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Life Extension Magazine

LE Magazine May 2004
The Role of Nutrition in Macular Degeneration
By Dennis L. Gierhard, PhD
Figure 2

How Many Xanthophylls Do We Need?
Determining a daily intake of lutein and zeaxanthin is problematic because food composition tables often do not analyze or report lutein and zeaxanthin separately, and comparisons of published data are often inconsistent. Despite the recommendation by many health agencies to eat at least five servings of fruits and vegetables per day, consumption varies widely.

Several major epidemiological studies have linked dietary carotenoid consumption with reduced risks of macular degeneration and cataract. The dietary gap between low-and high-risk individuals was equivalent to about 6 mg/day of lutein and zeaxanthin.22,25,29-32,39 The data suggest that a difference of 4-5 mg/day in consumption of xanthophylls could influence the risks of contracting eye disease and may be a basis for a maintenance or preventive dosage.

For low-risk individuals, perhaps 3-6 mg/day of zeaxanthin may be extrapolated as a preventive dosage for degenerative eye diseases, though a dose as low as 0.5 mg/day over an entire lifetime may be sufficient. A number of other clinical trials are using 20-30 mg/day of zeaxanthin.

Differences Between Zeaxanthin and Lutein
Zeaxanthin and its chemical cousin, lutein, differ in several important ways. Lutein’s three-dimensional structure is asymmetrical and bent, a perfect fit for its role in harvesting and transferring light energy in the photoreaction center of the chloroplast of a plant cell. As noted previously, this means that the human diet contains 5-20 times more lutein than zeaxanthin. In human blood serum, lutein is 3-10 times more predominant than zeaxanthin.1,2,5,6,38 Zeaxanthin is a straight, symmetrical molecule that can perfectly transverse a biological membrane and influence and protect membrane-bound cellular functions more effectively than lutein, regardless of its orientation.42 This may account for the ocular preference of zeaxanthin over lutein. This selective preference has also been seen recently in human cadaver brain.43 This membrane spanning and greater antioxidant properties may also explain why the retina makes the unusual isomer meso-zeaxanthin (which is structurally closer) from the more abundant lutein. Most likely this is because the eye attempts to supplement the lower intake of preferred dietary zeaxanthin by converting lutein to meso-zeaxanthin, which is better than lutein but not as good as dietary zeaxanthin. This selective deposition and concentration of dietary antioxidants in the macula’s center has also been demonstrated with vitamin E and selenium.7

A misconception among consumers is that they get enough dietary zeaxanthin from their lutein products. A second misconception, even among eye specialists, is that lutein is converted to zeaxanthin in the eye. In fact, lutein comes from marigold flowers and contains only a tiny amount of zeaxanthin compared to the 2:1 ratio seen in the section of the macula that seems to be protected. A second fact is that lutein is converted into a compromise structure, meso-zeaxanthin, in the eye.

Zeaxanthin’s Protective Effects Against Eye Disease
The epidemiological evidence for a protective effect of zeaxanthin in eye health seems reasonably clear but not entirely consistent.3,4,7,9 The surveys from both dietary and blood serum relations of zeaxanthin and eye disease progression of incidence show the normal inconsistencies. Most of the surveys, however, show a clear relationship to both macular degeneration and cataract for dietary intake of fruits and vegetables containing significant quantities of zeaxanthin and lutein. The blood serum relationship data have been less consistent but may have been clarified by the Medical Research Council in England last year.41 Gale and colleagues completed analysis on fasting blood serum levels and analyzed lutein and zeaxanthin separately. They stated, for the first time, that the greatest increased risks of both wet and dry macular degeneration were correlated with low blood serum levels of zeaxanthin, not lutein.

With trials in Japanese quail and primates, the evidence from animal trials has recently become much stronger. In the early 1980s, researchers depleted primate diets of carotenoids and demonstrated retinal pathologies consistent with symptoms of macular degeneration. The studies were extended in the mid-1990s when Dr. C.K. Dorey and colleagues at Harvard Medical School and the Schepens Eye Institute established the Japanese quail as a model for studying degenerative eye disease and xanthophylls.16,44-46 Using aging and light-insult models, Dr. Dorey was the first to show directly that the photo-protective effects of zeaxanthin were related to the retinal levels of zeaxanthin that she controlled by feeding. This retinal protection extended to both rods and cones, and prevented the massive losses seen in late-stage dry macular degeneration. The team also went on to show that zeaxanthin:

  • Protects the eye via reduced cell death
  • Prevents age-related changes
  • Showed a four times greater “retinal capture efficiency” compared to lutein
  • Demonstrated for the first time that dietary manipulation could increase lens levels as much as fivefold, setting up a model for further work in cataract prevention.

