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Caenorhabditis elegans PI3K mutants reveal novel genes underlying exceptional stress resistance and lifespan

Two age‐1 nonsense mutants, truncating the class‐I phosphatidylinositol 3‐kinase catalytic subunit (PI3KCS) before its kinase domain, confer extraordinary longevity and stress‐resistance to Caenorhabditis elegans. These traits, unique to second‐generation homozygotes, are blunted at the first generation and are largely reversed by additional mutations to DAF‐16/FOXO, a transcription factor downstream of AGE‐1 in insulin‐like signaling. The strong age‐1 alleles (mg44, m333) were compared with the weaker hx546 allele on expression microarrays, testing four independent cohorts of each allele. Among 276 genes with significantly differential expression, 92% showed fewer transcripts in adults carrying strong age‐1 alleles rather than hx546. This proportion is significantly greater than the slight bias observed when contrasting age‐1 alleles to wild‐type worms. Thus, transcriptional changes peculiar to nonsense alleles primarily involve either gene silencing or failure of transcriptional activation. A subset of genes responding preferentially to age‐1‐nonsense alleles was reassessed by real‐time polymerase chain reaction, in worms bearing strong or weak age‐1 alleles; nearly all of these were significantly more responsive to the age‐1(mg44) allele than to age‐1(hx546). Additional mutation of daf‐16 reverted the majority of altered mg44‐F2 expression levels to approximately wild‐type values, although a substantial number of genes remained significantly distinct from wild‐type, implying that age‐1(mg44) modulates transcription through both DAF‐16/FOXO‐dependent and independent channels. When age‐1‐inhibited genes were targeted by RNA interference (RNAi) in wild‐type or age‐1(hx546) adults, most conferred significant oxidative‐stress protection. RNAi constructs targeting two of those genes were shown previously to extend life, and RNAi’s targeting five novel genes were found here to increase lifespan. PI3K‐null mutants may thus implicate novel mechanisms of life extension.