PMID- 29378959 OWN - NLM STAT- MEDLINE DCOM- 20180801 LR - 20220211 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 115 IP - 7 DP - 2018 Feb 13 TI - Effects of rapamycin on growth hormone receptor knockout mice. PG - E1495-E1503 LID - 10.1073/pnas.1717065115 [doi] AB - It is well documented that inhibition of mTORC1 (defined by Raptor), a complex of mechanistic target of rapamycin (mTOR), extends life span, but less is known about the mechanisms by which mTORC2 (defined by Rictor) impacts longevity. Here, rapamycin (an inhibitor of mTOR) was used in GHR-KO (growth hormone receptor knockout) mice, which have suppressed mTORC1 and up-regulated mTORC2 signaling, to determine the effect of concurrently decreased mTORC1 and mTORC2 signaling on life span. We found that rapamycin extended life span in control normal (N) mice, whereas it had the opposite effect in GHR-KO mice. In the rapamycin-treated GHR-KO mice, mTORC2 signaling was reduced without further inhibition of mTORC1 in the liver, muscle, and s.c. fat. Glucose and lipid homeostasis were impaired, and old GHR-KO mice treated with rapamycin lost functional immune cells and had increased inflammation. In GHR-KO MEF cells, knockdown of Rictor, but not Raptor, decreased mTORC2 signaling. We conclude that drastic reduction of mTORC2 plays important roles in impaired longevity in GHR-KO mice via disruption of whole-body homeostasis. FAU - Fang, Yimin AU - Fang Y AUID- ORCID: 0000-0001-9270-5857 AD - Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62702; yfang@siumed.edu. FAU - Hill, Cristal M AU - Hill CM AD - Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62702. FAU - Darcy, Justin AU - Darcy J AD - Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62702. FAU - Reyes-Ordonez, Adriana AU - Reyes-Ordonez A AD - Department of Cell and Developmental Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801. FAU - Arauz, Edwin AU - Arauz E AD - Department of Cell and Developmental Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801. FAU - McFadden, Samuel AU - McFadden S AD - Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62702. FAU - Zhang, Chi AU - Zhang C AD - Institute of Cardiovascular Research, University of South China, Hunan 421001, China. FAU - Osland, Jared AU - Osland J AD - Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62702. FAU - Gao, John AU - Gao J AD - Department of Pathology & Laboratory Medicine, Southern Illinois University School of Medicine, Springfield, IL 62702. FAU - Zhang, Tian AU - Zhang T AD - Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL 62702. FAU - Frank, Stuart J AU - Frank SJ AD - Department of Medicine, University of Alabama, Birmingham, AL 35294. FAU - Javors, Martin A AU - Javors MA AD - Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX 78229. FAU - Yuan, Rong AU - Yuan R AD - Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62702. FAU - Kopchick, John J AU - Kopchick JJ AD - Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701. FAU - Sun, Liou Y AU - Sun LY AD - Department of Biology, University of Alabama, Birmingham, AL 35294. FAU - Chen, Jie AU - Chen J AD - Department of Cell and Developmental Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801. FAU - Bartke, Andrzej AU - Bartke A AD - Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62702. LA - eng GR - K01 AG048264/AG/NIA NIH HHS/United States GR - R01 AG019899/AG/NIA NIH HHS/United States GR - P30 DK079626/DK/NIDDK NIH HHS/United States GR - R56 AG050531/AG/NIA NIH HHS/United States GR - R21 AG038850/AG/NIA NIH HHS/United States GR - R21 AG051869/AG/NIA NIH HHS/United States GR - P01 AG031736/AG/NIA NIH HHS/United States GR - R56 AG057734/AG/NIA NIH HHS/United States GR - R01 AR048914/AR/NIAMS NIH HHS/United States GR - R01 GM089771/GM/NIGMS NIH HHS/United States GR - R21 AG050225/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20180129 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Immunosuppressive Agents) RN - 0 (Receptors, Somatotropin) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Cytoplasm/drug effects/metabolism MH - Female MH - Immunosuppressive Agents/*pharmacology MH - Insulin Resistance MH - Longevity/*drug effects MH - Male MH - Mechanistic Target of Rapamycin Complex 1/*metabolism MH - Mechanistic Target of Rapamycin Complex 2/*metabolism MH - Mice MH - Mice, Inbred BALB C MH - Mice, Knockout MH - Receptors, Somatotropin/*physiology MH - Signal Transduction MH - Sirolimus/*pharmacology PMC - PMC5816183 OTO - NOTNLM OT - GHR-KO OT - homeostasis OT - longevity OT - mTORC2 OT - rapamycin COIS- The authors declare no conflict of interest. EDAT- 2018/01/31 06:00 MHDA- 2018/08/02 06:00 PMCR- 2018/08/13 CRDT- 2018/01/31 06:00 PHST- 2018/01/31 06:00 [pubmed] PHST- 2018/08/02 06:00 [medline] PHST- 2018/01/31 06:00 [entrez] PHST- 2018/08/13 00:00 [pmc-release] AID - 1717065115 [pii] AID - 201717065 [pii] AID - 10.1073/pnas.1717065115 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):E1495-E1503. doi: 10.1073/pnas.1717065115. Epub 2018 Jan 29.