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While there are several major clinical intervention trials in early stages of execution, the critical, convincing evidence for the ophthalmology community is not yet in. In the absence of this clinical evidence, a critical systematic evaluation of other evidence is warranted. For this review, the Mares-Perlman 2002 modification of Hill's classic guideline for linking causal relationships between environmental factors and disease state will be used. In addition, a short summary of interesting ancillary evidence will also be listed.
1. Biological Plausibility. Evidence that a valid, scientific theory for ocular protection is consistent with and backed up by evidence from animal or cell culture experiment is very important. Good correlation between experimental theories and actual observations in cell culture, animal models, or humans greatly enhances the validity of a concept. There are currently two leading theories of how lutein and zeaxanthin may protect the eye, the UV-blue light filtering, and the antioxidant mechanisms. Neither mechanism is mutually exclusive nor the only possible mechanism.
a. Antioxidants. Both lutein and zeaxanthin are capable of quenching free-radical reactions that create Reactive Oxygen Species (ROS) that 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 due to the presence of light (which accelerates photooxidation), extremely high metabolic rates (retina) and by the highly poly-unsaturated 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 photooxidation likely generates excited triplet state species that also causes severe oxidative damage. It is firmly established that plants use lutein to dissipate excessive photon and heat energy from the reaction center. However, under very stressful or high light exposure conditions, plants use the "zeaxanthin cycle" or even zeaxanthin directly to protect the plant cell. As stated earlier, zeaxanthin is a better antioxidant and is more directly embedded in a manner to protect cell membranes than 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, and, 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.
b. UV and Blue Light Filtering. The xanthophylls are also excellent light filters and absorb that part of the UV and blue spectrum thought to be most damaging to the eye. In the lens, the xanthophylls absorb the U.V. light thought to be a principal oxidative stress that results in cross-linking of the component crystallins that in turn reduces the clearness of the lens. The lens 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. This blue light filtering may directly reduce the photooxidation in the susceptible axons (Henle fiber) and likely reduces photooxidative damage directly in the photoreceptors and posterior RPE cells that support and maintain the photoreceptors. Besides antioxidant and UV-near blue light filtering protective mechanisms there are other plausible mechanisms possible. Because eye diseases have multi-factorial causes, it is reasonable that xanthophylls may intervene in other possible routes to pathogenesis. These are listed below:
c. Xanthophylls and Other Plausible Biological Mechanism for Preventing Eye Disease
i. Reduced Drusen Accumulation. The progression of drusen, a lipid rich compound observable in eye exams, is a major AMD biomarker.
ii. Inflammation. Inflammatory responses have been implicated in AMD pathology possibly through ROS production. Carotenoids have been inversely related in epidemiological studies to the inflammation biomarker, c-reactive protein.
iii. Cell to Cell Communications. Xanthophylls can modify communications between cells through modification of gap-junction proteins. Zeaxanthin is, perhaps, the only natural molecule that could directly link the inside of a cell to the outside of a cell membrane. Could they modify communications between RPE cells and photoreceptors?
iv. Gene Expression. Xanthophylls can modify gene expression and have been postulated to be an internal "Red-ox indicator."
v. Apoptosis (programmed cell death). Zeaxanthin has been directly shown in animal models to directly slow and/or prevent apoptosis of photoreceptors presumable by interfering upstream from the genes and cell signals responsible.
vi. Lysosomal Stability. By stabilizing lysosomal membranes, xanthophylls may allow natural clean-up processes to proceed.
vii. Membrane Ordering. The membranes in ocular tissues consist of highly polyunsaturated lipids. While xanthophylls clearly provide antioxidant support, these membranes would be highly fluid.
2. Consistency of Protective Effect in relationships across human population and among various studies.
3. Temporality. The evidence for the protective effect of the xanthophylls is strengthened when the development of the eye diseases are measured before, during, and late in the disease state. Such evidence rules out the possibility that diet, serum, or eye levels are a consequence of the disease and not an antecedent or preventative effect. This data is provided by prospective epidemiological and clinical intervention data.
4. Strength of Relationship Between Xanthophyll Intake and Risks for Eye Disease. Strong relationships are indicated by large odds rations or relative risks and consistent findings lower the likelihood of the observations being artifacts.
5. Specificity of the Relationship of Xanthophylls to Eye Disease. This evidence, gathered from large prospective studies, rules out that the relationship is some other non-causal effect like other lifestyle, environmental or other dietary effects. This is difficult data to generate. |