title: mTORC1 and SIRT1 Cooperate to Foster Expansion of Gut Adult Stem Cells during Calorie Restriction.
abstract: Longevity-promoting caloric restriction is thought to trigger downregulation of mammalian target of rapamycin complex 1 (mTORC1) signaling and upregulation of SIRT1 activity with associated health benefits. Here, we show that mTORC1 signaling in intestinal stem cells (ISCs) is instead upregulated during calorie restriction (CR). SIRT1 deacetylates S6K1, thereby enhancing its phosphorylation by mTORC1, which leads to an increase in protein synthesis and an increase in ISC number. Paneth cells in the ISC niche secrete cyclic ADP ribose that triggers SIRT1 activity and mTORC1 signaling in neighboring ISCs. Notably, the mTOR inhibitor rapamycin, previously reported to mimic effects of CR, abolishes this expansion of ISCs. We suggest that Paneth cell signaling overrides any direct nutrient sensing in ISCs to sculpt the observed response to CR. Moreover, drugs that modulate pathways important in CR may exert opposing effects on different cell types.
authors.affiliation: Department of Biology, Glenn Labs for the Science of Aging and Koch Institute, MIT, Cambridge, MA 02139, USA.
authors.forename: Masaki
authors.initials: M
authors.lastname: Igarashi
authors.affiliation: Department of Biology, Glenn Labs for the Science of Aging and Koch Institute, MIT, Cambridge, MA 02139, USA. Electronic address: leng@mit.edu.
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism*; D000818:Animals; D031204:Caloric Restriction; D049109:Cell Proliferation; D036563:Cyclic ADP-Ribose / Q000378:metabolism; D004032:Diet; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009940:Organoids / Q000378:metabolism; D010766:Phosphorylation; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*; D056565:Sirtuin 2 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D009243:NAD; D036563:Cyclic ADP-Ribose; D000076222:Mechanistic Target of Rapamycin Complex 1; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D056565:Sirtuin 2