Remarkable longevity and stress resistance of nematode PI3K-null mutants

Abstract

The great majority of lifespan-augmenting mutations were discovered in the nematode Caenorhabditis elegans. In particular, genetic disruption of insulin-like signaling extends longevity 1.5- to 3-fold in the nematode, and to lesser degrees in other taxa, including fruit flies and mice. C. elegans strains bearing homozygous nonsense mutations in the age-1 gene, which encodes the class-I phosphatidylinositol 3-kinase catalytic subunit (PI3K(CS)), produce progeny that were thought to undergo obligatory developmental arrest. We now find that, after prolonged developmental times at 15-20 degrees C, they mature into extremely long-lived adults with near-normal feeding rates and motility. They survive to a median of 145-190 days at 20 degrees C, with nearly 10-fold extension of both median and maximum adult lifespan relative to N2DRM, a long-lived wild-type stock into which the null mutant was outcrossed. PI3K-null adults, although a little less thermotolerant, are considerably more resistant to oxidative and electrophilic stresses than worms bearing normal or less long-lived alleles. Their unprecedented factorial gains in survival, under both normal and toxic environments, are attributed to elimination of residual and maternally contributed PI3K(CS) or its products, and consequent modification of kinase signaling cascades.