RPE cell senescence: A key contributor to age-related macular degeneration
Introduction
Age related macular degeneration (AMD) was responsible for 8.7% of all blindness worldwide in 2007, and this figure is expected to double by 2020 as a result of population aging [1]. AMD is the most common cause of blindness in industrialized countries [1]. In the United States, for example, 10% of all individuals between 65 and 75 years of age, and 30% of those over 75 years of age, have a visual impairment related to AMD [2].
A number of risk factors have been discovered for the development and progression of AMD. They include age, smoking, obesity, female gender, Caucasian race, positive family history, hypertension, cardiac disease, atherosclerosis, high dietary intake of certain types of fats (exclusive of omega-3 fatty acids), heavy alcohol consumption, Alzheimer’s disease, hearing loss, and low circulating levels of endogenous antioxidants (for reviews see [3], [4]). Several complement system-related genes have also been linked to increased risk for AMD, including a polymorphism in the complement factor H gene that may be responsible for over half of the attributable AMD risk (for review see [5]). Other factors have been identified that decrease AMD risk, including elevated dietary intake of omega-3 fatty acids [6], high serum levels of vitamin D [7], [8], exposure to exogenous estrogen [9], [10], and exercise [11].
The pathognomonic signs of early AMD are the presence in the macula of pigmentary changes and of discrete extracellular depositions of abnormal material, called drusen [2], [3], [4]. The pigmentary changes take place at the level of the retinal pigmented epithelial (RPE) cells, and are believed to reflect a dysfunction or partial loss of these cells [3], [4], [12]. Late in the disease, pigmentation may be disrupted across large areas of the macula with attendant loss of central vision, a condition known as geographic atrophy [2], [3], [4], [12]. Production of the material comprising drusen may also result from a deficit in RPE functioning involving the metabolism of photoreceptor end segments [3], [4], [5], [12]. As the disease progresses, small discrete drusen coalesce into larger deposits with indistinct borders called soft drusen [2], [3], [4]. These structures form between the basement membrane of the RPE and the outer layer of the choroid, and may promote the growth of the choroidal blood vessels through this area and into the retina [2], [3], [4]. When choroidal neovascularization (CNV) occurs, the newly-formed vessels are leaky and the material that is released can produce rapid and severe macular damage and vision loss [2], [4]. AMD in which CNV has developed is called “wet” AMD, and it is less common than other manifestations of the disease, which are considered “dry” AMD [2], [4], [12].
There are several hypotheses concerning the cause of AMD. One which has received considerable attention proposes that oxidative damage to the RPE cells is chiefly responsible (for review see [4], [13]). Increased oxidative stress is an element of several of the risk factors associated with AMD, such as cigarette smoking and lower circulating levels of endogenous anti-oxidant molecules. Normal structural changes in the retina that occur with aging, such as the thickening of Bruch’s membrane, which separates the choroid from the retina, could elevate oxidative stress by producing poorer perfusion of RPE cells by the choroidal circulation [4], [14]. Oxidative damage could also occur through the accumulation of reactive waste products such as A2E, a component of lipofuscin which is formed during the catabolism of photoreceptor outer segments by RPE cells [4], [13]. A2E forms reactive epoxides when exposed to short wavelength light [13]. Another proposed cause of AMD is the presence of chronic inflammation in the retina (for review see Refs. [5], [15]). This mechanism is consistent with the increased risk for AMD associated with certain polymorphisms in immune mediator genes [5], [16], [17], [18]. It would also account for the frequent presence of immune response products in drusen [5]. Yet another proposed cause of AMD is a reduction in the level of the miRNA-processing enzyme, DICER1 [19]. Reduced levels of this enzyme were found in the retinas of patients with geographic atrophy, and conditional ablation of the dicer1 gene in mice induced RPE cell degeneration.
