AgingTemplate (Caenorhabditis elegans)

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PBlocks action, inhibitsKEYLongevity promoting actionActivates in generalActivates through modificationBinds toPhosphorylatedConverts toLongevity reducing actionTranslocatesProcessDAF-18/PTENAGE-1/PI3K14-3-3DAF-2/InRPDK-1/PKD1AKT-1/Akt/PKBAKT-2/Akt/PKBJNK-1PJKK-1PRMT-1DAF-16/FOXOPMeRLE-1SMK-1SGK-1daf-15MeMethylatedDAF-16/FOXO


Description

Aging in C. elegans involves measurable declines in morphology, reproduction, and behavior. Understanding the cellular and molecular processes leading to senescence in this nematode began in the early 1980s with the targeted identification of mutants that extended life span (an AGE phenotype). These studies identified at least two key regulators of life span, DAF-2, an insulin/IGF receptor ortholog, and DAF-16, a Forkhead-related transcription factor. Since then many more genes and pathways involved in senescence have been identified. Almost all of these genes play important roles in cellular and organismal-level processes other than aging, such as dauer formation, stress response, feeding, and chemosensation.

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Bibliography

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  1. Takahashi Y, Daitoku H, Hirota K, Tamiya H, Yokoyama A, Kako K, Nagashima Y, Nakamura A, Shimada T, Watanabe S, Yamagata K, Yasuda K, Ishii N, Fukamizu A; ''Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16.''; Cell Metab, 2011 PubMed Europe PMC Scholia
  2. Paradis S, Ruvkun G; ''Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor.''; Genes Dev, 1998 PubMed Europe PMC Scholia
  3. Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, Ruvkun G; ''The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans.''; Nature, 1997 PubMed Europe PMC Scholia
  4. Lin K, Dorman JB, Rodan A, Kenyon C; ''daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans.''; Science, 1997 PubMed Europe PMC Scholia
  5. Li W, Gao B, Lee SM, Bennett K, Fang D; ''RLE-1, an E3 ubiquitin ligase, regulates C. elegans aging by catalyzing DAF-16 polyubiquitination.''; Dev Cell, 2007 PubMed Europe PMC Scholia
  6. Oh SW, Mukhopadhyay A, Svrzikapa N, Jiang F, Davis RJ, Tissenbaum HA; ''JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16.''; Proc Natl Acad Sci U S A, 2005 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
71436view19:05, 17 October 2013MaintBotAutomated update of data sources
71141view05:27, 10 October 2013KhanspersPeriodical save, work in progress
70065view08:10, 12 July 2013Mkutmonchanging interactions in legend to graphical lines
66547view23:33, 19 June 2013KyookModified title
66546view23:31, 19 June 2013KyookNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
14-3-3GeneProduct
AGE-1/PI3KGeneProductB0334.8 (WormBase) age-1 encodes a homologue of mammalian phosphatidylinositol-3-OH kinase catalytic subunit.
AKT-1/Akt/PKBGeneProductC12D8.10 (WormBase)
AKT-2/Akt/PKBGeneProductF28H6.1 (WormBase)
DAF-16/FOXOGeneProductR13H8.1 (WormBase)
  • PRMT-1 specifically methylates the C terminus of the forkhead domain (FH-C) in DAF-16 blocking binding to 14-3-3 protein.
  • DAF-16 is predominantly localized in the cytoplasm as a result of inhibitory phosphorylation of Ser/Thr residues by the AKT and SGK kinases.
  • T242 is an AKT-mediated phosphorylation site in DAF-16
DAF-18/PTENGeneProductT07A9.6 (WormBase)
  • daf-18 functions upstream to akt-1 and akt-2
  • daf-18 acts downstream of age-1
DAF-2/InRGeneProductY55D5A.5 (WormBase) insulin/IGF-1 pathway can diverge to regulate the timing of reproduction independently of longevity (Dillin et al., 2002a).
JKK-1GeneProductF35C8.3 (WormBase)
JNK-1GeneProductB0478.1 (WormBase)
  • DAF-16 binds to JNK-1.
  • JNK-1 binds and phosphorylates DAF-16.
PDK-1/PKD1GeneProductH42K12.1 (WormBase)
PRMT-1GeneProductY113G7B.17 (WormBase)
RLE-1GeneProductM142.6 (WormBase)
  • age-1 encodes a homologue of mammalian phosphatidylinositol-3-OH kinase catalytic subunit.
  • RLE-1 physically interacts with DAF-16. RLE-1 C terminus is required for the interaction of RLE-1 with DAF-16.
SGK-1GeneProductW10G6.2 (WormBase) DAF-16 is predominantly localized in the cytoplasm as a result of inhibitory phosphorylation of Ser/Thr residues by the AKT and SGK kinases.
SMK-1GeneProductF41E6.4 (WormBase)
  • SMK-1 was temporally and spatially colocalized with active DAF-16.
  • smk-1 RNAi does not cause a general sickness in long-lived animals but rather specifically affects IIS-regulated life span.
  • DAF-16 and SMK-1 do not directly or indirectly regulate expression or localization of one another.
  • SMK-1 specifies the longevity function of DAF-16 by affecting the efficiency of transcription of DAF-16 target genes involved in oxidative and UV stress response and innate immunity but is not required for DAF-16 regulation of heat-stress-response genes.
daf-15GeneProductC10C5.6 (WormBase) Reduced smk-1 resulted in increased expression of daf-15 mRNA, suggesting that SMK-1 is required for the transcriptional repressor activity of DAF-16

Annotated Interactions

No annotated interactions

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