title: mTORC2-SGK-1 acts in two environmentally responsive pathways with opposing effects on longevity.
abstract: The nematode worm Caenorhabditis elegans provides a powerful system for elucidating how genetic, metabolic, nutritional, and environmental factors influence aging. The mechanistic target of rapamycin (mTOR) kinase is important in growth, disease, and aging and is present in the mTORC1 and mTORC2 complexes. In diverse eukaryotes, lifespan can be increased by inhibition of mTORC1, which transduces anabolic signals to stimulate protein synthesis and inhibit autophagy. Less is understood about mTORC2, which affects C. elegans lifespan in a complex manner that is influenced by the bacterial food source. mTORC2 regulates C. elegans growth, reproduction, and lipid metabolism by activating the SGK-1 kinase, but current data on SGK-1 and lifespan seem to be conflicting. Here, by analyzing the mTORC2 component Rictor (RICT-1), we show that mTORC2 modulates longevity by activating SGK-1 in two pathways that affect lifespan oppositely. RICT-1/mTORC2 limits longevity by directing SGK-1 to inhibit the stress-response transcription factor SKN-1/Nrf in the intestine. Signals produced by the bacterial food source determine how this pathway affects SKN-1 and lifespan. In addition, RICT-1/mTORC2 functions in neurons in an SGK-1-mediated pathway that increases lifespan at lower temperatures. RICT-1/mTORC2 and SGK-1 therefore oppose or accelerate aging depending upon the context in which they are active. Our findings reconcile data on SGK-1 and aging, show that the bacterial microenvironment influences SKN-1/Nrf, mTORC2 functions, and aging, and identify two longevity-related mTORC2 functions that involve SGK-regulated responses to environmental cues.
authors.affiliation: Joslin Diabetes Center, Harvard Stem Cell Institute, Harvard Medical School Department of Genetics, Boston, MA, 02215, USA; Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima, 739-8530, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mizunuma
authors.forename: Elke
authors.initials: E
authors.lastname: Neumann-Haefelin
authors.forename: Natalie
authors.initials: N
authors.lastname: Moroz
authors.forename: Yujie
authors.initials: Y
authors.lastname: Li
authors.forename: T Keith
authors.initials: TK
authors.lastname: Blackwell
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism*; D008136:Longevity / Q000235:genetics*; D000076225:Mechanistic Target of Rapamycin Complex 2; D064307:Microbiota; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D017874:Immediate-Early Proteins; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D000099184:Serum-Glucocorticoid Regulated Kinases
keywords: SKN-1/Nrf; aging; mTORC2; microbiome; rictor; serum- and glucocorticoid-regulated kinase