Nutritional, Alternative, and Complementary Therapies for Age-related Macular Degeneration

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in people over the age of 65 particularly in those who are smokers, obese, White race, genetically predisposed and environmentally exposed. The root cause is thought to be photochemical damage causing oxidative stress to the macula coupled with low grade inflammation over many years which also contributes to the progression of the disease. The hallmark studies Age-Related Eye Disease Study (AREDS) and AREDS2 found a formulation consisting of 500 mg vitamin C, 400 IU vitamin E, 25 mg zinc, 2 mg copper, 10 mg lutein and 2 mg zeaxanthin effective for slowing the progression AMD. Subsequent studies suggest diet therapy, higher dosages of zeaxanthin and supplementing with vitamin D, vitamin B₁₂, and omega-3 fatty acids may further reduce the progression of the disease.

Introduction

Age-related macular degeneration (AMD) is an eye condition that starts at the age of 50 in those who are genetically or environmentally predisposed and is the leading cause of blindness, particularly central vision, in people over the age of 65.¹ The risk factors for developing AMD are age, smoking, White race, obesity and genetics; genome studies have established many genetic variants associated with a higher risk of AMD.^2,3 Population statistics (2010) indicate that 2.5% of White adults over the age of 50 are affected by AMD and this number is expected to double by 2050 with the Hispanic population seeing the highest increases.4

Age related macular degeneration pathogenesis is not completely understood but there are many complex theories. The root cause is thought to be photochemical damage to the macula by oxidative stress and inflammation causing accumulation of free radicals.^5,6 Chronic low grade inflammation over several years is thought to damage the eyes leading to a disease state.⁷ Once AMD is diagnosed it’s progression is classified as early, intermediate or late based on the condition of the eye.⁸ Early AMD starts with thickening of the eye membranes due to lipid and protein accumulation, known as drusen, which interferes with fluid crossing the membranes causing physiological stress and atrophy. Physiological stress and low-grade Inflammation play a role in the progression of the disease to the intermediate stage which is characterized by numerous drusen or at least one large drusen. Of the population with early or intermediate AMD 15% to 20% will progress to late AMD.³ As the disease progresses to the late phase there is loss of photoreceptors in the macula, known as geographic atrophy or “dry” AMD followed by abnormalities in the blood vessels that leak fluid causing further damage, referred to as choroidal neovascularization or “wet” AMD. Dry AMD is the most common form of AMD occurring in 9 of 10 cases, but regardless of the type of AMD the result is declining central and night vision leading to blindness. As there are no medical interventions for repairing the damage or curing the disease the focus has been on halting the onset and progressive damage with pharmaceutical, nutrition and alternative therapies.

Clinical Trials

The hallmark study Age-Related Eye Disease Study (AREDS) and the subsequent study, AREDS2, determined that a combination of antioxidant vitamins including vitamin C (500 mg), vitamin E (400 IU), minerals including zinc (25 mg), and copper (2 mg) and the antioxidant carotenoids lutein (10 mg), and zeaxanthin (2 mg) may be effective in slowing the progression of AMD.^9,10 Copper was included due to the metabolic competition with zinc which may cause copper deficiencies with zinc supplementation.

Chew et al¹¹ (2013) reported on the first AREDS multi-center (11 sites), randomized controlled trial (RCT) conducted from 1992 to 1998 with 4757 participants between the ages of 55 and 80 years. Participants were stratified into four categories based on severity of AMD; category 1 consisted of those without the disease and category 4 consisted of those with late stage disease. Participants were then assigned to four treatment groups: group 1 placebo, group 2 zinc (80 mg) plus copper (2 mg), group 3 antioxidants (500 mg vitamin C, 400 IU vitamin E, 15 mg beta-carotene), or group 4 antioxidants plus zinc. Every participant was provided with a Centrum^® multivitamin and mineral supplement (Table 1). The outcomes measured were advancement of the disease and changes in visual acuity. The participants who consumed antioxidants with zinc showed reduced odds of advancing to late stage AMD. Regardless of the total supplementation of zinc, vitamin C and vitamin E far exceeding the recommended daily allowance (RDA) there were no adverse events reported. The minimal effective dosages for delaying the progression of AMD and the maximum tolerated dose for the individual nutrients is still not known.¹²

Table 1.

