We propose that establishing 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 carotinoids 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 that that reduces that 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 inflamation 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 inflamation 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. Malfuntioning 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.
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 Cummulative Blue Light Exposure Substantially
Promotes the Development of Age-related Macular Degeneration (AMD) is scientifically valid unless it can be
1) Any of the 4 premises stated above is not valid,
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.
1. 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."
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, according to Dr Bernstein.
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."
Current 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.
A recent review, Effects of Blue Light on the Circadian System and Eye Physiology. Molecular Vison:(2016) summarizes current understanding of the role of blue light in the development of AMD.
"Experimental evidence indicates that wavelengths in the blue part of the spectrum (400-490 nm) can induce damage in the retina, and although the initial damage following exposure to blue light may be confined to the RPE, a damaged RPE eventually leads to photoreceptor death. Although most studies on the effects of blue light have focused on the mechanisms responsible for the damage to the photoreceptors following an acute exposure to high intensity light, some studies have reported that sub-threshold exposure to blue light can also induce damage in photoreceptors. In addition, several authors have proposed that the amount of blue light received during an individual's entire lifespan can be an important factor in the development of age-related macular degeneration (AMD)."
The paper concludes:
"Because light has a cumulative effect and many different characteristics (e.g., wavelength, intensity, duration of the exposure, time of day), it is important to consider the spectral output of the light source to minimize the danger that may be associated with blue light exposure....Although we are convinced that exposure to blue light from LEDs in the range 470-480 nm for a short to medium period (days to a few weeks) should not significantly increase the risk of development of ocular pathologies, this conclusion cannot be generalized to a long-term exposure (months to years)."
The concern these authors express relates to blue light wavelengths from indirect ambient lighting emitted by LEDs providing white light. As the authors explain:
"The white-light LED (i.e., the most common type of LED) is essentially a bichromatic source that couples the emission from a blue LED (peak of emission around 450-470 nm with a full width at half max of 30-40 nm) with a yellow phosphor (peak of emission around 580 nm with a full width at half max of 160 nm) that appears white to the eye when viewed directly. ...
The specific pump wavelength of the phosphor in the range 450-470 nm depends critically on the absorption properties of the phosphor. ... white-light LEDs degrade over time primarily through bleaching of phosphors so that they no longer efficiently absorb blue light. This shifts the color temperature of the device over time, with a corresponding change in the color-rendering index but, more importantly, an increasing blue emission from the device with time."
Several papers in the February 2016 issue of the journal Eye discussed the hazardous effect of blue light exposure on the retina. These papers related to studies on the effect of blue light wavelengths from indoor and outdoor lighting on people with artificial lenses implanted due to cataracts, or concerns about blue light exposure from the increased use of LEDs in general indoor lighting. These concerns relate to exposure to the relatively low intensities of indirect indoor ambient lighting. These intensities are much, much lower than the high intensities of light emitted by white or blue light therapy lamps, which provide direct light exposure of the eye from the therapy lamp.
With regard to blue light exposure of people undergoing cataract surgery, one paper, Ultraviolet or Blue-Filtering Intraocular Lenses: What is the Evidence?, stated:
"With the arrival of blue-filtering intraocular lenses (BFIOLs) in 1990's, a further debate was ignited as to their safety and potential disadvantages. ... The potential disadvantages raised in the literature over the last 25 years since their introduction, regarding compromise of visual function and disruption of the circadian system, have been largely dispelled. The clear benefits of protecting the retina from short-wavelength light make [blue-filtering intraocular lenses] BFIOLs a sensible choice"
With respect to ambient lighting, another paper Light in Man's Environment by a different research group, stated:
"Many studies have demonstrated the spectral dependence of eye health, with the retinal hazard zone associated with wavelengths in the blue, peaking at 441 nm - many of today's low-energy sources peak in this region. Given the increased longevity and artificial light sources emitting at biologically unfriendly wavelengths, attention has to be directed towards light in man's environment as a risk factor in age-related ocular diseases."
Some studies that discuss the state of retinal damage from blue light exposure examine the protective proprties of the carotinoids lutein, zeaxanthin, and meso-zeaxanthin that make up the layer of blue light filtering macular pigment that forms in the inner retina, and through which light must pass to reach the photoreceptors adn RPE cels in the outer retina. These carotinoids are not produced by the body and are obtained though diet or supplements. Several studies have shown that the lower the density of this pigment, that is, the more blue light that is able to pass throgh this layer to reach the outer retina the greater the likelihood of developing AMD.
A few comments from one of these studies, The Photobiology of Lutein and Zeaxanthin in the Eye. Journal of Ophthalmology, Dec 2015, are:
"In adults, the lens absorbs UV-B and all the UV-A (295-400 nm); therefore only visible light ([wavelengths] >400 nm) reaches the retina".
"short-wavelength blue visible light damages the retinas of those over 50 years of age through a photooxidation reaction with an accumulated chromophore, lipofuscin. Lipofuscin...is mainly derived from the chemically modified residues of incompletely digested photoreceptor outer segments. Photoreceptor cells (rods and cones) shed their outer segments (disc shedding) daily to be finally phagocytosed (digested) by RPE cells." ... "In response to [Upon the absorption of] short blue visible light, lipofuscin efficiently produces singlet oxygen and lipid peroxy radicals; there is also some production of superoxide and hydroxyl radicals."
"short-wavelength blue visible light damages the retinas of those over 50 years of age through a photooxidation reaction with an accumulated chromophore, lipofuscin ... a blue light singlet oxygen photosensitizer, leading to damage to RPE cells. Because the rods and cones survival is dependent on healthy RPE, these primary vision cells will eventually die, resulting in a loss of (central) vision (macular degeneration) and other retinopathies"
"Ocular exposure to sunlight, UV, and short blue light-emitting lamps directed at the human eye can lead to the induction of cataracts and retinal degeneration. This process is particularly hazardous after the age of 40 because there is a decrease in naturally protective antioxidant systems and an increase in UV and visible light-absorbing endogenous phototoxic chromophores that efficiently produce singlet oxygen and other reactive oxygen species."
Current studies, including History of Sunlight Exposure is a Risk Factor for Age-Related Macular Degeneration. Retina, 2016 Apr;36(4):787-90. continue to find that increased exposure to sunlight over a lifetime increases the likelihood of developing AMD. Since only the visible light wavelengths from sunlight reach the retina, see previous reference, these studies support the premise that cumulative exposure to visible blue light wavelengths contributes to the development of AMD.
PURPOSE: To evaluate effects of current and past sunlight exposure and iris color on early and late age-related macular degeneration (AMD)
CONCLUSION: Sunlight exposure during working life is an important risk factor for AMD, ... Therefore, preventive measures, for example, wearing sunglasses to minimize sunlight exposure, should start early to prevent development of AMD later in life.
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