What is Macular Degeneration?

Age-related macular degeneration (AMD) is a condition where the macula, the area of the eye responsible for the most distinct (central) vision, deteriorates and causes vision loss. AMD can be characterized as either atrophic (dry) or neovascular (wet). An eye doctor can recognize macular degeneration by the appearance of drusen (ie, cellular debris near the back of the eye) or hemorrhaging.

The exact cause of macular degeneration is not well understood, but chronic vascular disease could play an important role. Biomarkers predictive of cardiovascular risk (eg, elevated homocysteine and C-reactive protein levels) are also risk factors for AMD.

Natural interventions such as antioxidant vitamins, zinc, and carotenoids may help prevent degeneration and support healthy eyes.

What are the Risk Factors for Macular Degeneration?

• Family history
• Ethnicity—Caucasian-Americans are more likely than African-Americans
• Vascular diseases (including cardiovascular disease)
• Smoking
• Phototoxicity (caused by exposure to blue and ultraviolet rays from sunlight)
• Hypertension
• Diet—including low intake of carotenoids and B vitamins, and high intake of saturated and trans fats

What are the Signs and Symptoms of Macular Degeneration?

• Distorted central vision
• Appearance of dark spots
• Other visual distortions

What are Conventional Medical Treatments for Macular Degeneration?

• Supplementation with antioxidant vitamins, carotenoids, and zinc
• Intravitreous (injected into the vitreous humor in the eye) anti-vascular endothelial growth factor (anti-VEGF) inhibitors such as Macugen, Lucentis, and Avastin
• Photodynamic therapy
• Laser photocoagulation
• Surgery (not usually recommended)
• Visual aids such as implantable miniature telescopes

What are Emerging Therapies for Macular Degeneration?

• Hormone replacement therapy

What Dietary and Lifestyle Changes Can Be Beneficial for Macular Degeneration?

• Eat a healthy, well-balanced diet rich in omega-3 fatty acids (found in oily fish and flax seeds) and carotenoids (found in orange and yellow fruits and vegetables).
• Quit smoking

What Natural Interventions May Be Beneficial for Macular Degeneration?

• Vitamins A, C, and E, zinc, and copper. The Age-Related Eye Disease Study (AREDS), the largest and most important study of nutritional supplements in AMD, found this combination of nutrient improved AMD in most patients.
• Carotenoids. Intake of carotenoids lutein, zeaxanthin, and meso-zeaxanthin is essential for eye health. Patients with AMD have sharply decreased levels.
• Omega-3 fatty acids. Independent of supplementation with the AREDS nutrients, higher intakes of DHA and EPA were associated with a lower risk for progression to advanced AMD.
• Bilberry. Anthocyanidins and cyanidin-3-glucoside (C3G) found in bilberry have been shown in preclinical studies to protect eye health.
• Melatonin. The eye has multiple melatonin receptors. A clinical study showed AMD patients receiving melatonin did not experience further vision loss and had reduced pathologic macular changes.
• Grape seed extract. Preclinical studies have shown grape seed extract may exert a protective effect against AMD and neurodegenerative disorders, as well as improve eye health.
• L-carnosine. L-carnosine is important for protecting cells from free radical damage. Topically applied L-carnosine improved visual acuity, glare, and lens opacification in animals and humans with advanced cataracts.
• Coenzyme Q10 (CoQ10). CoQ10 may protect eyes from free radical damage. Combined supplementation with CoQ10, acetyl-L-carnitine, and omega-3 fatty acids stabilized visual functions in patients affected by early AMD.
• B vitamins. Elevated homocysteine levels and low B-vitamin levels are associated with an increased risk of AMD and vision loss in older adults. A large study found supplementing with folic acid, B6, and B12 significantly reduced the risk of AMD in adults with cardiovascular risk factors.
• Other natural interventions that may benefit eye health include resveratrol, ginkgo biloba, selenium, lipoic acid, among others.

The macula or macula lutea (from Latin macula, "spot" + lutea, "yellow") is a highly pigmented yellow spot near the center of the retina of the human eye, providing the clearest, most distinct vision needed in reading, driving, seeing fine detail, and recognizing facial features.

Age-related macular degeneration (AMD) is a devastating condition characterized by the deterioration of the macula in which central vision becomes severely impaired. There are two forms of macular degeneration: atrophic (dry) and neovascular (wet). Both forms of the disease may affect both eyes simultaneously.

Age-related declines in the retinal carotenoid pigment content, coupled with photo damage induced by harmful Ultraviolet (UV) rays, give rise to this debilitating condition. The progression and severity of macular degeneration, as with all age-related diseases, are exacerbated by factors such as oxidative stress, inflammation, high blood sugar, and poor vascular health.

Scientifically studied natural compounds which help restore waning carotenoid levels within the macula, boost the antioxidant defenses of the eye, and support healthy circulation offer an effective adjunct to conventional treatment that may greatly improve the outlook for those with AMD.

This protocol will explore the pathology, weigh the risks and benefits of conventional treatment, and reveal exciting new scientific findings on innovative natural approaches for ameliorating the effects of AMD.

Prevalence

AMD is the leading cause of irreversible visual impairment and blindness among North Americans and Europeans 60 and older. According to the National Institute of Health, more Americans are affected by AMD than cataracts and glaucoma combined. The eye-health organization Macular Degeneration Partnership estimates that as many as 15 million Americans currently exhibit evidence of macular degeneration (www.amd.org).

