studies demonstrate that this form offers superior bioavailability and is better retained in tissues. It also delivers broad spectrum vitamin E from alpha to gamma tocopherol, that together play a health-protective role. MacularProtect Plus includes 400 IU of vitamin E, the level used in AREDS .

Zinc (80 mg)
Zinc is an essential mineral that is selectively concentrated in the eye. It is found in the retina and choroid, ciliary body, iris, optic nerve, sclera, cornea and lens. Within these ocular structures zinc is believed to interact with vitamin A and taurine to modify photoreceptor membranes, to help regulate the light-rhodopsin reaction, to influence nerve transmission and to serve as an antioxidant. MacularProtect Plus provides 80 mg of zinc, the form and level administered in AREDS

Lutein, FloraGLO^® (15 mg) and Zeaxanthin (1 mg)
Lutein and zeaxanthin are two similarly-structured carotenoids found in green leafy vegetables like spinach, kale and mustard greens. These carotenoids make up the macular pigment of the retina, the tissue with the highest concentration of lutein and zeaxanthin in the body. As part of the macular pigment, lutein and zeaxanthin filter blue (visible) light that causes photo-oxidative stress. Population health studies have noted that macular pigment density is positively associated with age-related macular health. Several intervention studies also indicate that consumption of these carotenoids from foods or supplements can favorably modify the density of macular pigment.

The amount of lutein supplied by MacularProtect Plus is within the range of lutein intake (approximately 10-20 mg) found in studies to increase macular pigment density on average by about 18-19%, although the response appears to vary among individuals. MacularProtect Plus provides FloraGLO® lutein, a premium source with proven bioavailability. The ratio of zeaxanthin to lutein within this formula reflects the levels naturally present in the diet.

Selenium (70 mcg)
Selenium is an essential mineral required for the proper function of glutathione peroxidase, an antioxidant enzyme found in the eye’s lens and localized in photoreceptor and retinal pigment epithelial cells. MacularProtect Plus delivers Selenium as selenomethionine, a bioavailable source. Selenium is included in MacularProtect Plus at 100% of the recommended Daily Value.

Copper (2 mg)
Copper is a mineral that is necessary for normal development of connective tissue, nerve sheaths, skin pigment and for the proper utilization of iron. Since high levels of zinc compete with copper for absorption, copper is included in MacularProtect Plus to help ensure an adequate level of this essential mineral in the body. MacularProtect Plus features 2 mg of copper oxide, the form and level administered in the AREDS clinical trial.

1. AREDS Report No. 8. A randomized, placebo-controlled clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. Arch Ophthalmol 119: 1417-1436, 2001.
   
2. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 330: 1029-1035, 1994.
   
3. Omenn GS, et al. Effects of a combination of beta-carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334: 1150-1155, 1996.
   
4. Bruno RS, et al. Alpha tocopherol disappearance is faster in cigarette smokers and is inversely related to their ascorbic acid status. Am J Clin Nutr 81: 95-103, 2005.
   
5. Kelly G. (Review) The interaction of cigarette smoking and antioxidants Part III: Ascorbic acid. Alt Med Rev 8: 43-54, 2003.
   
6. Moeller SM, et al. The potential role of dietary xanthophylls in cataract and age-related macular degeneration. J Am Coll Nutr 19: 522S-527S, 2000.
   
7. Ferslew KE, Acuff RV, Daigneault EA, Woolley TW and Stanton PE. Pharmacokinetics and bioavailability of the RRR and all racemic stereoisomers of alpha-tocopherol in humans after single oral administration. J Clin Pharmacol 33: 84-88, 1993.
   
8. Traber MG, Elsner A and Brigelius-Flohe R. Synthetic as compared with natural vitamin E is preferentially excreted as alpha-CEHC in human urine: studies using deuterated alpha-tocopheryl acetates. FEBS Letters 437: 145-148, 1998.
   
9. Weinstein SJ. Serum alpha-tocopherol and gamma-tocopherol in relation to prostate cancer risk in a prospective study. J Natl Cancer Inst. 97: 396-399, 2005.
   
10. Morris MC, et al. Relation of the tocopherol forms to incident Alzheimer disease and to cognitive change. A J Clinc Nutr 81: 508-514, 2005.14. Stahl. W. Review: Macular carotenoids: lutein and zeaxanthin. Dev Ophthalmol 38: 70-88, 2005.
    
11. Grahn BH, et al. Review: Zinc and the eye. J Am Coll Nutr 20: 106-118, 2001.
    
12. Landrum JT, et al. Lutein, zeaxanthin and the macular pigment. Arch Biochem Biophys 385: 28-40, 2001.
    
13. Beatty S, et al. Macular pigment and risk for age-related macular degeneration in subjects from a Northern European population. Invest Ophthalmol Vis Sci 42: 439-446, 2001.
    
14. Bone RA, et al. Macular pigment in donor eyes with and without AMD: a case-control study. Invest Ophthalmol Vis Sci 42: 235-240, 2001.
    
15. Johnson EJ, et al. Relation among serum and tissue concentrations of lutein and zeaxanthin and macular pigment density. Am J Clin Nutr 71: 1555-1562, 2000.
    
16. Berendschot TT, et al. Influence of lutein supplementation on macular pigment, assessed with two objective techniques. Invest Ophthalmol Vis Sci 41: 3322-3326, 2000.
    
17. Hammond BR, et al. Dietary modification of human macular pigment density. Invest Ophthalmol Vis Sci 38: 1795-1801, 1997.
    
18. Humphries JM, et al. Distribution of lutein, zeaxanthin, and related geometrical isomers in fruit, vegetables, wheat, and pasta products. J Agric Food Chem 51: 1322-1327, 2003.
    
