Aging is not a disease: Distinguishing age-related macular degeneration from aging

doi:10.1016/j.preteyeres.2013.07.003

Progress in Retinal and Eye Research

Volume 37, November 2013, Pages 68-89

https://doi.org/10.1016/j.preteyeres.2013.07.003 Get rights and content

Abstract

Age-related macular degeneration (AMD) is a disease of the outer retina, characterized most significantly by atrophy of photoreceptors and retinal pigment epithelium accompanied with or without choroidal neovascularization. Development of AMD has been recognized as contingent on environmental and genetic risk factors, the strongest being advanced age. In this review, we highlight pathogenic changes that destabilize ocular homeostasis and promote AMD development. With normal aging, photoreceptors are steadily lost, Bruch's membrane thickens, the choroid thins, and hard drusen may form in the periphery. In AMD, many of these changes are exacerbated in addition to the development of disease-specific factors such as soft macular drusen. Para-inflammation, which can be thought of as an intermediate between basal and robust levels of inflammation, develops within the retina in an attempt to maintain ocular homeostasis, reflected by increased expression of the anti-inflammatory cytokine IL-10 coupled with shifts in macrophage plasticity from the pro-inflammatory M1 to the anti-inflammatory M2 polarization. In AMD, imbalances in the M1 and M2 populations together with activation of retinal microglia are observed and potentially contribute to tissue degeneration. Nonetheless, the retina persists in a state of chronic inflammation and increased expression of certain cytokines and inflammasomes is observed. Since not everyone develops AMD, the vital question to ask is how the body establishes a balance between normal age-related changes and the pathological phenotypes in AMD.

Section snippets

Introduction: aging, homeostasis, and age-related macular degeneration

Age-related macular degeneration (AMD) is a degenerative disease of the photoreceptors and retinal pigment epithelium (RPE) in the human macula. Early stages of the disease feature deposition of extracellular debris, known as drusen, from the basal side of the RPE into Bruch's membrane. From this point on, the disease may progress to one of two forms, known as geographic atrophy (GA) and neovascular AMD (nAMD). Patients with GA AMD exhibit areolar loss of the photoreceptors and RPE in the

The aging paradigm

On the street, it is relatively simple to categorize individuals into one of a few subsets based on perceived biological age, including childhood, adulthood, and old age. Childhood, from infancy through adolescence, is very much a continuation of the developmental processes that begin during fertilization and terminate only when the body has reached maturity. It is from this point on that we call someone an adult, though there is no gold standard for distinguishing a 20-year-old from a

Extracellular drusen formation

Drusen typically appear with age and fall into several categories depending on their appearance (Fig. 2). Under the ophthalmoscope, hard drusen appear to be yellow dots, usually smaller than 63 μm in diameter, and have sharp borders. Soft drusen, which are not considered a part of normal aging, are larger, typically greater than 125 μm in diameter, and may have either sharply defined borders or fuzzy, indistinct borders. Basal linear deposits are composed of primarily membranous material in the

Para-inflammation and immunity

The physiologic changes described in Section 3 detail the many aspects of aging and AMD seen in the retina. However, none of these changes occur in isolation and none alone have been shown to be sufficient to cause AMD either in a model system or in the AMD patient. The immune system is a major player in AMD, as it is this homeostatic agent in the body which continually and throughout the life of the organism interacts with and potentially influences the many age-related and pathological

Suppress excessive inflammation

The purpose of the tissue inflammatory response is to restore homeostasis in the face of injury or stress. In the case of AMD, however, this attempt to restore homeostasis fails and instead propagates the disease, ultimately resulting in blindness of the patient. Blocking the deleterious inflammatory response can be achieved from a variety of angles by targeting either the many contributors to the para-inflammatory state of the retina (e.g., complement, macrophages, or microglia) or those

Summary

Broadly defined, homeostasis is a process whereby a dynamic system maintains a stable equilibrium. AMD can be thought of as a loss of retinal homeostasis, whereby a series of age-related changes are permissive for age-related pathology, and it is with the combination of environmental and genetic risk factors that disease manifests. This becomes apparent when comparing the changes that occur as a result of aging with those that occur during the AMD disease process (Table 1).