There are currently no approved therapies for AMD when it is in its early stages. Moderate to late stages can be treated with an antioxidant vitamin cocktail that decreases the risk of further progression by approximately 30% (AREDS formulation; [20]). The effectiveness of antioxidant treatment is consistent with the hypothesis that oxidative damage causes the pathology of AMD. VEGF inhibitors have proven effective in treating the CNV that occurs in wet AMD, suggesting that new vessel growth is VEGF dependent (for review see Ref. [21]). Other treatments that have shown positive results in treating AMD include intraocular implants that release ciliary neurotrophic factor (CNTF), which is thought to improve the viability of photoreceptors; systemic administration of fenretidine to block A2E production [22], [23]; RPE transplantation [24], [25]; and subretinal implantation of RPE cells derived from stem cells (thus far only shown effective in animal models, but currently in human trials) [26].
Advancing age is the most obvious predisposing factor for the development of AMD. Visual loss from AMD is uncommon in people under 50 years of age but rises to a prevalence of nearly one-third in those over 75 [1]. A biological change linked to many other diseases associated with aging is cell senescence (for review see Refs. [27], [28], [29], [30], [31]). Several lines of evidence suggest that senescence also contributes to AMD. First, RPE cells exhibit senescence when grown continuously in culture [32], [33]. Second, senescent RPE cells have been observed in primate retinas [34]. Finally, several of the proposed causes of AMD can be linked to senescence. For example, oxidative cell damage accelerates senescence and immune dysregulation can be produced by senescence [35], [36]. Findings such as these raise the possibility that RPE cell senescence plays a key role in the pathology of AMD. This paper will explore whether or not such a role is consistent with what is currently known about the signs, risk factors, and successful treatments of AMD.
Section snippets
Senescence and it effect on RPE cells
Senescence, also known as replicative senescence, refers to the induction of a non-dividing state in otherwise mitotically competent cells. Telomere erosion is a major biological trigger for senescence (for review see Ref. [27]). Telomeres are long stretches of DNA found at the ends of chromosomes that consist of tandem repeats of a short sequence element. Loss of telomeric DNA occurs during cell division because the end of the lagging strand of the chromosome cannot be fully replicated [37].
Choroidal neovascularization (CNV)
CNV is an extension of new choroidal vasculature through Bruch’s membrane, the outer boundary of the choroid, and into the space under the RPE or the retina [2], [3], [4]. The process of new blood vessel growth in the adult eye is controlled by a balance between endogenous promoters of new vessel formation, such as VEGF, and endogenous inhibitors. In addition, discontinuities in the RPE cell layer and its underlying membrane promote the development of CNV [42].
Cell senescence has been shown to
Omega-3 fatty acid intake
A recent study has shown that women with the highest intake of omega-3 fatty acids or the highest dietary intake of fish, a source of omega-3 fatty acids, had a significantly reduced risk for developing AMD [6]. Another study also found higher levels of omega-3 fatty acids associated with a reduced risk for AMD, but only when levels of linoleic acid (an omega-6 fatty acid) were low [53]. The latter result may be due to the risk-lowering effect of omega-3 fatty acids being eclipsed by the
High levels of antioxidant vitamins and zinc
In the AREDS study [20], a combination of high doses of vitamins A, C, and E together with a high dose of zinc (and copper to prevent zinc toxicity) reduced the odds of progressing from moderate to advanced stages of AMD by approximately 30%. Interestingly, both the vitamins alone and the zinc alone significantly reduced progression. The combination of the two was more effect than either alone, but the increase was less than additive. This suggests the possibility of two interacting mechanisms
Summary and conclusions
The hypotheses that RPE cell senescence plays a key role in the pathology of AMD is able to account for the majority of the signs and risk factors of AMD, and to rationalize the success of effective treatment regimens. None of the other mechanisms proposed for the etiology of AMD, including oxidative damage [4], [13] and chronic inflammation [5], [15], has such broad explanatory power. A central role of RPE cell senescence in AMD would mirror the important contribution of cell senescence to
Conflict of interest statement
None declared.
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