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At least 19 recordsLinked to original sources
PubMed2002

Action spectra for the photoconsumption of oxygen by human ocular lipofuscin and lipofuscin extracts.

The action spectra for the photoconsumption of oxygen by lipofuscin isolated from human retinal pigment epithelium cells and liposomal suspensions containing extracts of lipofuscin are reported. The lipofuscin and lipofuscin extract action spectra are similar, demonstrating the phototoxic constituents of lipofuscin are present in the lipofuscin solvent extract. 2-[2,6-Dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetraenyl]-1-(2-hydroxyethyl)-4-[4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E-hexatrienyl]-pyridinium (A2E), present in both intact granules and the solvent extract, has been invoked as an important contributor to the phototoxicity of lipofuscin. The action spectrum for oxygen photoconsumption by A2E follows its absorption spectrum but does not resemble the action spectrum for photoconsumption of oxygen by lipofuscin granules or lipofuscin extract. These results combined with recently reported experimental studies on the aerobic photoreactivity of A2E indicate that it is not a major contributor to the phototoxicity of lipofuscin.

Aged↗
PubMed1993

Accumulation of cardiac lipofuscin in crab-eating monkeys (Macaca fasicularis): the same rate of lipofuscin accumulation in several species of primates.

Previously, we have reported that the aging process begins at sexual maturation (Nakano, M. et al., Mech. Ageing Dev., 52 (1990) 93-106). In this paper, we reported the cardiac lipofuscin accumulation of crab-eating monkeys. The first appearance of cardiac lipofuscin was around sexual maturation, and the rate of accumulation in crab-eating monkey was 0.45. Several primates which have different life spans show the same rate of lipofuscin accumulation in the life stage. Namely, even in a different life span, the amount of lipofuscin accumulation in a given period of life such as puberty, middle age, old age was the same. From these results, it is suggested that the amount of lipofuscin accumulation is the same in the life span of primates having different life spans.

Aging↗
PubMed1990

Accumulation of cardiac lipofuscin in mammals: correlation between sexual maturation and the first appearance of lipofuscin.

Accumulation of lipofuscin is an important phenomenon of the cellular aging process. The first appearance of cardiac lipofuscin showed a good correlation with sexual maturation, which was correlated with maximum life-span of mammals. Large metabolic changes occurred at sexual maturation. From these results, it is suggested that sexual maturation of mammals is the initiation period of the aging process. Correlation between sexual maturation and longevity was re-evaluated using many mammals. Domestic and laboratory animals showed an earlier sexual maturation than other mammals, including rodents.

Aging↗
PubMedDate not supplied

Lipofuscin and lipofuscin-like substances.

Lipofuscin is defined as being a yellowish brown, lipid-rich, heterogeneous, cytoplasmic granular pigment emitting an intense yellow autofluorescence when excited with ultraviolet light, which accumulates in various tissues of animals during their aging. It is believed that the pigments are derived from the reaction of some of reactive secondary products including malonaldehyde, formed during membranous lipid peroxidation, with amino groups of phospholipids and proteins, etc., and that these formations are accompanied by alteration of the membrane structure and inactivation of the enzymes. The fluorescence measurement of the pigments is widely used as a parameter of lipid peroxidation in vivo as well as in vitro. However, their origin, chemical structure, biological significance or fate has not as yet been fully elucidated. This article introduces and discusses the recent studies on these problems.

Animals↗
PubMed1998

Lipofuscin accumulation in cultured retinal pigment epithelial cells reduces their phagocytic capacity.