Approximately 85-90 percent of AMD cases are the dry form. Wet AMD, which represents only 10-15 percent of AMD cases, is responsible for more than 80 percent of blindness. AMD is equally common in men and women, and has a heritable nature (Klein 2011; Haddad 2006). A positive development is that the estimated prevalence of AMD in Americans 40 and older has decreased from 9.4% in the years 1988-1994 to 6.5% in the years 2005-2008 (Klein 2011).

The retina is the innermost layer of the eye, which contains nerves that communicate sight. Behind the retina is the choroid, which supplies the blood to the macula and retina. In the atrophic (dry) form of AMD, cellular debris called drusen accumulate between the retina and the choroid. The macular degeneration progresses slowly with vision lost painlessly. In the wet form of AMD, blood vessels below the retina undergo abnormal growth into the retina beneath the macula. These newly formed blood vessels frequently bleed, causing the macula to bulge or form a mound, often surrounded by small hemorrhages and tissue scarring. The results are a distortion in central vision and the appearance of dark spots. Whereas the progression of atrophic AMD may take place over years, neovascular AMD can progress in mere months or even weeks (de Jong 2006).

While the exact causes of AMD are not fully understood, recent scientific evidence points to chronic vascular disease, including cardiovascular disease, as a potential cause. Scientists believe that slow degradation of the blood vessels in the choroid, which provides blood to the retina, may lead to macular degeneration.

A complementary theory suggests an alteration in the dynamics of the choroidal blood circulation as an important pathophysiological mechanism. Blockages within the choroidal blood vessels, possibly due to vascular disease, lead to increased ocular rigidity and decreased efficiency in the choroidal blood circulation system. Specifically, the increased capillary resistance (due to blockages) causes elevated pressure, resulting in the extracellular release of proteins and lipids that form deposits known as drusen (Kaufmen 2003).

Cholesterol exists within the drusen. Researchers suggest that the formation of AMD lesions and their aftermath may be a pathological response to the retention of a sub-endothelial apolipoprotein B, similar to a widely accepted model of atherosclerotic coronary artery disease (Curcio 2010). As such, researchers have now found that bio-markers predictive of cardiovascular risk (e.g., elevated homocysteine and C-reactive protein (CRP) levels) are risk factors for AMD (Seddon 2006).

Small drusen are extremely common, with approximately 80% of the general population over 30 manifesting at least one. The depositing of large drusen (≥ 63µm) are characteristic of atrophic AMD, in which this drusen causes thinning of macular tissue, experienced as blurry or distorted vision with possible blank spots in central vision. Drusen continue to accumulate and aggregate with advancing age; those over 75 are 16 times more likely to develop aggregated large drusen compared to those 43-54 (Klein 2007).

Along with drusen formation, there may be deterioration in the elastin and collagen in Bruch’s membrane—the barrier between the retina and the choroids—causing calcification and fragmentation. This, coupled with an increase in a protein called vascular endothelial growth factor (VEGF), allows capillaries (or very small blood vessels) to grow up from the choroid into the retina, ultimately leading to blood and protein leakage below the macula (wet form AMD) (Friedman 2004; Bird 2010).

Other theories postulate that abnormalities in the enzymatic activity of aged retinal pigment epithelium (RPE) cells lead to the accumulation of metabolic byproducts. When the RPE cells become engorged, their normal cellular metabolism is obstructed, resulting in extracellular excretions that produce drusen and lead to neovascularization.

People who have a close relative with AMD have a 50% higher risk of eventually developing it compared to 12% for other people. Scientists believe a newly discovered genetic association will better help predict those at risk and ultimately lead to better treatments (Patel 2008).

Cigarette Smoking. An increased incidence of neovascular and atrophic AMD has been consistently demonstrated among smokers (Thornton 2005; Chakravarthy 2010).

The macular pigment (MP) optical density in 34 cigarette smokers was compared against the MP optical density in 34 non-smokers matched for age, sex, and dietary patterns. It was found that tobacco users had significantly less MP than control subjects. Further, smoking frequency (cigarettes per day) was inversely related to MP density (Hammond 1996).

In a study investigating the relationship between smoking and the risk of developing AMD in Caucasians, 435 cases with end stage AMD were compared to 280 controls. The authors demonstrated a strong association between the risk of both dry and wet form AMD and the amount of cigarette smoking. More specifically, for subjects with 40 pack years (number of pack years = packs smoked per day [x] years as a smoker) of smoking, the odds ratio (probability of the condition occurring) was 2.75 compared with non-smokers. Both types of AMD showed a similar relation; smoking more than 40 pack years of cigarettes was associated with an odds ratio of 3.43 for dry AMD and 2.49 for wet AMD. Stopping smoking was associated with reduced odds of AMD. Also, the risk in those who had not smoked for over 20 years was comparable to non-smokers. The risk profile was similar for males and females. Passive smoking exposure was also associated with an increased risk of AMD in non-smokers (Khan 2006).

Oxidative Stress. The retina is particularly susceptible to oxidative stress because of its high consumption of oxygen, high proportion of polyunsaturated fatty acids, and exposure to visible light. In vitro studies have consistently shown that photochemical retinal injury is attributable to oxidative stress. Furthermore, there is strong evidence suggesting that lipofuscin (a photoreactive substance) is derived, at least in part, from oxidatively damaged photoreceptor outer segments (Drobek-Slowik 2007). While naturally occurring antioxidants typically manage this, environmental factors and stress can decrease circulating antioxidants. For example, levels of the endogenous antioxidant glutathione decrease as people age, making the lens nucleus and retina susceptible to oxidative stress (Babizhayev 2010).