19. De la Paz MA, et al. Antioxidant enzymes of the human retina. Curr Eye Res 15: 273-278, 1996.

• The AREDS Clinical Trial
   
  The findings for the Age-Related Disease Study (AREDS) were released in October, 2001. The AREDS clinical trial has been heralded by doctors and nutrition experts as the most significant clinical trial on nutrition and age-related macular degeneration (AMD) ever. Findings of the 6 ½ year AREDS clinical trial, published in the October 2001 issue of Archives of Ophthalmology, demonstrated a statistically significant reduction in the rate of progression of AMD in 3,640 patients taking a supplement containing vitamins, antioxidants and zinc.
   
  Click here to read the full text of the AREDS clinical trial on the Archives of Opthalmology website
  
• Is AREDS Changing Practice Patterns? - Ophthalmology Management, July, 2002

Take the Right Steps to Fend Off Macular Degeneration (AMD)

AMD Forecasters Call for Wider Vitamin Use
In a newly published analysis (1), researchers predict that cases of age-related macular degeneration (AMD) will nearly double in the coming decades, increasing from 9.1 million in 2010 to 17.8 million in 2050. The study also found that newer therapies have the potential to reduce AMD-related visual impairment and blindness by as much as 35%.
According to the authors, the use of antioxidant vitamins - specifically those used in the Age-Related Eye Disease Study (AREDS) - is a key preventive strategy in slowing the progression of AMD from early to late stages. The authors point out that AREDS formulas are not widely used among patients with early-stage disease, and suggest that public prevention efforts should focus on expanding the use of antioxidant vitamins in people with early AMD, and making sure those people are getting the correct vitamin doses.
So for those who have been diagnosed with AMD, a first step is to talk with your eye care professional about high dose antioxidants, and to be consistent with supplementation when it is recommended.
Genetic Risk Factors May Be Critical
It's now understood that those with a family history of AMD have a greater risk of getting the disease. Scientists have identified a number of genes that seem to make some people more susceptible to AMD by creating inflammation or increasing oxidative damage (2). Adopting good dietary and lifestyle habits early may help prolong health and save eyesight later in life, especially for susceptible individuals.
Food Combinations Reduce AMD Risk
Foods provide many nutrients that may work together to help counter AMD from developing. Researchers from Tufts University developed a scoring system to examine the combined effect of nutrients, and applied this to the diets of people in the AREDS trial. Those whose diets were high in protective nutrients and low-GI (glycemic index) foods had a much lower risk of getting early and advanced AMD (3). A food's GI value is based on how fast its carbohydrates raise the body's blood sugar levels; low GI foods like whole grains have less impact on blood sugar fluctuations.
Protective foods included good sources of the AREDS trial nutrients: vitamin C, vitamin E and zinc, as well as the nutrients being tested in AREDS 2: the omega-3s from fish oil - DHA and EPA, plus lutein and zeaxanthin. (Another antioxidant included in the original AREDS clinical trial, beta-carotene, did not affect AMD risk levels).
Putting it All Together: Preventive Actions
• Avoid smoking - or take steps to stop if you do. Smokers with susceptibility genes have an even greater risk of AMD.
  
  
• Stay physically active. Helps keep weight and blood pressure down which may slow AMD progression.
  
  
• Wear protective sunglasses - those that block 100% of UV-B rays.
  
  
• Eat ample amounts of colorful fruits and vegetables - rich sources of antioxidants including lutein/ zeaxanthin (green leafy vegetables), and flavonoids.
  
  
• Enjoy fish, whole grains, beans and nuts. Fatty fish supply EPA and DHA, and whole grains and cereals are low-GI. Beans, cereals, fish and poultry provide zinc and protective B-vitamins, while nuts and beans can help keep cholesterol levels in check.
  
  
• Supplements - can help close dietary gaps for those who don't always consume the recommended 5 daily servings of fruits and veggies, 2-3 weekly servings of cold-water fish, or the higher levels of lutein and zeaxanthin linked with better visual health.
References

1. Rein DB et al. Forecasting age-related macular degeneration through the year 2050: the potential impact of new treatments. Arch Ophthalmol127:533-40, 2009.
   
2. Chiu, C-J et al. Dietary compound score and risk of age-related macular degeneration in the AREDS. Ophthalmology 116:939-46, 2009.
3. NEI (http://www.nei.nih.gov/news/congresstest/budget2009.asp)
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Lutein and AMD: Results from CAREDS
The CAREDS Study
A number of studies have looked at the relationship between dietary lutein and zeaxanthin intake and the risk for age-related macular degeneration (AMD). Many - though not all - of the findings from these population health studies suggest that eating more lutein-rich foods is beneficial.
The authors of the Carotenoids in Age-Related Eye Disease Study (CAREDS) now report that a stable intake of these nutrients over time could reduce the risk of AMD by 43% in healthy women under 75.
CAREDS, an off shoot of the Women's Health Initiative (WHI), looked at over 1780 women aged 50-79 who had either high or low intake of lutein plus zeaxanthin when they entered the WHI study. These women were later asked to participate in CAREDS, and researchers determined which of them had developed AMD using special photographic techniques.
Regular Lutein Intake Supports Visual Health
Women with higher intakes of lutein plus zeaxanthin (at least about 3 milligrams or more daily) had a substantial 43% lower risk for intermediate AMD compared to those eating about ¾ of a milligram or less every day. This protective effect was seen in women 75 years and younger who had stable intakes of these nutrients.
Safely Achieving a Lutein-Rich Diet
If a higher and consistent intake of lutein and zeaxanthin is important, how do we go about achieving it?
A commonly eaten, concentrated source of lutein is green leafy vegetables such as spinach. Some people are leery of eating fresh spinach because of the recent contamination of certain fresh spinach brands with the illness-causing, bad bug E. coli 0157:H7. Information about the brands and batches that were recalled can be found at the Center for Food Safety and Applied Nutrition (CFSAN) (http://www.cfsan.fda.gov/list.html).
According to CFSAN, no frozen or canned spinach was implicated in this most recent outbreak.
Should an E. coli 157:H7- related outbreak occur in the future, CFSAN indicates that cooking fresh spinach at 160 degrees Fahrenheit for at least 15 seconds will kill any E. coli O157:H7 present.
Eat a Variety of Lutein-Containing Foods
While terrific, spinach isn't the only source of lutein and zeaxanthin. These nutrients can also be obtained from eating corn, broccoli, peas, squash and other green leafy vegetables like kale, collards and mustard greens. Consuming a wide variety of produce is healthful overall, and the CFSAN website offers a handy booklet of general safety tips for storing and preparing fresh produce and juices called Safe Handling.
Eggs yolks are another excellent source. Though they contain considerably less of these nutrients than spinach, the lutein and zeaxanthin they do contain is very well absorbed according to several recent studies. The good bioavailability is likely due to the fats found in egg yolk. Lutein and zeaxanthin are fat-soluble, so absorption is enhanced when fat is present. While eggs contain 213 mg of cholesterol - and the recommended intake of dietary cholesterol is 300 mg. daily - eggs can fit into the daily cholesterol budget several times weekly if you limit cholesterol from other sources such as meats, poultry and dairy products.
Lutein Supplements Can Also Play a Role
While the ideal intake of lutein has not been pinned down, we do know that the typical American intake of 1-2 mg daily from foods falls short of the 3-7 mg daily that studies suggest may be beneficial. Supplements of lutein and zeaxanthin can also be of help in closing this dietary gap and ensuring regular intake.
Reference

