title: Diacylglycerol lipase regulates lifespan and oxidative stress response by inversely modulating TOR signaling in Drosophila and C. elegans.
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.
authors.affiliation: Institute of Biotechnology, National Tsing Hua University, HsinChu, 30013, Taiwan.
authors.forename: Yen-Hung
authors.initials: YH
authors.lastname: Lin
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Chen
authors.forename: Tzu-Yu
authors.initials: TY
authors.lastname: Kao
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Lin
authors.forename: Tzu-En
authors.initials: TE
authors.lastname: Hsu
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Wu
authors.forename: William W
authors.initials: WW
authors.lastname: Ja
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Brummel
authors.forename: Pankaj
authors.initials: P
authors.lastname: Kapahi
authors.forename: Chiou-Hwa
authors.initials: CH
authors.lastname: Yuh
authors.forename: Lin-Kwei
authors.initials: LK
authors.lastname: Yu
authors.forename: Zhi-Han
authors.initials: ZH
authors.lastname: Lin
authors.forename: Ru-Jing
authors.initials: RJ
authors.lastname: You
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Jhong
authors.forename: Horng-Dar
authors.initials: HD
authors.lastname: Wang
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000502:physiology; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000502:physiology; D004843:Epistasis, Genetic; D055785:Gene Knockdown Techniques; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008136:Longevity; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress; D010766:Phosphorylation; D034622:RNA Interference; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D008071:Lipoprotein Lipase
keywords: S6 kinase; aging; diacylglycerol; diacylglycerol kinase; metabolism; phosphatidic acid