Avid lysosomal acidification in fibroblasts of the Mediterranean mouse Mus spretus

Failures of the lysosome-autophagy system are a hallmark of aging and many disease states. As a consequence, interventions that enhance lysosome function are of keen interest in the context of drug development. Throughout the biomedical literature, evolutionary biologists have discovered that challenges faced by humans in clinical settings have been resolved by non-model organisms adapting to wild environments. Here, we used a primary cell culture approach to survey lysosomal characteristics in selected species of the genus Mus. We found that cells from M. musculus, mice adapted to human environments, had weak lysosomal acidification and high expression and activity of the lysosomal enzyme β-galactosidase, a classic marker of cellular senescence. Cells of wild relatives, especially the Mediterranean mouse M. spretus, had more robustly performing lysosomes and dampened β-galactosidase levels. We propose that classic laboratory models of lysosome function and senescence may reflect characters that diverge from the phenotypes of wild mice. The M. spretus phenotype may ultimately provide a blueprint for interventions that ameliorate lysosome breakdown in stress and disease.