Similarities and Differences Between DC and Ageing

An important feature of human ageing is increased risk of disease, such as cancer and a decrease in maintenance and function of almost all organs. Greying of hair is another obvious feature of the ageing population. In accordance with these, both DC patients and late generations of mTR knockout mice were observed to have increased incidence of malignancy and hair greying. The occurrence of cancer in these situations probably arises from chromosomal instability due to critically short telomeres (Counter et al. 1992, Dokal et al. 1992), whereas in ageing, additional factors also contribute to carcinogenesis. Such factors include free-radical-induced DNA damage, the accumulation of DNA mutations, changes in metabolic rate, and oxidative stress (Sohal et al. 2002, Frisard and Ravussin 2006). Another distinction between DC patients and the ageing population is the occurrence of hematological disorders. While hematological disorders are usually seen in DC patients and mTR knockout mice, severe dysfunction of the hematological system does not necessarily occur in natural ageing, though the proliferative capacity of the hematopoietic system in response to stress or environmental insult, such as drugs and viruses, does decrease with age; age-related anemia and lymphopenia are frequently seen. Early studies have shown that while the hematological disorder is manifested as bone marrow failure in DC patients (Dokal 2001, Vulliamy et al. 2001a), mTR knockout mice showed lymphocytopenia and inhibited response to hematopoietic ablation (Rudolph et Al. 1999, Herrera et al. 1999). Furthermore, unlike patients with some progeria syndromes, DC patients do not look older than they are, probably reflecting the fact that DC affects some but not all tissues.

Most clinical presentations of DC are associated with impaired proliferative capacity of tissues (Luzzatto and Karadimitris 1998). One example is that skin fibrob-

lasts from DC patients had shorter telomeres and had decreased population doubling and abnormal chromosomal rearrangements in in vitro culture (Dokal et al. 1992). In addition, the number of hematopoietic progenitor cells was decreased (Marsh et al. 1992). As a consequence, tissues requiring constant renewal, i.e., skin, oral mucosa, and bone marrow are affected most frequently in DC.

As mentioned above, DC patients have a median life span of 16 years, while some can survive up to 50 years old and milder cases even longer. The shorter life span in DC patients could be inferred to be the result of dysfunctional telomerase. The death of DC patients is usually caused by complications of bone marrow failure (immune deficiency or bleeding), pulmonary fibrosis, or malignancies. These are extreme examples of some of the organ or tissue dysfunction that takes place in normal ageing. Perhaps a key feature of the disease process in DC is that it involves the failure of some tissues, principally highly proliferative tissues that are dependent on renewal by stem cell activity. Ageing, however, can affect the entire organism. Nevertheless, in the first generation of mice carrying a deletion of mTR, when no hematopoietic disorders were apparent, the longevity was reduced in comparison to wild-type mice (Geserick and Blasco 2006). This observation supports a role of telomerase in overall life span of organisms.

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