The Age-Related Eye Disease Study (AREDS) and its follow-up, AREDS2, are landmark studies, conducted under the auspices of the National Eye Institute, that have shaped the formulation of supplements that are widely available today for macular degeneration.
While AREDS2 has become synonymous with macular health support, many consumers, and even healthcare providers, are not fully aware of the associated risks and limitations.
In this article, we’ll delve into the history and findings of the AREDS and AREDS2 studies, and highlight some of the less commonly discussed issues including it’s limitations and risks.
AREDS Original Formula
The original AREDS trial marked a significant milestone in the field of eye health research. It was the first large scale trial that showed that a specific combination of antioxidants could slow the progression of age-related macular degeneration (AMD) from the intermediate stages to the advanced disease.
This pioneering formula included vitamin A or beta-carotene, vitamin C, vitamin E, zinc, and copper.
However, subsequent research funded by the National Cancer Institute, revealed a troubling link between beta-carotene supplementation and an increased risk of lung cancer, especially among smokers. These findings raised significant concerns about the inclusion of beta-carotene in the original AREDS formula.
In light of this new evidence, a revision of the formula was necessary. This led to the development of the AREDS2 formula, which sought to maintain the protective benefits of the original while addressing and mitigating the associated risks.
The Formulation of AREDS2
The goal of the AREDS2 study was clear: to preserve the protective macular health benefits while eliminating the potential lung cancer risks.
This led to a significant shift in the formulation, with beta-carotene being replaced by the macular carotenoids lutein and zeaxanthin. Alongside these carotenoids, the revised formula also retains vitamin C, vitamin E, zinc, and copper from the original formula.
The introduction of the AREDS2 formula marked a substantial advancement. It effectively reduced the risk of intermediate AMD progressing to more advanced stages, without the heightened lung cancer risk associated with beta-carotene.
However, the study did not demonstrate any preventive effect for those in the early stages of AMD, nor did it show significant benefits for individuals using it solely as a preventive measure. This is a critical aspect that is often overlooked, as many people turn to AREDS2 supplements with the expectation that they will prevent the onset of AMD, despite the lack of evidence supporting this use.
Risks and Side Effects of AREDS2
The AREDS2 vitamins have now become a popular choice for those looking to support their macular health, but despite their widespread use, the potential side effects of the AREDS2 formula are often underemphasised. High doses of vitamin C, vitamin E, and zinc—key components of this formula—are potentially harmful when taken over the long term.
Vitamin C
Vitamin C is often hailed as a powerful antioxidant, essential for overall health and well-being. However, there’s a less commonly discussed aspect of this nutrient that warrants attention. At high doses—500 mg or more per day—vitamin C can have a pro-oxidant effect, particularly on the lens of the eye. This paradoxical effect may increase the risk of cataract development. Research has found that women aged 65 and above who regularly use vitamin C supplements at this dose may face up to a 38% increased risk of developing cataracts.
Vitamin E
Studies have indicated that taking vitamin E at the level found in the AREDS2 formula—400 IU or more daily—may be linked to a small but notable increase in the risk of death from all causes.
Additionally, there is concern regarding the long-term effects of high-dose vitamin E supplementation. The 2011 Selenium and Vitamin E Cancer Prevention Trial highlighted a 17% increase in prostate cancer risk among men who consumed 400 IU of vitamin E daily over seven years. This evidence suggests that, while vitamin E has its benefits, caution is warranted, especially at higher dosages.
Zinc
Zinc is an essential mineral, which is vital for many bodily functions. In the AREDS2 formula, zinc is included at a dose of 80 mg—double the tolerable upper intake level recommended by most health authorities, which is set at 40 mg daily for adults.
This high dose of zinc poses significant health risks. For instance, a study published in the Journal of Urology revealed that individuals taking the AREDS formula with 80 mg of zinc were more likely to be hospitalised for urinary complications compared to those on a placebo.
Of more concern is the Health Professionals Follow-up Study, which found that long-term zinc supplementation—exceeding 75 mg daily over a period of 15 years—could nearly double the risk of developing lethal and aggressive prostate cancer.
Additionally, the zinc in the AREDS2 formula may also pose specific risks for individuals with certain genetic variations, particularly in the CFH and ARMS2 genes. These gene variations make the macula more sensitive to zinc, potentially accelerating the progression to advanced AMD rather than slowing it.
“In my practice, I educate all my patients that the standard AREDS 2 formulation with zinc and copper does more harm than good for 15% of people.”
Dr. Paul Krawitz, Ophthalmologist, New York
For individuals who are sensitive to zinc, as indicated by genetic testing, a much lower intake of 8–11 mg daily is advisable. At this lower dose, no negative impacts were observed across any genetic variations, making it a safer choice for those with increased sensitivity, particularly those with the CFH and ARMS2 gene variations.
Reduced Effectiveness in Prevention
When considering the AREDS2 formula, it’s crucial to understand its limitations in terms of prevention. Despite its widespread use, the AREDS2 formula has not been shown to offer benefits for individuals in the early stages of AMD, nor does it prevent the onset of the condition.