Moeller SM et al. Age-Related Macular Degeneration
and Lutein and Zeaxanthin in the Carotenoids in Age-Related Eye Disease Study (CAREDS). Archives of Ophthalmology 124:1151-1162, 2006.

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"Benchmark" Findings from New Lutein, Vitamin C Studies
New Study Shows Lutein Improves Eyesight for AMD Patients
The Lutein Antioxidant Supplement Trial (LAST) is the first study to report actual improvement in key visual functions among patients who already have "dry" age-related macular degeneration (AMD), the most common form of this disease. Prior to the publication of LAST in April (1), studies had linked greater consumption of lutein solely to a lower risk of AMD in healthy people.
This double-blind, year long study looked at the effects of 10 mg of lutein alone or combined with other antioxidants, on a number of visual measures in 90 patients with atrophic AMD. The amount of lutein supplemented in LAST is equivalent to eating about 3-4 ounces of spinach each day. While lutein is concentrated in dark green leafy vegetables such as spinach, collards and kale, the U.S. intake is estimated to be only 1-2 mg daily.
Compared to those getting a placebo, the lutein/antioxidant supplemented group experienced a 50% increase in macular pigment density, indicating an improved ability to filter out damaging UV light. Patients taking lutein or the combination showed improvement in quality of vision (measured by contrast sensitivity) and glare recovery, a test of macular function. They were also better able to distinguish near object details and shape (near visual acuity). According to lead author Dr. Stuart Richer, patients taking lutein were able to see the equivalent of one line more on standard eye tests at the end of the year, while those receiving placebo continued to decline-- a clinically meaningful finding for those trying to preserve their vision.
Vitamin C Fights Inflammation-Risk Factor for Heart Attack
A second study published in April is also a "first" of its kind--the first to report that vitamin C can lower C-reactive protein (CRP). CRP is a biomarker for inflammation that has garnered increasing attention as a new way to identify those at risk for heart attack (2). It's now understood that chronic inflammation can lead to heart attack and stroke by making cholesterol-laden artery plaque less stable and more likely to rupture (See newsletter issues for March & April, 2004).
CRP levels can rise up to a 100 fold for short periods during illness, because inflammation occurs as part of the body's normal defense against infection. However a persistent, moderately elevated level of CRP in the blood reflects chronic inflammation, and has been linked to increased risk of heart disease, diabetes, Alzheimer's disease, and even age-related macular degeneration.
In this double-blind study, researchers at University of California at Berkeley tested 160 healthy adults who either smoked or were exposed to second hand smoke. Those who had greatly elevated CRP likely due to existing illness were excluded from the study. The remaining participants were assigned to receive placebo, 500 mg of vitamin C, or a mixture of antioxidants (C, E and alpha-lipoic acid). Plasma levels of CRP in the volunteers were measured before and at the end of the two month trial.
Levels of CRP decreased a significant 24% among those supplementing with vitamin C compared to placebo takers. CRP levels also declined for those taking the antioxidant mixture, but not as much as vitamin C group. The researchers noted that much higher levels of vitamin E than were utilized in this study have previously been reported to lower CRP in diabetics and healthy individuals (3). These same investigators will be conducting a second trial in an attempt to replicate these findings. According to lead author Dr. Gladys Block, "If our finding of vitamin C's ability to lower CRP is confirmed, vitamin C could become an important public health intervention."
References

