Endogenous cGMP regulates adult longevity via the insulin signaling pathway in Caenorhabditis elegans

Abstract

SummaryG-proteins, including GPA-3, play an important role in regulating physiological responses in Caenorhabditis elegans. When confronted with an environmental stimulus such as dauer pheromone, or poor nutrients, C. elegans receives and integrates external signals through its nervous system (i.e. amphid neurons), which interprets and translates them into biological action. Here it is shown that a suppressed neuronal cGMP level caused by GPA-3 activation leads to a significant increase (47.3%) in the mean lifespan of adult C. elegans through forkhead transcription factor family O (FOXO)-mediated signal. A reduced neuronal cGMP level was found to be caused by an increased cGMP-specific phosphodiesterase activity at the transcriptional level. Our results using C. elegans mutants with specific deficits in TGF-b and FOXO RNAi system suggest a mechanism in that cGMP, TGF-b, and FOXO signaling interact to differentially produce the insulin-like molecules, ins-7 and daf-28, causing suppression of the insulin ⁄ IGF-1 pathway and promoting lifespan extension. Our findings provide not only a new mechanism of cGMPmediated induction of longevity in adult C. elegans but also a possible therapeutic strategy for neuronal disease, which has been likened to brain diabetes.

GPA‐9 is a novel regulator of innate immunity against Escherichia coli foods in adult Caenorhabditis elegans

“…(Hahm et al, 2009). From a mechanistic standpoint, our demonstration that ins-7 and daf-28 play a role in GPA-9-mediated innate immune response is consistent with the idea that ins-7 and daf-28 production are suppressed in head neurons when GPA-9-dependent mechanisms sense ingested OP50 metabolites (Fig.…”

“…Amphid neurons in C. elegans are known to govern not only memory, learning, hormone production and secretion (Kimura et al, 2004;Bishop & Guarente, 2007;Kao et al, 2007;Kuhara et al, 2008) but also various physiological processes, such as aging and dauer formation (Bargmann & Horvitz, 1991;Alcedo & Kenyon, 2004). These functions of amphid neurons are primarily mediated by G-protein signaling pathways (Zwaal et al, 1997;Lans & Jansen, 2007;Hahm et al, 2009), and a specific G-protein coupled receptor and G-protein signaling mechanism have recently been reported to control innate immunity (Styer et al, 2008;Ziegler et al, 2009).…”

Mitochondrial Function Is Required for Secretion of DAF-28/Insulin in C. elegans

“…While its regulation is complex and incompletely understood, it is notable that, like human insulin, its expression is high when food levels are high and low when food levels are low. daf-28 is regulated transcriptionally by the dauer pheromone, during ageing [7] and by daf-11/guanylyl cyclase [7], [47]. However, it has been noted that the magnitude of transcriptional control does not appear sufficient to modulate dauer formation.…”

GCY-8, PDE-2, and NCS-1 are critical elements of the cGMP-dependent thermotransduction cascade in the AFD neurons responsible for C. elegans thermotaxis

“…At present, our knowledge of PDE-mediated signaling in C. elegans is limited. Nevertheless, it has been reported that PDE-1 and PDE-5 are involved in the G proteinmediated, cGMP-dependent regulation of adult lifespan extension (Hahm et al, 2009), whereas PDE-1, PDE-2, PDE-3, and PDE-5 all contribute to phototransduction in C. elegans UV photoreceptors (Liu et al, 2010).…”