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Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age

Rossi, Derrick J; Bryder, David LU ; Seita, Jun; Nussenzweig, Andre; Hoeijmakers, Jan and Weissman, Irving L (2007) In Nature 447(7145). p.725-729
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 ageing. It has further been suggested that accumulated DNA damage could be a principal mechanism underlying age-dependent stem cell decline. 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, telomere maintenance and non-homologous end-joining. Here we show that although deficiencies in these pathways did not deplete stem cell reserves with age,... (More)
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 ageing. It has further been suggested that accumulated DNA damage could be a principal mechanism underlying age-dependent stem cell decline. 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, telomere maintenance and non-homologous end-joining. 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. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Nature
volume
447
issue
7145
pages
725 - 729
publisher
Nature Publishing Group
external identifiers
  • pmid:17554309
  • scopus:34250007142
ISSN
0028-0836
DOI
10.1038/nature05862
language
English
LU publication?
yes
id
fdf8a23e-6527-467b-a157-ba8c8d7d5272 (old id 1140364)
date added to LUP
2008-08-15 11:13:14
date last changed
2017-11-19 04:18:15
@article{fdf8a23e-6527-467b-a157-ba8c8d7d5272,
  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 ageing. It has further been suggested that accumulated DNA damage could be a principal mechanism underlying age-dependent stem cell decline. 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, telomere maintenance and non-homologous end-joining. 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.},
  author       = {Rossi, Derrick J and Bryder, David and Seita, Jun and Nussenzweig, Andre and Hoeijmakers, Jan and Weissman, Irving L},
  issn         = {0028-0836},
  language     = {eng},
  number       = {7145},
  pages        = {725--729},
  publisher    = {Nature Publishing Group},
  series       = {Nature},
  title        = {Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age},
  url          = {http://dx.doi.org/10.1038/nature05862},
  volume       = {447},
  year         = {2007},
}