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

Mar 30, 2026Aging cell

ATG-18’s role outside cell recycling is essential for reproductive system aging in Caenorhabditis elegans

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Abstract

Neuronal or intestinal knockdown of atg-18 abolishes gonadal longevity in C. elegans.

Knockdown of atg-18 specifically disrupts longevity conferred by germline ablation.
Inhibition of autophagic activity was observed with knockdown of all tested atgs in the targeted tissues.
ATG-18 exhibited an autophagy-independent function related to gonadal longevity.
Germline deficiency resulted in significant upregulation of ATG-18 in both neurons and the intestine.
ATG-18 interacts with PCK-2, which is upregulated in the intestine of germline-deficient animals.
PCK-2 overexpression required ATG-18 for longevity but not the interaction with ATG-2, which is involved in autophagy.

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Autophagy, 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.

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

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