Dataset Information

Effect of aging and lifestyle on photoreceptors and retinal pigment epithelium: cross-sectional study in a healthy Danish population.

ABSTRACT: Photoreceptors and their supporting retinal pigment epithelium constitute the key functional parts of the retina. Here, a study was undertaken to show how aging and lifestyle factors affect the photoreceptor layer and the retinal pigment epithelium and Bruch's membrane complex (RPE-BM) in vivo in a healthy Danish population using spectral-domain optical coherence tomography. This was a cross-sectional study of healthy humans aged ?50 years. All participants were interviewed for medical history and lifestyle factors. Maculae of all participants were scanned using spectral-domain optical coherence tomography. The thickness of the photoreceptor layer and the RPE-BM was measured on one eye from each participant. In 150 eyes of 150 participants, it was found that aging was associated with a decrease in the thickness of the photoreceptor layer (-0.143 ?m/year, P = 0.031) and an increase in the thickness of the RPE-BM layer (0.100 ?m/year, P = 0.029) at the foveal minimum. Regarding lifestyle factors, alcohol intake or BMI were not associated with any significant trend, but physical inactivity and smoking had effects on the photoreceptor layer (decreased thickness) and the RPE-BM layer (increased thickness) indicating an accelerated aging process of the macula. Taken together, aging affects photoreceptors and the RPE-BM, and these aging trends are accelerated in smokers and the physically inactive.

SUBMITTER: Harris J

PROVIDER: S-EPMC5678353 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effect of aging and lifestyle on photoreceptors and retinal pigment epithelium: cross-sectional study in a healthy Danish population.

Harris Jacob J Subhi Yousif Y Sørensen Torben L TL

Pathobiology of aging & age related diseases 20171105 1

Photoreceptors and their supporting retinal pigment epithelium constitute the key functional parts of the retina. Here, a study was undertaken to show how aging and lifestyle factors affect the photoreceptor layer and the retinal pigment epithelium and Bruch's membrane complex (RPE-BM) <i>in vivo</i> in a healthy Danish population using spectral-domain optical coherence tomography. This was a cross-sectional study of healthy humans aged ≥50 years. All participants were interviewed for medical hi ...[more]

PMID: 29152163

Similar Datasets

Project description:Lipofuscin accumulates with age in the retinal pigment epithelium (RPE) in discrete granular organelles and may contribute to age-related macular degeneration. Because previous studies suggest that lipofuscin contains protein that may impact pathogenic mechanisms, we pursued proteomics analysis of lipofuscin. The composition of RPE lipofuscin and its mechanisms of pathogenesis are poorly understood in part because of the heterogeneity of isolated preparations. We purified RPE lipofuscin granules by treatment with proteinase K or SDS and showed by light, confocal, and transmission electron microscopy that the purified granules are free of extragranular material and associated membranes. Crude and purified lipofuscin preparations were quantitatively compared by (i) LC MS/MS proteomics analyses, (ii) immunoanalyses of oxidative protein modifications, (iii) amino acid analysis, (iv) HPLC of bisretinoids, and (v) assaying phototoxicity to RPE cells. From crude lipofuscin preparations 186 proteins were identified, many of which appeared to be modified. In contrast, very little protein ( approximately 2% (w/w) by amino acid analysis) and no identifiable protein were found in the purified granules, which retained full phototoxicity to cultured RPE cells. Our analyses showed that granules in purified and crude lipofuscin preparations exhibit no statistically significant differences in diameter or circularity or in the content of the bisretinoids A2E, isoA2E, and all-trans-retinal dimer-phosphatidylethanolamine. The finding that the purified granules contain minimal protein yet retain phototoxic activity suggests that RPE lipofuscin pathogenesis is largely independent of associated protein. The purified granules also exhibited oxidative protein modifications, including nitrotyrosine generated from reactive nitrogen oxide species and carboxyethylpyrrole and iso[4]levuglandin E(2) adducts generated from reactive lipid fragments. This finding is consistent with previous studies demonstrating RPE lipofuscin to be a potent generator of reactive oxygen species and supports the hypothesis that such species, including reactive fragments from lipids and retinoids, contribute to the mechanisms of RPE lipofuscin pathogenesis.