1. Richer S, et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry 75:216-30, 2004.
2. Block G, et al. Plasma C-reactive protein concentrations in active and passive smokers: influence of antioxidant supplementation. J Am Coll Nutr 23:141-47, 2004.
3. Devaraj S, et al. Alpha tocopherol supplementation decreases serum C-reactive protein and monocyte interleukin-6 levels in normal volunteers and type 2 diabetic patients. Free Rad Biol Med 29:790-92, 2000.
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AREDS Study Finds Supplements Help People with Age-related Macular Degeneration Keep Their Vision
The Age-Related Eye Disease Study (AREDS) is a major study sponsored by the National Eye Institute and conducted at 11 medical research centers around the country. This large-scale clinical trial was undertaken because age-related macular degeneration (AMD) is the leading cause of vision impairment among people 65 and older, and because the treatments for preventing its advanced forms are very limited. Started in 1992, the results of this study were reported in mid-October.
Over 3,600 older participants were followed for about six years during the trial. Patients were initially assigned to different categories based on the extent and type of their disease €“ from early to intermediate, and more advanced stages of AMD. They then received one of four supplements: a placebo, high-dose zinc with copper and antioxidants (vitamins C, E and beta-carotene), or a combination of zinc and copper plus the antioxidants.
Both the antioxidants and the mineral supplements each appeared to offer protection. But the benefits were greatest for those who received the antioxidant and zinc combination, and who were in the highest-risk categories (patients with intermediate and advanced forms). Supplementation with antioxidants and zinc significantly reduced the risk of progressing to more advanced AMD in these groups by 25%, and reduced their risk of vision loss by 27%.
The study was not able to show that supplements could prevent AMD, or restore vision already lost. But supplements can play a key role in helping people at risk for advanced AMD curb its advancement and preserve their vision. With the caveats that high dose beta-carotene should be avoided by smokers and ex-smokers, and that supplement takers need to be routinely monitored, the study confirmed the general safety and benefit of these high-potency supplements in maintaining vision.
While the researchers considered including lutein along with vitamins C and E, this carotenoid was not available when the study started. Instead they chose beta-carotene, which was being studied at the time in heart disease.
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CVD and AMD: The Connection Grows Stronger
Is CVD a Major Risk Factor for AMD?
That very question was addressed in an editorial (1) appearing in the September issue of the American Journal of Ophthalmology, and the evidence to date suggests that CVD is an important risk factor for AMD. Epidemiologic studies conducted over the past two decades indicate (with the possible exception of diabetes) that all of the traditional cardiovascular risk factors such as smoking, hypertension, elevated cholesterol levels, and higher body mass index (BMI) are associated with AMD risk.
So far, the link between smoking, hypertension and AMD is stronger than that between cholesterol, BMI and AMD, while newer studies suggest that less traditional markers of CVD such as inflammation and endothelial dysfunction are also involved in AMD pathogenesis. Overall, there is good evidence that AMD and CVD share similar risk factors and mechanisms that underlie disease development, according to the editorial.
Are AMD Patients at Greater Risk for CVD?
Conversely, emerging data indicates that the presence of AMD also signals an increased risk of CVD, independent of the effects of age and shared risk factors. “Taken in totality, these newer data suggest that patients with signs of AMD, particularly younger patients, may be at increased risk of CVD”, the editorial concludes.
Newly published findings from The Cardiovascular Health Study (2) provide further support that AMD is associated with underlying systemic vascular disease.
Study Design and Methods
The Cardiovascular Health Study is a population-based prospective cohort study of CVD in adults 65 years of age and older. To examine the associations of AMD with incident coronary heart disease (CHD), AMD was evaluated by fundus photographs in 1,786 white and Afro-American participants free of CHD or 2,228 participants free of stroke, aged 69-97 years.
Early AMD was defined as the presence of soft drusen alone, retinal pigment epithelium (RPE) depigmentation alone, or a combination of soft drusen with increased retinal pigment or RPE depigmentation in the absence of late AMD. Late AMD was defined as the presence of signs of exudative AMD or pure geographic atrophy.
Incident CHD and stroke were ascertained using standardized methods. Participants underwent a
standardized assessment of cardiovascular risk factors, including examiner-administered questionnaires,
electrocardiography, carotid ultrasonography, echocardiography, and blood chemistry profiles.
Results
Of the 1786 persons free of CHD, 303 developed incident CHD over 7 years. The 277 participants with early AMD had a higher cumulative incidence of CHD than participants without early AMD (25.8% vs. 18.9%,
P = 0.001).
The presence of early AMD was associated with a 57% increased risk of CHD, after adjusting for age, gender, race, systolic and diastolic blood pressure, hypertension status, fasting glucose, triglyceride, low-density lipoprotein cholesterol, cigarette smoking, pack years of smoking, and C-reactive protein. Late AMD (n= 25) was not associated with incident CHD. Among 2228 persons at risk, 198 developed incident stroke; neither early nor late AMD was associated with incident stroke.
Comments
The findings suggest that early AMD raises the risk of CHD, though not stroke. According to the authors, the association may be explained by broad underlying pathogenic mechanisms shared with both conditions. For example, atherosclerosis may represent a pathogenic process in AMD development, based on its effects upon the choroid capillaries and extracellular drusen (lipid) deposits. Inflammatory mechanisms seem to be another plausible biological basis that may involve both coronary and retinal circulation.

