Abstract
Accumulation of lipofuscin is one of the most characteristic features of ageing observed in retinal pigment epithelial (RPE) cells. The lipofuscin found in RPE cells differs from that of other body tissues due to the fact that it is mainly derived from the chemically modified residues of incompletely digested photoreceptor outer segments. It is a heterogeneous material composed of a mixture of lipids, proteins, and different fluorescent compounds, the main fluorophore of which has recently been identified as a derivative of vitamin A. Research interest has variously focussed on the roles of age, light damage, free radicals, antioxidants, visual pigments, retinal locus, lysosomal enzymes, and pigmentation on lipofuscin formation, as well as the effects of lipofuscin on RPE cell function and causation of retinal disease. This article reviews the recent advances in knowledge of the composition, origin, and possible deleterious effects of RPE cell lipofuscin.
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Feeney-Burns L, Hilderbrand ES, Eldridge S . Aging human RPE: morphometric analysis of macular, equatorial and peripheral cells. Invest Ophthalmol Vis Sci 1984;25:195–200.
Feeney-Burns L, Eldred GE . The fate of the phagosome: conversion to ‘age pigment’ and impact in human retinal pigment epithelium. Trans Ophthalmol Soc UK 1983;103:416–21.
Boulton M, McKechnie NM, Breda J, Bayly M, Marshall J . The formation of autofluorescent granules in cultured human RPE. Invest Ophthalmol Vis Sci 1989;30:82–9.
Katz ML . Incomplete proteolysis may contribute to lipofuscin accumulation in the retinal pigment epithelium. Adv Exp Med Biol 1989;266:109–16.
Feeney-Burns L, Berman ER, Rothman H . Lipofuscin of the human retinal pigment epithelium. Am J Ophthalmol 1980;90:783–91.
Wing GL, Blanchard GC, Weiter JJ . The topography and age relationship of lipofuscin concentration in the retinal pigment epithelium. Invest Ophthalmol Vis Sci 1978;17:601–7.
Weiter JJ, Delori FC, Wing GL, Fitch KA . Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes. Invest Ophthalmol Vis Sci 1986;27:145–52.
Eldred GE, Katz ML . Fluorophores of the human retinal pigment epithelium: separation and spectral characterisation. Exp Eye Res 1988;47:71–86.
Eldred GE, Katz ML . The lipid peroxidation theory of lipofuscinogenesis cannot yet be confirmed. Free Radic Biol Med 1991;10:445–7.
Eldred GE, Miller GE, Stark WS, Feeney-Burns L . Lipofuscin: resolution of discrepant fluorescence data. Science 1982;216:757–9.
Eldred GE . Vitamins A and E in RPE lipofuscin formation and implications for age-related macular degeneration. Prog Clin Biol Res 1989;314:113–29.
Bazan HE, Bazan NG, Feeney-Burns L, Berman ER . Lipids in human lipofuscin-enriched subcellular fractions of two age populations: comparison with rod outer segments and neural retina. Invest Ophthalmol Vis Sci 1990;31:1433–43.
Eldred GE, Lansky MR . Retinal age pigments generated by self-assembling lysosomotropic detergents. Nature 1993;361:724–6.
Katz ML, Drea CM, Eldred GE, Hess HH, Robinson WG Jr. Influence of early photoreceptor degeneration on lipofuscin in the retinal pigment epithelium. Exp Eye Res 1986;43:561–73.
Robinson WG Jr, Kuwabara T, Bieri JG . Deficiencies of vitamins E and A in the rat: retinal damage and lipofuscin accumulation. Invest Ophthalmol Vis Sci 1980;19:1030–7.
Katz ML, Norberg M, Stientjes HJ . Reduced phagosomal content of the retinal pigment epithelium in response to retinoid deprivation. Invest Ophthalmol Vis Sci 1992;33:2612–8.
Young RW . The renewal of the photoreceptor cell outer segments. J Cell Biol 1967;33:61–72.
Newsome DA . Retinal pigmented epithelial cell culture: current applications. Trans Ophthalmol Soc UK 1983;103:458–66.
Feeney L, Mixon RN . An in vitro model of phagocytosis in bovine and human retinal pigment epithelium. Exp Eye Res 1976;22:533–48.
Bok D . Retinal photoreceptor-pigment epithelium interactions. Friedenwald Lecture. Invest Ophthalmol Vis Sci 1985;26:1659–94.
Hayasaka S, Hara S, Mizuno K . Degradation of rod outer segment proteins by cathepsin D. J Biochem 1975;78:1365–7.
Zimmerman WF, Godchaux W, Belkin M . The relative proportions of lysosomal enzyme activities in bovine retinal pigment epithelium. Exp Eye Res 1983;36:151–8.
