Genotoxic stress — particularly from damaged telomeres — would seem, on the surface, less relevant as a basis for age-progressive functional decline in relatively quiescent organs, such as the heart and liver. However, cardiomyopathy is a prominent phenotype in the late-generation Terc−/− mouse model85. Thus, to describe these highly metabolic organs, we propose a model whereby mitochondrial dysfunction underlies an escalating cycle of genotoxic damage leading to, in turn, p53 activation, mitochondrial dysfunction, increased ROS concentrations and, consequently, further DNA damage2. In particular, decreasing mitochondrial reserves and function as documented in aged human and mouse tissues would result in increased ROS production, owing mainly to complex I and complex III dysfunction. This boost in ROS production would set in motion a detrimental cycle of increased genotoxic damage with rapid erosion of telomeres, followed by sustained activation of p53, further mitochondrial decline, more ROS generation and so on34. This downward spiral might also explain the cumulative and precipitative nature of ageing symptoms observed late in life.