Project description:Age-related macular degeneration (AMD) is the leading cause of vision loss in the western world. Recent evidence suggests that RPE and photoreceptors have an interconnected metabolism and that mitochondrial damage in RPE is a trigger for degeneration in both RPE and photoreceptors in AMD. To test this hypothesis, this study was designed to induce mitochondrial damage in RPE in mice to determine whether this is sufficient to cause RPE and photoreceptor damage characteristic of AMD. In this study, we conditionally deleted the gene encoding the mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD encoded by Sod2) in the retinal pigment epithelium (RPE) of albino BALB/cJ mice. VMD2-Cre;Sod2flox/flox BALB/cJ mice were housed in either 12-h dark, 12-h 200 lux white lighting (normal light), or 12-h dark, 12-h <10 lux red lighting (dim light). Electroretinography (ERG) and spectral-domain optical coherence tomography (SD-OCT) were performed to assess retinal function and morphology. Immunofluorescence was used to examine protein expression; quantitative RT-PCR was used to measure gene expression. Sod2 knockout (KO) mice had reduced RPE function with age and increased oxidative stress compared to wild type (WT) controls as expected by the cell-specific deletion of Sod2. This was associated with alterations in RPE morphology and the structure and function of RPE mitochondria. In addition, data show a compensatory increase in RPE glycolytic metabolism. The metabolic shift in RPE correlated with severe disruption of photoreceptor mitochondria including a reduction in TOMM20 expression, mitochondrial fragmentation, and reduced COXIII/β-actin levels. These findings demonstrate that mitochondrial oxidative stress can lead to RPE dysfunction and metabolic reprogramming of RPE. Secondary to these changes, photoreceptors also undergo metabolic stress with increased mitochondrial damage. These data are consistent with the hypothesis of a linked metabolism between RPE and photoreceptors and suggest a mechanism of retinal degeneration in dry AMD.

Project description:BackgroundAge-related macular degeneration (AMD) is a result of degeneration/damage of the retinal pigment epithelium (RPE) while retinitis pigmentosa (RP), an inherited early-onset disease, results from premature loss of photoreceptors. A promising therapeutic approach for both is the replacement of lost/damaged cells with human induced pluripotent stem cell (hiPSC)-derived retinal cells.MethodsThe aim of this study was to investigate the in vivo functionality of RPE and photoreceptor progenitor (PRP) cells derived from a clinical-grade hiPSC line through a unified protocol. De novo-generated RPE and PRP were characterized extensively to validate their identity, purity, and potency.ResultsRPE expressed tight junction proteins, showed pigmentation and ciliation, and secreted polarization-related factors vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). PRP expressed neural retina proteins and cone and rod markers, and responded to KCl-induced polarization. Transcriptomic analysis demonstrated an increase in the expression of mature retinal tissue-specific genes coupled with concomitant downregulation of genes from undesired lineages. RPE transplantation rescued visual function in RCS rats shown via optokinetic tracking and photoreceptor rescue. PRP transplantation improved light perception in NOD.SCID-rd1 mice, and positive electroretinography signals indicated functional photoreceptor activity in the host's outer nuclear layer. Graft survival and integration were confirmed using immunohistochemistry, and no animals showed teratoma formation or any kind of ectopic growth in the eye.ConclusionsTo our knowledge, this is the first demonstration of a unified, scalable, and GMP-adaptable protocol indicating strong animal efficacy and safety data with hiPSC-derived RPE and PRP cells. These findings provide robust proof-of-principle results for IND-enabling studies to test these potential regenerative cell therapies in patients.

Dataset Information

Effect of aging and lifestyle on photoreceptors and retinal pigment epithelium: cross-sectional study in a healthy Danish population.

Publications

Effect of aging and lifestyle on photoreceptors and retinal pigment epithelium: cross-sectional study in a healthy Danish population.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets