The protease inhibitor leupeptin induces several signs of aging in brain, retina and internal organs of young rats.
The protease inhibitor leupeptin was administered to brain, retina and internal organs of young rats for up to two weeks in order to determine if specifically decreased proteolysis could cause symptoms of cellular aging in a variety of tissues. Electron microscopy showed that leupeptin induced the formation of dense substances with fine morphologies similar to and, in many cases, apparently identical with those of natural lipofuscin from aged tissues. Leupeptin also caused increased immunoreactivity to ubiquitin in cerebellar Purkinje cells and presumed Bergmann glia perikarya of brain tissue as well as in hepatocytes of liver tissue. Both of these effects were found in aged tissues as well. Finally, both leupeptin treatment and normal aging led to the onset of immunoreactivity in Purkinje cells to antibodies to the abnormal tau molecule of paired helical filaments from Alzheimer's disease brain. Together, these results indicate that inhibition of thiol (and possibly some serine) proteases by leupeptin is sufficient to cause obvious morphological manifestations of aging in several tissues, and are thus consistent with the hypothesis that lipofuscinogenesis as well as a build-up of ubiquilinated proteins with age is caused by decreased or defective proteolysis. These effects are likely secondary to the mechanism(s) interfering with proteolysis itself.
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Department of Psychology, University of Toronto, 1265 Military Trail, Scarborough, Ontario M1C 1A4, Canada.
Ihara
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Kitani
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