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Nature. 2019 Jul;571(7765):398-402. doi: 10.1038/s41586-019-1383-0. Epub 2019 Jul 10.

Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium.

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Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.
The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA, USA.
The Skaggs Institute for Chemical Biology, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.
Department of Medicine, Division of Gastroenterology, Duke University, Durham, NC, USA.
Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
Abdominal Center, Department of Gastrointestinal Surgery, Helsinki University Hospital, Helsinki, Finland.
Department of Pathology, Research Programs Unit and HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Atlanta Gastroenterology Associates, Atlanta, GA, USA.
Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Howard Hughes Medical Institute, MIT, Cambridge, MA, USA.
Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA, USA.
Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.
Molecular and Integrative Bioscience Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.


A decline in stem cell function impairs tissue regeneration during ageing, but the role of the stem-cell-supporting niche in ageing is not well understood. The small intestine is maintained by actively cycling intestinal stem cells that are regulated by the Paneth cell niche1,2. Here we show that the regenerative potential of human and mouse intestinal epithelium diminishes with age owing to defects in both stem cells and their niche. The functional decline was caused by a decrease in stemness-maintaining Wnt signalling due to production of Notum, an extracellular Wnt inhibitor, in aged Paneth cells. Mechanistically, high activity of mammalian target of rapamycin complex 1 (mTORC1) in aged Paneth cells inhibits activity of peroxisome proliferator activated receptor α (PPAR-α)3, and lowered PPAR-α activity increased Notum expression. Genetic targeting of Notum or Wnt supplementation restored function of aged intestinal organoids. Moreover, pharmacological inhibition of Notum in mice enhanced the regenerative capacity of aged stem cells and promoted recovery from chemotherapy-induced damage. Our results reveal a role of the stem cell niche in ageing and demonstrate that targeting of Notum can promote regeneration of aged tissues.

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