Ehrlich et al the ubiquitin processing enzymes (Shang and Taylor 2004). Therefore, changes in the ubiquitin pathway compromise protein degradation and contribute to subretinal pigment epithelial protein accumulation, which occurs in both advanced age and AMD. Drusen are subretinal pigment epithelium deposits that are the clinical hallmark of AMD (Sivaprasad et al 2005). There are two classiﬁcations of drusen, depending on where they are located: basal linear and basal laminar deposits. Basal linear deposits accumulate between the basal lamina of the retinal pigment epithelium and the inner collagenous zone of Bruch’s membrane (Sivaprasad et al 2005). Basal laminar deposits are found between the basement membrane and plasma membrane of the retinal pigment epithelium and consist of basement membrane proteins and collagen. The thickness of drusen deposits have been shown to correlate with the degree of retinal pigment epithelium degeneration, photoreceptor fallout, and vision loss (Sarks et al 2007). Drusen size, number, and degree of conﬂuence are signiﬁ- cant risk factors for the development of AMD (Bressler et al 1990). Soft and conﬂuent drusen are a classic clinical hall- mark of AMD. Interestingly, the molecular composition of drusen and the atherosclerotic deposits within blood vessels share many similarities (Sivaprasad et al 2005). Both con- tain vitronectin (a multifunctional plasma and extracellular matrix protein), apolipoprotein E, complement components and lipids (Mullins et al 2000). Nevertheless, a proteonomic analysis comparing drusen in AMD patients and age-matched controls found that although two-thirds of the proteins were similar between the two groups, one-third of the proteins detected in drusen from AMD patients were not found in controls (Crabb et al 2002). Furthermore, it is postulated that the development of drusen is most likely a selective and active process than a passive accumulation of proteins and lipids (Crabb et al 2002). Therefore, drusen formation may be inﬂuenced by an individual’s genetic predisposition or environmental stressors, which helps explain why all aged patients do not develop AMD (Figure 2). With age, drusen can further accumulate on either side of the elastin layer in Bruch’s membrane (Feeney-Burns and Ellersieck 1985). Bruch’s membrane is a connective tissue layer that lies between the metabolically active retinal pigment epithelial cells and the choriocapillaris. It supplies nutrition to retinal pigment epithelial cells (Sivaprasad et al 2005) and regulates ionic and metabolic exchange between the retinal pigment epithelium and choriocapillaries (Ramrattan et al 1994). With age, Bruch’s membrane increases in thickness from 2 μm in the ﬁrst decade of life to 4.7 μm in the 10th 476 decade (Ramrattan et al 1994). Thickened Bruch’s membrane can predispose itself to crack formation (Ciulla et al 2001). In patients with exudative AMD, Bruch’s membrane is more calciﬁed and fragmented than in age-matched controls or patients with nonexudative AMD. These cracks can facilitate the development of choroidal neovascular membranes thus transforming nonexudative to exudative AMD (Spraul and Grossniklaus 1997). The increased thickness of Bruch’s membrane involves both the elastin and collagenous layers and results from decreased degradation and increased production of the extracellular matrix (Zarbin 2004). Matrix mellatoproteinases (MMPs), which play a role in the degradation of extracellular matrix, and the tissue inhibitors of metalloproteinase (TIMPs), which regulate the activity of MMPs, have been found to change with age (Zarbin 2004). Increased content of the inactive form of MMP-2, MMP-9 as well as TIMP-3 have been found in the Bruch’s membrane of aged patients (Zarbin 2004). Additionally, MMPs can facilitate choroidal neovascularization. Activated by VEGF, MMPs break down the extracellular matrix, allowing the growth of new vessels (Steen et al 1998). MMP-2 and MMP-9 have been localized to areas of new vessel development and to the enveloping Bruch’s-like membrane suggesting that these enzymes may be cooperatively involved in the progressive growth of choroidal neovascular membranes in AMD. Neverthe- less, the amounts of noncollagen proteins, lipid deposits, heparin sulfate, laminin, and ﬁbronectin are also increased in Bruch’s membrane with age (Zarbin 2004). Additionally, glycosaminoglycans increase in size and advanced glycation end products accumulate within Bruch’s membrane over time (Zarbin 2004). The accumulation of cholesterol esters in Bruch’s membrane with advancing age is similar to that observed in the arterial intima in atherosclerosis (Curcio et al 2001). This increase in lipid content creates a hydro- phobic environment, which changes the ﬂux of solutes and ﬂuids across Bruch’s membrane (Bird and Marshall 1986). Therefore, changes in thickness, molecular composition and electric charge leads to an age-related loss of permeability in Bruch’s membrane and alters the movement of nutritional factors from the choriocapillaries toward the retinal pigment epithelial layer and subretinal space, thereby affecting the available nutrients for the outer retina (Zarbin 2004). Ocular blood ﬂow changes with age There is a progressive decrease in the thickness of the choroid from 193 μm in the ﬁrst decade of life to 84 μm in the 10th decade (Ramrattan et al 1994). There is also a Clinical Interventions in Aging 2008:3(3)