Hayasaka S . Lysosomal enzymes in ocular tissues and diseases. Surv Ophthalmol 1983;27:245–58.
Wyszynski RE, Bruner WE, Cano DB, Morgan KM, Davis CB, Sternberg P . A donor-age-dependent change in the activity of alpha-mannosidase in human cultured RPE cells. Invest Ophthalmol Vis Sci 1989;30:2341–7.
Rakoczy PE, Mann K, Cavaney DM, Robertson T, Papadimitriou J, Constable IJ . Detection and possible functions of a cysteine protease involved in digestion of rod outer segments by retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 1994;35:4100–8.
Dorey CK, Wu G, Ebenstein D, Garsd A, Weiter JJ . Cell loss in the aging retina: relationship to lipofuscin accumulation and macular degeneration. Invest Ophthalmol Vis Sci 1989;30:1691–9.
Feeney-Burns L, Gao CL, Berman ER . The fate of immunoreactive opsin following phagocytosis by pigment epithelium in human and monkey retinas. Invest Ophthalmol Vis Sci 1988;29:708–19.
Boulton M, Marshall J . Repigmentation of human retinal pigment epithelial cells in vitro. Exp Eye Res 1985;41:209–18.
Young RW . Solar radiation and age-related macular degeneration. Surv Ophthalmol 1988;32:252–69.
Feeney L . The phagosomal system of the pigment epithelium: a key to retinal disease. Invest Ophthalmol Vis Sci 1973;12:635–8.
Rakoczy P, Kennedy C, Thompson-Wallis, Mann K, Constable I . Changes in retinal pigment epithelial cell autofluorescence and protein expression associated with phagocytosis of rod outer segments. Biol Cell 1992;76:49–54.
Katz ML, Eldred GE . Retinal light damage reduces autofluorescent pigment deposition in the retinal pigment epithelium. Invest Ophthalmol Vis Sci 1989;30:37–43.
Boulton M, Marshall J . Effects of increasing numbers of phagocytic inclusions on human retinal pigment epithelial cells in culture: a model for aging. Br J Ophthalmol 1986;70:808–15.
Ivy GO, Kanai S, Ohta M, Smith G, Sato Y, Kobayashi M, Kitani K . Lipofuscin-like substances accumulate rapidly in brain, retina and internal organs with cysteine protease inhibition. Adv Exp Med Biol 1989;266:31–45.
Katz ML, Stone WI, Dratz EA . Fluorescent pigment accumulation in the retinal pigment epithelium of antioxidant-deficient rats. Invest Ophthalmol Vis Sci 1978;17:1049–58.
Tappel AL . Biological antioxidant protection against lipid peroxidation damage. Am J Clin Nutr 1970;23:1137–9.
Chio KS, Reiss U, Fletcher B, Tappel AL . Peroxidation of subcellular organelles: formation of lipofuscin-like fluorescent pigments. Science 1969;166:1535–6.
Chio KS, Tappel AL . Synthesis and characterisation of the fluorescent products derived from malonaldehyde and amino acids. Biochemistry 1969;8:2821–7.
Eldred GE, Katz ML . The autofluorescent products of lipid peroxidation may not be lipofuscin-like. Free Rad Biol Med 1989;7:157–63.
Katz ML, Stientjes HJ, Gao CL, Christianson JS . Iron-induced accumulation of lipofuscin-like fluorescent pigment in the retinal pigment epithelium. Invest Ophthalmol Vis Sci 1993;34:3161–71.
Fite KV, Bengston L, Donaghey B . Experimental light damage increases lipofuscin in the retinal pigment epithelium of Japanese quail (Coturnix coturnix japonica). Exp Eye Res 1993;57:449–60.
Newsome DA, Dobard EP, Liles MR, Oliver PD . Human retinal pigment epithelial cells contain two distinct species of Superoxide dismutase. Invest Ophthalmol Vis Sci 1990;31:2508–13.
Liles MR, Newsome DA, Oliver PD . Antioxidant enzymes in the aging human retinal pigment epithelium. Arch Ophthalmol 1991;109:1285–8.
Hayes KC . Retinal degeneration in monkeys induced by deficiencies of vitamin E or A. Invest Ophthalmol Vis Sci 1978;13:499–510.
Penn JS, Thum LA, Awner S . Protective effect of vitamin E in oxygen-induced retinopathy in the rat. Invest Ophthalmol Vis Sci 1989;30(Suppl):3090–0.
Katz ML, Robinson WG Jr, Herrmann RK, Groome AB, Bieri JG . Lipofuscin accumulation resulting from senescence and vitamin E deficiency: spectral properties and tissue distribution. Mech Ageing Dev 1984;25:149–59.
