Abstract
Dietary restriction (DR) and reduced insulin growth factor (IGF) signaling extend lifespan in Caenorhabditis elegans and other eukaryotic organisms. Autophagy, an evolutionarily conserved lysosomal degradation pathway, has emerged as a central pathway regulated by various longevity signals including DR and IGF signaling in promoting longevity in a variety of eukaryotic organisms. However, the mechanism remains unclear. Here we show that the autophagy protein ATG-18 acts cell non-autonomously in neuronal and intestinal tissues to maintain C. elegans wildtype lifespan and to respond to DR and IGF-mediated longevity signaling. Moreover, ATG-18 activity in chemosensory neurons that are involved in food detection sufficiently mediates the effect of these longevity pathways. Additionally, ATG-18-mediated cell non-autonomous signaling depends on the release of neurotransmitters and neuropeptides. Interestingly, our data suggest that neuronal and intestinal ATG-18 acts in parallel and converges on unidentified neurons that secrete neuropeptides to regulate C. elegans lifespan through the transcription factor DAF-16/FOXO in response to reduced IGF signaling.
Highlights
Limitation of food without causing malnutrition (DR: dietary restriction) extends lifespan in a wide range of species [1]
It was reported that fruit flies (Drosophila melanogaster) deficient in olfactory function live longer and that the longevity induced by food restriction is partially due to decreased olfaction
The insulin growth factor signaling pathway is regulated by nutrient levels and has been shown to mediate the lifespan extension conferred by food restriction and defective gustatory neurons in the nematode Caenorhabditis elegans
Summary
Limitation of food without causing malnutrition (DR: dietary restriction) extends lifespan in a wide range of species [1]. In C. elegans, multiple signaling transduction pathways are involved in response to DR, including the insulin-like growth factor pathway (IGF) [1]. The C. elegans daf-2 gene encodes an insulin receptor-like tyrosine kinase [2]. DAF-16, a FOXO (forkhead box O) transcription factor, is a major target of DAF-2 signaling and its activity is required for the longevity of daf-2 mutants [3, 4]. When DAF-2 signaling is inhibited, DAF-16 enters the nucleus and turns on the transcription of many longevity genes to increase lifespan [5]. The IGF and DR pathways can be separated as DAF-2 is not required for lifespan extension of C. elegans under all DR conditions [7, 8]
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