References
1. Wong TY. Age-related macular degeneration and cardiovascular disease in the era of anti-vascular endothelial growth factor therapies. Am J Ophthalmol 327-329, 2009.
2. 2. Sun C, et al. Age-related macular degeneration and risk of coronary heart disease and stroke: The Cardiovascular Health Study. July 8, 2009 Ophthalmology [Epub ahead of print]
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Nutrition Impacts AMD Risk & Health Costs
Preventive Steps May Lower AMD Costs
Preventing Age-Related Macular Degeneration (AMD) and delaying its progression would best preserve people's quality of life while containing health care system costs. The results from two new analyses suggest that adopting dietary habits or using supplements that slow progression from early to late stages, could ease the future burden of this disease.
Combined Dietary Factors Reduce AMD Risk
Foods provide many nutrients that may interact to modify the risk for AMD. Therefore, instead of looking at isolated nutrients, researchers from Tufts University developed a composite scoring system to examine the combined effect of dietary nutrients on AMD risk.
Study Design and Results
Data was analyzed for 4,003 Age-Related Eye Disease Study (AREDS) participants, involving 7,934 eyes. Levels of AMD-protective nutrients, including vitamins C and E, zinc, lutein, zeaxanthin, omega-3 fatty acids (DHA and EPA), as well as low-GI (Glycemic Index) foods, were assessed using participants' food intake reports. Each dietary factor was assigned a percentile score, and factor scores were added up to find each participant's compound score. Compound scores were related to participants' AMD risk, based on stereoscopic fundus photographs of the macula taken when they joined AREDS.
Participants whose diets included higher levels of these protective nutrients and of low-GI foods were at substantially lower risk for early and advanced AMD. Validation analyses showed the relationships to be robust.
Conclusion and Comments
The results suggest that the compound score summarizing the overall effect of diets rich in the AREDS trial nutrients (vitamin C, vitamin E, and zinc), the AREDS 2 trial nutrients (DHA, EPA, lutein and zeaxanthin), and low-GI foods are independently associated with lower risk for prevalent drusen and advanced AMD. Beta-carotene did not affect risk levels. The findings are in accord with earlier research linking low GI-diets with reduced risk of AMD and cataract, and further research is warranted.
New Therapies May Mitigate Rise in AMD
The Vision Health Cost-Effectiveness Study Group - encompassing investigators from the CDC, the National Center for Chronic Disease and Prevention and other institutions - report that while the prevalence of AMD will increase substantially by 2050, the use of new therapies can mitigate its effects.
Study Design and Results
The study simulated cases of early AMD, choroidal neovascularization (CNV), geographic atrophy (GA), and AMD-attributable visual impairment and blindness with five possible scenarios:
(1) No treatment; (2) Focal laser and photodynamic therapy (PDT) for CNV; (3) Vitamin prophylaxis at early-AMD incidence with focal laser/PDT for CNV; (4) No vitamin prophylaxis followed by focal laser treatment for extra and juxtafoveal CNV and anti-vascular endothelial growth factor treatment; (5) Vitamin prophylaxis at early-AMD incidence followed by CNV treatment, as in scenario (4).
Cases of early AMD nearly doubled, increasing from 9.1 million in 2010 to 17.8 million in 2050 across all scenarios. In non-vitamin-receiving scenarios, cases of CNV and GA increased from 1.7 million in 2010 to 3.8 million in 2050 (25% lower in vitamin-receiving scenarios). Cases of visual impairment and blindness increased from 620,000 in 2010 to 1.6 million in 2050 when given no treatment and were 2%, 22%, 17%, and 35% lower in scenarios 2, 3, 4, and 5, respectively (see Figure 2E).

Figure 2E
Number of Americans with pre-vision-threatening age-related macular degeneration (AMD) and blindness, with 5 alternative treatment scenarios from 2010 to 2050. Scenario 1 indicates no treatment (baseline); scenario 2, focal laser or photodynamic therapy (PDT) for CNV; scenario 3, universal vitamin prophylaxis at early AMD incidence with focal laser or PDT for CNV treatment; scenario 4, no vitamin prophylaxis followed by focal laser treatment for extrafoveal and juxtafoveal CNV and anti-vascular endothelial growth factor (anti-VEGF) treatments for subfoveal CNV for 2 years followed by PDT; scenario 5, universal vitamin prophylaxis followed by focal laser and anti-VEGF treatments for subfoveal CNV for 2 years followed by PDT.
Conclusion and Comments
The authors found that use of vitamins and existing therapies could reduce AMD by as much as 35%, translating to 565,000 fewer cases of visual impairment and blindness in 2050.
A 23% reduction in cases of visual impairment and blindness could be achieved using only vitamin prophylaxis in conjunction with focal laser and PDT therapies for patients who develop CNV - which amounts to a reduction of 375,000 cases of visual impairment and blindness five decades from now.
According to the authors, additional efforts to expand the use of AREDS level dietary supplements Is a cost-effective method of delaying AMD progression and cost-effective use of health care resources. However, research indicates it is not widely used among patients with early-stage disease and the correct dosage is seldom used. For example, though 68% of patients with early AMD who visited a retinal specialty practice in Edmonton, Canada, took some form of AREDS-recommended antioxidant supplement, no patients were taking the correct dosage of all 4 recommended vitamins. Public prevention efforts should focus on expanding the use of antioxidant vitamins in people with early AMD, and ensuring that these patients use the correct dosage.
References
1. Chiu, C-J, et al. Dietary compound score and risk of age-related macular degeneration in the AREDS. Ophthalmology 116:939-46, 2009.
2. Rein DB et al. Forecasting age-related macular degeneration through the year 2050: the potential impact of new treatments. Arch Ophthalmol 127:533-40, 2009.
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EUREYE Study: Blue Light Exposure & Low Antioxidants Increase AMD Risk
Retina is Vulnerable to Effects of Blue Light
While wavelengths in the UV radiation range are largely absorbed by the cornea and lens, the retina is exposed to visible light, including blue light. Animal and laboratory studies have shown that blue light damages the retinal pigment epithelium and choriocapillaris through generation of reactive oxygen species and may be a factor in the pathogenesis of age related macular degeneration (AMD).
Protection against the harmful effects of blue light is provided by the retinal antioxidant defense system, which includes antioxidant enzymes supported by vitamins C and E, lutein and zeaxanthin, and zinc. Lutein and zeaxanthin are highly concentrated in the macula, where they act as scavengers of reactive oxygen species and filter blue light.
Only a few studies have investigated associations of sunlight exposure with AMD in human populations, and the results have been inconsistent. Up to now, however, studies have paid little attention to possible interactions between antioxidant levels and light exposure, though the adverse effects of sunlight may be attenuated by the protective effects of antioxidants.
Now, the European Eye (EUREYE) Study has examined the association of sunlight exposure and antioxidant levels with AMD. The study was designed to maximize a diversity of sunlight exposure and antioxidant levels by selecting study centers throughout Europe.
Study Design and Methods
Four thousand seven hundred fifty-three participants 65 years or older in the EUREYE Study underwent fundus photography, were interviewed for adult lifetime sunlight exposure, and gave blood for antioxidant analysis. Blue light exposure was estimated by combining meteorological and questionnaire data.
Results
Data on sunlight exposure and antioxidants were available in 101 individuals with neovascular AMD, 2182 with early AMD, and 2117 controls. No link was found between blue light exposure and neovascular or early AMD. However significant associations were found between blue light exposure and wet AMD in participants in the lowest quartile of individual antioxidant levels - vitamin C, zeaxanthin, vitamin E, and dietary zinc - with an odds ratio (OR) of about 1.4, or a 40% higher risk, for 1 standard deviation unit increase in blue light exposure.
Low blood levels of certain antioxidant combinations showed higher ORs of blue light exposure compared with single antioxidants. Higher odds ratios for blue light were observed with low levels of vitamin C, zeaxanthin and vitamin E, especially (odds ratio, 3.7; 95% CI 1.6-8.9), which were also associated with early AMD stages.
Comments
These results suggest that higher UV exposure may contribute to AMD in those with sub-optimal levels of select antioxidants. The authors conclude that … " people in the general population should use ocular protection and follow dietary recommendations for the key antioxidant nutrients."