Tso MO . Pathogenic factors of aging macular degeneration. Ophthalmology 1985;92:628–35.
Gerster H . Review: antioxidant protection of the ageing macula. Age Ageing 1991;20:60–9.
Katz ML, White HA, Gao CL, Roth GS, Knapka JJ, Ingram DK . Dietary restriction slows age pigment accumulation in the retinal pigment epithelium. Invest Ophthalmol Vis Sci 1993;34:3297–302.
Katz ML, Shanker MJ . Development of lipofuscin-like fluorescence in the retinal pigment epithelium in response to protease inhibitor treatment. Mech Ageing Dev 1989;49:23–40.
Kennedy CJ, Rakoczy PE, Robertson TA, Padadimitriou JM, Constable IJ . Kinetic studies on phagocytosis and digestion of rod outer segments by human retinal pigment epithelial cells in vitro. Exp Cell Res 1994;210:209–14.
Feeney L . Lipofuscin and melanin of human retinal pigment epithelium: fluorescence, enzyme cytochemical, and ultrastructural studies. Invest Ophthalmol Vis Sci 1978;17:583–600.
Wiederanders B, Oelke B . Accumulation of inactive cathepsin D in old rats. Mech Ageing Dev 1984;24:265–71.
Wilcox DK . Vectorial accumulation of cathepsin D in retinal pigmentary epithelium: effects of age. Invest Ophthalmol Vis Sci 1988;29:1205–12.
Mainster MA . Light and macular degeneration: a biophysical and clinical perspective. Eye 1987;1:304–10.
Young RW . Pathophysiology of age-related macular degeneration. Surv Ophthalmol 1987;31:291–306.
Aguirre GD, Laties A . Pigment epithelial dystrophy in the dog. Exp Eye Res 1976;23:247–56.
Farkas TG, Sylvester V, Archer D, Altona M . The histochemistry of drusen. Am J Ophthalmol 1971;71:1206–15.
Gass JDM . Drusen and disciform macular detachment and degeneration. Arch Ophthalmol 1973;90:206–17.
Green WR, McDonnell PJ, Yeo JH . Pathologic features of senile macular degeneration. Ophthalmology 1985;92:615–27.
Sarks SH . Council lecture. Drusen and their relationship to senile macular degeneration. Aust J Ophthalmol 1980;8:117–30.
Sarks SH, Sarks J, Killingsworth C . Evolution of geographic atrophy of the retinal pigment epithelium. Eye 1988;2:552–77.
Kahn HA, Leibowitz HM, Ganley J, Kini MM, Colton T, Nickerson RJ, Dawber TR . The Framingham Eye Study. I. Outline and major prevalence findings. Am J Epidemiol 1977;106:17–32.
Sarks SH . Ageing and degeneration in the macular region: a clinicopathological study. Br J Ophthalmol 1976;60:324–41.
Ishibashi T, Sorgente N, Patterson R, Ryan SJ . Pathogenesis of drusen in the primate. Invest Ophthalmol Vis Sci 1986;27:184–93.
Ishibashi T, Patterson R, Ohnishi Y, Inomata H, Ryan SJ . Formation of drusen in the human eye. Am J Ophthalmol 1986;101:342–53.
Feeney-Burns L, Gao CL, Tidwell M . Lysosymal enzyme cytochemistry of human RPE, Bruch's membrane and drusen. Invest Ophthalmol Vis Sci 1987;28:1138–47.
Birnbach CD, Jarvelainen M, Possin DE, Milam AH . Histopathology and immunohistochemistry of the neurosensory retina in fundus flavimaculatus. Ophthalmology 1994;101:1211–9.
Lopez PF, Maumenee IH, de la Cruz Z, Green WR . Autosomal-dominant fundus flavimaculatus: clinicopathologic correlation. Ophthalmology 1990;97:798–809.
Weingeist TA, Kobrin JL, Watzke RC . Histopathology of Best's macular dystrophy. Arch Ophthalmol 1982;100:1108–14.
Damato BE, Foulds WS . Tumour-associated retinal pigment epitheliopathy. Eye 1990;4:382–7.
Ko MK, Lee WR, McKechnie NM, Hall-Parker B . Posttraumatic hyperlipofuscinosis in the human retinal pigment epithelium. Br J Ophthalmol 1991;75:54–60.
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Kennedy, C., Rakoczy, P. & Constable, I. Lipofuscin of the retinal pigment epithelium: A review. Eye 9, 763–771 (1995). https://doi.org/10.1038/eye.1995.192
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DOI: https://doi.org/10.1038/eye.1995.192
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