Metabolomics and Age-Related Macular Degeneration

Abstract

Age-related macular degeneration (AMD) leads to irreversible visual loss, therefore, early intervention is desirable, but due to its multifactorial nature, diagnosis of early disease might be challenging. Identification of early markers for disease development and progression is key for disease diagnosis. Suitable biomarkers can potentially provide opportunities for clinical intervention at a stage of the disease when irreversible changes are yet to take place. One of the most metabolically active tissues in the human body is the retina, making the use of hypothesis-free techniques, like metabolomics, to measure molecular changes in AMD appealing. Indeed, there is increasing evidence that metabolic dysfunction has an important role in the development and progression of AMD. Therefore, metabolomics appears to be an appropriate platform to investigate disease-associated biomarkers. In this review, we explored what is known about metabolic changes in the retina, in conjunction with the emerging literature in AMD metabolomics research. Methods for metabolic biomarker identification in the eye have also been discussed, including the use of tears, vitreous, and aqueous humor, as well as imaging methods, like fluorescence lifetime imaging, that could be translated into a clinical diagnostic tool with molecular level resolution.

Keywords: Age-related macular degeneration; biomarkers; drusen; metabolism; metabolomics; retinal pigment epithelium.

Figure 1

The metabolic flux of various lipids and their associated proteins in the retinal pigment epithelium (RPE). In addition to anabolic and catabolic lipid metabolism, the RPE also functions as a transfer site for lipids and proteins (yellow and green spheres) between the circulation and the photoreceptors. The influx of lipids from the RPE to the photoreceptors is represented on the left side, whilst the efflux of lipids is represented on the right side of the image. There is substantial recycling of lipids by the RPE, which are continuously provided through the phagocytosed membrane discs of photoreceptor outer segments (POS). The oxidized lipid species either enter the circulation as lipoprotein particles (green spheres) or are basally deposited into the sub-RPE space leading to the formation of drusen. LCAT, lecithin-cholesterol acyltransferase; APOA1, apolipoprotein A1; CETP, cholesteryl ester transfer protein. Colored arrows represent lipid receptors and their direction of transport. Reproduced with permission from van Leeuwen et al. [18].

Figure 2

Model of sub-RPE deposit formation. Graphical overview of the proposed mechanism for the growth of sub-RPE deposits containing hydroxyapatite (reproduced with permission from Thompson et al. [89]). Micrometer-sized, cholesterol-containing extracellular lipid droplets (black) provide a site of hydroxyapatite (HAP) (magenta) precipitation. Deposit growth follows, with the binding of various proteins (blue) to the surface of HAP, facilitating a self-driven oligomerization process forming the macroscopic sub-RPE deposits (yellow). The brown particles within the RPE represent melanocytes.

Figure 3

Overview of the various omics approaches that can be applied to assess the biological components that contribute to multifactorial diseases, such as age-related macular degeneration (AMD). Metabolomics is highlighted in green as an approach to test the effect of the environment and processes in the body on the development of disease. Microbiomics is growing in importance in understanding disease, but how it influences the whole system in a human, or in fact in animals, is yet to be determined. Adapted from Lauwen et al. [110].