Age-related macular degeneration (AMD) is the leading cause of blindness in much of the developed world, including the United Kingdom1. As the name suggests, the risk of AMD rises with increasing age, bringing with it serious implications for an ageing population.
AMD does not typically result in complete blindness as the peripheral retina is often left intact. However, damage to the macula (which is responsible for central vision) from the disease can severely affect an individual’s ability to do normal daily tasks often taken for granted, such as reading text or recognising faces, as the central vision deteriorates.
Age-Related Macular Degeneration
The retina is formed from ten layers of cells, all with a specific role to play in the perception of light and the sense of vision. The retinal tissue lines most the inside of the eyeball with the retinal nerve fibre layer exiting the globe via the optic nerve to carry signals to the brain.
The photoreceptor layer contains millions of light-sensing photoreceptor cells called cones and rods. Cone photoreceptors are found at highest concentrations at the macula as their role is the detection of fine detail and colour, and are therefore responsible for high resolution central vision in the human eye. Directly external to the photoreceptor layer lies the retinal pigment epithelium (RPE) layer. The role of the RPE is to support the nutritional and metabolic requirements of the photoreceptor layer in addition to providing protection from damaging short wavelength radiation exposure and the production of free oxygen radicals2. Considering the retina has one of the highest energy demands of any tissue in the body3, the RPE is exposed to significant amounts of oxidative stress; the accumulation of reactive oxygen species resulting in inflammation and oxidative damage in the ageing retina have long been implicated in the development of AMD3.
Two broad categories of AMD exist – the dry, or atrophic form, and the wet form, also known as exudative or neovascular AMD. The stages of AMD are further divided into early, intermediate, and late AMD.
Early AMD is characterised by the presence of drusen, yellowish deposits of waste material within the RPE layer of the macular area. Larger drusen (>125 micrometres in diameter) with associated RPE disruption around the macula is considered intermediate AMD. Late stage macular degeneration can apply to either the dry or wet form. In late stage dry AMD, confluent areas of atrophy develop within the RPE and overlying retinal layers, leading to patches of profound vision loss. Neovascular AMD is diagnosed with the formation of new fragile blood vessels from the choroid layer (carrying the blood supply external to the RPE), which may haemorrhage and cause significant central vision loss4.
The diagnosis of macular degeneration requires specialised equipment for a thorough ocular examination. This can typically be performed by either an ophthalmologist or an optometrist with the appropriate tools and training. Ophthalmoscopy is conducted at the slit lamp microscope to directly visualise the retina and macula; this is useful for detecting changes to the RPE layer, such as hypo- or hyperpigmentation, and also to note the presence of any drusen. Fundus photography of the retina is a useful method of documentation to monitor any changes to the macula over time. A test of visual acuity is important as it gives the eyecare practitioner an idea of the patient’s functional vision in the presence of macular degeneration, particularly if the patient continues to hold a driver’s licence. In the UK, the minimum standard of vision required is a binocular (with two eyes together) visual acuity of 6/12 and the patient must be able to read the size and design of a car number plate made after September 2001 at a distance of 20 metres5. Other requirements also apply to the vision standards for driving but are usually less relevant to AMD patients. Optical coherence tomography scanning is often utilised in the diagnosis and monitoring of AMD as it allows the practitioner to visualise the layers beneath the superficial retinal nerve fibre layer, such as the RPE itself.
The Age-Related Eye Disease Study
The Age-Related Eye Disease Study (AREDS) is a well-known large, multicentre clinical trial investigating the effects of certain antioxidants and zinc on the progression of AMD. The proposed vitamin and mineral supplement was comprised of:
- 500mg of vitamin C
- 400 IU of vitamin E
- 15mg of beta-carotene
- 80mg of zinc as zinc oxide
- 2mg of copper as cupric oxide6
The AREDS trial was successful in demonstrating that the risk of progression to advanced AMD could be reduced by 25% in patients with a high risk of progression. In patients with unilateral or bilateral intermediate AMD and patients with unilateral advanced AMD, the risk of vision loss from advanced macular degeneration was lowered by 19% with the AREDS supplementation6.
A follow-up trial several years later called the AREDS2 sought to determine whether the addition of carotenoids lutein and zeaxanthin to the original AREDS formula had the capability to further reduce the risk of progression to advanced AMD. This study was not able to demonstrate that these additional carotenoids for the eyes conferred any significant benefit as an addition to the AREDS supplementation but researchers did observe that the beta-carotene of the original formulation was associated with an increased incidence of lung cancer in smokers, suggesting that the substitution of lutein and zeaxanthin instead of beta-carotene was an appropriate modification to the initial AREDS nutrient formula7. This resulted in a final AREDS2 formulation of:
- 500mg of vitamin C
- 400IU of vitamin E
- 25mg or 80mg of zinc
- 2mg of copper
- 10mg of lutein
- 2mg of zeaxanthin7
The same AREDS2 trials also investigated the addition of omega-3 polyunsaturated fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), to the first AREDS formulation but no further substantial improvement to the risk of AMD progression was demonstrated and so the inclusion of DHA and EPA is not recommended in the AREDS2 formula7. One treatment arm of the AREDS2 trials included a decreased zinc dose of 25mg as research suggested this may be the maximum amount of zinc able to be absorbed at one time by the body7. The lowered zinc concentration was found to contribute just as well to reducing AMD progression as the higher 80mg dose and may be the preferred concentration in macular supplements due to the lower risk of adverse reactions such as anaemia and stomach disturbances.
