title: Extreme-longevity mutations orchestrate silencing of multiple signaling pathways.
abstract: Long-lived mutants provide unique insights into the genetic factors that limit lifespan in wild-type animals. Most mutants and RNA interference targets found to extend life, typically by 1.5- to 2.5-fold, were discovered in C. elegans. Several longevity-assurance pathways are conserved across widely divergent taxa, indicating that mechanisms of lifespan regulation evolved several hundred million years ago. Strong mutations to the C. elegans gene encoding AGE-1/PI3KCS achieve unprecedented longevity by orchestrating the modulation (predominantly silencing) of multiple signaling pathways. This is evident in a profound attenuation of total kinase activity, leading to reduced phosphoprotein content. Mutations to the gene encoding the catalytic subunit of PI3K (phosphatidylinositol 3-kinase) have the potential to modulate all enzymes that depend on its product, PIP3, for membrane tethering or activation by other kinases. Remarkably, strong mutants inactivating PI3K also silence multiple signaling pathways at the transcript level, partially but not entirely mediated by the DAF-16/FOXO transcription factor. Mammals have a relatively large proportion of somatic cells, and survival depends on their replication, whereas somatic cell divisions in nematodes are limited to development and reproductive tissues. Thus, translation of longevity gains from nematodes to mammals requires disentangling the downstream consequences of signaling mutations, to avoid their deleterious consequences.
authors.affiliation: Central Arkansas Veterans Healthcare System, 151/LR, 4300 West 7th Street, Little Rock, AR 72205, USA. rjsr@uams.edu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Shmookler Reis
authors.forename: Puneet
authors.initials: P
authors.lastname: Bharill
authors.forename: Cagdas
authors.initials: C
authors.lastname: Tazearslan
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ayyadevara
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D006801:Humans; D008136:Longevity / Q000235:genetics* / Q000502:physiology; D008954:Models, Biological; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D029742:Caenorhabditis elegans Proteins; D019869:Phosphatidylinositol 3-Kinases; C100662:AGE-1 protein, C elegans