Kyung Mok Kim^1,12, Anna Mura-Meszaros^1,12, Marie Tollot^1,12, Murali Shyam Krishnan¹, Marco Gründl ¹, Laura Neubert¹, Marco Groth ², Alejo Rodriguez-Fraticelli ^3,4,5, Arthur Flohr Svendsen ⁶, Stefano Campaner ⁷, Nico Andreas⁸, Thomas Kamradt⁸, Steve Hoffmann², Fernando D. Camargo ³, Florian H. Heidel ^2,9,10, Leonid V. Bystrykh ⁶, Gerald de Haan ^6,11 & Björn von Eyss ¹

¹Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V., Beutenbergstr. 11, 07745 Jena, Germany. 
²Leibniz Institute on Aging, Fritz Lipmann Institute e.V., Beutenbergstr. 11, 07745 Jena, Germany. 
³Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, 08028 Barcelona, Spain. 
⁴Stem Cell Program, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA. 
⁵Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA. 
⁶Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen (UMCG),
University of Groningen, Antonius Deusinglaan 1, 9700 AV Groningen, The Netherlands. 
⁷Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Via Adamello 16, 20139 Milan, Italy. 
⁸Institute of Immunology, Jena University Hospital, Am Leutragraben 3, 07743 Jena, Germany. 
⁹Internal Medicine II, Hematology and Oncology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. 
¹⁰Innere Medizin C, Universitätsmedizin Greifswald, Sauerbruchstrasse, 17475 Greifswald, Germany. 
¹¹Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 
¹²These authors contributed equally: Kyung Mok Kim, Anna Mura-Meszaros, Marie Tollot

Corresponding author: Correspondence to Björn von Eyss.

Specific functions of the immune system are essential to protect us from infections caused by pathogens such as viruses and bacteria. However, as we age, the immune system shows a functional decline that can be attributed in large part to age-associated defects in hematopoietic stem cells (HSCs)-the cells at the apex of the immune cell hierarchy. Here, we find that the Hippo pathway coactivator TAZ is potently induced in old HSCs and protects these cells from functional decline. We identify Clca3a1 as a TAZ-induced gene that allows us to trace TAZ activity in vivo. Using CLCA3A1 as a marker, we can isolate "young-like" HSCs from old mice. Mechanistically, Taz acts as coactivator of PU.1 and to some extent counteracts the gradual loss of PU.1 expression during HSC aging. Our work thus uncovers an essential role for Taz in a previously undescribed fail-safe mechanism in aging HSCs.