ATG-18 drives longevity in an HLH-30—dependent manner
Year: 2026
Type: preprint
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 discoveries ATG-18 overexpression increases C. elegans lifespan and plays an important role in resilience against starvation and heat stress. ATG-18 is required for nuclear translocation of HLH-30 HLH-30 is required for ATG-18—mediated lifespan extension ATG-18 positively regulates lysosomal biogenesis, suggesting a novel role as a molecular coordinator between autophagy and the lysosomal network.
Authors: Tomas Schmauck-Medina, Alexander Anisimov, David H. Meyer, Yue Hu, Zebo Huang, Yong Wu, Samuel J. Taylor, Michael Takla, Michael R. MacArthur, Sarah J. Mitchell, Ruixue Ai, Anne Simonsen, Vidar Jensen, John Labbadia, Han-Ming Shen, David Rubinsztein, Sofie Lautrup, Guang Lu, Evandro F. Fang
Institutions: University of Oslo, Akershus University Hospital, University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, University Hospital Cologne, Sun Yat-sen University, University College London, University of Cambridge, UK Dementia Research Institute, Princeton University, Oslo University Hospital, University of Macau
Subfield: Aging
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7126093459