The trial data confirms that the formula is primarily effective for those already experiencing intermediate AMD, helping to slow progression rather than prevent the condition from developing in the first place.
Understanding this limitation is key to making informed decisions about eye health and ensuring that preventive strategies are based on the best available evidence.
Alternative Nutrients to Support Macular Health
The AREDS2 study has undeniably cemented the importance of lutein and zeaxanthin in supporting macular health. These carotenoids are essential for protecting the macula from oxidative stress and harmful blue and UV light, making them vital for maintaining healthy vision as we age.
However, considering the potential risks associated with other components of the AREDS2 formula—vitamin C, vitamin E, and zinc—it’s worth exploring alternative nutrient combinations that could offer a safer and more comprehensive approach to macular health.
Botanical extracts like bilberry, saffron, ginkgo biloba, and grape seed extract, for example, offer powerful antioxidant properties and promote macular health without the concerns linked to high-dose supplementation of certain vitamins and minerals.
A holistic approach that integrates these alternative natural nutrients, alongside lutein and zeaxanthin, could provide a more balanced and effective strategy for maintaining macular health across the lifespan.
Vitamin B12 and Folate
Data from the Women’s Antioxidant and Folic Acid Cardiovascular Study highlights the significant role that B vitamins play in the prevention of age-related macular degeneration (AMD). This randomised trial revealed that long-term daily supplementation with vitamin B12, folate, and vitamin B6—over an average period of 7.3 years—resulted in a remarkable 35-40% reduction in the risk of developing AMD.
After two years of supplementation, the protective effects were already apparent and continued to strengthen throughout the study.
This level of protection achieved by the B vitamins was not achieved with the AREDS2 study.
“These findings apply to the early stages of AMD development in persons without a prior diagnosis of AMD, and appear to represent the first identified means, other than avoidance of cigarette smoking, of reducing risks of AMD in persons at usual risk.”
Dr. William Christen, Archives of Internal Medicine, 2009
Ginkgo Biloba
Ginkgo biloba is a remarkable plant extract with deep roots in traditional medicine. The extract from its leaves is rich in over 60 bioactive compounds, including flavonoids and terpenoids, which are particularly potent.
These phytonutrients have been shown to reduce blood viscosity, inhibit platelet aggregation, and enhance overall blood circulation—factors that are crucial for maintaining healthy macular function. Studies have shown that ginkgo biloba is able to improve visual function in those with dry macular degeneration.
There has been some concern regarding a possible bleeding risk associated with ginkgo biloba. However, data from. randomised clinical trials and meta-analyses have not supported these concerns. The evidence does not show a significant link between ginkgo biloba and increased bleeding risk, indicating that it can be a safe and effective, even for those on blood-thinning medications.
Grape Seed
Grape seed extract is an exceptional source of procyanidins, natural antioxidants that are particularly effective in safeguarding the retinal ganglion cells that are critical for vision.
What truly sets procyanidins apart is their extraordinary antioxidant potency. Research indicates that procyanidins have an antioxidant activity significantly greater than that of traditional antioxidants like vitamins C and E—boasting 50 times the potency of vitamin C and 20 times that of vitamin E.
This remarkable effectiveness makes procyanidins a compelling alternative to the more commonly used antioxidants in the AREDS2 formula, potentially offering superior and safer protection for your macula.
Saffron
Saffron, the vibrant and precious spice harvested from the Crocus sativus flower, is exciting the scientific community for its potential in the management of AMD.
Rich in potent carotenoids like crocin and crocetin, the clinical research suggests that saffron can enhance retinal function, improve visual acuity, and increase visual sensitivity in individuals with mild to moderate AMD, potentially slowing the progression of this prevalent eye condition.
But the benefits of saffron extend beyond AMD. This powerful spice has also shown promise in improving visual function for individuals with diabetic maculopathy, providing important natural eye support for those with diabetes.
“Saffron supplementation induces macular function improvements from baseline that are extended over a long-term follow up.”
Dr. Marco Piccardi, Evidence-Based Complementary & Alternative Medicine, 2012
Progressing Towards Enhanced Macular Health
The AREDS and AREDS2 formulations have undoubtedly advanced our understanding of nutritional support for macular health, but it’s essential to acknowledge their potential side effects and limitations.
For macular health, the key nutrients are lutein and zeaxanthin. However, enhancing the benefits of these nutrients with additional supportive ingredients—such as ginkgo biloba, grape seed extract, saffron, methylcobalamin (active vitamin B12), and L-methylfolate (active folate)—can provide a more comprehensive approach to maintaining macular health.
This combination of natural plant extracts and B-vitamins not only retains the benefits of the original formulations but also offers a more holistic strategy for supporting eye health across all stages of AMD.
By incorporating a broader range of nutrients that target various aspects of eye health, we will be able to support long-term macular health and optic nerve function effectively, while also minimising the potential risks associated with the AREDS2 formula.
For those seeking a safe and modern approach to preserving eyesight and macular health, nutrient combinations that go beyond the AREDS formulas can offer a balanced, effective and safe solution.
Supporting your eyes with a well-rounded nutritional approach ensures that you’re taking proactive steps to maintain your vision with confidence.