Further results with primates have shown that zeaxanthin is more photo-protective (blue laser light insult) than lutein or meso-zeaxanthin.

Increasing the Macular Pigment’s Thickness
It is well established that higher intakes of zeaxanthin and lutein maintain the structure of the macula. The question doctors then asked is whether consumption of these plant extracts can increase the density or thickness of the macula. Human studies have produced fascinating findings indicating that it may be possible to reverse some of the age-related deterioration of the macula.

Doctors can now measure “macular pigment optical density” indirectly and noninvasively by at least six different techniques, though some of these techniques have been subject to criticism. The human trials that measured macular pigment optical density in response to lutein and zeaxanthin intake are summarized in the next column:

  • Both food and supplements con- taining zeaxanthin and lutein are capable of raising retinal levels of the xanthophylls in most, but not all, volunteers. The reason for nonresponsive volunteers has not yet been delineated.4,47-51
  • The retinal response is very slow relative to the blood serum response (months versus days), but appears to remain stable for months upon cessation of supplementation. This suggests that an intervention dosage may need to be significantly higher than a preventive or maintenance dosage and must be maintained to provide the maximum benefit.44-49
  • Peak serum levels and ability to increase macular pigment opti- cal density appear to be related, suggesting that high dietary intake may raise retinal levels faster and more effectively.5,47-51
  • Factors other than peak blood serum levels appear to affect the ability to increase macular pig- ment optical density. These include many of the risk factors for macular degeneration but may also include genetics, obesity, and other serum or retinal transport/binding proteins for the xanthophylls.4,51
  • To date, only one small trial has directly compared the ability of lutein and zeaxanthin to influ- ence macular pigment optical density in humans where bioavailability was directly controlled.48 In this trial, blood serum responses were equal, but more individuals had a retinal response to zeaxanthin.

The association between macular pigment optical density and risk factors for macular degeneration and cataracts is compelling. Reduced macular pigment optical density in the target population has been related to smoking, obesity/high BMI, age, lens density and opacity, gender, light iris, and poor zeaxanthin intake.1,2,4,7,9,47-51

Top 10 Intriguing Facts about Zeaxanthin and the Eye

1. The human eye uses the same xanthophylls, zeaxanthin and lutein (to the exclusion of all others), that the plant world uses to harvest light and protect against excessive light levels.1,4

2. The macula selectively concentrates zeaxanthin and lutein at levels up to 1,000 times greater than found in any other body tissues.1,4

3. The macula selectively places zeaxanthin in its center where the greatest protection is needed and which is last to degenerate.18-20,36

4. The lens also selectively accumulates zeaxanthin and lutein.23

5. Biologically plausible theories for protection with zeaxanthin have been elucidated and are supported by direct experimental evidence in two animal models.16,44,45

6. The concentration of zeaxanthin and lutein in the retina can be increased by dietary manipulation.4

7. The evidence from epidemiological studies is relatively consistent in that high dietary intake of fruits and vegetables rich in xanthophylls reduces the risks of macular degeneration, lens opacity, onset of cataracts, and risks of cataract extraction.4 A recent study suggests serum zeaxanthin is strongly associated with reduced risk of advanced macular degeneration.41

8. Reduced macular pigment optical density is related in most subpopulation studies to major risk factors for macular degeneration and cataracts.4

9. The 2001 AREDS results demonstrate that other dietary antioxidants can intervene in the late stages of macular degeneration, significantly increasing the credibility of one of the theorized protective mechanisms of zeaxanthin.40 There is a good scientific basis for zeaxanthin acting synergistically with other proven dietary antioxidants.32,44,45,60

10. Early results from small clinical studies are consistent with a protective effect but not yet conclusive.

Zeaxanthin and Other Eye Diseases
A half dozen smaller intervention trials using xanthophylls in degenerative eye disease have been completed. Several small trials have shown xanthophylls’ positive impact on visual activity and drusen progression in early maculopathy,52,53 on retinitis pigmentosa, and on visual activity and glare sensitivity in early age-related cataracts.54 (Drusen are nodules beneath the retina in a layer called Bruch’s membrane, which lies beneath the retina and the adjacent retina pigment epithelium layer). Dr. Stuart Richer and colleagues conducted a year-long trial of 90 males with dry macular degeneration, which showed improvements in glare recovery, contrast sensitivity, and near/distant visual activity. 55

The results to date are promising, but larger and longer clinical trials will be necessary to clarify the benefits for patients and eye-care professionals before zeaxanthin supplements will receive an unqualified recommendation. The FDA will need to see statistically relevant data, and the medical community will need to see these functional improvements along with reduced progression of symptoms like area of atrophy, drusen and lipofuscin progression, and reduced risk of neo-vascularization or its progression.

