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Journal of Inherited Metabolic Disease

, Volume 25, Issue 3, pp 197–206 | Cite as

Longevity genes in the nematode Caenorhabditis elegans also mediate increased resistance to stress and prevent disease

  • T. E. Johnson
  • S. Henderson
  • S. Murakami
  • E. de Castro
  • S. H. de Castro
  • J. Cypser
  • B. Rikke
  • P. Tedesco
  • C. Link
Article

Abstract

More than 40 single-gene mutants in Caenorhabditis elegans have been demonstrated to lead to increased lifespan (a rigorous, operational test for being a gerontogene) of 20% or more; these are referred to collectively as ‘Age’ mutants. Age mutants must change key functions that are rate-limiting determinants of longevity; moreover, important genes can be identified independently of prior hypotheses as to actual mode of gene action in extending longevity and/or ‘slowing’ of ageing. These Age mutants define as many as nine (possibly) distinct pathways and/or modes of action, as defined by primary phenotype. Each of three well-studied mutants (age-1, clk-1, and spe-26) alters age-specific mortality rates in a fashion unique to itself. In age-1 mutants, the decreases in mortality rates are quite dramatic, with an almost tenfold drop in mortality throughout most of life. All Age mutants (so far without exception) increase the ability of the worm to respond to several (but not all) stresses, including heat, UV, and reactive oxidants. We have used directed strategies as well as random mutagenesis to identify novel genes that increase the worm's ability to resist stress. Two genes (daf-16 and old-1) are epistatic to the long-life phenotype of most mutants and also yield over-expression strains that are stress-resistant and long-lived. We have also used a variety of approaches to determine what transcriptional alterations are associated with increased longevity (and with ageing itself), including whole-genome expression studies using microarrays and GFP reporter constructs. We suggest that the role of the Age genes in both longevity and stress resistance indicates that a major evolutionary determinant of longevity is the ability to respond to stress. In mammals, both dietary restriction and hormesis are phenomena in which the endogenous level of resistance to stress has been upregulated; both of these interventions extend longevity, suggesting possible evolutionary conservation.

Keywords

Caenorhabditis Elegans Reporter Construct Evolutionary Conservation Random Mutagenesis Nematode Caenorhabditis Elegans 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • T. E. Johnson
    • 1
    • 2
  • S. Henderson
    • 1
  • S. Murakami
    • 1
  • E. de Castro
    • 1
  • S. H. de Castro
    • 1
  • J. Cypser
    • 1
  • B. Rikke
    • 1
  • P. Tedesco
    • 1
  • C. Link
    • 1
  1. 1.Institute for Behavioral GeneticsUniversity of Colorado at BoulderBoulderUSA
  2. 2.Institute for Behavioral GeneticsUniversity of Colorado at BoulderBoulderUSA

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