Reference
Fletcher AE, et al. Sunlight exposure, antioxidants, and age-related macular degeneration. Archives Ophthalmology 126:1396-1403, 2008.
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Zinc & Lutein Protect Against AMD in Blue Mountains Eye Study
Oxidative Stress and AMD
Oxidative stress is one of the pathogenic mechanisms in AMD. The retina is thought to be highly susceptible to oxidative stress given its high oxygen consumption, high concentration of polyunsaturated fatty acids and photosensitizers, and exposure to light. Phagocytosis by the retinal pigment epithelium also leads to oxidative stress.
AREDS provided evidence that high dose zinc and antioxidant vitamin supplementation can slow AMD progression in relatively advanced early AMD cases (1). Additionally, the Rotterdam Study reported that above-median dietary intake of all 4 of the nutrients studied in the AREDS trial was associated with a statistically significant 35% reduction in incident AMD risk (2).
The Blue Mountains Eye Study is a population-based cohort study of vision, common eye diseases, and other health outcomes in an urban Australian population. A new analysis from this study confirmed the AREDS result that zinc is protective against AMD, and found that higher intake of lutein and zeaxanthin reduced the risk of long-term incident AMD (3).
Study Design and Methods
Of the 3,654 participants in the study at baseline, 2,454 were re-examined after 5 years, 10 years, or both. The Wisconsin Grading System was used to evaluate stereoscopic retinal photographs. Risk ratios and 95% confidence intervals were calculated after adjusting for age, gender, smoking and other factors. Energy-adjusted intakes of vitamins A, C, and E; alpha-carotene; beta-carotene; beta-cryptoxanthin; lutein and zeaxanthin; lycopene; iron and zinc were assessed via food frequency questionnaires.
Results
Those in the highest decile of total zinc intake (> or = 15.8 mg/day) were found to be significantly less likely to develop early or any AMD compared with the remaining population (RR 0.54; CI 0.30-0.97 and RR 0.56; CI 0.32-0.97 respectively).
Similarly, for dietary lutein and zeaxanthin intake, those in the top tertile (> or = 972 mcg/day) had a 65% reduced risk of incident neovascular AMD (RR 0.35; CI 0.13-0.92). For those with above-median intakes, 34% reduction in risk of incident indistinct soft or reticular drusen was noted (RR 0.66; CI 0.48-0.92).
In contrast, the highest vs. the lowest tertile of total beta-carotene intake from diet predicted incident neovascular AMD in both smokers and non-smokers (RR 2.68; CI 1.03-6.96).
Comments
These results suggest a possible threshold effect of total zinc intake on risk of early or any AMD. A protective effect from high intakes of zinc is biologically plausible. Zinc is concentrated in the retina and is a cofactor for many enzymes, including the antioxidant enzymes present in human retinal pigment epithelium. Zinc is also a cofactor for vitamin A metabolism and is essential for the synthesis of retinol binding protein. In AREDS, the protective effect shown with combined zinc and antioxidants seemed driven largely by zinc. The recently reported findings from the Rotterdam Study also seemed to be driven by zinc, and perhaps vitamin E.
These results also suggest a possible threshold protective effect of dietary lutein and zeaxanthin intake on the risk of neovascular AMD or indistinct soft drusen. Lutein and zeaxanthin are the only carotenoids that concentrate in the macula, where they are the main components of macular pigment.
The finding of a link between higher intake of beta-carotene and increased risk of AMD are inconsistent with other reports. In addition to the previously mentioned findings of AREDS and the Rotterdam Study, the Eye Disease Case-Control Study Group also reported a reduced risk for AMD with higher dietary intakes of carotenoids, particularly beta-carotene, lutein and zeaxanthin.
References
1. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 119:1417-36, 2001.
2. van Leeuwen R, et al. Dietary intake of antioxidants and risk of age-related macular degeneration. JAMA 294:3101-7, 2005.
3. Tan JSL, et al. Dietary antioxidants and the long-term incidence of age-related macular degeneration: The Blue Mountains Eye Study. Ophthalmol 115:334-42, 2008.
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New Clues about Zinc's Protective Actions in AMD
Zinc and the AMD Disease Process
Zinc is concentrated in the choriocapillaries, retinal pigment epithelium (RPE) and retina. Long term supplementation with zinc, either alone or combined with antioxidants, was shown to slow AMD progression in the AREDS trial. Not much is known, however, about the effects elicited by this mineral.
Recent results from an ancillary study to AREDS suggest one way that zinc may help protect against AMD. Zinc appears to improve the transport and use of cysteine - a sulfur containing amino acid and rate limiting factor in the manufacture of glutathione, the major antioxidant within cells.
Glutathione helps inactivate the reactive oxygen species hydrogen peroxide by reducing it to water. In this process, the reduced form of glutathione (GSH) is oxidized to produce GSSG. Like glutathione, cysteine also contains a thiol or sulphhydryl group. Thiol groups can undergo oxidation/reduction (redox) reactions; when cysteine (Cys) is oxidized it forms cystine (CySS). Due to its ability to undergo redox reactions, cysteine has antioxidant properties.
Studies have shown that plasma levels of cysteine and glutathione become more oxidized with age, age-related diseases, and oxidative stress. Plasma levels of the reduced and oxidized forms of these metabolites are thought to be a reliable marker for oxidative stress and antioxidant defenses.
Methods
Plasma samples were obtained from AREDS participants at the Emory and Wilmer Eye Centers sites. At both study sites, blood specimens were obtained at two time points, an average of 1.7 and 6.7 years after enrollment. For this study, the four AREDS treatment groups were combined into two groups: zinc supplementation and no zinc. Plasma was analyzed for the reduced and oxidized forms of glutathione and cysteine (GSH / GSSG and cysteine / cystine), and their redox status.
Results
To control for factors that may have an effect on the plasma levels of these metabolites, demographic characteristics were compared. There were no significant differences in these characteristics between subjects receiving zinc or no zinc at either blood draw.
At the first blood draw (20 months), most subjects had already entered the study and were receiving zinc or placebo. No differences were seen in any of the thiols, disulfides or redox states between the two groups.
At the second blood draw (80 months), a significant decrease in plasma levels of oxidized cysteine (cystine, CySS) was found in the group receiving zinc compared to the non-zinc group (Fig. 1 below).

