Establishing that Blue Light Exposure Contributes
to the Development of AMD

Repetitive Exposure to Blue Light Contributes to Advanced Onset of AMD

We believe that a strong case can be made for the proposition that increased macular pigment optical density (MPOD)is protective of AMD, and that it is independent from other risk factors for AMD provides a logically sufficient basis to demonstrate that blue light exposure contributes to the development of AMD*.

Macular pigment (MP) is located in the inner retina above the macular region of the retina. Light must pass through this layer of MP to reach the macular region of the outer retina. The outer retina contains the photoreceptor cells, and is adjacent to a monolayer of retinal pigment epithelial (RPE) cells and the Bruch's membrane complex. AMD develops in the macular region of the outer retina and is characterized by the malfunctioning and death of the RPE cells and an alteration of the properties of the Bruch's membrane complex which results in the death of photoreceptor cells in this region of the retina.

MP is a blue-light absorbing yellow pigment containing the xanthophyll carotenoids, lutein, zeaxanthin and meso-zeaxanthin. In some people macular pigment prevents up to 95% of incident blue light wavelengths from reaching the outer retina, but does not appear to adversely affect vision or color acuity. Macular pigment density is affected by diet or supplements, specifically by consumption of the carotenoids lutein and zeaxanthin, as these carotenoids are not produced within the body. The amount of blue light reaching the outer retinal region is inversely proportional to macular pigment density. There is a growing consensus that an increased density of MP, and the corresponding reduction in blue light reaching the outer retina, results in a substantial delay in the onset of AMD.^{1, 1a}

As the layer of macular pigment is located in the inner retina, it is remote from the metabolic activities involved in the pathogenesis of AMD which occur in the outer retina. The generation of radical oxygen species(ROS) in RPE cells and the resulting increase in oxidative retinal stress in the outer retina is integral to the development of AMD. The primary mechanisms by which ROS are generated in RPE cells are dependent upon, or substantially enhanced by the absorption of blue light. Increased absorption of sub-lethal amounts of blue light by RPE cells contributes to long-term increased generation of ROS. When ROS levels exceed the RPE cell's anti-oxidative capacity, the result is increased levels of retinal oxidative stress which induces a low grade chronic inflammatory response in the outer retina and adjacent tissues.

The most obvious manner by which an increased density of MP can influence the development of AMD is through the filtration of ROS-generating blue light, thus reducing the amount of blue light that reaches the outer retina. This would reduce the production of ROS and the retinal stress in the macular region. However, because the retina is very thin in the region of the foveal pit, located near the center of the macula, and since constituent macular pigment carotenoid molecules have been found in outer retina in that region, some have posited it is the increased levels of these carotenoid molecules, which have strongly anti-oxidative properties, that give rise to the protective quality of increased macular pigment density. The possibility cannot yet be ruled out that of the multitude of endogenous and nutritional molecules that contribute to protection of the retina from oxidative stress, it is the increase in the number of carotenoid molecules from a denser macular pigment diffusing into the outer retina that is the dominant protective factor for AMD.

It immaterial to this proposition whether the protection from AMD is provided by increased macular pigment density limiting the amount of ROS-generating blue light that reaches the outer retina, or whether the protection from AMD is the consequence of the increased neutralization of radical oxygen species generated by higher number of macular pigment carotenoid molecules within the outer retina. A measurable inverse relationship between MPOD and susceptibility to AMD establishes that blue light exposure contributes substantially to the development of AMD. The increased oxidative retinal stress and resulting chronic low grade inflammation in the outer retina is integral to the development of AMD.^2,3 Unless there is an alternative method not involving the countering of the effects from exposure to blue light by which an increase of MPOD can inhibit the development of AMD this inverse relationship between MPOD and susceptibility to AMD establishes the relationship between blue light exposure and AMD.

To summarize, we propose it can now be established that chronic low grade inflammation of the outer retina, which involves the activation of complement as an element of the inflammatory response, is a fundamental element in the development of AMD. We assert that the chronic inflammation in the macular region of the outer retina is caused by heightened levels of oxidative stress, ie. the production of levels of ROS that exceed the capacity of endogenous anti-oxidative protective mechanisms to keep retinal stress below the threshold that induces an inflammatory response and the activation of the complement system.

We further assert that it is the absorption of blue light by elements within the outer retina that is responsible for chronically elevated levels of ROS production within the RPE cells adjacent to the macular region of the retina that is the cause of long term oxidative stress in the outer retina. As well, over time, blue light absorption in retinal and RPE cells s contributes to the permanent destruction of protective mechanisms in the outer retina. The increased levels of ROS generation in older, malfunctioning RPE cells, together with the reduced capacity of protective mechanisms of older RPE cells to alleviate oxidative stress, results in a chronic low grade inflammatory responses and the development of AMD.

We propose that the following 4 premises are sufficient to establish that blue light exposure substantially advances the onset of AMD. Based on the considerable published evidence that supports each of these 4 statements there appears to be a general consensus on the validity of these premises. Thus, while there are many gaps in the understanding of the pathogenesis of AMD, we believe it can still be established that blue light exposure substantially contributes to the pathological development of this debilitating condition.
The 4 premises are:

1) Chronic low grade inflammation in RPE cells is implicated in the pathogenesis of AMD.

