Telomere Shortening and Stem Cell Ageing

A gradual decline in regeneration and organ homeostasis is an important aspect of human ageing, which is associated with impaired function and maintenance of stem cells (Schlessinger and Van Zant 2001; see Waterstrat et al., this volume). The extent to which the ageing of stem cells determines impaired maintenance of organs and tissues during ageing remains to be defined. It is possible that stem cell function is a major determinant of declining organ homeostasis and repair capacity, specifically in tissues with high rates of cell turnover. In line with this assumption, genetic experiments on telomerase knockout mice have shown that telomere dysfunction severely affects the maintenance of high-proliferative organs (Lee et al. 1998, Rudolph et al. 1999, Herrera et al. 1999, Choudhury et al. 2007). Similarly, DKC patients with decreased telomerase function die from bone marrow failure, which points again to high-turnover organs as being most sensitive to telomere shortening (see Du et al., this volume). However, there is also evidence that telomere shortening can negatively influence postmitotic organs. Studies on human ageing have shown correlations between telomere shortening and Alzheimer disease (Panossian et al. 2003) and heart disease (Leri et al. 2001, Leri et al. 2003). Moreover, telomerase gene mutation is the underlying cause in some cases of idiopathic lung fibrosis (see above). There is evidence that adult stem cells reside in all organs, including heart, brain, muscle, and lung. It is possible that the negative influence of telomere shortening on organ function (both in low and high turnover organs) is caused by an inhibition of adult stem cells in response to telomere dysfunction. In agreement with this hypothesis, a reduction in adult neurogenesis occurs in telomerase knockout mice with shortened telomeres (Ferron et al. 2004).

Stem cells are functionally defined by their ability to differentiate and self-renew. Over the life span, adult stem cells have the ability to regenerate the tissue from which they are derived. However, accumulating evidence suggests that stem cells do age (Van Zant and Liang 2003; see Waterstrat et al., this volume). Serial transplantation experiments show that the self-renewal capacity of hematopoietic stem cells (HSCs) is finite (Harrison and Astle 1982).

Telomerase is active in some human stem cell compartments, such as HSCs and intestinal basal crypts which represent the stem and progenitor cell compartment of the gut. Telomerase activity in stem cells seems to be important in maintaining their self-renewal ability (Morrison et al. 1996, Allsopp and Weissman 2002).

In humans, telomere shortening occurs in HSCs during ageing (Vaziri et al. 1994), which suggests that the low level of telomerase activity is not sufficient to maintain telomere length during ageing. In addition, accelerated telomere shortening occurs in response to replicative stress after bone marrow transplantation (Engelhardt et al. 1997, Wynn et al. 1998). Similarly, mouse experiments have also revealed an accelerated telomere shortening in HSCs in response to serial transplantation (Allsopp et al. 2001). HSCs from first-generation telomerase-deficient mice show normal repopulating capacity after transplantation into lethally irradiated recipients. However, these G1 Terc~'~ HSCs are exhausted after only two rounds of serial transplantation, while wild-type HSCs can be serially transplanted four times (Allsopp et al. 2003a). A possible explanation for these findings is that telomerase is required to slow down telomere shortening in order to maintain the replicative life span of HSCs. Alternatively, telomerase deletion could directly impair the self-renewal of HSCs, leading to a depletion of HSCs under stress conditions.

Research work on telomerase transgenic mice has revealed experimental evidence for the telomere length-independent effects of TERT expression on the function and maintenance of stem cells in the hair bulge (see Artandi, this volume). However, overexpression of telomerase does not increase the proliferative capacity of mouse HSCs in serial transplantation experiments, although it stabilized telomere length in HSCs (Allsopp et al. 2003b). Together, these data suggest that telomere-ength-independent barriers can limit the self-renewing capacity of HSCs during serial transplantation. The molecular basis of these checkpoints remains to be determined and could involve the accumulation of reactive oxygen species (Ito et al. 2006; see Passos et al., this volume) or p16 (see Sharpless, this volume), as well as the induction of stress-induced senescence, among other possibilities. In summary, it is likely that telomere-dependent and telomere-independent mechanisms limit stem cell function during ageing. In the following sections we focus on telomere-dependent mechanisms of stem cell ageing.

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