Autophagy‐Independent Function of ATG‐18 Is Essential for Gonadal Longevity in Caenorhabditis elegans

Autophagy(definition), a highly conserved cellular degradation process, plays essential roles in various physiological processes including aging. Though autophagy is required for lifespan extension in multiple longevity paradigms, the tissue-specific roles of autophagy-related genes (atgs) in longevity remain incompletely understood. Here, we investigate the tissue-specific requirements of atgs to promote longevity conferred by germline ablation (called gonadal longevity) using C. elegans. Remarkably, we discovered that neuronal or intestinal knockdown of atg-18, but not other atgs, specifically abolished gonadal longevity, although knockdown of all tested atgs effectively inhibited autophagic activity in these targeted tissues, implying the presence of an autophagy-independent function of ATG-18 in gonadal longevity. We demonstrated that germline deficiency triggered significant upregulation of ATG-18 in neurons and the intestine. From the proteomics analysis and subsequent screening, we found ATG-18 interacts with PCK-2, a phosphoenolpyruvate carboxykinase. PCK-2 is upregulated within the intestine of germline-deficient animals, but this depends on the non-autophagic function of ATG-18. Consistently, we showed that PCK-2 overexpression mediated longevity required ATG-18 but not its potential interacting partner to regulate autophagy, ATG-2. These findings reveal a previously unrecognized autophagy-independent role for ATG-18 in regulating lifespan in response to germline signals, expanding our understanding of how this evolutionarily conserved protein coordinates organism-wide responses to promote longevity.