PURPOSE: Retinal pigment epithelial (RPE) cells slowly accumulate lipofuscin pigment within their acidic vacuolar apparatus as a result of extra- and/or intralysosomal oxidative alterations of phagocytosed photoreceptor outer segments (POS) with consequent imperfect degradation of these structures. In old age, lipofuscin accumulation may become quite substantial. It has been suggested that pronounced accumulation of lipofuscin is related to decreased RPE function and, possibly, to age-related macular degeneration. The aim of the present investigation was to study whether heavy loading with lipofuscin of RPE acidic lysosomes would affect the further phagocytic ability of the cells. METHODS: In the first section of the investigation, cultures of rabbit RPE cells were exposed daily to bovine UV-irradiated POS (artificial lipofuscin) for 4 weeks, resulting in a pronounced lipofuscin accumulation of the cells. Fluorescent latex beads (labelled with a red fluorophore) were added to unloaded control cultures at O and 4 weeks after their establishment, and to lipofuscin loaded cells after 4 weeks of feeding with artificial lipofuscin. Cellular amounts of lipofuscin, and their phagocytotic activity, were quantified by static fluorometry measuring lipofuscin-specific and red bead-specific fluorescence, respectively. The intracellular location of the beads was verified by confocal laser scanning microscopy. RESULTS: Unloaded, and thus almost lipofuscin-free, control cells exposed to latex beads showed numerous cytoplasmic particles emitting reddish fluorescence, while few particles were taken up by cells initially loaded with artificial, POS-derived, lipofuscin. Measurement of the latex bead-specific fluorescence showed significantly (p < 0.001) higher levels in unloaded control cells than in lipofuscin-loaded ones. In the second part of the investigation, unloaded control cultures and lipofuscin-loaded cultures were exposed to native bovine Texas Red-X-labelled POS 4 weeks after the establishment of the cultures. Unloaded control cells showed a large number of cytoplasmic POS emitting reddish fluorescence, while fewer POS were phagocytosed by cells loaded with artificial lipofuscin. Measurement of the Texas Red-X-specific fluorescence, thus quantifying the phagocytic ability of the cells, showed significantly (p < 0.001) higher levels in control cells than in lipofuscin-loaded ones. CONCLUSIONS: Severe lipofuscin accumulation of RPE cells appears to result in a greatly decreased phagocytic capacity. The resulting reduction in ability to cope with the needs of the overlying photoreceptor cells, in order to eliminate the obsolete tips of their POS, may well be of significance in the development of age-related macular degeneration.

Animals↗
PubMed1999

Long-term variations in cyclic light intensity and dietary vitamin A intake modulate lipofuscin content of the retinal pigment epithelium.

Experiments were conducted to determine whether the intensity of cyclic light exposure to the retina over a long period of time affects retinoid-dependent accumulation of lipofuscin in the retinal pigment epithelium (RPE). Albino rats were maintained from weaning on diets either containing (+A) or lacking (-A) retinyl palmitate, which can be metabolized to the retinoids involved in the visual cycle. Animals in each dietary group were divided between bright (L) and dim (D) cyclic light treatments. Thus, the experiments employed the following four treatment groups: +A/D, +A/L, -A/D, and -A/L. After 6, 12, and 15 months from the start of the treatments, animals in each group were killed for quantitative determination of: 1) retinal photoreceptor densities; 2) RPE lipofuscin content; and 3) RPE lipofuscin fluorescence intensity. Animals in the L groups had a lower volume of RPE lipofuscin than those in the D groups fed the same diet. Among the -A rats, this reduced lipofuscin volume could be attributed to a light-enhanced depletion of vitamin A from the retina and an accompanying loss of photoreceptor cells. In the +A animals, however, there were no differences in photoreceptor densities between the D and L groups. In the -A rats, the volume of RPE lipofuscin decreased between 6 and 15 months of age, whereas it increased in the +A animals. In contrast, lipofuscin fluorescence intensity increased between 6 and 15 months of age in all four treatment groups. However, in the +A rats, the fluorescence intensity was lower in the L than in the D group at all three ages. In the -A groups, light level had no effect on lipofuscin fluorescence intensity. At all three ages, fluorescence intensity was lower in the -A animals than in +A rats. Thus, at light intensities below those that induce acute retinal degeneration, long-term exposure to higher intensity light inhibits the age-related increase in RPE lipofuscin volume. A decrease in the volume of RPE lipofuscin after the retina is depleted of vitamin A suggests that lipofuscin is turned over, and that RPE lipofuscin content is determined by a balance between the rates at which lipofuscin is formed and at which it is eliminated from the RPE. An age-related increase in lipofuscin-specific fluorescence intensity after vitamin A depletion from the retina suggests that lipofuscin fluorophores may continue to form slowly from retinoids that have been modified such that they can no longer enter the visual cycle.