FIGURE 1. Long-term zinc supplementation resulted in lower plasma cystine (CySS) in the AREDS patients. Plasma CySS was measured in AMD patients before and after five years of zinc supplementation. Subjects who had received zinc had significantly lower CySS than their baseline values (P= .05). Additionally, at draw 2, plasma CySS was significantly higher in the no zinc group compared to the zinc group (P = .02).
Discussion
How might the lower plasma levels of oxidized cysteine (CySS) affect retinal cells? Whether the magnitude of change found in this study affects RPE function remains to be determined. However, earlier studies found that exposing cultured human RPE cells to a more oxidized "cystine environment" makes them more susceptible to apoptosis or programmed death.
Reference
Moriarty-Craige BS, et al. Effects of long-term zinc supplementation on plasma thiol metabolites and redox status in patients with age-related macular degeneration. Am J Ophthalmol 143:206-11, 2007.
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More Support for Lutein & Zeaxanthin in AMD Risk Reduction
Lutein/Zeaxanthin and AMD Risk
Lutein and zeaxanthin are the only carotenoids that concentrate in the macula. There is evidence of three mechanisms by which lutein and zeaxanthin may afford protection against AMD: by absorbing blue light, by quenching free radicals and by increasing membrane stability.
Many previously published studies which have examined the relationship between AMD and these carotenoids have reported an inverse association between the disease and intake of lutein plus zeaxanthin. These carotenoids are commonly obtained from leafy green vegetables, corn, egg yolks, broccoli, peas, squash - as well as from supplements.
The authors of the Carotenoids in Age-Related Eye Disease Study (CAREDS) now report that a stable intake of these carotenoids over time could reduce the risk of AMD by about 43% in healthy women under 75.
Design and Methods
CAREDS is an ancillary study of the Women's Health Initiative (WHI), a prospective cohort study. CAREDS was designed, in part, to evaluate the relationship between lutein/zeaxanthin and the prevalence of intermediate AMD. Over 1780 women aged 50-79 who had high or low intake of lutein plus zeaxanthin at WHI enrollment were recruited into CAREDS 4-7 years later, when the presence of AMD was determined by fundus photographs.
To maximize extremes in intake of these carotenoids in the study sample, women with intakes of lutein plus zeaxanthin above the 78th (high) and below the 28th (low) percentiles at baseline in the WHI were recruited. Dietary assessments were performed by means of food frequency questionnaires administered at the study's start and over the previous 15 years. Logistic regression analyses examined the prevalence of AMD, after accounting for potential covariates.
Results
While an association between dietary intake of these carotenoids and AMD was not observed in the overall study population, secondary analyses disclosed a statistically significant protective effect in women younger than 75 with stable intakes of lutein and zeaxanthin.
Higher intakes of lutein/zeaxanthin (2,868 mcg or more daily) compared to lower consumption (792 mcg daily) in women with stable intakes resulted in a substantial 43% lower risk of intermediate AMD (odds ratios [0.57; 95% confidence interval, 0.34-0.95]). The younger women (< 75 years) did not have a history of chronic diseases such as cardiovascular disease and diabetes that are often associated with diet changes and instable intakes of lutein/zeaxanthin rich foods.
Similar protective associations were observed for large drusen. While not statistically significant, associations in this sub-sample were in the protective direction for the more advanced lesions of pigmentary abnormalities, as well as for the exploratory outcome, advanced AMD.
The researchers observed the strongest inverse associations between intermediate AMD and high intake of vegetables in general, as well as of green vegetables. Blood levels of the carotenoids were not associated with risk of AMD.
Comments
According to lead author Dr. Suzen Moeller of the University of Wisconsin, the findings are consistent with a broad body of evidence from observational and experimental studies suggesting that these carotenoids may protect against AMD. There was evidence that diet instability may have biased the associations and, together with the possibility of selective mortality bias, may explain our inability to detect the hypothesized association in the full study population, wrote Dr Moeller.
Reference
Moeller SM et al. Age-Related Macular Degeneration and Lutein and Zeaxanthin in the Carotenoids in Age-Related Eye Disease Study (CAREDS). Archives of Ophthalmology 124:1151-1162, 2006.
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Antioxidants Substantially Lower the Risk of Developing AMD
The Rotterdam Study Findings
The Rotterdam Study is an ongoing population-based, prospective cohort study of the factors influencing cardiovascular, neurologic and ophthalmologic diseases. Unlike AREDS, which focused on antioxidant supplementation for people who already had signs of AMD, the current investigation examined whether regular dietary intake of antioxidants could impact the risk of developing AMD in an older Dutch population free of clinical signs of the disease at baseline.
The results, reported in the December 28, 2005 issue of JAMA, strongly suggest that regular intake of antioxidants can markedly lower the risk of developing AMD, in this case by approximately one third (1).
Study Design
Dietary intake was assessed at baseline for 4,170 people who were at risk of AMD and who completed the follow-up. This at risk population was 55 or older and had no AMD in either eye. Participants had no drusen or pigment irregularities, hard drusen only, or soft drusen without pigment changes.