Carotenoids and the Macula
Carotenoids are fat-soluble pigments found in dark green, red, yellow, and orange vegetables and fruits8. Lutein, zeaxanthin, and meso-zeaxanthin carotenoid pigments in particular are highly concentrated in the macula at about five times more than the peripheral retina9 and 1000 times more than found in the blood10. Zeaxanthin is found at its highest levels within the fovea of the macula while lutein accumulates preferentially in the perifoveal area9. Meso-zeaxanthin is dominant at the epicentre of the macula11. The three macular carotenoids differ slightly in their chemical structure (despite similar nomenclature between zeaxanthin and meso-zeaxanthin). This confers subtle differences in their physical properties, the most important of these being the distinctions in relative absorbances (of short wavelength radiation) and intensities. The slight variation in absorption spectra across lutein, zeaxanthin, and meso-zeaxanthin provide an optimal total filtration of UV and short wavelength light at the macula11. Together, these three carotenoids are considered the major functional component of macular pigment and play an important role in the healthy functioning of the macula and central vision by defending the macula from the oxidative damage due to reactive oxygen species and short wavelength light8, 10, and thereby offering some protection from macular degeneration. It then stands to reason that a higher density of macular pigment is protective from AMD while lower macular pigment may be a risk factor for degenerative eye diseases arising from oxidative damage.
A large prospective cohort study in the USA involving over 90 000 participants with a follow-up over the course of almost three decades yielded promising results for lutein and zeaxanthin supplementation in the reduction of AMD risk. Higher intake levels of the macular carotenoids, lutein and zeaxanthin, were associated with a 40% lowered risk of advanced AMD in both men and women though was not observed to have any effect on intermediate AMD8. Other non-macular pigment carotenoids were also investigated in the course of the study, including beta-cryptoxanthin, alpha-carotene, and beta-carotene, and were found to confer a 25-35% lowered risk of advanced AMD8; this may be due to an indirect antioxidant effect on the macula. It is important to realise the results of this study indicate an effect of carotenoid intake on the progression of existing AMD, rather than the initial development of it.
Another study investigating the effect of macular carotenoid supplementation found that not only did nutritional supplements of lutein and zeaxanthin increase macular pigment density but the inclusion of meso-zeaxanthin further increased the amount of macular pigment when compared to supplements without this carotenoid10. Intake of these three carotenoids in supplement form for longer than a year was found to be the most effective for improving macular pigment density for both AMD patients and healthy patients without macular degeneration10.
Despite the results from multiple studies and trials, including the AREDS2, leading to the marketing of many nutritional supplements purportedly benefitting the macula, the role of supplementation of the carotenoids lutein, zeaxanthin, and meso-zeaxanthin, has not been unanimously supported by all researchers. Several epidemiological studies were unable to demonstrate the association between higher intake of macular carotenoids in the diet and a lower risk of AMD, or were only able to do so in certain population subgroups9. As with much medical research, study design and the control of external and confounding variables may play a significant role in determining the final results and their interpretation. In the ophthalmology and optometry industry, the results and clinical recommendations arising from the AREDS and AREDS2 trials are largely accepted and implemented in the clinical setting.
Practical Advice for Patients
Though the evidence for the role of macular carotenoid supplementation, namely lutein, zeaxanthin, and meso-zeaxanthin, in the presence of age-related macular degeneration may be controversial, researchers continue to advise healthcare clinicians to encourage their patients to eat a healthy diet rich in carotenoids8,9.
Zeaxanthin can be found in dietary sources such as corn, squash, oranges, nectarines, though in very small quantities. Orange capsicum is considered to contain a high amount of zeaxanthin9. Kale, spinach, and melons contain a significant amount of lutein, which is typically found in most fruits and vegetables to some degree. Egg yolk and maize contain the highest mole percentage of both carotenoids9.
Meso-zeaxanthin is considered a non-dietary carotenoid, though some researchers contest this claim11. While one study reported meso-zeaxanthin to be found in numerous species of edible fish, shrimp, and sea turtles11, 12, subsequent independent studies were unable to confirm this12. A geometric isomer of zeaxanthin, meso-zeaxanthin is known to result from the biosynthesis of lutein, leading some researchers to consider identifying meso-zeaxanthin as a “dietary supplement” to be misleading12. As meso-zeaxanthin cannot be acquired in any significant amount directly from the diet, supplementation is an advisable method of obtaining this carotenoid.
