A lysosomal surveillance response to stress extends healthspan [Exp1]

Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homeostasis and health. However, how lysosomal activity can be boosted to counteract aging and aging-related diseases remains elusive. Here, we reveal that silencing specific vacuolar H+-ATPase subunits (e.g. vha-6), that are essential for intestinal lumen acidification in Caenorhabditis elegans, extends lifespan by ~60%. This longevity phenotype can be explained by an adaptive transcriptional response typified by induction of a set of transcripts involved in lysosomal function and proteolysis, which we termed the lysosomal surveillance response (LySR). LySR activation is characterized by boosted lysosomal activity, enhanced clearance of protein aggregates in worm models of Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis, thereby improving fitness. The GATA transcription factor ELT-2 governs the LySR program and its associated beneficial effects. Activating the LySR pathway may therefore represent an attractive mechanism to reduce proteotoxicity and, as such, potentially extend healthspan. Overall design: Wild-type C. elegans fed with control, vha-6, vha-16, and vha-19 RNAi