Vitamin C, normally highly concentrated in the aqueous humor and corneal epithelium, helps absorb damaging ultraviolet radiation, protect the basal layer of the epithelium, and prevent AMD (Brubaker 2000). L-carnosine and vitamin E also mitigate oxidative stress and free-radical damage (Babizhayev 2010).

Inflammation. Injury and inflammation to the pigmented layer of the retina (retinal pigment epithelium or RPE) as well as the choroid cause an altered and abnormal diffusion of nutrients to the retina and RPE, possibly precipitating further RPE and retinal damage (Zarbin 2004). Animal studies show that oxidative stress-induced injury to the RPE results in an immune-mediated chronic inflammatory response, drusen formation, and RPE atrophy (Hollyfield 2008).

Research has identified specific genetic changes, which can lead to an inappropriate inflammatory response and set the stage for AMD onset (Augustin 2009). Other studies looking at whether inflammatory markers predicted AMD risk found that higher levels of C-reactive protein (CRP) were predictive of AMD after controlling for genotype, demographic and behavioral risk factors (Seddon 2010; Boekhoorn 2007).

Phototoxicity. Another risk factor for AMD is phototoxicity caused by exposure to blue and ultraviolet (UV) radiation, both of which adversely affect the functioning of RPE cells. Cultured human RPE cells are susceptible to apoptotic cell death induced by Ultraviolet B (UVB) irradiation. Absorption of UV light by the innermost layer of the choroid can largely prevent the cytotoxic effect. (Krohne 2009). Exposure to sunlight without protective sunglasses is a risk factor for AMD (Fletcher 2008).

Hypertension. A study of 5,875 Latino men and women identified a pronounced risk for wet AMD if diastolic blood pressure was high, or if individuals had uncontrolled diastolic hypertension (Fraser-Bell 2008). Prolonged treatment of hypertension with a thiazide diuretic, however, was associated with a more significant incidence of neovascular AMD, possibly due to the known phototoxic effects of thiazide diuretics (De la Marnierre 2003).

Low Carotenoid Intake. Insufficient intake of the following carotenoids is linked to AMD: lutein, zeaxanthin, and meso-zeaxanthin. Lutein, zeaxanthin, and meso-zeaxanthin are carotenoids present in the retina and positively affect MP density (Ahmed 2005). Lutein and zeaxanthin help to prevent AMD by maintaining denser MP, resulting in less retinal tearing or degeneration (Stahl 2005). The therapeutic efficacy of lutein and zeaxanthin in AMD is significant, according to the Lutein Antioxidant Supplementation Trial (LAST), which showed improvement in several symptoms accompanying AMD (Richer 2004).

Low Vitamin B Intake. Several studies show that low levels of certain B vitamins are associated with an increased risk for AMD. The Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS) in 5,442 female health professionals showed that daily supplementation with folic acid, B6 and B12 resulted in significantly fewer AMD diagnoses compared to placebo (Christen 2009).

High Fat Intake. Higher intake of specific types of fat, rather than total fat, may be associated with a greater risk of advanced AMD. Diets high in omega-3 fatty acids, fish and nuts were inversely associated with AMD risk when intakes of linoleic acid (an omega-6 fatty acid) was low (Tan 2009).

A French study found that high total fat, saturated fat and monounsaturated fat intake were all associated with an increased risk of developing AMD (Delcourt 2007). Eating red meat 10 or more times per week appears to increase risk for developing early AMD, while eating chicken more than 3 times per week may confer protection against the disease (Chong 2009a).

High trans fat consumption has been linked to an increased prevalence of late (more advanced) AMD in a study of 6,734 individuals. In the same study, olive oil consumption offered a protective effect (Chong 2009b).

Ethnicity. Studies in the USA indicate that a higher percentage of Caucasian-Americans get macular degeneration compared to African-Americans (Klein 2011).

Dry type macular degeneration develops gradually. Supplementation with antioxidants, lutein and zeaxanthin has been suggested by the National Eye Institute and others to slow the progression of dry macular degeneration and, in some patients, improve visual acuity (Tan AG 2008).

Wet macular degeneration can develop more quickly. Patients require treatment soon after symptoms appear. There were no effective treatments for wet macular degeneration until recently. New drugs, called anti-Vascular Endothelial Growth Factor (anti-VEGF) agents, can promote regression of the abnormal blood vessels and improve vision when injected directly into the vitreous humor of the eye (Chakravarthy 2006; Rosenfeld 2006a,b; Anon 2011b). Photodynamic therapy, a systemic treatment used in oncology to eradicate early-stage cancer and reduce the tumor size in end-stage cancers, has also been used to treat wet AMD (Wormald 2007).

Anti-VEGF Medications. Macugen®, Lucentis®, Avastin®, and others are the newest conventional treatments for wet macular degeneration.

VEGF’s main role is to induce new blood vessel formation. It also functions to increase inflammation and cause fluid to leak out of blood vessels. In wet macular degeneration, VEGF stimulates the formation of abnormal blood vessels in the macular area of the retina. Bleeding, leaking, and scarring from these blood vessels eventually causes irreversible damage to the photoreceptors as well as rapid vision loss if left untreated.

