Lysosome activity is modulated by multiple longevity pathways and is important for lifespan extension in <i>C. elegans</i>.

Abstract

Lysosomes play important roles in cellular degradation to maintain cell homeostasis. In order to understand whether and how lysosomes alter with age and contribute to lifespan regulation, we characterized multiple properties of lysosomes during the aging process in <i>C. elegans</i>. We uncovered age-dependent alterations in lysosomal morphology, motility, acidity and degradation activity, all of which indicate a decline in lysosome function with age. The age-associated lysosomal changes are suppressed in the long-lived mutants <i>daf-2</i>, <i>eat-2</i> and <i>isp-1</i>, which extend lifespan by inhibiting insulin/IGF-1 signaling, reducing food intake and impairing mitochondrial function, respectively. We found that 43 lysosome genes exhibit reduced expression with age, including genes encoding subunits of the proton pump V-ATPase and cathepsin proteases. The expression of lysosome genes is upregulated in the long-lived mutants, and this upregulation requires the functions of DAF-16/FOXO and SKN-1/NRF2 transcription factors. Impairing lysosome function affects clearance of aggregate-prone proteins and disrupts lifespan extension in <i>daf-2</i>, <i>eat-2</i> and <i>isp-1</i> worms. Our data indicate that lysosome function is modulated by multiple longevity pathways and is important for lifespan extension.