Lipofuscin: mechanisms of age-related accumulation and influence on cell function12 1Guest Editor: Rajindar S. Sohal 2This article is part of a series of reviews on “Oxidative Stress and Aging.” The full list of papers may be found on the homepage of the journal.

Brunk, Ulf T.; Terman, Alexei

doi:10.1016/s0891-5849(02)00959-0

Cited by 771 publications

(241 citation statements)

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“…Chemical analysis indicates that LF granules are 30-70% protein. Thus, the insoluble material is believed to be mostly cross-linked proteins, damaged by interactions with reactive oxygen intermediates (48). Recently, Schütt et al (49) showed that LF granules contain 70 different proteins, as identified by 2D gel electrophoresis and MS.…”

Section: Resultsmentioning

confidence: 99%

Spectroscopic and morphological studies of human retinal lipofuscin granules

Haralampus-Grynaviski

Lamb²,

Clancy³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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The emission properties of ocular lipofuscin granules isolated from human retinal pigment epithelial cells are examined by using steady-state fluorescence spectroscopy and spectrally resolved confocal microscopy. The shape of the emission spectrum of a thick sample of lipofuscin granules dried on glass varies with excitation energy. The polarization of this emission is wavelength-dependent, exhibiting significant polarization near the excitation wavelength and becoming mostly depolarized over the majority of the emission spectrum. These results show that the yellow-emitting fluorophores [e.g., A2E (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)] are excited as a result of energy transfer within the granules and therefore are not the dominant blue-absorbing chromophores within lipofuscin granules. Atomic force microscopy images show lipofuscin granules to be an aggregated structure. Bulk and in vivo emission measurements must therefore take into account the effect of Raleigh scattering. When corrected for scattering, the emission spectrum of a thick lipofuscin deposit or intracellular lipofuscin resembles that for A2E. The sum of the emission spectra of a collection of individual granules also resembles the emission spectrum of A2E, but the spectrum of individual granules varies significantly. This result suggests that the agreement between the emission spectra of lipofuscin and A2E is fortuitous, and the collective data indicate the presence of several blue-absorbing chromophores in lipofuscin and show A2E is not the dominant yellow-emitting fluorophore in many of the granules studied.L ipofuscin (LF) is a common morphological result of the aging process and is manifested as a heterogeneous complex of fluorescent, lipid-protein aggregates found in the cytoplasm of postmitotic cells (1-5). In the retinal pigment epithelium (RPE) of the human eye, the formation of LF is attributed to the accumulation of indigestible end-products from the phagocytosis of photoreceptor outer segments (1, 6-8). LF accumulates in RPE cells as clusters of granules and can occupy Ϸ20% of the cytoplasmic space by 80 yr of age (9). LF exhibits a yellow fluorescence ( max Ϸ 600 nm) upon blue-light excitation (10). In vitro experiments also show that blue-light excitation of cultured RPE cells ʈ fed LF generates a variety of reactive oxygen intermediates (including hydrogen peroxide, singlet oxygen, and superoxide radical anion), which renders LF phototoxic to cultured RPE cells (11)(12)(13).Determining the molecule(s) responsible for the aerobic photoreactivity and emissive properties of LF is the focus of current research. In a groundbreaking paper in 1988, Eldred and Katz (14) analyzed chloroform:methanol (2:1, vol͞vol) extracts of RPE cells and separated several emissive bands by using TLC. A variety of yellow-emitting fluorophores were found. To date, only two isomers of a pyridinium bis-retinoid, A...

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Section: Resultsmentioning

confidence: 99%

Spectroscopic and morphological studies of human retinal lipofuscin granules

Haralampus-Grynaviski

Lamb²,

Clancy³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…LF is a lysosomal, brown-yellow, autofluorescent and electron-dense pigment [9]. It is a complex mixture resulting from the oxidative breakdown and rearrangement of different molecules including polyunsaturated fatty acids, retinoids and proteins.…”

Section: Introductionmentioning

confidence: 99%

Fundus Autofluorescence, Optical Coherence Tomography and Visual Acuity in Adult-Onset Foveomacular Dystrophy

Furino

Boscia²,

Cardascia³

et al. 2008

Ophthalmologica

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Aim: We investigated fundus autofluorescence (FA) patterns and tomographic retinal changes by means of optical coherence tomography (OCT 3) in adult-onset foveomacular vitelliform dystrophy (AOFVD) and their possible correlation with best-corrected visual acuity (BCVA). Methods: Eighteen eyes of 15 consecutive patients (mean age: 73.73 ± 9.5 years) presented to our observation with a diagnosis of AOFVD underwent BCVA measurement, evaluation of FA distribution by means of a confocal laser scanning ophthalmoscope and OCT 3 tomography. Results: The mean BCVA was 20/40 (range: 20/20–20/100). The FA pattern was patchy in 9 eyes (50%), ring-like in 5 (27.7%), focal in 3 (16.6%) and linear in 1 (5.5%). No correlation between FA patterns and BCVA was found. OCT 3 showed accumulation of highly reflective material between the neurosensory retina and retinal pigment epithelium (RPE) in 12 eyes (66.6%) with an evident overlying photoreceptor layer (PRL). In 5 eyes the highly reflective material was built up between the neurosensory retina and RPE without evidence of PRL (27.7%). Only in 1 eye was the subretinal accumulation site not well defined (5.5%). The mean thickness of the deposit was 135.52 ± 47.53 µm, while the residual neurosensory retina thickness was 103.94 ± 24.21 µm. The relationship between BCVA and the thickness of the neurosensory retina over the lesion was not significant (p = 0.016, r = 0.33), while the correlation between BCVA and the material deposit thickness (p = 0.017, r = 0.12) was significant. Conclusions: In AOFVD, FA presented different patterns, while OCT usually shows a well-defined material accumulation with a generally reduced neurosensory thickness between PRL and RPE. FA imaging and OCT are useful and safe for the diagnosis and follow-up of AOFVD.

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“…Gradual intralysosomal accumulation of lipofuscin, particularly in terminally differentiated cells (i.e., neurons, retinal pigment epithelium, cardiac myocytes, and muscle cells) is a characteristic sign of cellular oxidative damage and aging (Brunk and Terman, 2002;. Given the unique role of autophagy and lysosomes in mitochondrial degradation, the diminished degradative capacity of lysosomes due to the progressive deposition of lipofuscin in these organelles would lead to a decrease in the autophagic turnover of damaged mitochondria, which in turn would result in the generation of reactive oxygen species and formation of oxidized proteins and aggregates, thus perpetuating the production of lipofuscin.…”

Section: Lipofuscinosismentioning

confidence: 99%

“…In addition, intralysosomal accumulation of lipofuscin affects the trafficking of the newly synthesized lysosomal enzymes, thus further diminishing the degrading capacity of the lysosomes. This "vicious circle" of mitochondrial oxidative damage and lysosomal deposition of lipofuscin is at the heart of a well-known "mitochondrial-lysosomal axis theory of ageing", which was put forward by Ulf Brunk and Alexei Terman (Brunk and Terman, 2002). According to this model, accumulation of "biological garbage" results from the natural decline in the ability of the cellular degradative machinery to efficiently clear the cells from damaged structures (Terman et al, 2010).…”

Section: Lipofuscinosismentioning

confidence: 99%