Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging

Maria M Mihaylova; Chia-Wei Cheng; Amanda Q Cao; Surya Tripathi; Miyeko D Mana; Khristian E Bauer-Rowe; Monther Abu-Remaileh; Laura Clavain; Aysegul Erdemir; Caroline A Lewis; Elizaveta Freinkman; Audrey S Dickey; Albert R La Spada; Yanmei Huang; George W Bell; Vikram Deshpande; Peter Carmeliet; Pekka Katajisto; David M Sabatini; Ömer H Yilmaz

doi:10.1016/j.stem.2018.04.001

Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging

Cell Stem Cell. 2018 May 3;22(5):769-778.e4. doi: 10.1016/j.stem.2018.04.001.

Authors

Maria M Mihaylova¹, Chia-Wei Cheng², Amanda Q Cao¹, Surya Tripathi³, Miyeko D Mana², Khristian E Bauer-Rowe², Monther Abu-Remaileh¹, Laura Clavain¹, Aysegul Erdemir⁴, Caroline A Lewis⁵, Elizaveta Freinkman⁵, Audrey S Dickey⁶, Albert R La Spada⁶, Yanmei Huang⁵, George W Bell⁵, Vikram Deshpande⁷, Peter Carmeliet⁸, Pekka Katajisto⁹, David M Sabatini¹⁰, Ömer H Yilmaz¹¹

Affiliations

¹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
² The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
³ The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA.
⁴ The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA; Faculty of Arts & Sciences, Department of Molecular Biology and Genetics, Yildiz Technical University, 34210 Istanbul, Turkey.
⁵ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
⁶ Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA.
⁷ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁸ Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, 3000 Leuven, Belgium.
⁹ Institute of Biotechnology, HiLIFE, University of Helsinki, P.O. Box 56, Helsinki, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Stockholm, Sweden.
¹⁰ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA. Electronic address: sabatini@wi.mit.edu.
¹¹ The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: ohyilmaz@mit.edu.

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.

Keywords: aging; fasting; fatty acid oxidation; intestinal stem cells; intestine; metabolism; mitochondrial metabolism; stem cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aging*
Animals
Cells, Cultured
Fasting / metabolism*
Fatty Acids / metabolism*
Homeostasis*
Intestines / cytology*
Mice
Mice, Inbred Strains
Oxidation-Reduction
Stem Cells / cytology*
Stem Cells / metabolism*

Substances

Fatty Acids

Abstract

Publication types

MeSH terms

Substances

Grants and funding