Advanced glycation endproduct-induced aging of the retinal pigment epithelium and choroid: A comprehensive transcriptional response

Abstract

Advanced glycation endproduct (AGE) formation is a trigger for the onset of age-related disease. To evaluate AGE-induced change in the ocular fundus, 5-mo-old C57BL͞6 mice were given low-dose D-galactose (D-gal) for 8 wk and evaluated by AGE fluorescence, electroretinography (ERG), electron microscopy, and microarray analysis for 20 wk. Although AGE fluorescence was increased in D-gal-treated retinal pigment epithelium (RPE)-choroid compared with controls at all time points, ERG showed no AGE-induced functional toxicity. Progressive ultrastructural aging in the RPEchoroid was associated temporally with a transcriptional response of early inflammation, matrix expansion, and aberrant lipid processing and, later, down-regulation of energy metabolism genes, up-regulation of crystallin genes, and altered expression of cell structure genes. The overall transcriptome is similar to the generalized aging response of unrelated cell types. A subset of transcriptional changes is similar to early atherosclerosis, a chronic inflammatory disease characterized by matrix expansion and lipid deposition. These changes suggest an important contribution of a single environmental stimulus to the complex aging response.transcriptome ͉ basal deposit ͉ Bruch's membrane A ging is a multifactorial process associated with physiological decline. Prior efforts to comprehensively identify and evaluate contributory factors have benefited from global assessment strategies such as microarray analysis. Although some general trends in the transcriptional responses to aging have been identified in diverse tissues such as skeletal muscle, cardiac muscle, and brain, the aging kidney is without modification (1-4).Normal vision requires a functional retinal pigment epithelium (RPE)-Bruch's membrane (BM)-choroid to sustain the neurosensory retina. Photooxidative stress, photoreceptor outer segment shedding, lipid peroxidation, high metabolic requirements, and increased oxygen demand result in high levels of oxidative stress to the fundus. As a result, with aging, the RPE and choriocapillaris endothelium dedifferentiate (5, 6). The most significant changes are basal deposits that develop within BM, a pentalaminar matrix that includes the RPE and choriocapillaris endothelial basement membrane (5, 6). The location and composition of the deposits correlates with the development of age-related disease (5, 6). The molecular events surrounding basal deposit formation, however, are poorly characterized.Advanced glycation endproducts (AGEs) are a heterogeneous group of reaction products that form between a protein's primary amino group and a carbohydrate-derived aldehyde group. A substantial amount of literature indicates that AGEs exacerbate and accelerate aging change and contribute to the early phases of age-related disease, including atherosclerosis, cataract, neurodegenerative disease, renal failure, arthritis, and age-related macular degeneration (AMD) (7,8). We found that AGEs accumulate with age in human BM and immunolocalize to basal deposits (9-11). We...

The expression of advanced glycation endproduct receptors in rpe cells associated with basal deposits in human maculas

“…Our long term hypothesis is that AGEs trigger accelerated RPE aging and promote the transition to age-related macular disease. In mice given an AGE stimulus, we showed ultrastructural aging to Bruch's membrane including basal laminar deposits and transcriptional evidence of aging including induction of inflammation, extracellular matrix expansion, lipid processing abnormalities, cell structure abnormalities, and induction of cell stress molecules by the RPE-choroid (Tian et al, 2005). Beside alterations to the supramolecular structure of Bruch's membrane, AGEs induce an altered cellular phenotype through interaction with a number of receptors.…”

Vascular endothelial growth factor in eye disease

“…Oxidative stress and VEGF expression in AMD-Oxidative stress has been proposed in AMD through several mechanisms (Cai et al, 2000;Spaide et al, 2003), including blue light-induced photochemically released oxidants that damage photoreceptors (Margrain et al, 2004), cigarette smoke-related oxidants such as hydroquinone that alter Bruch's membrane (Espinosa-Heidmann et al, 2006), iron induced oxidative damage to the outer retina (Dunaief, 2006), and possibly through AGE within Bruch's membrane (Tian et al, 2005). Oxidants have been reported to increase the deposition of oxidized proteins or other compounds in Bruch's membrane (Espinosa-Heidmann et al, 2006).…”

D-Galactose Induces a Mitochondrial Complex I Deficiency in Mouse Skeletal Muscle: Potential Benefits of Nutrient Combination in Ameliorating Muscle Impairment

“…Although some researchers have challenged the D-gal-induced aging model, 2,3 some other researchers indicate that D-gal-treated animals showed some hallmarks of aging, such as a shortened lifespan, 4 cognitive dysfunction, 5 presbycusis, 6 increased oxidative stress, 4,7 decreased antioxidant enzyme activity, 8 diminished immune responses, 9 increased advanced glycation endproducts, 10 accumulation of mitochondrial DNA mutations, 11 and mitochondrial dysfunction. 5,12 Mitochondria are not only the major sites of intracellular reactive oxygen species (ROS) production, but also targets of ROS.…”