All anti-VEGF medications work in a similar fashion. They bind to and inhibit the biologic activity of VEGF. By preventing VEGF’s action, they effectively reduce and prevent the formation of abnormal blood vessels. They also reduce the amount of leakage and therefore reduce swelling in the macula. These actions lead to preservation of vision in patients with wet macular degeneration.

There are three anti-VEGF medications currently being used. Pegaptanib (Macugen®) selectively binds to a specific type of VEGF called VEGF 165, which is one of the most dangerous forms of VEGF (Chakravarthy 2006). Macugen® has been approved by the Food and Drug Administration (FDA) for treatment of wet AMD. It is administered via intraocular injection given every six weeks.

Ranibizumab (Lucentis®) is also FDA-approved to treat wet macular degeneration. Lucentis® inhibits all forms of VEGF. Lucentis® is administered via monthly intraocular injection.

Bevacizumab (Avastin®) is similar to Lucentis® and works to inhibit all forms of VEGF. Avastin® is currently approved by the FDA for metastatic cancer (cancer that has spread to other parts of the body). This drug is commonly used but is not approved by the FDA for wet AMD. The cost of Avastin® is approximately 90% less than the other two agents.

Since VEGF has also been associated with poor prognosis in breast cancer, Avastin® was previously used as treatment. However, the FDA to pulled approval of Avastin® for breast cancer treatment in November 2011after a review of four clinical studies (FDA 2012). These studies concluded that the drug does not prolong breast cancer patients’ overall survival or slow disease progression significantly. Rigorous clinical trials for Avastin® are being performed by the National Eye Institute. Lucentis® is available free in the UK as long as patients meet certain criteria related to vision. Although the mechanisms of action of the anti-VEGF agents are similar, the success rates between the treatments vary. When Macugen® was first approved, seventy percent of patients stabilized with no further severe visual loss (Gragoudas 2004). Macugen® has not been found to improve vision. Lucentis® improved on the results of Macugen®. Ninety-five percent of Lucentis® patients kept their vision, and nearly 40% of Lucentis® patients completing one year of treatment improved their vision to 20/40 or better (Rosenfeld 2006b).

Because Avastin® is used off-label, and its makers do not plan to seek approval of the drug for AMD, it has not been as thoroughly investigated as either Lucentis® or Macugen® (Gillies 2006). However, many retina specialists believe that Avastin’s® efficacy parallels that of Lucentis® (Rosenfeld 2006b).

Lucentis®, Macugen®, and Avastin® are all administered via intraocular injection. In other words, these medications are injected directly into the eye. The injections are given after the surface of the eye has been cleansed and sterilized. Some doctors will give antibiotic drops prior to the injection. Some form of anesthesia is usually administered. This can be given in the form of drops or as a very small injection of anesthetic around the eye. A very fine needle is used and the actual injection takes only a few seconds.

A fourth intraocular anti-VEGF treatment, the VEGF Trap-Eye, approved in November 2011, appears to require fewer injections compared to Lucentis®, while still offering the same improvements in eyesight over a one year period. In trials of more than 2,400 patients, VEGF Trap-Eye intraocular injections dosed every two months offered the same benefits as Lucentis® dosing monthly (Anon 2011b).

Possible complications are retinal detachment and the development of a cataract. High intraocular pressure usually follows the injection but generally resolves within an hour.

Possible adverse effects of intraocular injections occur in less than 1 percent of every 100 injections (Rosenfeld 2006b). When adverse effects occur, however, they can be very serious and threatening to eyesight. One possible adverse reaction is a serious eye infection known as endophthalmitis, an inflammation of the internal tissues of the eyeball, which sometimes leads to loss of vision or severe damage to the eye.

Photodynamic Therapy (PDT) is a systemic treatment used in oncology by a variety of specialists to eradicate premalignant and early-stage cancer and reduce the tumor size in end-stage cancers. PDT involves three key components: a photosensitizer, light, and tissue oxygen.

Photosensitizing agents are drugs that become active when light of a certain wavelength is directed onto the anatomical area where they are concentrated. It is an approved treatment for wet macular degeneration, and is a more widely preferred treatment that takes advantage of certain unique properties of subretinal neovascular vessels.

Compared with normal blood vessels, neovascular tissue appears to retain the light-sensitive medicine used in photodynamic therapy. After the medicine, verteporfin (Visudyne®) for example, has been injected into a peripheral vein, it can detect abnormal blood vessels in the macula and attach itself to the proteins in the abnormal blood vessels. Laser light of specific wavelengths, which activates photosensitive drugs like verteporfin, is focused through the eye for about one minute. When verteporfin is activated by the laser, the abnormal blood vessels in the macula are destroyed. This happens without any damage to surrounding eye tissue. Because normal retinal vessels retain very little verteprofin, the abnormal subretinal vessels are selectively destroyed. Blood or fluid cannot leak out and damage the macula any further (Wormald 2007).

While verteporfin PDT slowed wet AMD progression, newer anti-VEGF therapies have shown vision improvement in many patients. Combination therapies (PDT + corticosteroid + anti-VEGF) have shown some promise, particularly in certain classes of disease (Miller 2010).

Laser Photocoagulation. Laser photocoagulation (LP) is an effective treatment for wet type AMD. However, LP is limited to the treatment of well-defined, or "classic" subretinal neovascularization, present in only 25% of those with wet type AMD (Anon 2011a). In eligible patients, LP is effective at preventing future vision loss, but it cannot restore or improve vision. In addition, choroidal neovascularization can recur after treatment and cause further vision loss (Yanoff 2004). LP has not worked well on atrophic (dry) AMD.