Incident AMD until final follow-up in 2004 was determined by grading fundus color transparencies. Potential for bias was minimized by grading the photographs in a blinded manner. The main outcome measure was incident AMD, defined as soft distinct drusen with pigment changes, indistinct or reticular drusen, geographic atrophy, or choroidal neo-vascularization.
Results
After a mean follow-up of 8 years (0.3-13.9 years), AMD occurred in 560 participants. After adjusting for known confounders such as atherosclerosis and smoking, dietary intake of vitamin E and zinc were found to be inversely associated with incident AMD. A dose-response relationship between both vitamin E and zinc intake and a reduced risk of AMD was noted.
The researchers also analyzed the combined intake of all 4 antioxidants studied in the AREDS trial: vitamins E and C, zinc and beta-carotene. An intake above the median for all 4 nutrients reduced AMD risk by 35%.
While no relationship between lutein consumption and risk of AMD risk was seen, the difference in intake levels among the lowest and highest quartiles of dietary intake (1.4 vs. 3.6 mg) was small.
Commentary
These findings may have important public health implications, for they strongly suggest that long-term consumption of antioxidants could prevent or delay the development of early AMD. Recent data, in fact, suggests that oxidative modification of retinal proteins play a critical role in the formation of drusen, implying that antioxidants may have their strongest effect at the initiation of AMD (2).
Risk reduction was observed for dietary intake above the RDA for all 4 antioxidant nutrients compared to each one alone. This indicates that the combination acted synergistically in exerting a protective effect, and underscores the need to maintain a regular, above-RDA intake of all of 4 nutrients over time.
The majority of people in this Dutch cohort appeared to consume a healthy diet. Additionally, the independent relationship between antioxidant supplements and AMD could not be examined in this study since the number of antioxidant supplement users was relatively small, and the necessary data on dose and duration of use was lacking. However supplementation may be helpful in US populations where subgroups fail to consistently consume adequate amounts of antioxidant nutrients.
References
1. van Leeuwen R, et al. Dietary intake of antioxidants and risk of age-related macular degeneration. JAMA 2034:3101-7, 2005.
2. Crabb JW, et al. Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci USA. 99:14682-7, Epub Oct 21st, 2002.
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The AREDS Clinical Trial: Antioxidant & Zinc Supplementation for AMD
Findings from this multicenter, NEI and NIH sponsored study were reported in the October 2001 issue of Archives of Ophthalmology. The study followed 3,640 participants, aged 55-80, for an average of 6.3 years. Patients were initially enrolled in four AMD categories based on the size and extent of retinal drusen and level of visual acuity decline (Table 1), and were randomly assigned to one of four treatment arms:
• Antioxidants plus zinc (500 mg vitamin C, 400 IU vitamin E, 15 mg beta-carotene, 80 mg zinc)
• Antioxidants alone
• Zinc alone
• Placebo
While the investigators acknowledged the importance of lutein and zeaxanthin for macular health, these carotenoids were not available for use in supplements when the study began. Instead, the investigators chose beta-carotene, which was then being studied for heart disease and cancer.
Table 1 AMD Categories In AREDS Category 1: few small or no drusen Category 2: several small drusen or a few medium-sized drusen in one or both eyes, or pigment abnormalities Category 3: many medium-sized drusen or one or more large drusen in one or both eyes Category 4: advanced AMD in one eye, or vision loss due to AMD in one eye only
Although the antioxidant and zinc supplements each appeared to offer some protection, the benefits of supplementation were greatest for those patients who received the antioxidant and zinc combination, and who were in the highest-risk category groups.
Supplementation with combined antioxidants and zinc significantly reduced the risk of progression to advanced AMD in these groups by 25%. A significant risk reduction in vision loss was also seen in the higher-risk groups taking both zinc and antioxidants, with an odds reduction of 27% (Table 2).
Very few patients with less severe AMD went on to develop advanced cases. Therefore the study was unable to detect whether the zinc and antioxidant combination might delay or prevent progression in subjects at an earlier stage. However, when the researchers included the less severe category (category 2) with the more advanced categories (3 and 4), the combined supplements showed an odds reduction in the visual acuity outcome that approached statistical significance (Table 2).
Most of the participants experienced few side effects. People in the zinc groups had more frequent urinary-tract related problems than placebo-takers (7.5% vs. 5%), although it's not clear whether zinc played a role in their occurrence. Another caveat is that high dose beta-carotene is contra-indicated for smokers and recent ex-smokers. The ARED Study confirmed the general safety and benefit of these high-potency nutrients in preserving vision among well-nourished, older people with intermediate to more advanced AMD.
Table 2 Effect of Treatment on Risk of Visual Acuity Loss Score Greater or Equal to 15 Letters from baseline   Participants in AMD Categories 2, 3 & 4 (n=3597) Participants in AMD Categories 3 and 4 (n=2549) Treatment OR (99% CL) &nbspP&nbspvalue OR (99% CL) &nbspP&nbspvalue Antioxidants vs. placebo 0.88     (0.67-1.15) .22 0.85     (0.63-1.14) .16 zinc vs. placebo 0.87 (0.66-1.13) .17 0.83 (0.62-1.11) .10 Antioxidant + zinc - Combination vs. Placebo 0.79 (0.60-1.04) .03 0.73 (0.54-0.99) .008* *Significant at p≤.01
Click here to read the full text of the AREDS clinical trial on the Archives of Opthalmology website.
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