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.
"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 "
"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). "
"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 . "
[Show abstract][Hide abstract] 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.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.