D by DAG kinase (DGK) resulting in its conversion to phophatidic acid (PA) for phosphoinositide turnover (Cai et al., 2009; Raghu Hardie, 2009). PA, at the same time because the attenuation DAG levels in the cell membrane, affects many intracellular signaling pathways, such as these regulating cell growth, differentiation, and membrane trafficking (Merida et al., 2008). PA can bind to mammalian TOR (mTOR) and promote mTORC1 and mTORC2 formation, which in turn induce the TOR signaling pathway (Toschi et al., 2009; Foster, 2013) and result in elevated phosphorylation levels of S6K and 4EBP (Fang et al., 2001). Previously, we’ve shown that a multi-stress screening tactic may be used to determine genes or mutants involved in the regulation of longevity (Wang et al., 2004, 2012; Liu et al., 2009). Right here, we report the characterization of one such gene, identified inside a Drosophila multistress resistant strain DAGL/inaEEP1101. This EP-element generated line is long-lived and resistant to oxidative anxiety. DAGL/inaEEP1101 shows upregulation of DAGL/inaE, a homolog of diacylglycerol lipase, and reduced levels of phosphorylated S6 kinase (p-S6K), consistent with all the hypothesis that DAGL/inaE up-regulation causes a reduction in TOR signaling. Conversely, a second mutant with lowered DAGL/inaE expression, DAGL/inaEKG08585, displays shortened lifespan, decreased tolerance to oxidative pressure and elevated levels of p-S6K. Genetic manipulation of DAGL/inaE, rdgA, or S6KKQ (a dominant-negative kind of S6 kinase) also suggest that lowered TOR signaling mediates the effects of DAGL/inaE overexpression on lifespan and anxiety resistance. Making use of Caenorhabditis elegans, we show that, as in flies, the nematode ortholog of DAGL/inaE, F42G9.six (herein named dagl-1), also regulates lifespan and oxidative pressure response by way of TOR. We propose that DAGL/ inaE and DGK regulate competing branches of pathways that metabolizeInstitute of Biotechnology, National Tsing Hua University, HsinChu 30013, Taiwan two Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 10617, Taiwan three Division of Metabolism and Aging, The Scripps Investigation Institute, Jupiter, FL 33458, USA 4 Department of Biology, Lengthy Island University, Brookville, NY 11548, USA five Buck Institute for Study on Aging, Novato, CA 94945, USA six Institute of Molecular and Genomic Medicine, National Wellness Investigation Institutes, Zhunan, Miaoli County 35053, Taiwan 7 Division of Life Science, National Tsing Hua University, HsinChu 30013, Taiwan 8 Institute of Systems Neuroscience, National Tsing Hua University, HsinChu 30013, TaiwanSummaryTarget of rapamycin (TOR) signaling is often a nutrient-sensing pathway controlling metabolism and lifespan.CPS2 Even though TOR signaling can be activated by a metabolite of diacylglycerol (DAG), phosphatidic acid (PA), the precise genetic mechanism by way of which DAG metabolism influences lifespan remains unknown.Triheptanoin DAG is metabolized to either PA by way of the action of DAG kinase or 2-arachidonoyl-sn-glycerol by diacylglycerol lipase (DAGL).PMID:23833812 Right here, we report that in Drosophila and Caenorhabditis elegans, overexpression of diacylglycerol lipase (DAGL/inaE/dagl-1) or knockdown of diacylglycerol kinase (DGK/rdgA/dgk-5) extends lifespan and enhances response to oxidative pressure. Phosphorylated S6 kinase (p-S6K) levels are lowered following these manipulations, implying the involvement of TOR signaling. Conversely, DAGL/ inaE/dagl-1 mutants exhibit shortened lifespan, lowered tolerance to ox.
