Longevity often associates with resistance to environmental stress. In C. elegans , long-lived (Age) mutants such as
age-1 and
daf-2 are more resistant to oxidative, UV-radiation, or thermal stresses. To get at the proximal causes for this longevity-associated stress resistance, we are focusing on the worm stress-response gene
hsp90 because it is a molecular chaperone; in contrast to many other 'house-keeping' genes, its mRNA level is dramatically increased in the dauer compared to other developmental stages (Dalley & Golomb 1992, Dev Biol 151: 80). The Thomas lab found that
daf-21(
p673) has a missense mutation in the worm
hsp90 gene (Malone and Thomas, WBG14.4: 52).
daf-21(
p673) has a temperature-sensitive dauer constitutive (Daf-c) phenotype. Based on this phenotype, genetic analysis showed that
p673 is a recessive, possibly neomorphic mutation that encourages dauer formation by affecting chemosensory neuron function (Malone et al, IWM93: 297). We found that
daf-21(
p673) mutant lived about 40-50% longer (mean and maximal adult lifespan) than wild-type animals when shifted from the permissive (15deg) to the restrictive (25deg) temperature at the L4 or young adult stages. Whereas either
daf-16(mgDf47) or
daf-12(
m20) efficiently suppressed the Daf-c phenotype (Thomas et al 1993, Genetics 134: 1105), only
daf-16 suppressed Age, suggesting that
daf-21 may affect dauer formation and lifespan independantly.
daf-16 is a member of the Forkhead class of transcription factors; and it mediates all of the effects caused by
daf-2 insulin-like signaling, including lifespan (Ogg et al 1997, Nature 389: 994; Lin et al 1997, Science 278: 1319). One possible explanation for the observation that a
daf-16 null mutation is epistatic to
daf-21 is that
daf-21 expression is positively regulated by
daf-16 . We are testing this hypothesis. We are also asking if Age mutants in general have an elevated
hsp90 expression or function. We thank Jim Thomas for providing
daf-21 mutant strains.