Abstract
Lysosomal dysfunction is associated with a number of age-related pathologies that affect all organ systems. While much research has focused on neurodegenerative diseases and aging-induced changes in neurons, much less is known about the impact that aging has on lower urinary tract function. Our studies explored age-dependent changes in the content of endo-lysosomal organelles (i.e., multivesicular bodies, lysosomes, and the product of their fusion, endolysosomes) and age-induced effects on lysosomal degradation in the urothelium, the epithelial tissue that lines the inner surface of the bladder, ureters, and renal pelvis. When examined by transmission electron microscopy, the urothelium from young adult rats (~3 months), mature adult rats (~12 months), and aged rats (~26 months old) demonstrated a progressive age-related accumulation of aberrantly large endolysosomes (up to 7μm in diameter) that contained undigested content, likely indicating impaired degradation. Stereological analysis confirmed that aged endolysosomes occupied approximately 300% more volume than their younger counterparts while no age-related change was observed in multivesicular bodies or lysosomes. Consistent with diminished endolysosomal degradation, we observed that cathepsin B activity was significantly decreased in aged versus young urothelial cell lysates as well as in live cells. Further, the endolysosomal pH of aged urothelium was higher than that of young adult (pH 6.0 vs pH 4.6). Our results indicate that there is a progressive decline in urothelial endolysosomal function during aging. How this contributes to bladder dysfunction in the elderly is discussed.
Highlights
The endo-lysosomal system consists of interconnected organelles and pathways that are involved in internalization, recycling, and degradation of internalized membrane and fluid
As lysosomes have been proposed to lie at the heart of many age-related pathologies, we first sought to characterize any morphological changes in the endo-lysosomal system of the urothelium, in particular, the umbrella cells
Previous studies showed that in umbrella cells apically internalized cargoes, which are endocytosed by a clathrin-independent pathway, first enter small membrane-delimited structures that depending on species can have an ovoid to polygonal morphology when examined in cross section [26, 30,31,32,33]
Summary
The endo-lysosomal system consists of interconnected organelles and pathways that are involved in internalization, recycling, and degradation of internalized membrane and fluid. Central to these pathways is the lysosome, a pleomorphic organelle that contains greater than 60 hydrolytic enzymes that allow for degradation of all macromolecules in the cell including proteins, lipids, carbohydrates, and nucleic acids [1].
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