ATG-18 drives longevity in an HLH-30-dependent manner

Abstract

Enhancing autophagy increases lifespan and healthspan in animal models, yet the precise molecular mechanisms underlying these effects are not fully understood. Here we show that overexpression of the essential autophagic gene atg-18 extends the lifespan of C. elegans. We describe a previously unknown, pleiotropic mechanism by which atg-18 impacts lysosomes and extends lifespan through the transcription factor hlh-30, the master regulator of lysosomal biogenesis. We show that, under stress conditions, HLH-30 requires atg-18 for nuclear translocation. Furthermore, atg-18 overexpression broadly improves health and stress resilience yet paradoxically increases early-life susceptibility to lethal heat stress. In contrast, enhances heat-stress survival a loss-of-function of function mutation in atg-18 enhances heat-stress survival, uncovering a temporal-specific effect of atg-18. These finding suggest an ATG-18--HLH-30 autophagy--lysosome pathway that plays a key role in lifespan and healthspan. Bulleted main discoveriesO_LIATG-18 overexpression increases C. elegans lifespan and plays an important role in resilience against starvation and heat stress. C_LIO_LIATG-18 is required for nuclear translocation of HLH-30 C_LIO_LIHLH-30 is required for ATG-18--mediated lifespan extension C_LIO_LIATG-18 positively regulates lysosomal biogenesis, suggesting a novel role as a molecular coordinator between autophagy and the lysosomal network. C_LI