Total Intake of AREDS Key Nutrients Combined with Centrum

Key Nutrient	AREDS formulation	Centruma	Total	Recommended Daily Allowance for Adults¥
				M	F
Zinc	80 mg	-	80 mg	11 mg	8 mg
Copper	2 mg	1 mg	3 mg	-	-
Vitamin C	500 mg	90 mg	590 mg	90 mg	75 mg
Vitamin E	400 IU	25 IU	425 IU	22.4 IU	22.4 IU
Beta-carotene	15 mg	0	15 mg	-	-

^aCurrent Centrum formulation

¥ Recommended daily allowance for adults taken from the Office of Dietary Supplements retrieved from https://ods.od.nih.gov/

The secondary epidemiological analysis of the AREDS, including 3549 of the 4757 participants, showed a statistically significant benefit to consuming the AREDS formula with a risk reduction for the progression of AMD by 25% over 5 years (2000 to 2005); vision loss continued to occur but at a slower rate with a reduced risk of developing neovascularization.^9,11 There was a gap in the consumption of the AREDS formulation as it was not available for purchase for the first 2 years of the follow up period; once available 70% of the study participants consumed the formulation for the remaining 3 years.^9,11

The AREDS had a rigorous study design utilizing both an RCT and epidemiological analysis with a large cohort, minimal loss to follow up (2% to 4%) and no demographic differences between the treatment groups. The compliance rate with taking the study tablets was 75% determined by tablet counts. The limitations of this study are that the participants were better educated, had less health concerns and were considered better nourished. It is unknown what the outcome would have been if the formulation had been available for the entire 5 years of the follow up period. The length of follow up of 5 years was not adequate to determine the progression beyond early AMD as advancement to the late stage may take 10 or more years.

The AREDS2 was also a double blind RCT multi-center (82 sites) study with an additional 2x2 factorial study design that included 4203 participants between the ages of 50 and 85 years (mean age 73.1) with high risk of developing late AMD.⁹ Recruitment occurred between the years 2006 and 2008 with each participant followed for 5 years. The primary intervention consisted of participants randomized into one of four treatment groups all receiving the first AREDS formula: group 1 received an additional 10 mg lutein and 2 mg zeaxanthin, group 2 an additional 350 mg docosahexaenoic acid (DHA) and 650 mg eicosapentaenoic acid (EPA) and group 3 an additional lutein, zeaxanthin, DHA and EPA and group 4 who consumed the AREDS first formulation only (see Table 2).

Table 2.

AREDS2 Formulation Treatment Groups

Primary Intervention
Group 1	AREDSa + 10 mg Lutein + 2 mg zeaxanthin
Group 2	AREDSa + 350 mg DHA + 650 mg EPA
Group 3	AREDS* + 10 mg Lutein + 2 mg zeaxanthin +350 mg DHA + 650 mg EPA
Group 4 (Placebo)	AREDSa only
Secondary Intervention
Group 1	AREDSa zinc reduced to 25 mg
Group 2	AREDSa without beta-carotene

^azinc 80 mg, copper 2 mg, antioxidants (500 mg vitamin C, 400 IU vitamin E, 15 mg beta-carotene)

Randomized secondary groups were assigned a lower dose of zinc and no beta-carotene. Zinc was reduced from 80 mg to 25 mg due to suspected maximal absorption of 25 mg and increased risk of gastrointestinal symptoms with zinc supplementation above 25 mg.¹¹ Another group received a formula without beta-carotene as supplementation among smokers had been linked to lung cancer; beta-carotene is pro-vitamin A whereas lutein and zeaxanthin are not.¹³ The AREDS2 study did not include a Centrum^® vitamin and mineral supplement.

Demographic characteristics were similar between the groups with 13% of participants lost to follow up over the 5 years of the study. Compliance was high determined by each participant taking at least 75% of the formulation and increased serum levels of lutein, zeaxanthin, DHA and EPA. In the primary analysis there were no significant differences in vision acuity or progression to late AMD with the addition of lutein, zeaxanthin, DHA or EPA to the AREDS formulation when comparing placebo to treatment groups.¹¹ There was a slightly slower, non-significant, progression to late AMD.¹⁴ In the secondary analysis there was no significant effect on vison acuity or progression to late AMD by reducing zinc to 25 mg and eliminating beta-carotene in the formulation. There were no clinical or significant adverse effects reported from consuming the various formulations. There was no additional benefit shown in those consuming omega-3 fatty acids which may be related to inadequate dosage or duration as follow up was limited to 5 years and the outcome was limited to looking at the progression to late AMD. The outcomes may have been affected by confounding factors such as nutrition status.