Surgery. Subretinal surgery has been attempted for AMD. Some surgeries were geared toward the removal of blood and the subretinal neovascular membrane. Another type of surgery attempted to physically displace the macula and move it onto a bed of healthier tissue. Overall, research studies show that the results of surgery are disappointing (Bressler 2004). Vision has generally not improved after surgery (Hawkins 2004). Additionally, the frequency and severity of surgical complications were generally thought to be unacceptably high.

In late 2010, the FDA approved a device called the Implantable Miniature Telescope (IMT) to improve vision in some patients with end-stage AMD. The IMT replaces the natural lens through surgery in only one eye and provides 2X magnification. The other eye is used for peripheral vision. In the clinical trials upon which FDA approval was based, at 1 and 2 years post-surgery, 75 percent of patients had an improvement in their visual acuity of two lines of more, 60 percent improved their vision by three lines, and 40 percent had a four-line improvement on the eye chart (Hudson 2008 and www.accessdata.fda.gov).

Each person may respond differently to the various conventional treatments available for macular degeneration. From a patient’s perspective, it is very important to thoroughly understand wet macular degeneration and its treatment in order to be able to discuss a therapeutic plan with his or her doctor. A specific treatment plan should be tailored to each patient’s needs and disease activity.

The advent of anti-VEGF therapies, for example, has been seen as a significant advancement for patients with wet macular degeneration. It is important to speak with a specialist regarding the benefits and side effects of anti-VEGF drugs to determine if they are appropriate for your specific case. It should be noted that there is some speculation, which is not supported by strong human data, that anti-VEGF macular degeneration treatments may exert systemic effects and negatively impact vascular health by “leaking” from the eye. It is, therefore, important to evaluate your cardiovascular health if you are receiving anti-VEGF treatment for macular degeneration. For instance, a person who recently had a heart attack or has extensive atherosclerosis may opt to avoid anti-VEGF treatments in favor of photodynamic therapy or laser photocoagulation. Individuals receiving anti-VEGF treatments should target an optimal cardiovascular health profile, which includes low-density lipoprotein (LDL) levels below 100 mg/dL, fasting glucose between 80 - 86 mg/dL, etc. For more tips on supporting your cardiovascular health, read our Atherosclerosis and Cardiovascular Disease Protocol.

Research has shown that the hormone dehydroepiandrosterone (DHEA) is abnormally low in patients with AMD (Bucolo 2005). DHEA has been shown to protect the eyes against oxidative damage (Tamer 2007). Because the macula requires hormones to function, an emerging theory hypothesizes that low blood sex hormone levels cause the retinal macula to accumulate cholesterol in an attempt to produce its own hormones (Dzugan 2002). The accumulation of cholesterol in macula may lead to the production of pathologic drusen and subsequent macular degeneration. An inverse association of female hormone with neovascular AMD was observed with current and former use of hormone replacement therapy among Caucasian and Latino women (Edwards 2010). Restoring optimal hormone balance with bioidentical hormones may be an effective new treatment for both men and women. Clinical studies are underway to test this hypothesis and possible hormonal treatment options.

Soy. Soy contains the phytonutrient genistein, which has documented antiangiogenesis properties postulated to be the result of inhibiting VEGF (Yu 2010). This property of inhibiting blood vessel growth is important in limiting abnormal ingrowth of choroidal blood vessels. In mice, genistein inhibited retinal neovascularization and expression of VEGF (Wang 2005).

Food rich in Omega-3 fatty acids. Oily fish (e.g., salmon, tuna, and mackerel) as well as flax seeds are important sources of omega-3 fatty acids, essential for protection against macular degeneration and other diseases (Landrum 2001). A meta-analysis found that patients with a high dietary intake of omega-3 fatty acids had a 38% lower risk of late (more advanced) AMD. Additionally, an association was observed between eating fish two times a week and having a reduced risk of both early and late AMD (Chong 2008).

Macular Pigments: Lutein, Zeaxanthin, and Meso-Zeaxanthin

The relationship between the density of macular pigment (MP) and the onset of AMD is well established. The MP is composed principally of three carotenoids: lutein, zeaxanthin, and meso-zeaxanthin. They represent roughly 36, 18, and 18 percent, respectively, of the total carotenoid content of the retina. They are found within the macula and surrounding tissues, including blood vessels and capillaries which nourish the retina (Rapp 2000).

Lutein, zeaxanthin and meso-zeaxanthin ensure proper functioning of the macula by filtering out harmful ultraviolet light and acting as antioxidants (Beatty 2000; Kaya 2010). During the aging process, there is a decrease in levels of lutein and zeaxanthin; low levels of MPs are linked to AMD (Johnson 2010). An autopsy study on donated eyes found that levels of all three carotenoids were reduced in those with macular degeneration compared to control subjects. The most significant finding, however, was the sharp decrease in meso-zeaxanthin in the macula of macular degeneration subjects (Bone 2000). This postmortem study helped confirm other studies indicating the importance of all three carotenoids in maintaining the structural integrity of the macula (Krinsky 2003). These carotenoids protect the macula and the photoreceptor cells beneath via their antioxidant properties and light-filtering capabilities (Landrum 2001).

