Ageing mechanisms: the role of telomere loss

The ends of the chromosomes are capped by specialized structures, the telomeres. These are comprised of tracts of hexanucleotid sequences and, in combination with specific proteins, protect the chromosome against degradation, fusion events and as being recognized as 'damaged' DNA; thus, they guarantee chromosomal integrity. Due to deficiencies during DNA replication, the telomeres continuously loose part of their sequences and it has been proposed that this loss is the liming factor for the replicative capacity of a cell, i.e. telomeric loss is the counting mechanism - the internal clock of ageing. In order to proliferate indefinitely, the cells must prevent telomere erosion and this is mostly achieved by upregulation or de novo expression of the ribonucleoprotein complex telomerase. This enzyme, which has a reverse-transcriptase activity, is able to add telomeric sequences to the outer most ends off the telomeres and thereby stabilize or even elongate the telomeres. As telomerase is expressed in about 90% of all tumours while expression is absent in many somatic tissues, it is not surprising that the causal role of telomere erosion is presently the most favoured hypothesis of cellular ageing.