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Proposed Mechanisms of Action of the AREDS 2 Supplements

Home / Retina and Vitreous / Age-Related Macular Degeneration and other Causes of Choroidal Neovascularization

Title: Proposed Mechanisms of Action of the AREDS 2 Supplements
Authors: Andy Renschler MS3, Paul Bernstein MD, PhD
Date: 10/24/24
Keywords/Main Subjects: AREDS, vitamins, oxidation, antioxidant, supplements
Diagnosis: Age-related macular degeneration
Description: Proposed mechanisms in which vitamin C, vitamin E, lutein, zeaxanthin, zinc, and copper act to slow the progression of AMD

 

Vitamin C 500 mg
Vitamin E 400 mg
Lutein 10 mg
Zeaxanthin 2 mg
Zinc 80 mg
Copper 2 mg

Figure A: AREDS 2 supplements with dosage

 

Up to 20% of people over the age of 85 are affected by some form of age-related macular degeneration (AMD)1. AMD is an irreversible disease that affects central vision. The cause and development of AMD is not fully understood; proposed mechanisms include oxidative stress, environmental factors, and genetics2.  Progression of the condition can be slowed with injections of anti-VEGF agents 3. Additionally, a combination of vitamins and minerals were evaluated in the AREDS and AREDS 2 studies demonstrating promising results4,5. Figure A shows the supplements evaluated in the AREDS 2 study, which was an extension of the original AREDS study testing the effects of dosage modifications to the original supplement formula. Beta-carotene was an ingredient in the original AREDS study, but researchers removed it due to its link to lung cancer in smokers and added lutein and zeaxanthin (carotenoids naturally found in the eye). The study confirmed that the new formulation reduced the risk of progression to advanced AMD by about 25% similarly to the original AREDS in patients with intermediate to advanced AMD in 1 or both eyes5.

Many of the supplements in the AREDS 2 formulation have proposed mechanism of countering sources of oxidation within the retina. The photoreceptor/pigment epithelium complex is exposed to sunlight, is bathed in a near-arterial level of oxygen, and membranes in this complex contain high concentrations of polyunsaturated fatty acids, all considered to be potential factors leading to oxidative damage6.

Vitamin C

Vitamin C is a water-soluble antioxidant that works in conjunction with glutathione to scavenge damaging free radicals within the cells of the retina photoreceptors and the retinal pigment epithelium (RPE). When vitamin C absorbs a free radical, the oxidation product is dehydroascorbic acid. Glutathione has the remarkable ability to reduce dehydroascorbic acid back to vitamin C maintaining an ample supply of antioxidants within the cells. Dehydroascorbic acid is the only oxidation product that can be reduced back to vitamin C. Winkler et al. demonstrated human RPE cells with low levels of vitamin C, dehydroascorbic acid, or glutathione have reduced ability to regenerate vitamin C when under oxidative stress6. Vitamin C is a supplement in the AREDS 2 pill to provide cells with an ample supply of extra cellular vitamin C that can be transported intracellularly during times of oxidative stress.

Vitamin E

Vitamin E is a lipid-soluble antioxidant that plays a significant role in minimizing the oxidative effects of polyunsaturated fatty acids6. Polyunsaturated fatty acids are important components of the outer segments of the retina photoreceptors. These fatty acids are shed from the outer segment membrane daily and are ultimately phagocytosed by the RPE for recycling7. Accumulation of unrecycled fatty acids can result in free radical formation, so vitamin E is included as an AREDS 2 supplement to reduce this oxidative effect.

Lutein and Zeaxanthin

Lutein and zeaxanthin are unsaturated polyene hydrocarbon carotenoids that accumulate in the macula giving it a yellow color. The presence of the double bonds in the carbon chain provides for strong antioxidant activity. Additionally, lutein and zeaxanthin accumulate in a pre-receptor layer of the retina providing some protection for the receptors against damaging short-wave blue light (400-525 nm)8. It has also been suggested that these macular carotenoids have an even greater chain-breaking activity than vitamin E9. Studies have demonstrated that the macula, where pigment concentration is the highest, is most resistant to degeneration. Studies have also shown patients with AMD have lower macular pigment concentrations, which correlates with lower serum concentrations and dietary supply. Therefore, providing a dietary source of lutein and zeaxanthin is recommended either through supplements or diets high in leafy green vegetables10.

Zinc

The role of zinc in slowing AMD progression has numerous proposed mechanisms. It has been suggested that zinc may promote autophagy (the breakdown and recycling of damaged/old cellular components) by acting as a transcription factor promoting gene expression of proteins useful for phagocytosis11,12. Studies have demonstrated there is impaired autophagy in AMD resulting in accumulation of metabolic and cellular products13.

In patients with AMD, the content of zinc in human RPE/choroid is decreased 24%; therefore, diet supplementation may be an efficient and inexpensive strategy to slow AMD progression14.

Copper

Copper is also an ingredient in the AREDS 2 supplements, because high levels of zinc induces the synthesis of metallothionein, a copper-binding protein, trapping copper within intestinal cells preventing its systemic absorption15.

Considerations of an AREDS 3 formulation

Omega 3 fatty acids are often recommended for patients with AMD given they may reduce inflammation and oxidative stress on the retina. There was discussion of incorporating omega 3 fatty acids with the AREDS 2 formulation, but ancillary data analysis from the  VITAL randomized clinical trial and data from the AREDS 2 trial itself show omega 3 fatty acid supplementation had no significant overall effect on AMD incidence or progression16. These results suggest prescribing supplemental omega 3 fatty acids offers little benefit; however, observational studies still demonstrate benefits of diets rich in omega 3 fatty acids suggesting there may be a synergistic interaction between fatty acids and other nutrients in whole foods17,18.

Conclusion

It’s important to note the AREDS 2 supplements are not used to cure AMD. This combination of supplements have only been shown to reduce the progression of AMD in some patient populations5. Additionally, rich dietary sources of omega 3 fatty acids may offer more benefits than supplemental omega 3 fatty acids.

 

Summary:

The AREDS 2 vitamins are often prescribed to patients with age-related macular degeneration in an effort to slow the progression of the disease. The ingredients act as anti-inflammatory agents via different mechanisms described in this text. Omega 3 fatty acids also may play a beneficial role in patients with age-related macular degeneration but have not demonstrated effectiveness in clinical trials.

Format: Text

References:

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  2. What Is Macular Degeneration? American Academy of Ophthalmology. November 13, 2023. Accessed August 13, 2024. https://www.aao.org/eye-health/diseases/amd-macular-degeneration
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Faculty Approval by: Dr. Paul Bernstein MD, PhD

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