Abstract
Target of rapamycin (TOR) signaling is a nutrient-sensing pathway controlling metabolism and lifespan. Although TOR signaling can be activated by a metabolite of diacylglycerol (DAG), phosphatidic acid (PA), the precise genetic mechanism through which DAG metabolism influences lifespan remains unknown. DAG is metabolized to either PA via the action of DAG kinase or 2-arachidonoyl-sn-glycerol by diacylglycerol lipase (DAGL). 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 stress. Phosphorylated S6 kinase (p-S6K) levels are reduced following these manipulations, implying the involvement of TOR signaling. Conversely, DAGL/inaE/dagl-1 mutants exhibit shortened lifespan, reduced tolerance to oxidative stress, and elevated levels of p-S6K. Additional results from genetic interaction studies are consistent with the hypothesis that DAG metabolism interacts with TOR and S6K signaling to affect longevity and oxidative stress resistance. These findings highlight conserved metabolic and genetic pathways that regulate aging.
Highlights
Longevity is regulated by conserved signaling pathways that modulate aging-associated stress responses (Haigis & Yankner, 2010; Lapierre & Hansen, 2012)
Semi-quantitative reverse-transcription following by semi-quantitative polymerase chain reaction (RT-PCR) analysis revealed a threefold increase of diacylglycerol lipase (DAGL)/inaE mRNA levels in DAGL/inaEEP1101 compared with the control (Fig. 1C)
DAGL/inaEKG08585 exhibited a 50% decrease (P < 0.001) in mean lifespan and a 34% reduction (P < 0.001) in mean survival time on oxidative stress compared to w1118 (Fig. 1E,F)
Summary
Longevity is regulated by conserved signaling pathways that modulate aging-associated stress responses (Haigis & Yankner, 2010; Lapierre & Hansen, 2012). Reduction in the activity of S6 protein kinase, a downstream signaling component in the TOR pathway, leads to lifespan extension and resistance to age-related pathologies in mice (Selman et al, 2009), while the activation of Rheb-TOR signaling activity reduces oxidative stress tolerance and hastens emergence of age-related phenotypes in Drosophila (Patel & Tamanoi, 2006). PA, as well as the attenuation DAG levels in the cell membrane, affects numerous intracellular signaling pathways, including those 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 lead to elevated phosphorylation levels of S6K and 4EBP (Fang et al, 2001)
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