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 (RP Es) of mammalian eyes. This increase in lipofuscin content may result from a failure of the RPE to dispose of any lipofuscin constituents once they ha ve formed. Alternatively, the RPE may eliminate lipofuscin but at a rate in sufficient to prevent its accumulation. Experiments were conducted to disti nguish between these two possibilities. METHODS. Albino rats were given intravitreal injections of the protease inh ibitor leupeptin, which induces a rapid accumulation of lipofuscin-like inc lusions in the RPE. The amount of these inclusions in the RPE was monitored as a function of time after the leupeptin treatment with quantitative ultr astructural analysis. In addition, the intensity of lipofuscin-specific flu orescence in the RPE was monitored over the same time period with the use o f quantitative microfluorometry. These parameters were also followed in unt reated control eyes of age-matched animals. RESULTS. A Single leupeptin injection resulted in a rapid massive accumulat ion of electron-dense inclusion bodies in the RPE. These inclusions appeare d to be derived primarily from phagocytosed photoreceptor outer segments. A ccompanying the accumulation of these inclusions was a significant increase in lipofuscin-specific fluorescence in the RPE. Over a 12-week period afte r the leupeptin treatment, the amounts of inclusion material and the fluore scence intensities returned to normal levels. CONCLUSIONS. These findings suggest that the age-related increase in RPE li pofuscin content results from an imbalance in the rates of lipofuscin forma tion and disposal rather than from a complete absence of a disposal mechani sm. 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 re verse the age-related increase in RPE lipofuscin content by either inhibiti ng the processes involved in lipofuscin formation or enhancing the disposal processes.