Animals↗
PubMed1993

Experimental light damage increases lipofuscin in the retinal pigment epithelium of Japanese quail (Coturnix coturnix japonica).

Lipofuscin accumulation in the retinal pigment epithelium (RPE) of Japanese quail was investigated in normal and light-damaged animals at 4 months and 12 months of age following a single, 18-hr light-damaging exposure (3000-3200 lx) evaluated 6 weeks postexposure. Quail in a second experimental group light-damaged at 4 months of age were exposed to a second, identical light-damaging exposure at 12 months of age. RPE lipofuscin was quantitatively assessed in three ways: (1) total lipofuscin, expressed as a percentage of the basal RPE cell area, (2) mean number of lipofuscin granules per RPE cell, and (3) mean area of lipofuscin granules. At 12 months of age, control female RPE cells showed substantially more lipofuscin than did males. Animals that received a single damaging light-exposure showed no significant differences in lipofuscin at either age when compared with controls, and none were observed between males and females. However, in the double light-exposure condition, both total lipofuscin and the number of lipofuscin granules were significantly higher in females compared to controls and also, when compared with animals in the single light-exposure condition. Mean lipofuscin granule size decreased in females in the double light-exposure condition when compared with control values. Histopathological evaluation of photoreceptor outer segments and outer nuclear layer indicated that double-exposed, 12-month-old females showed the most severe effects, including a substantial decrease (70%) in rod photoreceptor densities. However, only a small change was observed in cone densities for either sex (12-15%) in this condition. Overall, a strong, negative correlation (r = -0.78) was obtained between total lipofuscin and average rod density across age, sex, control and experimental conditions. A somewhat greater correlation (r = -0.82) was obtained for females, alone. These results suggest that rods, when severely damaged by light exposure, contribute to increased RPE lipofuscin. Age, sex and light-exposure history appear to be critical variables that can influence both the amount of lipofuscin present in RPE cells as well as the relative vulnerability of rod and cone photoreceptors to cumulative light-exposure damage. These results have implications for the development of a variety of age-related changes and diseases of the outer retina, including age-related macular degeneration.

Age Factors↗
PubMed2001

Effect of Rpe65 knockout on accumulation of lipofuscin fluorophores in the retinal pigment epithelium.

PURPOSE: In all mammalian species examined to date the retinal pigment epithelium (RPE) has been found to accumulate autofluorescent lysosomal storage bodies (lipofuscin) during senescence. Substantial evidence indicates that retinoids in the RPE-retina complex play a major role in RPE lipofuscin formation. Indeed, at least one RPE lipofuscin fluorophore is derived in part from vitamin A aldehyde. However, the precise mechanisms by which retinoids modulate RPE lipofuscin accumulation have not been elucidated. In mice without a functional Rpe65 gene, isomerization of all-trans- to 11-cis-retinol is blocked. Experiments were performed to determine whether this impairment of retinoid metabolism alters RPE lipofuscin accumulation. METHODS: RPE lipofuscin fluorophore content was compared in 12- to 13-month-old Rpe65(+/+), Rpe65(+/-), and Rpe65(-/-) mice. Lipofuscin fluorophore content was determined using quantitative fluorometric measurements. RPE lipofuscin content was also estimated with quantitative ultrastructural techniques. RESULTS: In the Rpe65(-/-) mice, RPE lipofuscin fluorophore accumulation was almost abolished. In addition, a significantly reduced accumulation of lipofuscin fluorophores was also observed in the Rpe65(+/-) animals. The inability of the RPE of)Rpe65(-/-) mice to supply 11-cis-retinal from the RPE to the retinal photoreceptors was accompanied by a massive accumulation of lipid droplets in the RPE that appeared to contain substantial amounts of retinoids. CONCLUSIONS: These findings indicate that formation of RPE lipofuscin fluorophores is almost completely dependent on a normal visual cycle. The absence of retinal (both all-trans and 11-cis) in Rpe65 knockout mice drastically reduced formation of lipofuscin fluorophores in these animals. Even an excessive accumulation of retinyl fatty acid esters in the RPE of Rpe65 knockout mice did not contribute to lipofuscin accumulation.

