As people age, their bodies change, so do their eyes. Biologic eye changes are strong factors resulting in Age-Related Macular Degeneration. Retinal aging and AMD shape a fraction of a continuous worsening, in which the change between aging and disease is signaled by the start of blindness. Scientists however, thought that the Retinal Pigment epithelium is the main factor that causes ADM, but current studies has shown other multiple causes to this disease. As people age, oxidative stress, genetic factors, vascular factors such as hypertension and arteriosclerosis, and environmental factors had more time acting upon them and cause alterations that lead to disorders such as AMD (Ioseliani, 2005).

With aging, DNA slowly becomes deleted and rearranged which causes abnormalities in the cells and extracellular matrix of the eye. This results in the ECM’s abnormal biosynthesis, post-synthetic modifications, and degradation. The cells become slowly altered, has less proliferation, and the components of the ECM becomes over expressed. Apoptosis or programmed cell death and anoikis, detachment of a cell from the basement membrane, is caused by this abnormal ECM and cell interactions (Zarbin, 2004).

There are changes that occur in the RPE, Bruch’s membrane and choriocapillary that causes a chronic inflammatory response in the eye. These damages cause basal laminar and drugen deposits that hinder the normal distribution of nutrients to the retina therefore causing an injury to the outer retina. Neovascularization and retinal choroidal atrophy then results. Moreover, retinal ischemia results in injury to its internal part due to losing of blood vessels and basal vascular membrane and internal limiting membrane thickening (Ioseliani, 2005). In turn, the retinal macroglia (Astrocytes and Muller cells) are induced to become reactivated and eventually die. As a result, the inner retina experiences induced neuronal death.  Retinal ischemia could arouse the movement of Muller cells and Astrocytes to the vitreous humor in search for metabolic reserves, comprising the epiretinal membranes. Inspite of every factor that may have contributed to ADM, ischemia may be the primary reason for exhibiting this disease (Ioseliani, 2005).

As in the case of a lot of postmitotic cells, lipofuscin collects in RPE cells throughout life. Lipofuscin has taken 1% of the RPE’s cytoplasmic volume at some point in the initial decade of life and 19% of the cytoplasmic’s volume by the period 80 years (Zarbin, 2004). Decrease in purposeful cytoplasmic volume may compromise RPE’s function that can direct to photoreceptor loss. By production of reactive oxygen class, lipofuscin might encourage oxidative injury in the RPE and nearby tissues and may reduce RPE lysosomal enzyme action. Studies found a linear affiliation among Bruch membrane thickness and RPE autofluorescence, which states that aging changes in the RPE and Bruch membrane may be linked (Okubo, 1999).

During the tenth decade of life, the Bruch membrane thickness can linearly increase from about 2 ?m at birth to about 4 to 6 ?m (Ramrattan, 1994). The thickening of the Bruch membrane can be caused by the over production and low levels of dilapidation of the extracellulcar material. Throughout the process of aging, the abnormal RPE cells can produce dysfunctional amounts of ECM matter, including collagen, other basement membrane material and other cell fragments. Age-related Bruch membrane thickening may also be strengthened by an impaired capability for ECM degradation. Age-related declines in choriocapillaris lumen width and thickness may as well lessen clearance of remains from the Bruch membrane that could have a way to thickening with time (Zarbin, 2004).

There is continuous diminishing in the width of the choroid beginning from 200 ?m at birth to 80 ?m by 90 years old (Pauleikhoff, 1990). The choriocapillaris’ bulk and lumen diameter is reduced, and the breadth of the intercapillary pillars adds with aging.  In examination of these various histologic changes, it is not unexpected that subfoveolar choroidal blood surge will diminish with time. Bruch membrane thickening may be the reason for age-related choriocapillary changes by impairing distribution of these materials to the choriocapillaris.