Although the AREDS2 study did not show a risk reduction associated with the consumption of omega-3 fatty acid supplementation and developing AMD a subsequent nested cohort of the AREDS data set showed a 30% reduction in risk for disease progression over 12 years of follow up in those with the highest consumption of dietary omega-3 fatty acids.¹⁵ The limitations were the observational study design and potential confounders such as a healthier lifestyle in those with the largest intake of dietary omega-3 fatty acids. Souided et al in their study, utilizing a food frequency questionnaire, showed similar results with fish consumption exhibiting a protective effect on the development of AMD. They also showed that consuming a diet high in animal fats had a negative effect on the progression of AMD. They suggest that dietary omega-3 fatty acids may counterbalance the predisposition of developing AMD with certain genotypes. Although, there are a number of confounders as those who consume a diet high in omega-3 fatty acids may also consume more antioxidants and engage in physical activity.^16,17

A Cochrane systematic review found no beneficial effects of omega 3 fatty acid supplementation for preventing the progression of AMD even though individual studies have shown a risk reduction.¹⁸ As omega-3 fatty acids are anti-inflammatory, supplementation is suspected to be a viable intervention for AMD and therefore higher dosages than provided in the AREDS and other studies may be needed to see a beneficial effect.¹⁸ A study by Souied et al showed that a daily intake of 840 mg docosahexaenoic acid (DHA) and 270 mg eicosapentaenoic acid (EPA) over 3 years reduce the risk of advancing to wet AMD by 68%.¹⁶ Most omega-3 fatty acid formulations contain about 50% more EPA than DHA which may explain the inconsistencies in the research findings. The consistent message in the research is that omega-3 fatty acids should provide protection for AMD, but large clinical trials are needed to test the hypothesis and determine the best dose of omega-3 fatty acid supplementation. Several studies in progress are looking at omega-3 supplementation ranging from 1 to 4 grams daily and the effect on AMD.¹⁹

A subgroup analysis on the participant data with dietary consumption of lutein and zeaxanthin showed a protective effect for the progression to late AMD. As beta-carotene competes for absorption with lutein and zeaxanthin it is hypothesized that the beneficial effect of lutein and zeaxanthin may be limited due to beta-carotene in the AREDS formulation.

A secondary analyses was conducted to determine the effects of the AREDS formulation with lutein and zeaxanthins with and without beta-carotene on late AMD.²⁰ Participants were followed until 2012 (additional 4.9 years) to analyze a head to head comparison of the two formulations showing better outcomes with the lutein and zeaxanthin without beta-carotene. As with the other AREDS the strengths of the study included adequate sample size for statistical power, good adherence to the treatments and low attrition rates but generalization is cautioned as the AREDS subjects tended to be of a higher socio-economic status with suspected better nutrition. The AREDS2 appears to be the most recent research conducted utilizing all the key nutrients to determine the effects on AMD.

A Cochrane Review published in 2017 included studies, with both AREDS, published up to August 2102 utilizing search terms related to antioxidant, vitamin and mineral supplementation and AMD showed inconclusive results of the key nutrients reducing the progression of the disease.²¹ The results did show adverse events, with some studies, associated with the safety of the supplements at high dosages but the review did not describe the age range of those presenting with adverse effects.²¹ Considering AMD is usually limited to elderly people it can be surmised that they are likely to have deficiencies due to age related reduced nutrient intake and absorption, changes in metabolism and drug nutrient interactions especially in those with a family history or genetic predisposition to AMD.²² Schultz et al²³ argues that study outcomes, particularly secondary analysis designs, can be influenced by confounding factors such as diet and activity. He also states that the results of AREDS2 is compelling and should be utilized for individuals that may benefit from the supplementation regardless of the safety concerns.²³

A double blind RCT was conducted in China with 112 subjects over 50 years of age randomized to one of three groups utilizing higher dosages of lutein and zeaxanthin: group 1 was assigned 10 grams lutein, group 2 assigned 20 grams lutein and group 3 assigned 10 mg of both lutein and zeaxanthin.^24,25 Over 2 years there was a statistically significant increase in serum levels of both flavonoids and improved vision among participants with early AMD due to increasing the zeaxanthin and lutein to 10 mg. There were no reported adverse effects related to the supplementation. The limitation was the study length of 2 years and therefore the effect of 10 mg of both lutein and zeaxanthin on the advancement from early to late AMD could not be determined.