Animals↗
PubMed1985

Localization of lipofuscin in the duodenums of vitamin E-deficient rats.

In human malabsorption syndromes, lipofuscin accumulation has been reported to occur exclusively within the muscle layers of the intestine. It has been widely speculated that this lipofuscin deposition is related to vitamin E deficiency. To determine whether vitamin E deficiency leads to the same pattern of intestinal lipofuscin accumulation as that seen in many human malabsorption syndromes, the duodenums of rats that had been fed a vitamin E-deficient diet for 17 or 34 wk were examined for the presence of lipofuscin. Lipofuscin did not appear in the muscle layers of the duodenum until 34 wk, at which time occasional fibers containing large amounts of lipofuscin were present. An earlier and more pronounced deposition of lipofuscin occurred within connective tissue cells of the intestinal villi. After 17 wk, many fibroblastlike cells in the lamina propria of the villi contained large amounts of lipofuscin. By 34 wk, the numbers of these lipofuscin-containing cells in the lamina propria had increased substantially, and scattered cells containing lipofuscin were also seen in the submucosa. The difference in intestinal lipofuscin distribution between vitamin E-deficient rats and humans with malabsorption syndromes suggests that other factors, in addition to vitamin E, probably play important roles in regulating lipofuscin accumulation in the intestine.

Animals↗
PubMed1999

Reversible accumulation of lipofuscin-like inclusions in the retinal pigment epithelium.

PURPOSE: The amounts of autofluorescent lysosomal storage bodies, known as lipofuscin, increase during senescence in the retinal pigment epithelia (RPEs) of mammalian eyes. This increase in lipofuscin content may result from a failure of the RPE to dispose of any lipofuscin constituents once they have formed. Alternatively, the RPE may eliminate lipofuscin but at a rate insufficient to prevent its accumulation. Experiments were conducted to distinguish between these two possibilities. METHODS: Albino rats were given intravitreal injections of the protease inhibitor leupeptin, which induces a rapid accumulation of lipofuscin-like inclusions in the RPE. The amount of these inclusions in the RPE was monitored as a function of time after the leupeptin treatment with quantitative ultrastructural analysis. In addition, the intensity of lipofuscin-specific fluorescence in the RPE was monitored over the same time period with the use of quantitative microfluorometry. These parameters were also followed in untreated control eyes of age-matched animals. RESULTS: A single leupeptin injection resulted in a rapid massive accumulation of electron-dense inclusion bodies in the RPE. These inclusions appeared to be derived primarily from phagocytosed photoreceptor outer segments. Accompanying the accumulation of these inclusions was a significant increase in lipofuscin-specific fluorescence in the RPE. Over a 12-week period after the leupeptin treatment, the amounts of inclusion material and the fluorescence intensities returned to normal levels. CONCLUSIONS: These findings suggest that the age-related increase in RPE lipofuscin content results from an imbalance in the rates of lipofuscin formation and disposal rather than from a complete absence of a disposal mechanism. The results imply that turnover of lipofuscin constituents may be rapid relative to the animals' life span. Thus, it may be possible to slow or reverse the age-related increase in RPE lipofuscin content by either inhibiting the processes involved in lipofuscin formation or enhancing the disposal processes.

Aging↗
PubMed1985

[Ultrastructural studies on the lipofuscin in the cerebral cortex of aged men and rats].

