Telomere shortening limits the proliferative lifespan of human cells by activation of DNA damage pathways, including upregulation of the cell cycle inhibitor p21 (encoded by Cdkn1a, also known as Cip1 and Waf1)) (refs. 1–5). Telomere shortening in response to mutation of the gene encoding telomerase is associated with impaired organ maintenance and shortened lifespan in humans⁶ and in mice^{7, 8, 9}. The in vivo function of p21 in the context of telomere dysfunction is unknown. Here we show that deletion of p21 prolongs the lifespan of telomerase-deficient mice with dysfunctional telomeres. p21 deletion improved hematolymphopoiesis and the maintenance of intestinal epithelia without rescuing telomere function. Moreover, deletion of p21 rescued proliferation of intestinal progenitor cells and improved the repopulation capacity and self-renewal of hematopoietic stem cells from mice with dysfunctional telomeres. In these mice, apoptotic responses remained intact, and p21 deletion did not accelerate chromosomal instability or cancer formation. This study provides experimental evidence that telomere dysfunction induces p21-dependent checkpoints in vivo that can limit longevity at the organismal level.

1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
2. Department of Mucosal Immunity, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
3. Institute for Aging and Health, University of Newcastle Upon Tyne, NE46BE Newcastle, UK.
4. Institute of Medical Microbiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
5. College of Science, Yonsei University, 120-749 Seoul, Korea.
6. Department of Hematology and Oncology, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
7. Institute of Pathology, University Hospital, Im Neuenheimer Feld 220/221, 69120 Heidelberg, Germany.
8. Laboratory of Stem Cell Therapy, Institute of Medical Science, University of Tokyo, 108-8693 Tokyo, Japan.
9. These authors contributed equally to this work.

Correspondence to: K Lenhard Rudolph¹ e-mail: Rudolph.Lenhard@MH-Hannover.de

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