There currently are no recommended intakes or safe upper limits assigned for lutein or zeaxanthins. The data on population intakes of lutein and zeaxanthin is limited but varies from 3.5 mg to 5.33 mg in Europeans and 1 mg to 2 mg in Americans.²⁶ A study conducted in Spain with 52 participants with a mean age of 78.9 years showed those diagnosed with wet AMD had inadequate intakes of all the nutrients (lutein, zeaxanthin, vitamins A, E, C and zinc) associated with AMD.²⁷ Considering that lutein and zeaxanthins are fat soluble nutrients the long-term effects of high dosages by supplementation should be investigated.

Observational Studies

Vitamin D

A systematic review conducted in 2015 showed circulating serum vitamin D (25OH) levels less than 50 nmol/l was associated with late AMD.²⁸ The carotenoids in Age-Related Disease Study (CAREDS) with 913 women was conducted to study lutein and zeaxanthin, that included vitamin D, to determine the effects of these nutrients on aging.²⁹ It was hypothesized that vitamin D exhibits anti-inflammatory properties in the eye by inhibiting the immune response and cytokine production. Participants with low serum vitamin D status (<30 mmol/l) were at higher risk for developing AMD particularly with certain genotypes, specifically CFI and CFH. The study limitations were the small sample size for an observational study and the possibility of multiple confounders. Another SR published in 2016 showed that there were no associations between low vitamin D serum levels and progression of AMD.³⁰ Another study in 2017 showed that higher intakes of dietary sources of vitamin D (600 IU vitamin D daily), determined by food frequency questionnaires, was associated with slower AMD progression and 40% lower risk of progressing to late AMD.³¹

B₁₂

A systematic review with meta-analysis showed that AMD was associated with elevated plasma homocysteine levels and reduced serum vitamin B₁₂. The mechanism is unclear but it is known that homocysteine levels can increase disease progression due to exacerbating oxidative stress and epithelium damage.²⁴ The participants with wet AMD showed significantly lower levels of serum B₁₂, but not serum folate, compared to the control group. Considering AMD shares risk factors associated with cardiovascular disease, monitoring serum vitamin B₁₂ and supplementing when needed may be prudent for those at risk of developing AMD or as an additional therapy for those with the pre-existing disease.³² The limitations were the small number of studies included in the meta-analysis.

Dietary Patterns

A Mediterranean-type diet promotes the intake of vegetables and fruit, fish, nuts, legumes, unprocessed cereals, and monounsaturated fats.³³ It is mainly a plant-based diet but not in the strictest sense as it may include some organic meat, poultry and dairy. It promotes high quality carbohydrates in modest amounts but is devoid of processed foods typical of a Western-type diet. It is the most researched diet and has been shown to be related to many health benefits due to its anti-inflammatory properties, immune modulating effects and high nutrient content.

Unfortunately, there is a limited amount of research regarding AMD and the Mediterranean diet. A prospective cohort study showed that consuming a Mediterranean-type diet significantly reduced the risk and progression of AMD by 26% after adjusting for covariates (HR: 0.74; 95% CI: 0.61,0.91) due to influencing gene and diet interactions.³⁴ The study included 2525 subjects at risk of developing or progressing to advanced AMD; their DNA samples were analyzed for 10 single nucleotide polymorphisms (SNPs). Risk reduction was only seen for those who carried the low risk genotypes. Individual food group items showed vegetable intake was associated with lower risk of disease progression as was fish. Docosahexaenoic acid intake, from fish consumption, provided a significant protective effect for the low risk genotype but not for those with a risk genotype.

There are mixed results in the studies regarding the risk of AMD and dietary fat intake. Saturated fats and cholesterol have been investigated due to their role in cardiovascular disease and it was speculated that the same mechanism could be applied to the macula.³⁵ There is a possible association with age as a high fat intake before the age of 75 years may increase the prevalence and advancement of AMD. There was a non-significant association with olive oil consumption and reduced risk of early AMD.³⁶ Another study with olive oil, after controlling for nutritional confounders, showed no significant relationship between its consumption and early onset of AMD but did show a reduced risk of developing late AMD.³⁶ Components of olive oil have anti-inflammatory and anti-oxidant properties which may be providing the effect seen in these studies. Oils also facilitate the absorption of lutein and zeaxanthin.