The ultrastructural features of lipofuscins in the cerebral cortex in both aged men and rats were observed with an electron microscope and the author discussed the significance of morphological differences of the lipofuscins in both specimens. The lipofuscins observed in aged men consist of an electron dense structure with or without vacuoles, and each of the lipofuscin is enveloped by a single unit membrane. The inside of the vacuole is homogeneous and structureless. The electron dense area of the lipofuscin shows fine granular structures with various degrees of electron density. The lipofuscin observed in aged rats (730 days) shows roughly the same appearance essentially as those in aged men, but reveals more complex internal structure. Therefore, the lipofuscins in aged rats can be classified into four types as follows: Type 1: finely granular type consisting of fine granules of almost uniform size. Type 2: coarsely granular type consisting of both fine granules and coarse granules; each of the coarse granules is 200 to 600 A in diameter. Type 3: lamellated type consisting of both fine granules and lamellae; the lamellae are 130 A in width with a repeated pattern of five bands. Type 4: mixed type consisting of fine granules, coarse granules and lamellae. In addition, it was observed that lipofuscins rarely existed in both 12-day and 25-day rats, but that the all four types of lipofuscins existed in 85-day rats. The cause of the morphological difference between lipofuscins in aged men and aged rats is still unknown. However, it has been reported that the rats and degree of autophagocytosis differs between different species of animals, even in same cell types, the author therefore considered that such a difference in intracellular metabolic processes could be one of the factors causing the morphological difference of lipofuscins in old men and old rats.

Aged↗
PubMed1998

ECL cells of the rat stomach: development of lipofuscin in response to sustained gastrin stimulation.

Ageing cells, especially post-mitotic cells, are known to accumulate pigments, i.e. highly electron-dense material, referred to as ceroid or lipofuscin. This material is formed as a consequence of autophagocytosis and peroxidation of the products undergoing degradation. The present study describes the development of lipofuscin in the ECL cells of the rat stomach. These cells produce and secrete histamine in response to gastrin. They are rich in secretory vesicles, which fuse to form vacuoles in hypergastrinaemic rats. Hypergastrinaemia was induced by continuous infusion of human Leu15-gastrin-17 for 6 days or by daily treatment with omeprazole for 10 weeks. Either treatment caused both vacuoles and lipofuscin bodies to appear in large numbers; the vacuoles disappeared promptly after interruption of the hypergastrinaemia, whereas the lipofuscin bodies remained. Antrectomy-evoked hypogastrinaemia was associated with a reduced number and volume density of lipofuscin bodies. Treatment with alpha-fluoromethylhistidine, an irreversible inhibitor of the histamine-forming enzyme, resulted in depletion of ECL-cell histamine and was found to prevent the omeprazole-evoked formation of vacuoles and lipofuscin. The numbers of both vacuoles and lipofuscin bodies were well-correlated with the serum gastrin concentration, suggesting that gastrin stimulates the development not only of vacuoles but also of lipofuscin, perhaps through enhanced autophagocytosis and/or oxidative stress. Thus, lipofuscin bodies may develop from vacuoles, and both vacuoles and lipofuscin bodies may reflect the efforts of overstimulated ECL cells to cope with the excessive formation of secretory products.

Animals↗
PubMed1996

Formation of lipofuscin in cultured retinal pigment epithelial cells exposed to pre-oxidized photoreceptor outer segments.

Accumulation of lipofuscin in the retinal pigment epithelium (RPE) with increasing age may affect essential supportive functions for the photoreceptors. Earlier, we described a model system for the study of lipofuscinogenesis in RPE cell cultures and showed that mild oxidative stress enhances lipofuscin formation from phagocytized photoreceptor outer segments (POS). In the present study, bovine POS were photo-oxidized, and turned into a lipofuscin-like material, by irradiation with UV light. Transmission electron microscopy of irradiated POS showed loss of the normal stacks of the disk membranes with conversion into an amorphous osmiophilic electron-dense mass. The formation of thiobarbituric acid reactive substances (TBARS), estimated during the irradiation process, indicated lipid peroxidation. Irradiated POS also showed a strong granular yellow autofluorescence. RPE cell cultures, kept at 21% ambient oxygen, were fed daily for 3, 5 or 7 days with either (i) UV-peroxidized POS, (ii) native POS or (iii) culture medium only. RPE cells fed irradiated POS showed significantly higher levels of lipofuscin-specific autofluorescence compared to cells exposed to native POS after 3 days (p = 0.0056), 5 days (p = 0.0037) and 7 days (p = 0.0020), and to the non-exposed control cells (3 days: p = 0.005, 5 days: p = 0.0037, 7 days: p = 0.0094). The lipofuscin content of cells exposed to irradiated POS increased significantly between days 3 and 7 (p = 0.0335). Ultrastructural studies showed much more numerous and larger lipofuscin-like inclusions in RPE cells fed irradiated POS compared to cells exposed to native POS. In the control cells, lipofuscin-like granules were small and sparse. It appears that exposing RPE cells to previously peroxidized POS, thus artificially converted to lipofuscin and obviously not digestible by the lysosomal enzymes, accelerates the formation of severely lipofuscin-loaded cells. The results will be useful for further studies of possible harmful effects of lipofuscin in heavily loaded RPE cells.

