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.
National Institutes of Health (U.S.) (Grant R00 AG045144)
National Institutes of Health (U.S.) (Grant R01CA211184)
National Institutes of Health (U.S.) (Grant R01CA034992)
National Institutes of Health (U.S.) (Grant CA103866)
National Institutes of Health (U.S.) (K99 Pathway to Independence award K99AG054760)