Complementary & Alternative Therapies

The Healing Eye Wellness Center in Tampa, Florida provided a program on an organic farm from which food is grown and prepared with a variety of physical activity options available.³⁷ The nutrition component of the program included testing saliva zinc levels for deficiencies and providing a raw food diet. The program included stress reduction, detoxification and tests for diabetic retinopathy, heavy-metal poisoning, sleep apnea, and eye function. The interventions utilized to treat AMD included intravenous infusion of vitamins and minerals, oxidative therapy (ozone therapy), micro-current stimulation and syntonic light therapy. These treatments target improved blood flow, reduced inflammation and cellular and stem cell stimulation. The therapies were considered safe, painless, non-toxic and free of side effects. An evaluation of the program, utilizing pre and post eye tests, included 152 participants of which 70 had dry AMD and 20 had wet AMD. Of the participants with wet AMD one experienced no change in acuity, seven with no change in contrast and six with no change in visual field expansion. Of the participants with dry AMD 15 showed no change in acuity, 13 with no change in contrast and 23 with no change in visual field expansion. Follow up was not conducted so it is unknown if the improvements continued, stabilized or declined.

Medical Treatment Options

Medical treatments target wet AMD as these individuals are at the highest risk for permanent blindness. Wet AMD treatments include pharmaceutical intravitreal injections of anti-vascular endothelial growth factor (VEGF) that targets angiogenesis and vascular permeability. The injections are not curative and not successful in all cases with a high rate of recurrence.³⁸ The off-label drug Avastin^® has been approved in Canada for intravitreal eye injection and Lucentis has been approved in the US.³⁹ As with most medical interventions the injection may cause blood clots, strokes, or heart attacks.⁴⁰ Avastin has the additional side effect of gastrointestinal discomfort and possible disease. Nanoparticle technology is used with the injections for slow release delivery to specific tissues.⁴¹ The downside is that monthly injections are required to maintain eyesight and complications due to repeat injections may occur.⁴²

Full macular translocation (FMT) surgery for patients with wet AMD not responding to VEGF treatment is conducted in Italy by Dr. Grazia Pertile who has co-authored a study of 255 patients with advanced AMD disease.⁴³ Visual acuity improvements were clinically and statistically significant for up to 5 years of the study follow up. The macula regained some of its function in most patients with almost half the patients experiencing an improvement in vision by three lines on the eye chart. The number of legally blind patients declined from 48% to 30% 1 year after FMT but for some patients’ disease progression continued.

Future Therapies

Stem cell research with AMD over the past several decades has produced very few usable results.⁴⁴ Stem cell therapy to replace damaged cells has shown variations in effectiveness in test tube and animal studies.⁸ Mandai et al³⁸ describes stem cell transplantation in a patient with wet AMD who showed no improvement in vision after 1 year. Song et al⁴⁴ describes four cases with stem cell therapy for AMD and found beneficial effects in three of the four cases with no adverse effects. It appears that the risks of rejection and tumor development currently outweigh the benefits and further research and development is needed before stem cell therapy becomes a suitable treatment for AMD.

The CAREDS study found the inflammatory gene CFH and the ARMS2 genotype to be risk factors for AMD.⁴⁵ Gene therapy might become a viable technique to supress ocular angiogenesis. Askou et al⁴² developed an RNA interference that silenced the vascular endothelial growth factor contributing to the advancement of AMD in mice with favorable results. Currently clinical trials with humans and gene therapy have not resulted in improved vision.⁴⁵

Conclusion

The second Age-Related Eye Disease Study (AREDS2) determined that a combination of vitamin C, vitamin E, zinc, copper, lutein and zeaxanthin, provided as an AREDS2 formulation, may be effective in slowing the progression of age-related macular degeneration (AMD).^9,11 Although, a Cochrane Review that included these nutrients showed inclusive results for age-related macular degeneration (AMD).²¹ But the results of the research reviewed are compelling, with low risk of harm, suggesting an intervention that includes the AREDS2 formula in clinical practice may be warranted.²² Unfortunately, the developers of vitamin and mineral formulations for AMD are not always producing a supplement based on the AREDS2 study, therefore supplement formulations should be investigated before recommendations are made to clients.

Nutrition interventions should focus on both food and supplements. Observational evidence suggests that nutrition therapy may prevent the onset and delay the progression of AMD. Although not well supported by research, a Mediterranean-type diet to reduce inflammation as a risk factor, may be the best diet intervention for preventing or delaying the onset of AMD.⁴⁶ The literature also suggests that additional zeaxanthins and lutein consumed as food may provide additional protection. Consuming a Mediterranean- type diet provides zeaxanthin and lutein rich foods, with the addition of olive oil to increase the absorption.²⁶ It also emphasizes fish consumption which will increased the intake of docosahexaenoic acid which may also provide additional protection.³⁴ At the age of 65 for those who are genetically predisposed or diagnosed with AMD, a supplement consistent with the AREDS2 formulation may be beneficial.