Animals↗
PubMed1995

Age-related changes in the lipofuscin accumulation of brain and heart.

Lipofuscin is the end-product of intracellular lipid peroxidation and the accumulation results from the cellular metabolism during aging (life stage). We suggested that the accumulation of cardiac lipofuscin was dependent on the specific metabolic rate of mammals. Slower rate of cardiac lipofuscin accumulation (against absolute lifespan) was observed in the animals of larger body size. The rate of cardiac lipofuscin accumulation was correlated with the specific metabolic rate, and inversely correlated with the brain weight of mammals. The first appearance of lipofuscin granules was 8 weeks of age in the hippocampus and in the thalamus. In the case of cerebral cortex (laminae III), lipofuscin granules were first found at 3-month-old rats. The rate of lipofuscin accumulation was the highest in the hippocampus (y = 0.286x - 0.099, r = 0.963) among the three regions examined. In the case of cerebral cortex and thalamus, the slower rate of lipofuscin accumulation was observed (y = 0.072x - 0.14, r = 0.797 for cerebral cortex; y = 0.067X - 0.14, r = 0.953 for thalamus). It is noticed that the most abundant accumulation and the highest rate of lipofuscin accumulation are the hippocampus. Even the hippocampus, the rate and the magnitude of lipofuscin accumulation was low as compared with cardiac muscles. From these results, it is suggested that brains have better protective system against oxidative stress than other organs do.

Aging↗
PubMed1990

Lipids in human lipofuscin-enriched subcellular fractions of two age populations. Comparison with rod outer segments and neural retina.

The fatty acid composition and content of total phospholipids, free fatty acids (FFA), diacylglycerols (DG), phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylethanolamine (PE) were studied in lipofuscin granules of human donors in two age groups, young (less than 40 yr old) and old (more than 47 yr old), and compared with lipids of the photoreceptor rod outer segments (ROS). Neural retina (NR) and retinal pigment epithelium (RPE) also were studied. In both age groups, the lipid composition of the lipofuscin granules differed from that of the ROS, with a decrease in the proportion of phospholipid and an increase in FFA, suggesting very high phospholipase activity in the lipofuscin granules. In ROS, docosahexaenoic acid (22:6) was the predominant FFA, whereas palmitic acid (16:0), arachidonic acid (20:4) and oleic acid (18:1) were the major fatty acids in the lipofuscin granules. The fatty acid compositions of PC, PE, and PS of lipofuscin granules were different from those of the retina. There was proportionally less 22:6 in lipofuscin, and the amounts of saturated and monounsaturated fatty acyl chains such as 16:0, stearate (18:0), and 18:1 were greater than in retina. Compared to ROS, the lipofuscin granules showed a significant decrease in DG containing 20:4 but not 22:6. With aging, there was a decrease in the amount of total polyunsaturated fatty acyl chains (22:6 and 20:4) in the lipofuscin granules. These results show that the lipid composition of lipofuscin is different from that of ingested ROS, probably because of increased phospholipase and peroxidative activities in lipofuscin, directed toward ingested ROS as well as toward other materials from the RPE and blood.

Adolescent↗