Aging (WP2313)

Caenorhabditis elegans

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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.

Authors

Karen Yook , Akshat , Martina Summer-Kutmon , Christian Grove , Anders Riutta , and Egon Willighagen

Activity

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Organisms

Caenorhabditis elegans

Communities

WormBase

Annotations

Pathway Ontology

insulin signaling pathway aging pathway

Participants

Label Type Compact URI Comment
PIP2 Metabolite chebi:18348
PIP3 Metabolite chebi:16618
AGE-1/PI3K GeneProduct ensembl:WBGene00000090 age-1 encodes a homologue of mammalian phosphatidylinositol-3-OH kinase catalytic subunit.
14-3-3 GeneProduct wormbase:F52D10.3
DAF-18/PTEN GeneProduct ensembl:WBGene00000913 daf-18 functions upstream to akt-1 and akt-2
daf-18 acts downstream of age-1
DAF-2/InR GeneProduct ensembl:WBGene00000898 insulin/IGF-1 pathway can diverge to regulate the timing of reproduction independently of longevity (Dillin et al., 2002a).
PDK-1/PKD1 GeneProduct ensembl:WBGene00003965
AKT-1/Akt/PKB GeneProduct ensembl:WBGene00000102
AKT-2/Akt/PKB GeneProduct ensembl:WBGene00000103
DAF-16/FOXO GeneProduct ensembl:WBGene00000912 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
JNK-1 GeneProduct wormbase:B0478.1 DAF-16 binds to JNK-1.
JNK-1 binds and phosphorylates DAF-16.
DAF-16/FOXO GeneProduct ensembl:WBGene00000912
JKK-1 GeneProduct ensembl:WBGene00002177
PRMT-1 GeneProduct ensembl:WBGene00013766
DAF-16/FOXO GeneProduct ensembl:WBGene00000912 DAF-16 bound directly to PRMT-1 in in vitro pulldown assays , HA-PRMT-1 was coimmunoprecipitated with FLAG-DAF-16 only when the both proteins were coexpressed.
RLE-1 GeneProduct ensembl:WBGene00010923 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.
SMK-1 GeneProduct ensembl:WBGene00018285 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.
SGK-1 GeneProduct ensembl:WBGene00004789 DAF-16 is predominantly localized in the cytoplasm as a result of inhibitory phosphorylation of Ser/Thr residues by the AKT and SGK kinases.
daf-15 GeneProduct ensembl:WBGene00000911 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

References

  1. Genes that regulate both development and longevity in Caenorhabditis elegans. Larsen PL, Albert PS, Riddle DL. Genetics. 1995 Apr;139(4):1567–83. PubMed Europe PMC Scholia
  2. A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Morris JZ, Tissenbaum HA, Ruvkun G. Nature. 1996 Aug 8;382(6591):536–9. PubMed Europe PMC Scholia
  3. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G. Science. 1997 Aug 15;277(5328):942–6. PubMed Europe PMC Scholia
  4. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, et al. Nature. 1997 Oct 30;389(6654):994–9. PubMed Europe PMC Scholia
  5. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Lin K, Dorman JB, Rodan A, Kenyon C. Science. 1997 Nov 14;278(5341):1319–22. PubMed Europe PMC Scholia
  6. Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Paradis S, Ruvkun G. Genes Dev. 1998 Aug 15;12(16):2488–98. PubMed Europe PMC Scholia
  7. The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway. Ogg S, Ruvkun G. Mol Cell. 1998 Dec;2(6):887–93. PubMed Europe PMC Scholia
  8. A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans. Paradis S, Ailion M, Toker A, Thomas JH, Ruvkun G. Genes Dev. 1999 Jun 1;13(11):1438–52. PubMed Europe PMC Scholia
  9. Timing requirements for insulin/IGF-1 signaling in C. elegans. Dillin A, Crawford DK, Kenyon C. Science. 2002 Oct 25;298(5594):830–4. PubMed Europe PMC Scholia
  10. JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. Oh SW, Mukhopadhyay A, Svrzikapa N, Jiang F, Davis RJ, Tissenbaum HA. Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4494–9. PubMed Europe PMC Scholia
  11. SMK-1, an essential regulator of DAF-16-mediated longevity. Wolff S, Ma H, Burch D, Maciel GA, Hunter T, Dillin A. Cell. 2006 Mar 10;124(5):1039–53. PubMed Europe PMC Scholia
  12. RLE-1, an E3 ubiquitin ligase, regulates C. elegans aging by catalyzing DAF-16 polyubiquitination. Li W, Gao B, Lee SM, Bennett K, Fang D. Dev Cell. 2007 Feb;12(2):235–46. PubMed Europe PMC Scholia
  13. Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16. Takahashi Y, Daitoku H, Hirota K, Tamiya H, Yokoyama A, Kako K, et al. Cell Metab. 2011 May 4;13(5):505–16. PubMed Europe PMC Scholia
  14. Longevity and stress in Caenorhabditis elegans. Zhou KI, Pincus Z, Slack FJ. Aging (Albany NY). 2011 Aug;3(8):733–53. PubMed Europe PMC Scholia
  15. Lessons from C. elegans: signaling pathways for longevity. Lapierre LR, Hansen M. Trends Endocrinol Metab. 2012 Dec;23(12):637–44. PubMed Europe PMC Scholia