Oxidative Stress and Environmental Factors

Free radical damage is the leading cause of oxidative stress and aging is highly linked with an increased rate of oxidative damage (Wallace, 1997). Even though the vision loss of AMD comes from photoreceptor injury in the central retina, the first pathogenesis involves deterioration of RPE cells. Facts from a number of researches propose that RPE cells are defenseless to oxidative damage. Mitochondrial DNA (mtDNA) is chiefly vulnerable to oxidative injury compared to nuclear DNA (Liang, 2003). RPE’s susceptibility to oxidative stress increases with age (Zarbin, 2004). The RPE’s component of lipofuscin is responsibe for attracting the oxidative damage. A number of stimulants of reactive oxygen specie production in the environment such as smoke, air pollutants, aging, inflammation, irradiation and increased partial pressure of oxygen target the retinal pigment epithelium. The metabolites derived causes damage to the nuclear and cytoplasmic components of the cell and trigger changes in the extracellular matrix. Qxidative stress destroys choriocapillary and retinal cells. For the choriocapillary cells, the vascular epithelium’s lesion makes changes within the vascular vessels, which alters the flow of blood that leads to ischemia. In the retina, oxidative stress causes deterioration of the RPE and an increased amount of lipofuscin adds up in its interior halting the normal functions of the cell (Ioseliani, 2005). This leads to chronic inflammatory reaction inside the choroid and Bruch membrane (Zarbin, 2004).

Plasma vitamin C, vitamin E, glutathione, macular pigment’s optical density and lipid peroxidation decreases due to oxidative damage. Zinc is vital for the role of a number of antioxidant enzymes (eg, catalase, metallothionein and superoxide dismutase) and is the main copious trace element in an individual’s eyes. Outcome of the Age-Related Eye Disease Study (2001) points to oxidative damage playing a function in the progression of the disease in its clinically obvious intermediate and delayed stages and that AMD progression can be changed with supplementation of antioxidants. This acts by halting the construction of initiating radicals, for binding metal ions, and removing injured molecules. The antioxidant enzymes make up the main defense in opposition to oxidative RPE injury (Cai, 1999).

The environment’s UV rays can also cause AMD. During an individual’s lifetime, light is being focused onto the retina. The consequential photooxidative stress causes chronic or acute damage to the retina. The pathogenesis of AMD is involved with oxidative stress and fatality of the RPE followed by loss of the overlying photoreceptors (King, 2004). Facts suggest that injury owing to exposure to light plays a function in AMD. Stimulation of mitochondria-derived reactive oxygen species (ROS) is publicized to engage a significant role in the loss of cells exposed to the short-wavelength blue light. Cell death and ROS are blocked either by mitochondria-specific antioxidants or stopping the mitochondrial electron transport chain. These outcomes confirm that mitochondria are a vital source of noxious oxygen radicals in the blue light-exposed cells of the RPE and might point out to new approaches for treatment of AMD by means of mitochondria-targeted antioxidants.

Genetic Factors

            At the present time, it seems probable that AMD is a polygenic disorder with several genes conferring resistance and vulnerability from the disease. Studies found out that degenerations connected with mineral/lipid deposits that are in the Bruch membrane are frequently autosomal dominant and that the patients are repeatedly asymptomatic until maturity (Kruntz, 1996). ABCR gene mutations have been linked with a high risk for atrophic AMD, but results from a few studies specify that the detected mutations might simply be polymorphisms (Allikmets, 1997). The ABCR, or also called rim protein, is a transmembrane protein that might be concerned in retinoid transport. Hereditary background interacts with contact to the environmental hazard and protecting factors to conclude period of disease onset for a certain individual. Genetics may have an effect on the defenselessness to develop AMD in the subsequent way (Robert, 1998). Cellular construction of ECM is hereditarily controlled. Epigenetic factors can modify the ECM.