Major trials on intervention in all stages of macular degeneration are in various stages of planning and execution. The largest of these may be the AREDSII trial, with more than 5,000 patients in late-stage macular degeneration. The National Eye Institute and National Institutes of Health are scheduled to begin this trial using lutein and zeaxanthin later this year. Zeaxanthin and lutein were not commercially available for the first trial.

Finally, since zeaxanthin supplements were introduced, many patients who were hypersensitive to light (i.e., photophobic) are reporting dramatic decreases in this unpleasant phenomenon within months of initiating 20 mg/day doses of zeaxanthin. These observations are now being assessed objectively at two colleges of optometry.

Dual Mechanisms of Action
There are currently two leading theories of how xanthophylls (lutein and zeaxanthin) may protect the eye: the first involves the xanthophylls’ antioxidant mechanisms, while the second considers the xanthophylls’ UV-blue light filtering properties. These mechanisms are not mutually exclusive, nor is either the only possible mechanism.1,3,4,7

Both lutein and zeaxanthin are capable of quenching free-radical reactions that create reactive oxygen species. These reactive oxygen species then react with cell membranes and macromolecules to create pathogenesis leading to many human degenerative conditions. In the eye tissues, these oxidative processes can be further enhanced by the presence of light (which accelerates photo-oxidation), extremely high metabolic rates (in the retina), and the highly polyunsaturated lipids found in the retina and other neural tissues. Both singlet oxygen and peroxyl radicals are likely generated in eye tissues and quenched by the xanthophylls.

Light-driven photo-oxidation likely generates excited triplet-state species that also cause severe oxidative damage. As noted earlier, zeaxanthin is a better antioxidant and is more directly embedded in a manner to protect biological cell membranes than is lutein. Xanthophylls are particularly effective at lower oxygen tensions (concentrations) like the interior of a cell membrane or the center of lens tissue. The tocopherols are more effective at higher oxygen tensions. Thus it is highly likely the two lipophilic antioxidants are synergistic and complement ascorbates and the metal-containing enzyme-based antioxidant enzymes that are active in ocular tissues for protection against oxidative damage.

The very earliest steps in eye cells showing oxidative stress are the generation of lipoperoxides.56 In 2000, these very early oxidation markers were shown to directly induce the pathways of angiogenesis or neovasularization.57,58 This means that the earliest step of oxidation may be capable of increasing the risk of progressing to wet macular degeneration.

The second biologically plausible mechanism is UV and blue-light filtering or absorption. The xanthophylls are excellent light filters and absorb that part of the UV and blue-light spectrum thought to be most damaging to the eye. In the lens, the xanthophylls absorb the UV light thought to be the principal initiator of oxidative stress that results in cross-linking of the component crystalline that in turn reduces the clearness of the lens. The xanthophylls would also reduce the amount of blue light reaching the retina. The absorption of blue light in the lens and from reflection in the retina would reduce light scatter and chromatic aberrations. This would suggest a more direct role in reducing visual effects like glare and starburst effects seen in early stages of these diseases.7

This blue-light filtering may directly reduce the photo-oxidation in the susceptible axons and likely reduces photo-oxidative damage directly in the photoreceptors and posterior retinal pigmented epithelium cells that support and maintain the photoreceptors.

In the critically important retinal pigmented epithelium cells insulted with blue light, zeaxanthin has been shown to prevent oxidative damage, apoptosis, DNA damage, and cell death. In these cell culture experiments, zeaxanthin shows synergy with the other cellular protectants vitamins C and E, glutathione, and melanin.60

Theories of Aging Explain Degenerative Eye Disease
Readers of this magazine are aware of most theories of aging, and almost all are implicated in degenerative, age-related changes in the human eye. The eye has several special considerations. It must deal with light-accelerated degeneration, and the back of the eye has one of the highest oxygen levels, metabolic rates, and cellular turnover rates, as well as susceptible components (polyunsaturated lipids).7 The back of the eye seems to be a microcosm for atherosclerosis susceptibility, and appears to be at the interface of the blood-brain barrier (i.e., neural retina). The lens is subject to constant ultraviolet insult, a low metabolic rate, and operating in a low oxygen context.

These two disparate and opposing functions are within an inch of each other inside the eye. Readers should also know that caloric restriction, the almost universal environmental anti-aging influence, has also been shown to slow degeneration or aging of the eye.

In addition to its role in the photo-oxidative mechanism of degenerative eye disease, it is likely that zeaxanthin also participates through other protective biological mechanisms. Because age-related eye degeneration is probably multi-etiological, it is likely zeaxanthin helps provide protection at multiple levels.1,4,7,35

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