Features that distinguish age-related macular degeneration from aging

Abstract

Age-related macular degeneration (AMD) is a complex, multifactorial retinal degenerative disease that is influenced by both genetic and environmental factors. However, the strongest risk factor for AMD is advanced age. Several physiological processes are observed in aging tissues including a low level of chronic inflammation (inflammaging), changed lipid and energy metabolism, and senescence. Nevertheless, whereas everyone ages, only a subset of the population develops AMD. The purpose of this review is to delineate the differences on a cellular and molecular level between natural aging changes and those observed in AMD. We provide a unique perspective on how genetic and environmental components modulate aging in the eye, as well as the specific role of the aging RPE and retina in the pathogenesis of AMD. Topics discussed include the mechanism of aging and its relation to the mechanism of AMD, current animal models that can be used to recapitulate some aspects of the pathology, and potential interventions that shift the balance towards healthy aging and therefore attenuate, prevent or delay the initiation of the disease.

Figure 1.. Homeostatic Balance in Aging.

Molecular and cellular damage caused by various stressors is countered by natural compensatory mechanisms to maintain equilibrium and preserve function. Inability to counteract or contain any of the pathological features will tip the balance toward aging.

Figure 2.. Representative histology and ultrastructure images showing aging and early age-related macular degeneration (AMD) changes.

(adapted from Chen S, Abu-Qamar O, Kar D, et al. Ultrahigh Resolution OCT Markers of Normal Aging and Early Age-related Macular Degeneration. Ophthalmol Sci. 2023;3(3):100277.) Retinal pigment epithelium (RPE), RPE basal lamina (RPE-BL), Bruch’s membrane (BrM) and choriocapillaris (ChC) complex under the fovea of the left eye of a 32-year-old White female and the right eye of a 65-year-old White male with early AMD. A, C, and E. In a young adult, the 3-layer BrM consists of inner collagenous layer (ICL), elastic layer (EL), and outer collagenous layer (OCL). It is flanked by the basal laminas, of the RPE above and of the ChC below. RPE cell bodies extend processes between the basal portions of the cell body toward the basal lamina. The magnified inset shows mitochondria (m) at close proximity to an infolding (arrowheads). B, D, and F. The eye of an older adult exhibits the same layers of BrM with marked loss of RPE basal infoldings and appearance of basal laminar deposit (BLamD) in the same plane. The RPE cell body is indented by the deposit. Soft drusen material (“membranous debris” or “lipoprotein-derived debris”) is found in the sub-RPE-BL space as basal linear deposit (BLinD) or crossing BLamD, where it may congregate as a basal mound (asterisk). Magnified inset shows BLamD and BLinD on either side of the RPE BL (blue) occupied by lipoprotein derived debris (arrowhead) and type VI collagen with a banded appearance. Note how the OCL of Bruch’s membrane extends further between the capillaries in the older adult (B, D, and F), compared to the young adult (A, C, and E). The ICL and EL remain flat between the capillaries. AP = apical process; L = lipofuscin; ML = melanolipofuscin; N = nucleus; OS = outer segment. Scale bars: Panels (A, B) = 10 μm; Panels (C–F) = 2 μm. Panels E and F are colored version of panels C and D, respectively.

Figure 3.. Aging and Pathogenic Inflammation in AMD.

The photoreceptor layer of the macula is physiologically devoid of resident immune cells. The hallmarks of aging in individuals predisposed to increased inflammation, due to an unfortunate combination of genetic and environmental risk factors, likely tip the balance from beneficial inflammation, which helps control debris accumulation in early AMD, to detrimental chronic inflammation that contributes to destructive late AMD.