The cellular organelles known as lysosomes are packed full of enzymes, enabling the recycling of metabolic waste and damaged or unwanted proteins and structures by breaking them down into their component parts. Lysosomes are a vital part of the mechanisms of autophagy, working to keep cells from being overtaken by damaged and dysfunctional components. Unfortunately, lysosomal function declines with age, particularly in long-lived cells of the nervous system. Not all metabolic waste is easily broken down, and lysosomes become bloated with a mix of compounds known as lipofuscin. This degrades their performance, and cells suffer accordingly. Lysosomal function is so critical to cell and tissue function that it isn't surprising to see that mutant lineages of laboratory species that exhibit slowed aging also exhibit better, more functional lysosomes.
One of the most universal hallmarks of aging is the decline in protein homeostasis. Studies in a variety of organisms have uncovered age-dependent accumulation of misfolded and damaged proteins, which may impair cell function and homeostasis, leading to the development of age-related diseases. Misfolded, aggregated and damaged proteins can be removed by the proteasome or cleared through the autophagy-lysosome pathway. As the key organelle for cellular degradation, lysosomes exhibit age-related changes. 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 C. elegans.
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 daf-2, eat-2, and isp-1, 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 daf-2, eat-2, and isp-1 worms.
Our data indicate that lysosome function is modulated by multiple longevity pathways and is important for lifespan extension. Further studies are required to understand whether lysosomes make tissue-specific contributions to aging and lifespan extension.