Intake of lutein and zeaxanthin is an important preventative measure, but may also reverse the degeneration process when it is ongoing (Richer 2004). Because lutein and zeaxanthin have the tissue-specific characteristic of all carotenoids, their natural tendency is to concentrate in the macula and retina. Consumption of foods rich in these substances is especially important, as they have a direct effect on macular pigment density -- the denser the pigment, the less likely a retinal tear or degeneration will occur (Stahl 2005). Fruits with a yellow or orange color (e.g., mangoes, kiwis, oranges, and vegetables of the dark green leafy, orange and yellow varieties) are sources of lutein and zeaxanthin (Bone 2000).

Unlike lutein and zeaxanthin, meso-zeaxanthin is not found in the diet, but is needed to maintain youthful macular density (Bone 2007). Patients with macular degeneration have been shown to have 30% less meso-zeaxanthin in their macula compared to individuals with healthy eyes (Quantum Nutritionals, data on file). When taken as a supplement, meso-zeaxanthin is absorbed into the blood stream and effectively increases macular pigment levels (Bone 2007).

Anthocyanidins and Cyanidin-3-Glucoside (C3G). C3Gs are critical components of bilberry as well as being powerful antioxidants (Amorini 2001; Zafra-Stone 2007). Positive results have been noted in many animal studies and some human studies using bilberry for macular degeneration as well as other eye disorders including diabetic retinopathy, retinitis pigmentosa, glaucoma, and cataracts (Fursova 2005; Milbury 2007). C3G has been shown to improve night vision in humans by enabling the rods in the eye responsible for night vision to resume functioning faster (Nakaishi 2000). In animal cells, C3G regenerated rhodopsin (the retinal complex that absorbs light) (Amorini 2001). The anthocyanidins in bilberry decrease vascular permeability by interacting with blood vessel collagen so as to slow down enzymatic attack on the blood vessel wall. This may prevent the leakage from capillaries that is prevalent in neovascular AMD. Studies also show that bilberry increases oxidative stress defense mechanisms in the eyes (Milbury 2007). There may be additional benefits by adding vitamin E (Roberts 2007).

C3G, which is highly bioavailable, enhances other functions in the body (Miyazawa 1999; Tsuda 1999; Matsumoto 2001). Its potent antioxidant properties protect tissues against DNA damage, often the first step in cancer formation and aging of tissues (Acquaviva 2003; Riso 2005).

C3G protects endothelial cells against peroxynitrite-induced endothelial dysfunction and vascular failure (Serraino 2003). In addition, C3G fights vascular inflammation by inhibiting inducible nitric oxide synthase (iNOS) (Pergola 2006). At the same time, C3G upregulates activity of endothelial nitric oxide synthase (eNOS), which helps maintain normal vascular function (Xu 2004). These effects on blood vessels are especially important in the retina, where delicate nerve cells depend on the single ophthalmic artery for their sustenance.

In animal models, C3G prevents obesity and ameliorates blood sugar elevations (Tsuda 2003). One way it does this is by increasing gene expression of the beneficial fat-related cytokine adiponectin (Tsuda 2004). Diabetics, of course, are predisposed to severe eye problems including blindness from elevated blood sugar levels.

C3G helps induce apoptosis (programmed cell death) in a number of human cancer lines, an important step in cancer prevention (Fimognari 2004; Chen 2005). In a similar fashion (but via a different mechanism), C3G stimulates rapidly proliferating human cancer cells to differentiate so they more closely resemble normal tissue (Serafino 2004).

Finally, it was discovered that C3G is neuroprotective in experimental cellular models of brain function, helping to prevent the negative effects of the Alzheimer’s-related protein amyloid beta on brain cells (Tarozzi 2010).

Grape Seed Extract. Grape seed extract, a bioflavonoid, is a potent antioxidant. Plant-derived bioflavonoids are readily assimilated into our body when consumed. Bioflavonoids appear to protect retinal ganglion cells (Majumdar 2010). Studies conducted in fruit flies have revealed that grape seed extract attenuates the aggregation of pathologic proteins, which suggests a protective effect against macular degeneration and neurodegenerative disorders. Accordingly, fruit flies administered grape seed extract exhibited improved eye health (Pfleger 2010). Similar experiments in diabetic animals indicate that grape seed extract limits the ocular blood vessel damage seen in diabetic retinopathy (degradation of the retina), which shares some pathological characteristics with AMD (Li 2008).

Compelling laboratory evidence demonstrates that grape extracts can inhibit angiogenesis in human cells (Liu 2010). This suggests that grape seed extract may suppress the aberrant blood vessel growth observed in wet AMD.

Resveratrol. Resveratrol is a potent polyphenolic antioxidant compound produced by grapes and other plants for protection against pathogens. In humans, it exerts a broad range of physiologic effects when ingested orally. Several studies have demonstrated cardioprotective properties of resveratrol, including endothelial protection and attenuation of oxidized-LDL-induced vascular damage (Rakici 2005; Lin 2010). In addition, emerging evidence indicates that resveratrol may combat macular degeneration and promote eye health via several mechanisms. In an animal model, resveratrol was able to stave off diabetes-induced vascular lesions (Kim 2011). Moreover, this same study showed that resveratrol was able to dampen VEGF signaling in mouse retinas, a key pathologic feature of AMD. Another study corroborated these results by showing that resveratrol inhibited angiogenesis and suppressed retinal neovascularization in mice prone to develop macular degeneration due to a genetic mutation (Hua 2011). Also, several laboratory experiments have suggested additional protective mechanisms of resveratrol in macular degeneration, including protecting retinal pigment epithelial cells from hydrogen peroxide-induced oxidative stress and light damage (Kubota 2010; Pintea 2011).

