Celecoxib extends C. elegans lifespan via inhibition of insulin-like signaling but not cyclooxygenase-2 activity

Aging Cell. 2011 Jun;10(3):506-19. doi: 10.1111/j.1474-9726.2011.00688.x. Epub 2011 Apr 7.

Abstract

One goal of aging research is to develop interventions that combat age-related illnesses and slow aging. Although numerous mutations have been shown to achieve this in various model organisms, only a handful of chemicals have been identified to slow aging. Here, we report that celecoxib, a nonsteroidal anti-inflammatory drug widely used to treat pain and inflammation, extends Caenorhabditis elegans lifespan and delays the age-associated physiological changes, such as motor activity decline. Celecoxib also delays the progression of age-related proteotoxicity as well as tumor growth in C. elegans. Celecoxib was originally developed as a potent cyclooxygenase-2 (COX-2) inhibitor. However, the result from a structural-activity analysis demonstrated that the antiaging effect of celecoxib might be independent of its COX-2 inhibitory activity, as analogs of celecoxib that lack COX-2 inhibitory activity produce a similar effect on lifespan. Furthermore, we found that celecoxib acts directly on 3'-phosphoinositide-dependent kinase-1, a component of the insulin/IGF-1 signaling cascade to increase lifespan.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Caenorhabditis elegans Proteins / metabolism
  • Caenorhabditis elegans* / drug effects
  • Caenorhabditis elegans* / genetics
  • Caenorhabditis elegans* / growth & development
  • Celecoxib
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Forkhead Transcription Factors
  • Insulin / metabolism
  • Insulin-Like Growth Factor I / antagonists & inhibitors*
  • Insulin-Like Growth Factor I / metabolism
  • Longevity*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyrazoles
  • Signal Transduction
  • Structure-Activity Relationship
  • Sulfonamides
  • Transcription Factors / metabolism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Caenorhabditis elegans Proteins
  • Cyclooxygenase 2 Inhibitors
  • Forkhead Transcription Factors
  • Insulin
  • Pyrazoles
  • Sulfonamides
  • Transcription Factors
  • daf-16 protein, C elegans
  • Insulin-Like Growth Factor I
  • Cyclooxygenase 2
  • 3-Phosphoinositide-Dependent Protein Kinases
  • Protein-Serine-Threonine Kinases
  • Celecoxib