DNA damage response, telomere maintenance and ageing in light of the integrative model

Abstract

The complexity of the ageing process is reflected in the fact that numerous models have been proposed to explain why and how organisms age and yet they address the problem only to a limited extent. A logical solution is to integrate individual models together into a wider theoretical framework now known as the "network" theory of ageing. The "network" approach overcomes reduction nature of individual models and allows for interactions between individual contributing mechanisms. This review focuses on some aspects of the "network" approach, namely interactions between two individual mechanisms that contribute to ageing: DNA damage response and telomere maintenance. The key framework for considering these interactions is the previously proposed integrative model, which predicts that telomere maintenance is an integral part of DNA damage response machinery. The integrative model predicts the dual phenotype, namely dysfunctional DNA damage response and dysfunctional telomere maintenance, when one of these mechanisms is the cause of ageing. In line with this prediction between 87 and 90% of mouse and human models of premature ageing show this dual phenotype. It is concluded that the integrative model is consistent with the "network" theory of ageing.