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

Abstract

SummaryTwo age-1 nonsense mutants, truncating the class-I phosphatidylinositol 3-kinase catalytic subunit (PI3K CS ) 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.

Modulation of lipid biosynthesis contributes to stress resistance and longevity of C. elegans mutants

“…They were then placed in bacteria-free medium containing 5-mM hydrogen peroxide, freshly diluted from stock solution, and survival was monitored as described previously [7,37,38]. A and B show replicate experiments, assessing effects of RNAi's targeting desaturase ( fat-2, -3, -4, -5, -6 or -7 ) or elongase genes ( elo-1, -2 or - 5 ).…”

The contribution of dietary restriction to extended longevity in the malaria vector Anopheles coluzzii

“…Dietary-restricted (DR) organisms across many taxa have been reported to survive longer than those with unlimited or normal access to food. For example, lifespan increased 30–70% in rodents, spiders, and grasshoppers [42–48], 2-fold in budding yeast and Drosophila [49–52], and up to 10-fold in C. elegans [53, 54]. Studies on yeast, C. elegans and Drosophila showed that DR can be viewed as a Gaussian curve of food intake, situated centrally between starvation and ad-libitum food intake [55–60].…”

Hc-daf-2 encodes an insulin-like receptor kinase in the barber’s pole worm, Haemonchus contortus, and restores partial dauer regulation

“…The “dauer hypothesis” or “daf-c paradigm” holds that the resumption of iL3 development in parasitic nematodes is developmentally and functionally analogous to the recovery from the dauer state in C. elegans and is governed by similar molecular mechanisms (Hotez et al, 1993; Blaxter, 1998; Bürglin et al, 1998; Hu, 2007). Dauer development is regulated by several signalling pathways including an insulin/insulin-like growth factor 1 (IGF1)-like signalling pathway, which contains a number of components such as the insulin-like receptor kinase DAF-2 (Kimura et al, 1997; Apfeld and Kenyon, 1998; Gems et al, 1998), the Phosphoinositide-3 (PI3) kinase AGE-1 (Vanhaesebroeck et al, 1997; Engelman et al, 2006; Ayyadevara et al, 2009) and the FOXO-class transcription factor DAF-16 (Lin et al, 1997; Ogg et al, 1997; Ogg and Ruvkun, 1998). Mutations in the daf-2 and age-1 genes result in dauer constitutive (daf-c) phenotypes, whereas mutations in daf-16 give dauer-defective (daf-d) phenotypes.…”