The DAF-2 insulin-like signaling pathway independently regulates aging and immunity in C. elegans

Aging Cell. 2008 Dec;7(6):879-93. doi: 10.1111/j.1474-9726.2008.00435.x. Epub 2008 Sep 8.


The Caenorhabditis elegans DAF-2 insulin-like signaling pathway, which regulates lifespan and stress resistance, has also been implicated in resistance to bacterial pathogens. Loss-of-function daf-2 and age-1 mutants have increased lifespans and are resistant to a variety of bacterial pathogens. This raises the possibility that the increased longevity and the pathogen resistance of insulin-like signaling pathway mutants are reflections of the same underlying mechanism. Here we report that regulation of lifespan and resistance to the bacterial pathogen Pseudomonas aeruginosa is mediated by both shared and genetically distinguishable mechanisms. We find that loss of germline proliferation enhances pathogen resistance and this effect requires daf-16, similar to the regulation of lifespan. In contrast, the regulation of pathogen resistance and lifespan is decoupled within the DAF-2 pathway. Long-lived mutants of genes downstream of daf-2, such as pdk-1 and sgk-1, show wildtype resistance to pathogens. However, mutants of akt-1 and akt-2, which we find to individually have modest effects on lifespan, show enhanced resistance to pathogens. We also demonstrate that pathogen resistance of daf-2, akt-1, and akt-2 mutants is associated with restricted bacterial colonization, and that daf-2 mutants are better able to clear an infection after challenge with P. aeruginosa. Moreover, we find that pathogen resistance among insulin-like signaling mutants is associated with increased expression of immunity genes during infection. Other processes that affect organismal longevity, including Jun kinase signaling and caloric restriction, do not affect resistance to bacterial pathogens, further establishing that aging and innate immunity are regulated by genetically distinct mechanisms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / genetics
  • Aging / immunology*
  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / immunology*
  • Caenorhabditis elegans / microbiology
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / physiology*
  • Female
  • Forkhead Transcription Factors
  • Gene Expression Regulation / immunology
  • Gene Knockdown Techniques
  • Immunity, Innate / genetics*
  • Insulin / physiology*
  • Longevity / genetics
  • Longevity / immunology
  • Male
  • Mutation
  • Proto-Oncogene Proteins c-akt / genetics
  • Pseudomonas Infections / genetics
  • Pseudomonas Infections / immunology
  • Pseudomonas Infections / microbiology
  • Receptor, Insulin / genetics
  • Receptor, Insulin / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Transcription Factors / physiology


  • Caenorhabditis elegans Proteins
  • Forkhead Transcription Factors
  • Insulin
  • Transcription Factors
  • daf-16 protein, C elegans
  • DAF-2 protein, C elegans
  • Receptor, Insulin
  • Proto-Oncogene Proteins c-akt
  • akt-1 protein, C elegans
  • akt-2 protein, C elegans