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

• Main Authors: Mihaylova, Maria M. (Author), Cheng, Chia-Wei (Author), Cao, Amanda Q. (Author), Tripathi, Surya (Author), Mana, Miyeko D. (Author), Bauer-Rowe, Khristian E. (Author), Abu-Remaileh, Monther (Author), Clavain, Laura (Author), Erdemir, Aysegul (Author), Lewis, Caroline A. (Author), Freinkman, Elizaveta (Author), Huang, Yanmei (Author), Bell, George W. (Author), Sabatini, David M. (Author), Yilmaz, Ömer H. (Author)
• Other Authors: Whitehead Institute for Biomedical Research (Contributor), Massachusetts Institute of Technology. Department of Biology (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor)
• Format: Article
• Language: English
• Published: Elsevier BV, 2020-04-17T13:27:03Z.
• Subjects: Article
• Online Access: Get fulltext

 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.