can precede the development of AMD (Liang and Godley 2003). With advancing age, retinal pigment epithelial cells undergo an increase in pleomorphism, a decrease in the concentration of cells in the posterior pole, and decreased melanin content (Salvi et al 2006). Senescent retinal pigment epithelial cells accumulate metabolic debris from remnants of incomplete degradation of phagocytized rod and cone membranes (Ciulla et al 2001). Fatty acids from the outer segment receptors are degraded by lipid peroxidation, a process that increases with age in the macula (Zarbin 2004). Susuki et al (2007) found oxidized phospholipids present in photoreceptors and retinal pigment epithelial cells in the macula of the normal eyes, with increased quantities with advanced age. Metabolic debris includes lipofuscin, an undegradable byproduct of outer segment photoreceptor metabolism, which increases in concentration within retinal pigment epithelial cell cytoplasm over time (Feeney-Burns et al 1984). It is believed that lipofuscin and fatty acids are continuously exposed to light and high oxygen tension, which initiates the production of reactive oxygen species (Zarbin 2004). It is further postulated that these cause oxidative damage to the cellular mitochondria and to mitochondrial DNA, which is most susceptible to this oxidative stress (Liang and Godley 2003). Injury to the mitochondria leads to a reduction in energy production, compromises cellular and physiologic functioning, and can subsequently signal apoptosis in retinal pigment epithelial cells (Liang and Godley 2003; Zarbin 2004). Increased apoptosis eventually causes a decreased number of retinal pigment epithelial cells (Cai et al 1999). In order to counteract the formation of reac- tive oxygen species, retinal pigment epithelial cells contain anti-oxidants, which decrease with age (Liang and Godley 2003). The Age-Related Eye Disease Study (AREDS) has demonstrated that the administration of anti-oxidants, such as vitamins B, C, E, and zinc, signiﬁcantly slows the rate of progression from high-risk nonexudative AMD to exudative AMD (AREDS 2001). Retinal pigment epithelial cell damage also leads to the production of an abnormal extracellular matrix, which alters retinal pigment epithelium function, and causes choriocapil- lary loss associated with geographic atrophy (Zarbin 2004). Damaged retinal pigment epithelial cells can promote an inﬂammatory response that has been implicated in the devel- opment of AMD and the development of neovascularization (Moshfeghi and Blumenkranz 2007). Once damaged, these retinal pigment epithelial cells can secrete growth factors, such as vascular endothelial growth factor (VEGF), basic ﬁbroblast growth factor (bFGF), and transforming growth Clinical Interventions in Aging 2008:3(3) AMD of the aging eye factor beta (TGF-ß). These cytokines play a major role in the formation of choroidal neovascularization in AMD (Lutty et al 1999). Recent evidence suggests that within the eye, there is a ﬁne balance between endogenous angiogenic and anti-angiogenic growth factors. Imbalances between these factors can lead to choroidal neovascularization (Bhutto et al 2006). VEGF has been found to be one of the key angiogenic growth factors. The family of VEGF proteins, including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PlGF, exert their function through tyrosine kinase receptors (Andreoli and Miller 2007). VEGF has been shown to be present in choroidal neovascularization membranes (Otani et al 2002). Conversely, pigment epithelium derived factor (PEDF) is a potent endogenous anti-angiogenic growth factor. PEDF has been shown to signiﬁcantly suppress VEGF-induced prolif- eration and migration of vascular endothelial cells (Bhutto et al 2006). Decreased PEDF levels have been reported in the vitreous samples of exudative AMD patients (Holekamp et al 2002). Choroidal PEDF immunoreactivity is also reduced in AMD patients compared to age-matched controls (Bhutto et al 2006). Currently, medications targeting VEGF, such as bevacizumab and ranibizumab, are widely used in the treat- ment of neovascular AMD. Future therapies may involve anti-angiogenic growth factors, such as PEDF. Various other proteins can also inﬂuence the pathogenesis of AMD. One such molecule, ubiquitin, is an intracellular protein that regulates numerous cellular processes, such as cell-cycle progression, signal transduction, transcriptional regulation, and endocytosis (Hershko and Ciechanover 1998). It has been implicated in immune responses and apoptosis (Hershko and Ciechanover 1998). Ubiquitin is prominent in ganglion cells, retinal pigment epithelium and age-related subretinal pigment epithelium deposits (Shang and Taylor 2004). The ubiquitin pathway involves two steps. The ﬁrst phase is ubiquitination whereby a substance that needs to be degraded is tagged with speciﬁc amino acid sequences. Subsequently, tagged molecules undergo proteolytic degra- dation through ubiquitin processing enzymes. This process allows damaged or obsolete proteins to be degraded before they aggregate within the cytoplasm. Over time, this pro- tective pathway becomes compromised (Shang and Taylor 2004). Additionally, hydrogen peroxide (H2O2) increases the level of oxidized glutathione, which further interferes with ubiquitination (Shang and Taylor 2004). Ubiquitin, without the active ubiquitin processing enzymes, is found in subretinal pigment epithelial deposits (Shang and Taylor 2004). It is speculated that with age, ubiquitinated proteins in retinal pigment epithelial cells do not undergo degradation by 475