Aging (Caenorhabditis elegans)

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2, 6710, 148, 1212358512153, 12515PConverts toLongevity reducing actionActivates in generalInsulin-like signalsActivates through modificationTranslocatesKEYBlocks action, inhibitsProcessPhosphorylatedLongevity promoting actionBinds toAGE-1/PI3KDAF-18/PTEN14-3-3DauerdevelopmentOxidative stress responseInnate ImmunityProteosome degradation pathwayPIP27, 119DAF-2/InRPIP31PDK-1/PKD1AKT-1/Akt/PKB53, 5AKT-2/Akt/PKB3, 5DAF-16/FOXOP3, 4, 12, 13JNK-18DAF-16/FOXOPMeP4, 8, 13JKK-188PRMT-112DAF-16/FOXOMeP12DAF-16/FOXORLE-11515SMK-110SGK-1daf-1510MethylatedDAF-16/FOXO3, 4, 12, 13DNA damagerepairReproductivelongevityMe


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. Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G; ''daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans.''; Science, 1997 PubMed Europe PMC
  2. Lapierre LR, Hansen M; ''Lessons from C. elegans: signaling pathways for longevity.''; Trends Endocrinol Metab, 2012 PubMed Europe PMC
  3. 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
  4. 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
  5. Paradis S, Ailion M, Toker A, Thomas JH, Ruvkun G; ''A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans.''; Genes Dev, 1999 PubMed Europe PMC
  6. Zhou KI, Pincus Z, Slack FJ; ''Longevity and stress in Caenorhabditis elegans.''; Aging (Albany NY), 2011 PubMed Europe PMC
  7. Ogg S, Ruvkun G; ''The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway.''; Mol Cell, 1998 PubMed Europe PMC
  8. 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
  9. Morris JZ, Tissenbaum HA, Ruvkun G; ''A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans.''; Nature, 1996 PubMed Europe PMC
  10. Wolff S, Ma H, Burch D, Maciel GA, Hunter T, Dillin A; ''SMK-1, an essential regulator of DAF-16-mediated longevity.''; Cell, 2006 PubMed Europe PMC
  11. Larsen PL, Albert PS, Riddle DL; ''Genes that regulate both development and longevity in Caenorhabditis elegans.''; Genetics, 1995 PubMed Europe PMC
  12. 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
  13. 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
  14. Dillin A, Crawford DK, Kenyon C; ''Timing requirements for insulin/IGF-1 signaling in C. elegans.''; Science, 2002 PubMed Europe PMC
  15. 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

History

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CompareRevisionActionTimeUserComment
107082view14:16, 17 September 2019MaintBotChEBI identifier normalization
95994view09:07, 13 February 2018MaintBotCosmetic changes, e.g., interactions black and 1px
95908view22:24, 2 February 2018Ariutta"Me" for methylation states now font-size 9.
95907view22:22, 2 February 2018Ariutta"State" in Key is not a Vesicle. Minor formatting updates for readability.
95906view22:13, 2 February 2018AriuttaClean up Key formatting
95901view21:56, 2 February 2018AriuttaLongetivity promoting uses ShapeType of Rectangle instead of RoundedRectangle. Key uses Shape instead of DataNode.
73766view00:25, 22 February 2014Kyookremoved colors, assigned related proceses
73765view00:20, 22 February 2014KyookPeriodical save, work in progress
73761view00:10, 22 February 2014MaintBotFixing empty labels on datanodes
71439view19:06, 17 October 2013MaintBotAutomated update of data sources
71241view19:15, 16 October 2013KyookAdding WBInteractionID PDK-1-AKT-1
71240view19:13, 16 October 2013KyookPeriodical save, work in progress
70498view00:13, 8 August 2013CgroveSpecify description
70064view08:05, 12 July 2013Mkutmonfixing unconnected lines
70063view08:03, 12 July 2013Mkutmonfixing unconnected lines (work in progress)
70001view23:02, 11 July 2013KyookReverted to version '19:51, 23 January 2013' by Kyook
66836view02:33, 24 June 2013Aks20588Periodical save, work in progress
66835view02:23, 24 June 2013Aks20588Periodical save, work in progress
66834view02:13, 24 June 2013Aks20588Periodical save, work in progress
66819view00:13, 24 June 2013Aks20588aks
57219view19:51, 23 January 2013KyookModified description
53185view20:49, 30 October 2012KyookSpecify description
53111view01:24, 30 October 2012MaintBotModified categories
52342view22:07, 11 October 2012KyookSpecify description
52341view21:39, 11 October 2012KyookPeriodical save, work in progress
52158view23:00, 5 October 2012Kyookadded SMK-1
52157view22:53, 5 October 2012KyookPeriodical save, work in progress
52156view22:43, 5 October 2012KyookPeriodical save, work in progress
52155view22:32, 5 October 2012KyookPeriodical save, work in progress
52154view22:22, 5 October 2012KyookPeriodical save, work in progress
52153view22:12, 5 October 2012KyookPeriodical save, work in progress
52152view22:02, 5 October 2012KyookPeriodical save, work in progress
52151view21:52, 5 October 2012KyookPeriodical save, work in progress
52150view21:39, 5 October 2012KyookPeriodical save, work in progress
52149view21:29, 5 October 2012KyookPeriodical save, work in progress
52075view01:25, 3 October 2012KyookSpecify description
52072view22:25, 2 October 2012Kyookadded RLE-1
52050view00:55, 2 October 2012Kyookadded review references
52004view18:31, 28 September 2012KyookPeriodical save, work in progress
51989view00:25, 28 September 2012KyookAdded PRMT-1
51988view00:17, 28 September 2012KyookPeriodical save, work in progress
51965view01:41, 27 September 2012KyookAdded JNK-1 pathway
51932view21:57, 25 September 2012KyookSpecify description
51931view21:54, 25 September 2012KyookSpecify description
51930view20:44, 25 September 2012KyookSpecify description
51906view01:56, 25 September 2012KyookModified description
51905view01:55, 25 September 2012KyookOntology Term : 'insulin signaling pathway' added !
51904view01:54, 25 September 2012KyookOntology Term : 'aging pathway' added !
51903view01:53, 25 September 2012Kyookinitiating aging pathways
51900view01:17, 25 September 2012KyookPeriodical save, work in progress

External references

DataNodes

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NameTypeDatabase referenceComment
14-3-3GeneProductF52D10.3 (WormBase)
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).
DNA

damage

repair
Pathway
Dauer developmentPathway
Innate ImmunityPathway
JKK-1GeneProductF35C8.3 (WormBase)
JNK-1GeneProductB0478.1 (WormBase)
  • DAF-16 binds to JNK-1.
  • JNK-1 binds and phosphorylates DAF-16.
Oxidative

stress

response
Pathway
PDK-1/PKD1GeneProductH42K12.1 (WormBase)
PIP2MetaboliteCHEBI:18348 (ChEBI)
PIP3MetaboliteCHEBI:16618 (ChEBI)
PRMT-1GeneProductY113G7B.17 (WormBase)
Proteosome

degradation

pathway
Pathway
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.
Reproductive longevityPathway
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

SourceTargetTypeDatabase referenceComment
PDK-1/PKD1mim-stimulationWBInteraction000518714 (WormBase)
PIP2PDK-1/PKD1mim-stimulationWBInteraction000518714 (WormBase)
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