Maintaining genetic integrity in aging: a zero sum game

Abstract

Aging of somatic cells can be defined as the gradual loss of the information embedded in the global and local properties of complex macromolecular networks. This loss of information may reflect the dynamic interplay between stochastic factors, such as the accumulation of unrepaired somatic damage, and gene-encoded programmatic responses. This would ultimately result in loss of function, impaired response to environmental challenge, and a progressively increased incidence of disease. Here the authors present the case for aging as a continuous battle between maintaining genomic integrity and ensuring sufficient cell functional mass. Focusing on aging of the liver in rodents, evidence is presented that normal aging is associated with a gradual accumulation of random alterations in the DNA of the genome as a consequence of imperfect DNA repair and a decrease in the rate of DNA damage-induced apoptosis. Apoptosis is the cell's genome maintenance mechanism of last resort and an imbalance towards apoptosis can contribute to manifestations of aging-related phenotypes, as exemplified by mouse models of premature aging due to genetic defects in genome maintenance. Prospects to reset the clock in this zero sum game between survival and the maintenance of phenotypic integrity will be discussed.