The various factors

Acknowledgments

The authors state no conflicts of interest. We appreciate Dr. Janet Sparrow's critical review of the manuscript. This work was supported by the NEI Intramural Fund.

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¹: Percentage of work contributed by each author in the production of the manuscript is as follows: Daniel Ardeljan: wrote the manuscript and created Figures 1 and 4–7. He contributed 70% of the work. Chi-Chao Chan: provided the conception of the manuscript, critically reviewed, and created Figures 2 and 3. She contributed 30% of the work.

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Published by Elsevier Ltd.

Aging is not a disease: Distinguishing age-related macular degeneration from aging

Abstract

Section snippets

Introduction: aging, homeostasis, and age-related macular degeneration

The aging paradigm

Extracellular drusen formation

Para-inflammation and immunity

Suppress excessive inflammation

Summary

Acknowledgments

Prog. Retin. Eye Res.

Ophthalmology

Exp. Eye Res.

Exp. Gerontol.

J. Lipid Res.

Am. J. Obstet. Gynecol.

Arch. Gerontol. Geriatr.

Mol. Aspects Med.

Exp. Eye Res.

Biochim. Biophys. Acta

Can. J. Ophthalmol.

Prog. Retin. Eye Res.

Ophthalmology

Ophthalmology

Exp. Eye Res.

Exp. Eye Res.

Exp. Eye Res.

Exp. Eye Res.

Cell Biosci.

Lancet

Prog. Retin. Eye Res.

J. Lipid Res.

Exp. Eye Res.

Lancet

Trends Immunol.

Am. J. Ophthalmol.

Neurobiol. Aging

Mol. Immunol.

Exp. Eye Res.

Brain Res. Rev.

Immunobiology

Human retinal pigment epithelium cells as functional models for the RPE in vivo

Invest. Ophthalmol. Vis. Sci.

Tissue inhibitor of metalloproteinases-3 induces apoptosis in melanoma cells by stabilization of death receptors

Oncogene

Structural and functional analysis of the complement component factor H with the use of different enzymes and monoclonal antibodies to factor H

Biochem. J.

An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice

Nat. Med.

Macrophages inhibit neovascularization in a murine model of age-related macular degeneration

PLoS Med.

Influence of TIMP3/SYN3 polymorphisms on the phenotypic presentation of age-related macular degeneration

Eur. J. Hum. Genet.

Carboxyethylpyrrole plasma biomarkers in age-related macular degeneration

Drugs Future

Interleukin-17 Neutralization Ameliorates Retinal Degeneration in Cx3cr1-/-/Ccl2-/-/Crb1rd8 Mice

Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial

JAMA

Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: age-related eye disease study report number 3

Ophthalmology

A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8

Arch. Ophthalmol.

The effect of five-year zinc supplementation on serum zinc, serum cholesterol and hematocrit in persons randomly assigned to treatment group in the age-related eye disease study: AREDS report no. 7

J. Nutr.

Nutritional manipulation of primate retinas, V: effects of lutein, zeaxanthin, and n-3 fatty acids on retinal sensitivity to blue-light-induced damage

Invest. Ophthalmol. Vis. Sci.

Mitochondrial abnormalities in ageing macular photoreceptors

Invest. Ophthalmol. Vis. Sci.

Neuroprotecting D1 (NPD1): a DHA-derived mediator that protects brain and retina against cell injury-induced oxidative stress

Brain Pathol.

Robust docosahexaenoic acid-mediated neuroprotection in a rat model of transient, focal cerebral ischemia

Stroke

C-reactive protein and complement factor H in aged human eyes and eyes with age-related macular degeneration

Br. J. Ophthalmol.

Genetic variability in DNA repair proteins in age-related macular degeneration

Int. J. Mol. Sci.

DNA damage and repair in age-related macular degeneration

Front. Biosci. A J. Virtual Lib.