2) The inflammatory response in the outer retina, which includes activation of the complement system, is induced by heightened levels of oxidative stress in the outer retina.

3) Blue light absorption (i.e. absorption of visible light with wavelengths shorter than 480 nm) is primarily responsible for photo-induced generation of ROS in the outer retina. This includes ROS generation within RPE cells resulting from absorption of blue light by mitochondria, nuclear DNA, lipofuscin, and remnants of photoreceptor cells. Malfunctioning of RPE cells contributes to the formation of basal deposits and drusen adjacent to PE cells and the Bruch's membrane complex.

4) Macular pigment optical density (MPOD) is an independent risk factor for AMD. While the acceptance of this premise is not universal, and some are awaiting the confirmation of this by AREDS II, a large scale study which is seeking to establish the veracity of this premise, there appears to be a growing consensus among the researchers most actively examining the effects of increased MP density that this is now established, We note that the determination that MPOD is an independent risk factor reflects a substantial time difference (several years) between the development of AMD in people with high MPOD as compared with people with low MPOD.

*Comments:

Scientific inference is a process by which a conclusion is arrived at through logical deduction based on a set of reasonable premises. Scientific inference, or logical deduction, is an essential process of science and widely used in theoretical physics and chemistry. While these logical deductions are often made using mathematical arguments, any logically based argument is equally valid. In biology scientific inference is not often applicable because the complexity of biological systems makes it difficult to formulate an adequate set of well established premises to describe the aspects of a biological system from which a logical conclusion can be derived.

It appears that sufficient knowledge now exists to allow the determination by scientific inference that cumulative blue light exposure promotes the development of AMD. Determination that the derived conclusion is not valid would rest on the demonstration that either one or more of the premises used are not correct, that a significant element has not been included in the premises, or that the process of logical deduction is faulty. Thus, if at any time the conclusion would be found to at variance with valid empirical results, this would establish that either one or more of the premises are not correct, significant information was not included in the premises, or that the process of logical deduction was flawed.

Therefore we believe the conclusion that Cumulative Blue Light Exposure Substantially Promotes the Development of Age-related Macular Degeneration (AMD) is scientifically valid unless it can be established that;
1) Any of the 4 premises stated above is not valid,
or
2) An alternate mechanism based on empirical evidence can be proposed in which increased macular pigment optical density can reduce the incidence of AMD without reducing the level of retinal oxidative stress resulting either from the generation of ROS by the absorption of blue light in the outer retina region, or by the reduction of oxidative stress in the outer retina through anti-oxidative actions of the constituent carotenoids of macular pigment.

REF¹ The following is taken from an interview with Dr. Paul Bernstein, one of the foremost experts on the formation and function of macular pigment, as quoted in Ophthalmology Times Europe, Apr 1, 2010. "Lutein and zeaxanthin are concentrated specifically in the macula and are derived exclusively from the diet. They act as antioxidants and light-screening compounds in the eye," he said. "The Eye Disease Case-Control Study showed that there is an inverse correlation between serum carotenoid levels and exudative AMD."
In a subsequent ancillary study, subjects who consumed the highest levels of lutein and zeaxanthin from sources such as spinach and collard greens had a 43% lower risk of AMD.
Dr Bernstein said. "Our research has shown that there is a decrease in the levels of macular pigment in patients at risk of developing AMD," "About thirty percent lower levels of macular pigment are found in patients with AMD or those who are at high risk of AMD. These levels can be modified by the diet."
According to Dr Bernstein, the location of the carotenoids in the retina is ideal to screen blue light. Animals raised on carotenoid-free diets appear to be more susceptible to light damage in their retinas.

REF^1a The following is taken from a report on a panel discussion by a group of experts on the relationship between Macular Pigment Optical Density and AMD held at the American Optometry Association in June 2010.
The panel discussion was titled "The Value of Macular Pigment Optical Density (MPOD) for Age-Related Eye Diseases and Visual Performance." The panel of experts including Paul S. Bernstein, M.D., Francois C. Delori, Stuart Richer, Erik J.M. van Kuijk and Adam J. Wenzel collectively reviewed the scientific literature. A key conclusion from the panel presented at a press conference was that "The current body of evidence supports the hypothesis that AMD is in part a manifestation of an ocular deficiency of lutein and zeaxanthin and that higher macular levels may protect against AMD." The report further explains - "MPOD is a measurement of the attenuation of blue light by the macular pigment and is linearly related to the amount of lutein and zeaxanthin in the macula. More than 250 published studies support that the macular pigments, lutein and zeaxanthin, are essential nutrients for maintaining healthy vision."

Research continues to validate and confirm the propositions outlined on these pages regarding the cumulative exposure of light on the retina and vision over a lifetime, and the role of blue light as a major contributing factor in the development of age-related blindness from macular degeneration. View a few of these recent references here.