Telomerase and Ageing

Because somatic cells that lose telomeres during cell division have a limited replicative life span, it has been hypothesized that telomere shortening is associated with the physiological process of ageing. Initial speculation about the relationship between telomere shortening and cellular senescence came from the observation that telomeres capping the long arms of human sex chromosomes were strikingly shorter in somatic cells than in germ line cells (Cooke and Smith 1986). Other evidence supporting this idea includes the correlation between the proliferative potential of primary human cells and their telomere length (Allsopp et al. 1992) and the fact that telomeres shorten during cellular ageing in culture (Harley et al. 1990) and ageing of human tissue in vivo (Allsopp et al. 1992). Furthermore, the finding that telomerase is activated in the majority of human tumors, which otherwise require an alternative mechanism to maintain telomeric DNA, substantiates the importance of telomere maintenance in the proliferation of human cells (Kim et al. 1994).

Most somatic cells do not express telomerase, and therefore telomeres undergo gradual shortening until a critical minimal telomere length is reached, when cells stop dividing and enter into a quiescent viable state called replicative senescence, which is proposed to prevent cells from excessive cell division and genetic instability (Harley 1991). Telomeres were observed to shorten in human tissues, including peripheral blood cells, liver, kidney, spleen, dermal fibroblasts, and mucosal keratinocytes (Broccoli et al. 1995, Hiyama et al. 1995, Harle-Bachor and Boukamp 1996, Yasumoto et al. 1996). On the other hand, a low level of telomerase activity is detected in cells that undergo rapid expansion, such as germ cells, certain populations of stem cells and their progeny, activated lymphocytes, keratinocytes, and the basal layer of the epidermis (Masutomi et al. 2003, Harrington 2004, Flores et al. 2005). To test the role of telomerase in the proliferative potential of primary human cells, Bodnar et al. reconstituted telomerase activity by expressing TERT in human cells, including retinal epithelial cells, foreskin fibroblasts, and vascular endothelial cells. It was found that activation of telomerase resulted in elongation of telomeres and bypass of senescence in these cells (Bodnar et al. 1998).

While accumulating evidence has supported the notion that telomerase insufficiency leads to telomere shortening and replicative senescence of cultured cells, the role of telomere maintenance in the ageing process has not been clear. Ageing as a physiological process or phenomenon is characterized by impaired response to stress, unbalanced homeostasis, and increased risk of disease (Weinert and Timiras 2003). The relevance of telomere shortening induced by dysfunctional telomerase to physiological ageing was first demonstrated by the generation of a mouse model devoid of telomerase activity (Blasco et al. 1997). It was observed that late-generation mice deficient for telomerase had a shorter life span than wild-type mice. In addition, although early generations of mTR-/- mice did not show abnormalities (laboratory mice have a much longer telomere length than humans or wild mice, and telomeres only become critically short after several generations with no telomerase (Herrera et al. 1999, Rudolph et al. 1999) defects in cell viability of highly proliferative tissues were observed in later generations. In human, a severe, inherited bone marrow failure syndrome associated with telomerase deficiency, known as dyskeratosis congenita (DC), has also been considered to be related to premature ageing (Dokal 2001, Vulliamy et al. 2001a).

Late generations of mTR knockout mice and DC patients share similar pheno-types in terms of hair loss or early greying of hair, increased incidence of malignancy, decreased capacity for wound healing, and telomere shortening, which are common to the process of normal ageing. Furthermore, several syndromes/diseases have also been considered to be related to telomere shortening, and have been referred to as premature ageing syndromes. These include cardiovascular disease (Cawthon et al. 2003), hypertension (Serrano and Andres 2004), paroxysmal nocturnal hemoglobinuria (PNH) (Beier et al. 2005), Fanconi anemia (Franco et al. 2004), Werner syndrome (Chang et al. 2004), ataxia telangiectasia (Metcalfe et al. 1996), Bloom syndrome (Cohen and Sinclair 2001), and Nijmegen breakage syndrome (Paull and Gellert 1999). In this chapter, DC, which is caused by mutations in the components of telomerase ribonucleoprotein complex, will be discussed in order to understand the role of telomerase in a premature ageing syndrome.

How To Deal With Rosacea and Eczema

How To Deal With Rosacea and Eczema

Rosacea and Eczema are two skin conditions that are fairly commonly found throughout the world. Each of them is characterized by different features, and can be both discomfiting as well as result in undesirable appearance features. In a nutshell, theyre problems that many would want to deal with.

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