Overview of Chromosomal Instability and Aging Mechanisms

DNA encodes information essential for cellular maintenance and survival. Over a lifetime, DNA is subjected to continual attack by external sources of damage, as well as damage from endogenous sources or errors during DNA replication. The resulting genomic instability would be overwhelming except for the presence of DNA repair systems. Some of the consequences of unrepaired DNA injury include cell cycle arrest, programmed cell death, or apoptosis, genetic diseases in offspring, or the development of cancer. Indeed, one of the striking characteristics of aging in many organisms is an increased risk of cancer. Age has been called “the most potent of all carcinogens” (1). Cancer is now understood to be a genetic disease resulting from the accumulation of a series of mutational events; tumor progression results from clonal selection and evolution of tumor cells (2,3). The underlying genetic instability implicit in this process suggests a close link between the study of DNA damage and repair on the one hand and cancer on the other. In addition, several Mendelian chromosomal instability disorders are caused by mutations in genes involved in DNA metabolism and repair, and are accompanied by many, although not all, of the features of accelerated aging. These conditions are therefore called segmental progeroid syndromes (4).