1. Department of Pathology, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA
2. Experimental Immunology Branch and Laboratory for Receptor Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
3. MGC-CBG Department of Cell Biology and Genetics, Erasmus Medical Center, PO Box 1738, 3000DR, Rotterdam, The Netherlands
4. These authors contributed equally to this work.
5. Present address: Lund University, Institute for Experimental Medical Science, BMC I13, 22184, Lund, Sweden.

Correspondence to: Derrick J. Rossi^1,4 Correspondence and requests for materials should be addressed to D.J.R. (Email: drossi@stanford.edu).

Abstract

A diminished capacity to maintain tissue homeostasis is a central physiological characteristic of ageing. As stem cells regulate tissue homeostasis, depletion of stem cell reserves and/or diminished stem cell function have been postulated to contribute to ageing¹. It has further been suggested that accumulated DNA damage could be a principal mechanism underlying age-dependent stem cell decline². We have tested these hypotheses by examining haematopoietic stem cell reserves and function with age in mice deficient in several genomic maintenance pathways including nucleotide excision repair^{3, 4}, telomere maintenance^{5, 6} and non-homologous end-joining^{7, 8}. Here we show that although deficiencies in these pathways did not deplete stem cell reserves with age, stem cell functional capacity was severely affected under conditions of stress, leading to loss of reconstitution and proliferative potential, diminished self-renewal, increased apoptosis and, ultimately, functional exhaustion. Moreover, we provide evidence that endogenous DNA damage accumulates with age in wild-type stem cells. These data are consistent with DNA damage accrual being a physiological mechanism of stem cell ageing that may contribute to the diminished capacity of aged tissues to return to homeostasis after exposure to acute stress or injury.

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.