Abstract

The lysosome, a membrane-bound organelle central to cellular catabolism, plays a critical role in maintaining cellular homeostasis through the degradation and recycling of macromolecules and damaged organelles, a process largely mediated by autophagy. A decline in lysosomal function and autophagic flux is a hallmark of cellular aging and is implicated in numerous age-related pathologies. This study investigates the hypothesis that the functional integrity of the lysosomal system is a key determinant of organismal lifespan and a potential target for anti-aging interventions. Using a combination of genetic models, high-resolution live-cell imaging, and biochemical assays, we characterized the dynamics of lysosomal membrane stability, acidification, and cargo processing efficiency across the lifespan of *C. elegans* and mammalian cell lines. Our findings reveal that specific interventions, such as the pharmacological activation of the transcription factor EB (TFEB) and the modulation of lysosomal membrane lipid composition, significantly enhance lysosomal proteolytic capacity and restore autophagic flux in aged cells. Crucially, these improvements correlate with a marked extension of healthspan and chronological lifespan in the model organism. The data suggest that maintaining robust lysosomal function, particularly its membrane integrity and degradative power, acts as a fundamental process that actively slows down the rate of cellular and organismal aging. These results underscore the lysosome as a central hub in the longevity pathway and identify novel therapeutic strategies for combating age-related decline.