Ultraviolet protection for the eyes in the form of sunglasses and hat continues to also be wise advice for all patients, both those with and without macular degeneration.
Due to the genetic factor implicated in the development and progression of AMD, patients should be counselled that neither the use of macular supplements nor a perfectly healthy diet guarantees protection from macular degeneration with age. In addition to this, those with existing AMD should be made aware that the intake of carotenoids for the eyes is not able to reverse damage and visual loss caused by AMD or any other eye disease. However, based on the current evidence in research, as an increased intake of the macular carotenoids lutein, zeaxanthin, and meso-zeaxanthin has demonstrated to confer a reduction in risk of progression of AMD by improving the protective effects of macular pigment density in the RPE, it is worthwhile recommending the use of supplementation to those patients at risk.
- Owen CG, Fletcher AE, Donoghue M, et al.How big is the burden of visual loss caused by age related macular degeneration in the United Kingdom? British Journal of Ophthalmology 2003;87:312-317.[ https://bjo.bmj.com/content/87/3/312. Accessed 10/7/19]
- Boulton, M., Dayhaw-Barker, P. (2001). The role of the retinal pigment epithelium: topographical variation and ageing changes. Eye (Lond), 15, 384-9. DOI:10.1038/eye.2001.141. [https://www.nature.com/articles/eye2001141.pdf. Accessed 8/7/19]
- Wong-Riley M. T. (2010). Energy metabolism of the visual system. Eye and brain, 2, 99–116. doi:10.2147/EB.S9078 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3515641/. Accessed 10/7/19]
- Optometry Australia Clinical Practice Guide. Clinical Classification for Age-Related Macular Degeneration (AMD). [https://www.optometry.org.au/wp-content/uploads/Publications/Pharma/2019/Clinical-classification-for-AMD.pdf. Accessed 10/7/19]
- Driving Eyesight Rules. [https://www.gov.uk/driving-eyesight-rules. Accessed 15/7/19]
- Age-Related Eye Disease Study Research Group (2001). 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. Archives of ophthalmology (Chicago, Ill. : 1960), 119(10), 1417–1436. doi:10.1001/archopht.119.10.1417 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1462955/. Accessed 8/7/19]
- The Age-Related Eye Disease Study 2 (AREDS2) Research Group. Lutein + Zeaxanthin and Omega-3 Fatty Acids for Age-Related Macular Degeneration: The Age-Related Eye Disease Study 2 (AREDS2) Randomized Clinical Trial. JAMA. 2013;309(19):2005–2015. doi:10.1001/jama.2013.4997. [https://jamanetwork.com/journals/jama/fullarticle/1684847. Accessed 8/7/19]
- Wu, J., Cho, E., Willett, W. C., Sastry, S. M., & Schaumberg, D. A. (2015). Intakes of Lutein, Zeaxanthin, and Other Carotenoids and Age-Related Macular Degeneration During 2 Decades of Prospective Follow-up. JAMA ophthalmology, 133(12), 1415–1424. doi:10.1001/jamaophthalmol.2015.3590 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119484/. Accessed 15/7/19]
- Mozaffarieh, M., Sacu, S., & Wedrich, A. (2003). The role of the carotenoids, lutein and zeaxanthin, in protecting against age-related macular degeneration: a review based on controversial evidence. Nutrition journal, 2, 20. doi:10.1186/1475-2891-2-20 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC305368/. Accessed 15/7/19]
- Ma, L., Liu, R., Du, J. H., Liu, T., Wu, S. S., & Liu, X. H. (2016). Lutein, Zeaxanthin and Meso-zeaxanthin Supplementation Associated with Macular Pigment Optical Density. Nutrients, 8(7), 426. doi:10.3390/nu8070426 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963902/. Accessed 15/7/19]
- Nolan, J. M., Meagher, K., Kashani, S., & Beatty, S. (2013). What is meso-zeaxanthin, and where does it come from?. Eye (London, England), 27(8), 899–905. doi:10.1038/eye.2013.98 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740325/. Accessed 15/7/19]
- Carotenoids for Ocular Health: An expert review on the scientific evidence and best nutritional practices. March 2014. [https://www.reviewofoptometry.com/CMSDocuments/2014/9/mednutrition0914i.pdf. Accessed 15/7/19]
The author of this article takes full responsibility for the accuracy of this article and is not in any way affiliated or employed by Intelligent Formula – any views stated is entirely the author’s view.
About the Author:
Jane Chong, B.Optom
Jane graduated from the University of Melbourne in 2012 with a Bachelor of Optometry and therapeutic endorsement. She has worked as a clinical optometrist ever since, gaining valuable experience across ocular disease management, contact lenses prescribing, paediatric optometry, and general optometry.
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