Given these exciting initial findings regarding resveratrol and macular degeneration, along with its stellar track record in a variety of other conditions, Life Extension believes that individuals with AMD (especially the “wet” variety) may benefit from supplementation with resveratrol.

Saffron Extract. Saffron (Crocus sativus) is commonly used as a culinary spice, particularly in regions of the Mediterranean and Middle East where it is native. It also has use as a medicinal herb and contains several carotenoids, including crocin, crocetin, and safranal (Alavizadeh 2014; Fernandez-Sanchez 2015). Preclinical research has found that saffron and its constituents promote healthy retinal blood flow and help protect retinal cells from damage due to light exposure and oxidative stress (Ahmadi 2020; Fernandez-Sanchez 2015; Chen 2015; Xuan 1999; Fernandez-Sanchez 2012).

Multiple clinical trials have shown that saffron may be a viable therapeutic in AMD. In a randomized, controlled, crossover trial, 25 subjects with early AMD were given either 20 mg saffron or placebo daily for three months and then switched to the alternate intervention. Retinal flicker sensitivity, a marker of macular health, improved with saffron but not placebo (Falsini 2010). The researchers then evaluated the longer-term benefits: when 29 subjects with early AMD were given the same dose of saffron for an average of 14 months, not only was retinal sensitivity improved by three months, but visual acuity also improved, with subjects being able to read an average of two more lines on standard vision test charts compared to baseline. Improvements were maintained through the follow-up period of up to 15 months (Piccardi 2012). In another study of people with early AMD, after taking 20 mg saffron per day for an average of 11 months, retinal sensitivity improved whether or not participants had a genetic vulnerability to the condition (Marangoni 2013).

In another study specifically considering dry AMD, 50 mg saffron daily for three months significantly improved visual acuity and contrast sensitivity versus no noted improvements in the control group (Riazi 2017). In a larger crossover study of 100 individuals with mild-to-moderate AMD, 20 mg of saffron given daily for three months significantly improved visual accuracy and a measure of retinal response speed compared with placebo (Broadhead 2019). Saffron has also been shown in clinical and preclinical research to help prevent other common ocular conditions (Jabbarpoor Bonyadi 2014; Makri 2013; Bahmani 2016).

Ginkgo Biloba. Ginko biloba improves microcapillary circulation in the eye and slows deterioration of the macula (Thiagarajan 2002). By inhibiting platelet aggregation and regulating blood vessel elasticity, ginko biloba improves blood flow through major blood vessels and capillaries. Ginkgo is also a powerful antioxidant (Mahadevan 2008).

Glutathione and Vitamin C. Glutathione and Vitamin C are antioxidants found in high concentrations in healthy eyes and in diminished quantities in the eyes of AMD patients. Vitamin C aids glutathione synthesis in the eye. When combined with cysteine, an amino acid antioxidant, cysteine remains stable in aqueous solutions and is a precursor to glutathione synthesis. Vitamin C is important because it absorbs ultraviolet radiation, which contributes to cataracts (Tan 2008). Topical Vitamin C inhibited angiogenesis in an animal model of inflammatory neovascularization (Peyman 2007).

L-Carnosine. L-Carnosine is a naturally occurring antioxidant and anti-glycation agent. Studies have shown that carnosine inhibits lipid peroxidation and free radical-induced cellular damage (Guiotto 2005). Topically applied N-acetyl-carnosine prevented light-induced DNA strand breaks and repaired damaged DNA strands (Specht 2000), as well as improved visual acuity, glare and lens opacification in animals and humans with advanced cataracts (Williams 2006; Babizhayez 2009).

Selenium. Selenium, an essential trace mineral, is a component of the antioxidant enzyme glutathione peroxidase, important in slowing the progression of AMD and other eye disorders including cataracts and glaucoma (Head 2001; King 2008). In mice, increased expression of glutathione peroxidase protected against oxidative-induced retinal degeneration (Lu 2009).

Coenzyme Q10 (CoQ10). CoQ10 is an important antioxidant that may protect against free radical damage within the eye (Blasi 2001). Mitochondrial DNA (mtDNA) instability is an important factor in mitochondrial impairment culminating in age-related changes and pathology. In all regions of the eye, mtDNA damage is increased as a consequence of aging and age-related disease (Jarratt 2010). In one study, a combination of antioxidants including CoQ10, acetyl-L-carnitine, and omega-3 fatty acids improved the function of mitochondria in retinal pigment epithelium and subsequently stabilized visual functions in patients affected by early AMD (Feher 2005).

Riboflavin, Taurine, and Lipoic Acid. Riboflavin (B2), taurine, and R- lipoic acid are other antioxidants utilized to prevent AMD. Riboflavin is a B complex vitamin that reduces oxidized glutathione and helps prevent light sensitivity, loss of visual acuity, as well as burning and itching in the eyes (Lopez 1993). Taurine is an amino acid found in high concentrations in the retina. A taurine deficiency alters the structure and function of the retina (Hussain 2008). R- lipoic acid is considered a “universal antioxidant” because it is fat and water soluble. It also reduces choroidal neovascularization in mice (Dong 2009).

