@article{028a04418cb743318b1530e3cf2b4de0,
title = "Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging",
abstract = "Diet has a profound effect on tissue regeneration in diverse organisms, and low caloric states such as intermittent fasting have beneficial effects on organismal health and age-associated loss of tissue function. The role of adult stem and progenitor cells in responding to short-term fasting and whether such responses improve regeneration are not well studied. Here we show that a 24 hr fast augments intestinal stem cell (ISC) function in young and aged mice by inducing a fatty acid oxidation (FAO) program and that pharmacological activation of this program mimics many effects of fasting. Acute genetic disruption of Cpt1a, the rate-limiting enzyme in FAO, abrogates ISC-enhancing effects of fasting, but long-term Cpt1a deletion decreases ISC numbers and function, implicating a role for FAO in ISC maintenance. These findings highlight a role for FAO in mediating pro-regenerative effects of fasting in intestinal biology, and they may represent a viable strategy for enhancing intestinal regeneration. Mihaylova et al. show that short-term fasting promotes intestinal stem and progenitor cell function in young and aged mice by inducing a robust fatty acid oxidation (FAO) program. PPARδ agonists emulate these effects, showing that fatty acid metabolism has positive effects on young and old ISCs.",
keywords = "aging, fasting, fatty acid oxidation, intestinal stem cells, intestine, metabolism, mitochondrial metabolism, stem cells",
author = "Mihaylova, {Maria M.} and Cheng, {Chia Wei} and Cao, {Amanda Q.} and Surya Tripathi and Mana, {Miyeko D.} and Bauer-Rowe, {Khristian E.} and Monther Abu-Remaileh and Laura Clavain and Aysegul Erdemir and Lewis, {Caroline A.} and Elizaveta Freinkman and Dickey, {Audrey S.} and {La Spada}, {Albert R.} and Yanmei Huang and Bell, {George W.} and Vikram Deshpande and Peter Carmeliet and Pekka Katajisto and Sabatini, {David M.} and Yilmaz, {{\"O}mer H.}",
note = "Funding Information: {\"O}.H.Y. is supported by NIH R00 AG045144 , R01 CA211184 , and R01 CA034992 ; the V Foundation V Scholar Award 6930750 ; the Sidney Kimmel Scholar Award 6934241 ; the MIT Stem Cell Initiative through Fondation MIT; the Pew-Stewart Trust Scholar Award 025887-00001 ; the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund ; and the American Federation of Aging Research (AFAR) 6932237 . D.M.S. is supported by NIH R01 CA103866 and the Glenn/AFAR Breakthroughs in Gerontology Award 6932237 and is an investigator of the Howard Hughes Medical Institute. M.M.M. is supported by a Damon Runyon Postdoctoral Fellowship DRG 2146-13 , where she is a Robert Black Foundation Fellow; a Ludwig Postdoctoral Fellowship 2036238 ; and NIH K99 Pathway to Independence award K99 AG054760 . C.-W.C. is supported by a Ludwig Postdoctoral Fellowship and a Helen Hay Whitney Postdoctoral Fellowship 16123046/ 2389185 . A.S.D. and A.R.L.S. are supported by NIH R01 AG033082 and R01 NS065874 . This work was supported in part by the Koch Institute Support Grant P30-CA14051 from the National Cancer Institute. We thank the Koch Institute{\textquoteright}s Robert A. Swanson Biotechnology Center, specifically members of the Hope Babette Tang (1983) Histology Facility and the Flow Cytometry Core. We also thank Sven Holder for histology support, the Whitehead Flow Cytometry Core, and Stuart Levine of the MIT BioMicro Center. We thank Heather Keys for figure suggestions and members of the Sabatini and Yilmaz laboratories for discussions. Funding Information: ?.H.Y. is supported by NIH R00 AG045144, R01 CA211184, and R01 CA034992; the V Foundation V Scholar Award 6930750; the Sidney Kimmel Scholar Award 6934241; the MIT Stem Cell Initiative through Fondation MIT; the Pew-Stewart Trust Scholar Award 025887-00001; the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund; and the American Federation of Aging Research (AFAR) 6932237. D.M.S. is supported by NIH R01 CA103866 and the Glenn/AFAR Breakthroughs in Gerontology Award 6932237 and is an investigator of the Howard Hughes Medical Institute. M.M.M. is supported by a Damon Runyon Postdoctoral Fellowship DRG 2146-13, where she is a Robert Black Foundation Fellow; a Ludwig Postdoctoral Fellowship 2036238; and NIH K99 Pathway to Independence award K99 AG054760. C.-W.C. is supported by a Ludwig Postdoctoral Fellowship and a Helen Hay Whitney Postdoctoral Fellowship 16123046/ 2389185. A.S.D. and A.R.L.S. are supported by NIH R01 AG033082 and R01 NS065874. This work was supported in part by the Koch Institute Support Grant P30-CA14051 from the National Cancer Institute. We thank the Koch Institute's Robert A. Swanson Biotechnology Center, specifically members of the Hope Babette Tang (1983) Histology Facility and the Flow Cytometry Core. We also thank Sven Holder for histology support, the Whitehead Flow Cytometry Core, and Stuart Levine of the MIT BioMicro Center. We thank Heather Keys for figure suggestions and members of the Sabatini and Yilmaz laboratories for discussions. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = may,
day = "3",
doi = "10.1016/j.stem.2018.04.001",
language = "English (US)",
volume = "22",
pages = "769--778.e4",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "5",
}