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How Short-term Fasting Affects Intestinal Stem Cell Function during Aging

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Review of “Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging” from Cell Stem Cell by Stuart P. Atkinson

Multiple recent studies have established that long-term calorie restriction (CR) in mammalians can prolong lifespan and enhance regeneration by reversing age-related losses to tissue-resident stem cell activity. In particular, the mammalian intestine loses Lgr5+ intestinal stem cell (ISC) activity and reparative function during normal aging [1, 2], although CR improves ISC function through Paneth cell niche-induced changes [3, 4]. 

Researchers from the laboratories of David M. Sabatini and Ömer H. Yilmaz recently sought to discover how ISCs adapt to shorter-term fasting in model mice [5] and their new study now suggests that short-term fasting induces the production of fatty acid oxidation (FAO) in ISCs, which then mediates pro-regenerative effects by modulating ISC function.

Mihaylova et al. confirmed that short-term fasting (24 hours) induced pro-regenerative effects on ISC function and discovered a correlated increase in FAO in intestinal stem and progenitor cells. Further analysis indicated that fasting increased FAO in ISCs through a peroxisome proliferator-activated receptor (PPAR)-driven program and by an increase in circulating levels of triglycerides and free fatty acids (FFA) employed by cells to generate acetyl-CoA (a fatty acid oxidation product) for energy. Interestingly, the observed reduction in ISC number and function during aging also correlated to a decrease in FAO levels; however, the augmentation of FAO levels by fasting or through supplementation with small molecule agonists of PPARδ improved ISC function during aging and regeneration

While the authors establish a role for FAO in the pro-regenerative effects of fasting in intestinal biology in this new study, they note the requirement for further studies to examine if FAO substrate supplementation represents a viable strategy to enhance intestinal regeneration and repair in both young and old patients.

Stay tuned to the Stem Cells Portal for more on short-term fasting, intestinal stem cell function, and aging!

References

  1. Nalapareddy K, Nattamai KJ, Kumar RS, et al., Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells. Cell Reports 2017;18:2608-2621.
  2. Potten CS, Martin K, and Kirkwood TB, Ageing of murine small intestinal stem cells. Novartis Found Symp 2001;235:66-79; discussion 79-84, 101-4.
  3. Igarashi M and Guarente L, mTORC1 and SIRT1 Cooperate to Foster Expansion of Gut Adult Stem Cells during Calorie Restriction. Cell 2016;166:436-450.
  4. Yilmaz ÖH, Katajisto P, Lamming DW, et al., mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 2012;486:490.
  5. Mihaylova MM, Cheng C-W, Cao AQ, et al., Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging. Cell Stem Cell 2018;22:769-778.e4.