B Vitamins. Recent advances surrounding the causes of AMD have unearthed shared risk factors with cardiovascular disease (CVD) as well as similar underlying mechanisms, particularly elevated biomarkers of inflammation and CVD including C-reactive protein (CRP) and homocysteine (Vine 2005). Researchers have identified that elevated levels of homocysteine, and low levels of certain B vitamins (critical to the metabolism of homocysteine), are associated with an increased risk of AMD and vision loss in older adults (Rochtchina 2007). A strong study found that supplementing with folic acid, B6, and B12 can significantly reduce the risk of AMD in adults with cardiovascular risk factors (Christen 2009). The data, along with additional confirmatory studies, have convinced physicians to recommend B vitamin supplementation in patients with AMD. A study in more than 5000 women indicates that including folic acid (2.5 mg/day), B6 (50 mg/day) and B12 (1 mg/day) in the diet may prevent and reduce the risk of AMD (Christen 2009).

Melatonin. Melatonin is a hormone that regulates circadian processes in the body and has strong anti-inflammatory and free radical-scavenging effects. Melatonin receptors have been identified in organ systems throughout the body, including the eye. In fact, melatonin is now known to be synthesized in the retina, uvea, lens, cornea and ciliary body of the eye, in addition to the pineal gland in the brain (Romeo 2024). Ocular melatonin not only protects the eye from oxidative and inflammatory damage, but it also influences retinal physiology and modulates intraocular pressure (Felder-Schmittbuhl 2024; Rusciano 2024). Because of these properties, it may have a role in mitigating age-related eye disorders like AMD and diabetic retinopathy (Rusciano 2024). The formation of new, abnormal blood vessels in the eye (neovascularization) is a key feature in AMD and diabetic retinopathy, and preclinical studies have shown that melatonin helps reduce the formation of these problematic blood vessels by regulating VEGF secretion (Ma 2024).

Melatonin levels decrease with aging, contributing to increased circadian dysregulation, sleep problems, and possibly AMD (Stepicheva 2019; Tsai 2020). One study that followed 108,255 individuals for an average of 5.1 years found insomnia was associated with an increased risk of developing AMD (Tsai 2020). Observational studies have found that individuals with AMD have lower melatonin levels than those without AMD (Rosen 2009; Lv 2016). Furthermore, preclinical findings suggest retinal melatonin production and receptor expression may also be reduced with aging, and administering melatonin may help reverse retinal degeneration (Parravano 2022; Ku 2023).

In an observational study that examined 15 years of medical data from 121,523 subjects who did not have AMD and 66,253 subjects who had dry AMD at baseline, all aged 50 years and older, supplemental melatonin use was associated with lower risk of developing AMD, as well as a lower risk of progressing from dry to wet AMD (Jeong 2024). A case-control study involving 55 patients with dry or wet AMD who received 3 mg of melatonin per night and were followed for more than six months found that visual acuity was generally stable and pathologic macular changes were reduced in the majority of participants (Yi 2005).

Nutrients Used in the Age-Related Eye Disease Study (AREDS & AREDS2)

The largest and most important studies of nutritional supplements in AMD are the Age-Related Eye Disease Studies (AREDS and AREDS2). The first AREDS demonstrated a reduction in the risk of progression to end-stage AMD when beta carotene (7,500 mcg RAE [15 mg]), vitamin C (500 mg), vitamin E (180 mg [400 IU]), zinc (80 mg), and copper (2 mg) were given daily to people with advanced forms of both wet and dry AMD. Thousands of patients were followed for over six years. The AREDS revealed significant improvements in those with AMD, leading to broad recommendations of the formulation for most patients with AMD, except those with advanced cases in both eyes (Fahed 2010).

Due to controversies surrounding supplementation with beta-carotene—namely, an increased risk of lung cancer observed in current and former smokers—the AREDS2 was conducted to assess the efficacy of an updated formulation. In AREDS2, beta-carotene was replaced with lutein (10 mg) plus zeaxanthin (2 mg). The AREDS2 trial also lowered the dose of zinc to 25 mg in some participants. Over 4,000 participants at risk for progression to advanced AMD were followed for a median of five years. The researchers concluded that lutein plus zeaxanthin could be an appropriate carotenoid substitute for beta-carotene, particularly for former smokers, as the substitution was comparable to the original AREDS formulation. Additionally, the lower dose of zinc did not affect the efficacy (Age-Related Eye Disease Study 2 Research Group 2013).

In a 10-year follow up to the AREDS2, participants who had been randomized to receive lutein plus zeaxanthin had a 20% lower risk of progressing to late AMD than those who had been given beta-carotene (Chew 2022). Importantly, those receiving lutein plus zeaxanthin did not experience a significantly higher risk of lung cancer as seen with beta-carotene, suggesting lutein plus zeaxanthin is an appropriate and effective replacement for beta-carotene in the AREDS2 formula.

Summary

There has been limited success within conventional medical treatment protocols to restore lost eyesight from either form of AMD. Leading researchers are documenting the benefits of more holistic approaches to AMD. Patients are encouraged to increase physical fitness, improve nutrition (including a reduction in saturated fats), abstain from smoking, and protect their eyes from excessive light. Dietary supplementation with trace elements, carotenoids, antioxidants, and vitamins is recommended for improving overall metabolic and vascular functioning. Early screening and patient education offer the most hope for reducing the debilitating effects of the disease.