20 Telomeres and Telomerase in Aging and Cancer

The role of telomeres in maintaining chromosomal integrity was proposed by Barbara McClintock (for review, see Blackburn 2006). Studying telomeres in maize chromosomes, McClintock observed that if not capped by telomeres, the ends of chromosomes had a tendency to fuse. Her observations were confirmed 50 years later in yeast and mice when it was demonstrated that without telomeric ends, chromosomes undergo aberrant end-to-end fusions, forming multicentric chromosomes with a propensity to break during mitosis, activating DNA-damage checkpoints and, in some cases, leading to widespread cell death (Zakian 1989). It is now known that the shortening of telomeres due to cell divisions forms the basis of replicative aging, the growth arrest originally described by Hayflick and Moorhead (1961). Aging is associated with the gradual decline in the performance of organ systems, resulting in the loss of reserve capacity, leading to an increased chance of death (Gompertz 1825). In some organ systems, this loss of reserve capacity with increasing age can be attributed to the loss of cell function (Martin et al. 1970). Chronic localized stress to specific tissues/cell types may result in increased cell turnover, and it has been hypothesized that this may lead to focal areas of replicative senescence (Hayflick and Moorhead 1961), followed by alterations in patterns of gene expression (West 1994;West et al. 1996). This could result in reduced tissue regeneration, culminating in some of the clinical pathologies that are often associated with increased age. In addition to replicative aging, a variety of mechanisms can induce an irreversible...