title: Synergism between soluble guanylate cyclase signaling and neuropeptides extends lifespan in the nematode Caenorhabditis elegans.
abstract: Oxygen (O2) homeostasis is important for all aerobic animals. However, the manner by which O2sensing and homeostasis contribute to lifespan regulation is poorly understood. Here, we use the nematode Caenorhabditis elegans to address this question. We demonstrate that a loss-of-function mutation in the neuropeptide receptor gene npr-1 and a deletion mutation in the atypical soluble guanylate cyclase gcy-35 O2sensor interact synergistically to extend worm lifespan. The function of npr-1 and gcy-35 in the O2-sensing neurons AQR, PQR, and URX shortens the lifespan of the worm. By contrast, the activity of the atypical soluble guanylate cyclase O2sensor gcy-33 in these neurons is crucial for lifespan extension. In addition to AQR, PQR, and URX, we show that the O2-sensing neuron BAG and the interneuron RIA are also important for the lifespan lengthening. Neuropeptide processing by the proprotein convertase EGL-3 is essential for lifespan extension, suggesting that the synergistic effect of joint loss of function of gcy-35 and npr-1 is mediated through neuropeptide signal transduction. The extended lifespan is regulated by hypoxia and insulin signaling pathways, mediated by the transcription factors HIF-1 and DAF-16. Moreover, reactive oxygen species (ROS) appear to play an important function in lifespan lengthening. As HIF-1 and DAF-16 activities are modulated by ROS, we speculate that joint loss of function of gcy-35 and npr-1 extends lifespan through ROS signaling.
authors.affiliation: Department of Biochemistry and Molecular Biology, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem. P.O. Box 12271, Jerusalem, 9112102, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Abergel
authors.affiliation: Department of Biochemistry and Molecular Biology, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem. P.O. Box 12271, Jerusalem, 9112102, Israel.
authors.forename: Leonid
authors.initials: L
authors.lastname: Livshits
authors.affiliation: Department of Biochemistry and Molecular Biology, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem. P.O. Box 12271, Jerusalem, 9112102, Israel.
authors.forename: Maayan
authors.initials: M
authors.lastname: Shaked
authors.affiliation: Department of Biochemistry and Molecular Biology, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem. P.O. Box 12271, Jerusalem, 9112102, Israel.
authors.forename: Arijit Kumar
authors.initials: AK
authors.lastname: Chatterjee
authors.affiliation: Department of Biochemistry and Molecular Biology, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem. P.O. Box 12271, Jerusalem, 9112102, Israel.
authors.forename: Einav
authors.initials: E
authors.lastname: Gross
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D005502:Food; D005786:Gene Expression Regulation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D008136:Longevity / Q000187:drug effects / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D009479:Neuropeptides / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D010269:Paraquat / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D013696:Temperature; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D029742:Caenorhabditis elegans Proteins; C468272:NPR-1 protein, C elegans; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D017382:Reactive Oxygen Species; D017476:Receptors, Neuropeptide Y; C488166:GCY-35 protein, C elegans; D006162:Guanylate Cyclase; D010269:Paraquat; D010100:Oxygen
keywords: 
  Caenorhabditis elegans
  ; NPR-1; lifespan; oxygen sensing; reactive oxygen species; soluble guanylate cyclase