See fig 1. Inhibition of DAF-2 (insulin-like growth factor 1 [IGF-1] receptor) or RSKS-1 (S6K), key molecules in the insulin/IGF-1 signaling (IIS) and target of rapamycin (TOR) pathways, respectively, extend lifespan in Caenorhabditis elegans. Surprisingly, the daf-2 rsks-1 double mutant showed a nearly 5-fold lifespan extension. This phenotype was defined as a synergistic lifespan extension, based on the observation that the longevity of the daf-2 rsks-1 double mutant is beyond the combined effects of rsks-1 and daf-2 single mutants. This synergistic longevity phenotype cannot be explained by the hypothesis that daf-2 and rsks-1 function in parallel to modulate lifespan independently, since an additive effect would be expected under such an assumption. Rapamycin treatment could not extend the lifespan of daf-2 animals as much as the rsks-1 deletion mutant did. Inhibition of heat-shock factor 1 (hsf-1) almost completely abolished the lifespan extension produced by daf-2 rsks-1. A genetic screen using RNAi helped to identify the AMPK complex as the key mediator of the synergistic longevity produced by daf-2 rsks-1. Inhibition of AMPK suppressed only the synergy part of the lifespan extension. Tissue-specific epistasis analysis suggests that this enhanced activation of DAF-16 is initiated by signals from the germline, and that the germline tissue may play a key role in integrating the interactions between daf-2 and rsks-1 to cause a synergistic lifespan extension. Since DAF-2, RSKS-1, AMPK, and DAF-16 are highly conserved molecules, similar regulation may also exist in mammals. cell/cell.../fulltext/S2211-1247(13)00685-2
Posted on: Mon, 04 Aug 2014 20:18:06 +0000
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