Retinal Aging Research Articles

Photoreceptor cell rescue by RPE transplants in the dystrophic and aging retina

Photoreceptor cell rescue by RPE transplants in the dystrophic and aging retina

Compensatory synaptic growth in the rod terminals as a sequel to partial photoreceptor cell loss in the retina of chimaeric mice.

In the retina of chimaeric mice of rd and wild-type genotypic combination, selective loss of rd/rd photoreceptor cells, after initial development, leads to a mosaic retina with variable amounts of normal photoreceptor cells present over the retinal surface. In some of the rod terminals of these retinas the synaptic complexes with the second order retinal neurons are seen to contain multiple synaptic ribbons and an increased number of profiles of the postsynaptic elements. These changes are observed only in the rod terminals and not in the cone pedicles. Computer aided three-dimensional reconstruction of the altered synapses shows that these changes result from an increase in the number of synaptic sites, characterized by multiplication of the synaptic ribbons and enlargement of the second order neuronal processes. A quantitative analysis of such synapses, based on serial electron micrographs, shows that these are most frequently located in the retinal regions of the chimaeric individuals that have suffered maximum photoreceptor cell loss. Thus synaptic growth appears to take place as a reaction to the reduction of afferent input to the postsynaptic components. These findings demonstrate persistent synaptic plasticity in the rod terminals of mammalian retina during the maturational phase of late postnatal development. Compensatory synaptic growth in the rod terminals, as recorded here, can have important implications for the maintenance of visual sensitivity in the diseased or ageing retina.

Effects of acute and chronic stress on the neural retina of young, mid-age, and aged Fischer-344 rats

Male Fischer-344 rats at 5 (young), 11 (mid-age) and 18 (aged) months of age were exposed either to a single, 1-h period of acute stress, or to daily 4-h periods (chronic) of escapable footshock stress for 6 months, and subsequently allowed a one month interval without stress. The influence of age and exposure to stress on the neural retina was examined by histopathologic and morphometric methods. Age changes in the retina of unstressed control animals included reduction in the thickness of the outer nuclear layer (ONL; photoreceptor nuclei) and of the retina, especially in the peripheral areas. The superior hemisphere was more severely affected than the inferior retina. Exposure to acute stress did not influence retinal histopathology. However, in mid-age and aged rats exposed to chronic stress, the ONL and retinal thicknesses were reduced significantly. Our results indicate for the first time that exposure of rats to chronic stress produces changes in retinal morphology that are associated commonly with aging, such as extensive loss of peripheral photoreceptor cells. In addition, the results show that the effects of chronic stress exposure are greatest in aged rats. The effect of light exposure on the aging retina was not investigated since all rats were exposed to the same total photoperiod.

Effects of aging on the composition and metabolism of docosahexaenoate‐containing lipids of retina

The amount of docosahexaenoate (22:6n-3)-containing phospholipid species decreases with aging in the rat retina. Most lipids, but especially choline and serine glycerophospholipids, show a significant fall in 22:6n-3, which is not compensated by increases in other polyenoic fatty acids. The decrease not only affects 22:6 but also various very long chain n-3 hexaenoic fatty acids which, in phosphatidylcholine, have up to 36 carbon atoms, and which are probably synthesized by successive elongations of 22:6n-3. The in vitro incorporation of [2-3H]glycerol into retinal lipids indicates that the de novo biosynthetic pathways are not impaired by aging. The incorporation of [1-14C]docosahexaenoate is significantly stimulated into all lipids of aged retinas, but to the largest extent in those showing the largest decreases in 22:6, especially in choline glycerophospholipids. The results indicate that the decreased levels of 22:6 with aging are due not to an impaired activity of the enzymes involved in the synthesis and turnover of phospholipids but to a decreased availability of this polyene in the retina. It is suggested that this may stem from a defect in some of the enzymatic steps that lead to the synthesis of 22:6n-3, probably that catalyzed by delta 4 desaturase, the effect on longer hexaenes being secondary to the decreased synthesis of 22:6.

Light and macular degeneration: a biophysical and clinical perspective.

The evidence linking photic retinopathy to ageing macular degeneration (AMD) is compelling but circumstantial. The biophysical foundations of ageing theory are presented, in addition to an analysis of retinal senescence and the potential contributory role of photochemical retinal damage. Although there is pressure to implement clinical therapy for AMD based on laboratory studies of photic retinopathy, there is no evidence at this time that any such therapy is effective. Nonetheless, until the relationship between photic retinopathy and AMD is better understood, it is appropriate for individuals to use ultraviolet and deep blue protective sunglasses in bright environments, particularly if they have reduced ocular pigmentation or if they are aphakes or pseudophakes without an ultraviolet-protective intraocular lens.

The ageing retina: physiology or pathology.

The human retina is a unique component of the nervous system in that throughout life it is continuously exposed to optical radiation between 400 and 1400 nm. The physiology of the ageing retina and the regression in visual performance with age cannot therefore be studied in isolation, or discriminated, from the life long cumulative effects of radiant exposure. This paper describes the spectrum of age related changes in the retina as they merge imperceptibly between declining visual function and overt pathology.

Macular degeneration in a community of rhesus monkeys. Ultrastructural observations.

