Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL.. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447: 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, 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.
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- "Thus, endogenous telomerase reactivation and extinction of DNA damage signaling restores the normal myeloid differentiation process, reinforcing the link between telomere dysfunction and aberrant myeloid differentiation. Nevertheless, the failure of telomerase reactivation to rescue the KS À L decline (Figure 2A) implicates the existence of additional upstream differentiation checkpoints involving the stem cell compartment as previously reported (Rossi et al., 2007; Wang et al., 2012). Consistent with the expansion of phenotypically primitive HSCs occurring in MDS (Will et al., 2012), the telomere dysfunctional HSC compartment (KSL) showed an increased expansion in the steady-state frequency of longterm HSC (LT-HSC; c-Kit "
ABSTRACT: Myelodysplastic syndrome (MDS) risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres, but whether telomere erosion directly induces MDS is unknown. Here, we provide the genetic evidence that telomere dysfunction-induced DNA damage drives classical MDS phenotypes and alters common myeloid progenitor (CMP) differentiation by repressing the expression of mRNA splicing/processing genes, including SRSF2. RNA-seq analyses of telomere dysfunctional CMP identified aberrantly spliced transcripts linked to pathways relevant to MDS pathogenesis such as genome stability, DNA repair, chromatin remodeling, and histone modification, which are also enriched in mouse CMP haploinsufficient for SRSF2 and in CD34(+) CMML patient cells harboring SRSF2 mutation. Together, our studies establish an intimate link across telomere biology, aberrant RNA splicing, and myeloid progenitor differentiation. Copyright © 2015 Elsevier Inc. All rights reserved.Cancer cell 05/2015; 27(5):644-657. DOI:10.1016/j.ccell.2015.04.007 · 23.89 Impact Factor
- "Auto-immune responses may also restrict the diversity of immune responsiveness to foreign antigens. We therefore evaluateding long-term and short-term immunological memory and autoimmune responses as potential biomarkers of ageing (Almanzar et al., 2005, Kovaiou et al., 2007, Weinberger et al., 2007, Herndler-Brandstetter et al., 2005). "
Article: MARK-AGE biomarkers of ageing[Show abstract] [Hide abstract]
ABSTRACT: Many candidate biomarkers of human ageing have been proposed in the scientific literature but in all cases their variability in cross-sectional studies is considerable, and therefore no single measurement has proven to serve a useful marker to determine, on its own, biological age. A plausible reason for this is the intrinsic multi-causal and multi-system nature of the ageing process. The recently performed MARK-AGE study was a large-scale integrated project supported by the European Commission. The major aim of this project was to conduct a population study comprising about 3300 subjects in order to identify a set of biomarkers of ageing which, as a combination of parameters with appropriate weighting, would measure biological age better than any marker in isolation. Copyright © 2015. Published by Elsevier Ireland Ltd.Mechanisms of ageing and development 03/2015; 11. DOI:10.1016/j.mad.2015.03.006 · 3.51 Impact Factor
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- "However, the level of telomerase activity apparently is not sufficient to prevent telomere shortening in HSCs and ISCs during ageing (Schepers et al., 2011; Vaziri et al., 1994). Studies on telomerase deficient mice provided the first experimental evidence that telomere shortening leads to p53/p21 dependent defects in self-renewal and functional capacity of germline stem cells (Chin et al., 1999) and somatic stem cells (Allsopp et al., 2003; Choudhury et al., 2007; Rossi et al., 2007a; Sperka et al., 2012). The contribution of telomere shortening to the functional decline of stem cells and disease evolution during 'physiological ageing' remains to be determined . "
ABSTRACT: The mammalian organism is comprised of tissue types with varying degrees of self-renewal and regenerative capacity. In most organs self-renewing tissue-specific stem and progenitor cells contribute to organ maintenance, and it is vital to maintain a functional stem cell pool to preserve organ homeostasis. Various conditions like tissue injury, stress responses, and regeneration challenge the stem cell pool to re-establish homeostasis (Figure 1). However, with increasing age the functionality of adult stem cells declines and genomic mutations accumulate. These defects affect different cellular response pathways and lead to impairments in regeneration, stress tolerance, and organ function as well as to an increased risk for the development of ageing associated diseases and cancer. Maintenance of the genome appears to be of utmost importance to preserve stem cell function and to reduce the risk of ageing associated dysfunctions and pathologies. In this review, we discuss the causal link between stem cell dysfunction and DNA damage accrual, different strategies how stem cells maintain genome integrity, and how these processes are affected during ageing.Ageing Research Reviews 02/2015; 102. DOI:10.1016/j.arr.2015.01.004 · 7.63 Impact Factor