DNA damage and epigenetic mechanisms of aging

Overview

DNA damage can lead not only to mutations and chromosome abnormalities, but also to epigenetic effects on gene expression. It is therefore very important to consider the possible effects of oxidative damage to DNA on epigenetic controls. In somatic cells of higher organisms there are two heritable systems which exist side by side (Holliday, 1990). Classical genetics is concerned with the inheritance of differences in DNA sequences. These differences are transmitted through mitosis and meiosis and can only be reversed or changed by rare mutations. Epigenetics is the study of the changes in gene activity during development. The epigenetic basis for gene expression can be stably inherited through mitosis, since specialised differentiated cells which divide maintain their phenotype. However, there can also be instability, since stem line cells can divide both to form cells which will later differentiate, and also cells which retain their stem cell function. Whereas classical genetic inheritance is concerned with individual cell lineages, epigenetic changes during development commonly occur in groups of cells sometimes called “polyclones” (Crick and Lawrence, 1975). Such changes may be strongly influenced by external effectors (morphogens, hormones, growth factors, or other diffusible agents), whereas the genetic information embodied in DNA sequences is not changed by external influences. Epigenetic changes are commonly reversed in each generation, for example, the inactive X chromosome in female mammals is reactivated before the gametes are produced. The process of genomic imprinting depends on the addition of information to DNA which is different in male and female gametes. Imprinting can also be regarded as an epigenetic mechanism, which can be reversed in each generation.