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Bo Yu, Zhen-Yang Zhao, Yiqin Zuo, Pei Xu, Paul Sternberg, Yan Chen; Age-Associated Changes of mTOR Signaling in The Retinal Pigment Epithelium. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1381.
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The mammalian target of rapamycin (mTOR)-mediated signaling network is a central regulator of aging. Inhibiting mTOR is a promising strategy for treating various age-related diseases including macular degeneration (AMD). The goals of our current study are to investigate whether mTOR signaling has age- and/or pathology-associated changes in the retinal pigment epithelium (RPE) and to explore the functional roles of mTOR pathway in RPE aging and degeneration.
Post-mitotic aging of cultured human RPE cells was induced by altering the medium nutrient compositions. Basal and stimulated activities of mTOR were determined by measuring the phosphorylation status of downstream substrate proteins including S6K and S6. Subcellular localization of mTOR was evaluated using flat mounts of RPE/choroid tissue obtained from wild type and knockout mice deficient of nuclear factor erythroid 2-related factor 2 (Nrf2) at different ages. The in vivo activity of mTOR was further assessed by immunofluorescence staining of histology sections from young and aged animals.
In the newly established in vitro aging model, post-mitotic RPE cells expressed typical markers of aging, such as senescence associated-beta-galactosidase and CDK inhibitor p16. Aged RPE cells showed increased sensitivity to amino acid-induced S6 phosphorylation and increased staining of lysosome marker proteins. Elevated mTOR activity was also detected in aged RPE in vivo. In addition, immunostaining of RPE flat mounts showed increased lysosome distribution of mTOR with aging.
mTOR-mediated signaling pathway displayed age-related changes in the RPE. The subcellular location of mTOR is related to its activity and can be influenced by lysosome function during the processes of RPE aging and degeneration. (Supported by NIH grants EY 019706, EY 021937 and Research to Prevent Blindness, Inc.)
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