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  • 1
    Publication Date: 2012-03-31
    Description: Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the life spans of yeast, flies, and mice. Calorie restriction, which increases life span and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Further, decreased mTORC1 signaling was sufficient to extend life span independently from changes in glucose homeostasis, as female mice heterozygous for both mTOR and mLST8 exhibited decreased mTORC1 activity and extended life span but had normal glucose tolerance and insulin sensitivity. Thus, mTORC2 disruption is an important mediator of the effects of rapamycin in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324089/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324089/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lamming, Dudley W -- Ye, Lan -- Katajisto, Pekka -- Goncalves, Marcus D -- Saitoh, Maki -- Stevens, Deanna M -- Davis, James G -- Salmon, Adam B -- Richardson, Arlan -- Ahima, Rexford S -- Guertin, David A -- Sabatini, David M -- Baur, Joseph A -- 1F32AG032833-01A1/AG/NIA NIH HHS/ -- CA129105/CA/NCI NIH HHS/ -- F32 AG032833/AG/NIA NIH HHS/ -- P30DK19525/DK/NIDDK NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA129105-05/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2012 Mar 30;335(6076):1638-43. doi: 10.1126/science.1215135.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22461615" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, White/metabolism ; Animals ; Carrier Proteins/genetics/metabolism ; Female ; Gluconeogenesis ; Glucose/metabolism ; Glucose Clamp Technique ; Homeostasis ; Insulin/administration & dosage/blood ; *Insulin Resistance ; Liver/metabolism ; *Longevity ; Male ; Mice ; Mice, Inbred C57BL ; Multiprotein Complexes ; Muscle, Skeletal/metabolism ; Phosphorylation ; Proteins/antagonists & inhibitors/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction ; Sirolimus/*pharmacology ; TOR Serine-Threonine Kinases/genetics/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2012-06-23
    Description: How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here we find that Paneth cells, a key constituent of the mammalian intestinal stem-cell (ISC) niche, augment stem-cell function in response to calorie restriction. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced activation of mTORC1 in Paneth cells during calorie restriction abolishes the ISC-augmenting effects of the niche. Finally, increased expression of bone stromal antigen 1 (Bst1) in Paneth cells-an ectoenzyme that produces the paracrine factor cyclic ADP ribose-mediates the effects of calorie restriction and rapamycin on ISC function. Our findings establish that mTORC1 non-cell-autonomously regulates stem-cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem-cell function to organismal physiology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387287/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387287/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yilmaz, Omer H -- Katajisto, Pekka -- Lamming, Dudley W -- Gultekin, Yetis -- Bauer-Rowe, Khristian E -- Sengupta, Shomit -- Birsoy, Kivanc -- Dursun, Abdulmetin -- Yilmaz, V Onur -- Selig, Martin -- Nielsen, G Petur -- Mino-Kenudson, Mari -- Zukerberg, Lawrence R -- Bhan, Atul K -- Deshpande, Vikram -- Sabatini, David M -- 1F32AG032833-01A1/AG/NIA NIH HHS/ -- CA103866/CA/NCI NIH HHS/ -- CA129105/CA/NCI NIH HHS/ -- F32 AG032833/AG/NIA NIH HHS/ -- P30 AG038072/AG/NIA NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- T32CA09216/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jun 28;486(7404):490-5. doi: 10.1038/nature11163.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722868" target="_blank"〉PubMed〈/a〉
    Keywords: ADP-ribosyl Cyclase/metabolism ; Animals ; Antigens, CD/metabolism ; Caloric Restriction ; Cell Count ; Cell Division/drug effects ; Cyclic ADP-Ribose/metabolism ; Energy Intake/*physiology ; Female ; GPI-Linked Proteins/agonists/metabolism ; Intestines/*cytology ; Longevity/physiology ; Male ; Mice ; Multiprotein Complexes ; Paneth Cells/*cytology/drug effects/*metabolism ; Paracrine Communication ; Proteins/antagonists & inhibitors/*metabolism ; Regeneration/drug effects ; Signal Transduction ; Sirolimus/pharmacology ; Stem Cell Niche/drug effects/*physiology ; Stem Cells/*cytology/drug effects/*metabolism ; TOR Serine-Threonine Kinases
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2015-04-04
    Description: By dividing asymmetrically, stem cells can generate two daughter cells with distinct fates. However, evidence is limited in mammalian systems for the selective apportioning of subcellular contents between daughters. We followed the fates of old and young organelles during the division of human mammary stemlike cells and found that such cells apportion aged mitochondria asymmetrically between daughter cells. Daughter cells that received fewer old mitochondria maintained stem cell traits. Inhibition of mitochondrial fission disrupted both the age-dependent subcellular localization and segregation of mitochondria and caused loss of stem cell properties in the progeny cells. Hence, mechanisms exist for mammalian stemlike cells to asymmetrically sort aged and young mitochondria, and these are important for maintaining stemness properties.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405120/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405120/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Katajisto, Pekka -- Dohla, Julia -- Chaffer, Christine L -- Pentinmikko, Nalle -- Marjanovic, Nemanja -- Iqbal, Sharif -- Zoncu, Roberto -- Chen, Walter -- Weinberg, Robert A -- Sabatini, David M -- P30 CA014051/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R37 AI047389/AI/NIAID NIH HHS/ -- T32 GM007287/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Apr 17;348(6232):340-3. doi: 10.1126/science.1260384. Epub 2015 Apr 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Boston, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA. Institute of Biotechnology, University of Helsinki, P.O. Box 00014, Helsinki, Finland. pekka.katajisto@helsinki.fi sabatini@wi.mit.edu. ; Institute of Biotechnology, University of Helsinki, P.O. Box 00014, Helsinki, Finland. ; Whitehead Institute for Biomedical Research, Boston, MA 02142, USA. ; Whitehead Institute for Biomedical Research, Boston, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. ; Whitehead Institute for Biomedical Research, Boston, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA. ; Whitehead Institute for Biomedical Research, Boston, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA. Broad Institute, Cambridge, MA 02142, USA. The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA. pekka.katajisto@helsinki.fi sabatini@wi.mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25837514" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Aging/genetics/*physiology ; Cell Division/genetics/*physiology ; Cell Line ; Humans ; Mitochondria/*physiology/ultrastructure ; Stem Cells/*physiology/*ultrastructure
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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