Modelling telomere shortening and the role of oxidative stress

Extensive evidence supports the idea that progressive telomere loss contributes to the phenomenon of cell replicative senescence, but the mechanisms responsible for telomere loss are still unclear. In addition to the widely recognized end-replication problem, there is evidence that oxidative stress plays a major role in determining the rate of loss of telomeric DNA, and the action of a C-strand-specific exonuclease is also suggested to be important. We describe a mathematical model which examines the different contributions of these mechanisms to telomere loss and its role in triggering cell senescence. The model allows us to make quantitative predictions about the rates of telomere loss resulting from these alternative mechanisms, and their interactions. By varying the key parameters of the model, it is possible to examine the extent to which the different hypotheses are compatible with quantitative and qualitative features of the experimental data. For example, the model predicts that under low levels of oxidative stress, the main mechanisms of telomere shortening are the end-replication problem plus C-strand processing. However, when levels of oxidative stress are higher, as in cell cultures grown under normoxic or hyperoxic conditions, the model predicts that single strand breaks make an important contribution to telomere loss and their inclusion within the model is necessary to explain the data. We suggest that theoretical models of this kind are valuable tools to bridge the gap between the verbal statements of hypotheses and their rigorous experimental test.