A universal biomarker of cellular aging in eukaryotic postmitotic cells
is the appearance over time of autofluorescent lysosomal residual
bodies that have been variously termed age pigments or lipofuscin
granules. The potential role of accumulation of lipofuscin granules in
RPE cells in age-related macular disease, and in many macular
dystrophies such as
fundus flavimaculatus and Bulls eye
dystrophy has been extensively studied.
1 2 3 4 5 6 7 8 9 10 11 12 13 Although
there is a linear relationship between the quantity of residual bodies
and autofluorescence, marked variation exists in the ratio between the
two in human donors,
14 and it can be manipulated by
varying dietary vitamin A.
15 Increase in lipofuscin-like
granules in the RPE has been reproduced experimentally by dietary
deficiency of antioxidants,
16 17 exposure of RPE to
oxidized photoreceptor OS components,
18 and intravitreal
injection of lysosomal enzyme inhibitors.
19 20 21 22 Lipofuscin
granules or residual bodies are generated by incomplete degradation of
both heterophagosomes produced by phagocytosis of shed OS and
autophagosomes. Efficiency of degradation of phagosomes may depend upon
the nature of the phagosomal contents,
17 18 23 24 25 and
on the qualitative or quantitative attributes of degradative
enzymes.
19 20 Despite increasing knowledge concerning the
mechanisms of lipofuscin granule accumulation, little is known of the
causal relationship between lipofuscin accumulation and RPE cell
dysfunction, which may in turn influence photoreceptors and choroidal
capillaries. It has been proposed that accumulation of lipofuscin
granules may interfere with cell function by reducing the cytoplasmic
space
26 or by acting as a free-radical
generator.
27 Eldred
28 hypothesized that one
of lipofuscin components (A2-E:
N-retinylidence-
N-retinylethanolamine) may
inhibit lysosomal enzyme activity by elevating lysosomal pH resulting
in accumulation of substrates and formation of residual storage
granules. A2-E, at a critical concentration, might cause leaky
lysosomes. Leaked A2-E may induce changes of cellular plasma membranes,
and leaked lysosomal enzymes may contribute to RPE cell death.