Dissecting Regulators of Aging and Age-Related Macular Degeneration in the Retinal Pigment Epithelium.

Autor: Karunadharma PP; Department of Ophthalmology and Visual Neurosciences, University of Minnesota Twin Cities, MN 55455, USA.; Graduate Program in Biochemistry, Molecular Biology, And Biophysics, University of Minnesota Twin Cities, Minneapolis, MN 55455, USA., Kapphahn RJ; Department of Ophthalmology and Visual Neurosciences, University of Minnesota Twin Cities, MN 55455, USA., Stahl MR; Department of Ophthalmology and Visual Neurosciences, University of Minnesota Twin Cities, MN 55455, USA., Olsen TW; Department of Ophthalmology and Visual Neurosciences, University of Minnesota Twin Cities, MN 55455, USA., Ferrington DA; Department of Ophthalmology and Visual Neurosciences, University of Minnesota Twin Cities, MN 55455, USA.; Graduate Program in Biochemistry, Molecular Biology, And Biophysics, University of Minnesota Twin Cities, Minneapolis, MN 55455, USA.
Jazyk: angličtina
Zdroj: Oxidative medicine and cellular longevity [Oxid Med Cell Longev] 2022 Nov 16; Vol. 2022, pp. 6009787. Date of Electronic Publication: 2022 Nov 16 (Print Publication: 2022).
DOI: 10.1155/2022/6009787
Abstrakt: Age-related macular degeneration (AMD), the leading cause of blindness in elderly populations, involves the loss of central vision due to progressive dysfunction of the retinal pigment epithelium (RPE) and subsequent loss of light-sensing photoreceptors. While age is a key risk factor, not every aged individual develops AMD. Thus, the critical question is what specific cellular changes tip the balance from healthy aging to disease. To distinguish between changes associated with aging and AMD, we compared the RPE proteome in human eye bank tissue from nondiseased donors during aging ( n = 50, 29-91 years) and in donors with AMD ( n = 36) compared to age-matched donors without disease ( n = 28). Proteins from RPE cells were separated on two-dimensional gels, analyzed for content, and identified using mass spectrometry. A total of 58 proteins displayed significantly altered content with either aging or AMD. Proteins involved in metabolism, protein turnover, stress response, and cell death were altered with both aging and AMD. However, the direction of change was predominantly opposite. With aging, we detected an overall decrease in metabolism and reductions in stress-associated proteins, proteases, and chaperones. With AMD, we observed upregulation of metabolic proteins involved in glycolysis, TCA, and fatty acid metabolism, with a concurrent decline in oxidative phosphorylation, suggesting a reprogramming of energy utilization. Additionally, we detected upregulation of proteins involved in the stress response and protein turnover. Predicted upstream regulators also showed divergent results, with inhibition of inflammation and immune response with aging and activation of these processes with AMD. Our results support the idea that AMD is not simply advanced aging but rather the culmination of perturbed protein homeostasis, defective bioenergetics, and increased oxidative stress within the aging RPE, exacerbated by environmental factors and the genetic background of an individual.
Competing Interests: The authors declare no conflict of interest for information presented in this study.
(Copyright © 2022 Pabalu P. Karunadharma et al.)
Databáze: MEDLINE
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