The eyes of 29 aged adult, (mean age, 20 years) rhesus monkeys were examined for the presence of age-related macular degeneration (AMD). This sample represented approximately 25% of the aged population in the seminatural colony at the Caribbean Primate Research Center (CPRC) of the University of Puerto Rico. Approximately 75% of the animals examined had drusen in the posterior pole. Ultrastructural analysis was used to determine whether the pathologic alteration of Bruch's membrane and drusen in the colony resembled those noted in aged or AMD-afflicted human retinas. There were abnormalities in all layers of Bruch's membrane. Deposits of heterogeneous material, comprised of membranous, granular, and cellular components, were seen in both the inner collagenous zone (ICZ) and the outer collagenous zone (OCZ). Accumulation of this drusenoid material in the ICZ produced a scalloping of the basal border of the retinal pigment epithelium (RPE). Dense bodies were seen in both Bruch's membrane and RPE cytoplasm near the basal infoldings. Cytoplasmic processes, as well as whole cells, were seen with regularity within the drusenoid material. In one case there was a cell with a basement membrane crossing the middle elastic layer of Bruch's membrane. These changes are consistent with those reported in human aging and AMD. Aged individuals in this colony appear to be predisposed to macular degenerative changes and may prove to be an invaluable animal model for studying AMD in humans.

Morphological changes in the retina of ageing rats

This paper deals with the morphological changes in the retina with ageing. The most significant result was a decrease in the thickness of the aged retina compared to that of the controls. Although all layers underwent reduction, the most affected were the outer nuclear layer (that was reduced to 90%) and the ganglion cell number (which was reduced to 40%). The surviving photoreceptors and ganglion cells showed structural changes. In the photoreceptors we found a disappearance of the outer segments, and in many instances the inner segment was in direct contact with microvilli from the pigment epithelium. In the ganglion cells we found an increase in Golgi apparatus, however, not at a uniform rate but to different degrees in the different cells.

A study of photoreceptor-retinal pigment epithelium complex: age-related changes in monkeys.

Retinas of 4-, 10-, and 20-year-old monkeys were studied by light microscopy, electron microscopy, and scanning electron microscopy. Sections from the midperipheral region of every retina were selected for comparison. Although no significant differences were found between 4- and 10-year-old retinas, four major changes were found in 20-year-old monkey retinas: (i) increased number of displaced photoreceptor cells (DPC), (ii) increased number of macrophages of different morphology in subretinal space, (iii) increase in pigment granules in retinal pigment epithelium (RPE) cells, and (iv) altered morphology of Muller cells. DPC included both rods and cones. Their location and morphology depended on the stage of their displacement. These cells were usually oval or rounded in shape and were found either among the outer segments of other photoreceptor cells, having stalks extending into the outer nuclear layer, or were located in the subretinal space and had no stalk. A narrow space around the DPC stalks, indicating a change in the intercellular connection between photoreceptor cells and Muller cells, was observed. Furthermore, the Muller cells related to DPC had shortened and markedly reduced microvilli. Two types of macrophages were found in the subretinal space of aged monkey retinas. One type was similar in morphology to RPE cells. Some of these cells were noticed detaching from RPE. Other types of macrophages were nonpigmented. The modifications in RPE were closely related to the changes in the associated neuroretina. The RPE cells in aged retina were devoid of microvilli or had a few thin microvilli. The pleomorphic pigment granules were dispersed throughout the cytoplasm. These cells varied in their size, shape, and surface features. These changes could significantly alter the retinal metabolic equilibrium and may be indicative of age related degenerative processes.

Choosing treatment for metastatic breast cancer

The membrane-associated palmitoylated protein 5 (MPP5 or PALS1) is thought to organize intracellular PALS1-CRB-MUPP1 protein scaffolds in the retina that are involved in maintenance of photoreceptor–Müller glia cell adhesion. In humans, the Crumbs homolog 1 (<i>CRB1</i>) gene is mutated in progressive types of autosomal recessive retinitis pigmentosa and Leber congenital amaurosis. However, there is no clear genotype–phenotype correlation for <i>CRB1</i> mutations, which suggests that other components of the CRB complex may influence the severity of retinal disease. Therefore, to understand the physiological role of the Crumbs complex proteins, especially PALS1, we generated and analyzed conditional knockdown mice for <i>Pals1</i>. Small irregularly shaped spots were detected throughout the PALS1 deficient retina by confocal scanning laser ophthalmoscopy and spectral domain optical coherence tomography. The electroretinography a- and b-wave was severely attenuated in the aged mutant retinas, suggesting progressive degeneration of photoreceptors. The histological analysis showed abnormal retinal pigment epithelium structure, ectopic photoreceptor nuclei in the subretinal space, an irregular outer limiting membrane, half rosettes of photoreceptors in the outer plexiform layer, and a thinner photoreceptor synaptic layer suggesting improper photoreceptor cell layering during retinal development. The PALS1 deficient retinas showed reduced levels of Crumbs complex proteins adjacent to adherens junctions, upregulation of glial fibrillary acidic protein indicative of gliosis, and persisting programmed cell death after retinal maturation. The phenotype suggests important functions of PALS1 in the retinal pigment epithelium in addition to the neural retina.

Retinal vessls of canine eyes at different ages—A qualitative and quantitative study

Diameter and number of cells per unit length of vessel wall and endothelial cell frequency were determined in capillaries of trypsin-digested Foxhound retinas from different age groups. Capillary diameters increased and number of cells per unit length of capillary wall decreased with age and distance from the optic disc. Endothelial cell frequency was constant at approximately 79% of the total cells in capillary walls in all areas measured. Peripheral cystoid degeneration and peripheral annular and focal degeneration were found in aged dog retinas. Sclerosis of retinal arterioles was observed ophthalmoscopically, histologically, and in trypsin-digested retinas from aged dogs. The significance of this change in relation to the peripheral retinal degeneration is undetermined. It is proposed that thickening of basement membranes observed in peripheral capillaries of retinas causes chronic, low-level hypoxia leading to peripheral retinal degeneration in aged retinas.