Three separate groups of researchers all pinpointed CRF gene, a complement for factor H, that is concerned in a material of the immune system for regulating inflammation (Herzlich, 2008). This adds a big answer to the many questions related to ADM. The important factor in determining the possibility of getting macular degeneration is a person’s family history (Schmidt, 2000).  The three groups at Yale University, Rockefeller University in New York, Duke University in North Carolina, UT Southwestern scanned the gene maps and DNA sequences of individuals with AMD and their family. Every group had CFH as a resulting gene. This is the primary study to spot a common variant of the gene being linked with AMD. Caucasian AMD patients are at the least three times further to contain one particular modification in the CFH gene that makes a dissimilar form of the CFH protein compared to persons without the disorder (Grassi, 2006). AMD takes decades to progress so scientists may use samples taken from individuals decades ago for more studies and analyze them to know more about CFH mutation

There are still numerous puzzling questions about AMD. For now, and always, prevention is still the best cure. The learning of genetic factors may give some insight to the state in which known mutations can be studied and the nature of the biochemical pathways that are concerned in AMD pathogenesis. Presently, nobody has the capacity tell precisely how this will add to a treatment. But this can lead to the best treatments someday. Today, more than 1.75 million people are affected by age-related macular degeneration in the United States. This number will reach at about 3 million by the year 2020 due to the fast aging of America’s population (Friedman, 2004). So it’s better for everyone to take measures to stop the progression of this disease. You’ll never know. It may be starting its development in any susceptible individual right now.

References

Age-Related Eye Disease Study Group. (2001) A randomized, placebo-controlled clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and visual loss. Arch Ophthalmol, 119 1417-1436.

Allikmets R, Shroyer NF, Singh N, et al. (1997) Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science. 277 1765-1766.

Cai J, Wu M, Nelson K, Jones DP, Sternberg P Jr. (1999). Oxidant induced apoptosis in cultured human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 40 959-966.

Friedman, D. (2004). Prevalence of age-related macular degeneration in the United States.Arch Ophthalmology, 122(4) 564-572.
Grassi, M. (2006). Ethnic variation in AMD-associated complement factor H polymorphism p.Tyr402His. Human Mutation, 27 921-925.

Herzlich, A. (2008). Peroxisome Proliferator-Activated Receptor and Age-RelatedMacular Degeneration. PPAR Research. 1-11.

Ioseliani, O. (2005) Focus on Eye Research. New York : Nova Science Publishers, Inc.
King A, Gottlieb E, Brooks DG, Murphy MP, Dunaief JL. (2004) Mitochondria-derived Reactive Oxygen Species Mediate Blue Light-induced Death of Retinal Pigment  Photochem Photobiol. 79(5) 470-475.
Kuntz CA, Jacobson SG, Cideciyan AV, et al. (1996) Subretinal pigment epithelial deposits in a dominant late-onset retinal degeneration. Invest Ophthalmol Vis Sci, 37 1772-1782.

Liang FQ, Godley BF. (2003) Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells Experimental Eye Research, 76(4) 397-403
Okubo A, Rosa RH Jr, Bunce CV, et al. (1999) The relationship of age changes in retinal pigment epithelium and Bruch’s membrane. Invest Ophthalmol Vis Sci., 40 443-449.

Pauleikhoff D, Harper CA, Marshall J, Bird AC. (1990 )Aging changes in Bruch’s membrane: a histochemical and morphologic study. Ophthalmology,97 171- 178.

Ramrattan RS, van der Schaft TL, Mooy CM, de Bruijn WC, Mulder PGH, de Jong PTVM. (1994) Morphometric analysis of Bruch’s membrane, the choriocapillaris and the choroid in ageing. Invest Ophthalmol Vis Sci.,35 2857-2864.

Robert L, Peterszegi G.(1998)Aging and matrix biology. Pathol Biol, 46 491-495.

Schmidt, S. (2000)Association of the Apolipoprotein E gene with age-related macular degeneration: Possible effect modification by family history, age, and genderMolecular Vision,  6 287-293.

Wallace DC, Brown MD, Melov S, Graham B, Lott M.(1998) Mitochondrial biology, degenerative diseases and aging. Biofactors. 7 187-190.

Zarbin, M. (2004) Current Concepts in the pathogenesis of Age Related Macular Degeneration. Arch Opthalmology, 122 598-614.