Aging affects the levels of DNA damage in postmitotic cells

Cells are continuously exposed to DNA damaging agents that may cause mutations or lead to cell death. To counter this constant, ubiquitous attack on the genetic material, cells possess highly diverse and efficient systems to repair a variety of DNA lesions. For cells that are nondividing and are expected to remain functionally viable for many years, it is important that damage not accumulate in those genes that are essential to maintaining differentiated gene expression. If damage were to accumulate slowly in working genes, then the outcomes might appear as biological changes typically associated with senescence. Estimates on the types of DNA damage believed to arise spontaneously suggest that methylation of N7-guanine is one of the more frequently occurring events, exceeded only by single-strand breaks and possibly depurination. Previous studies have shown that the steady-state levels of m7Gua increase during aging of postmitotic mammalian tissues. To test for the possibility that repair of m7Gua might decline in senescent animals, we induced methyl adducts in young and old mice with single doses of MNU, and determined the kinetics of adduct removal. Liver, kidney and brain all exhibited some active repair of m7Gua as characterized by the rapid removal of the adduct from DNA. However, a fraction of damage was refractory to repair and was lost from DNA much more slowly. This repair-resistant fraction of damage was greater in DNA from the old tissues, but the interpretation of the data is not straightforward, because different amounts of damage were induced in young and old tissues with the same weight-normalized dose of MNU. Although old cells had higher levels of persistent adducts, initial repair rates were similar between age-matched tissues. Furthermore, experiments indicated that mRNA levels for 3-methyladenine glycosylase repair enzyme did not change with age. Our working hypothesis is that repair enzymes are present and active in senescent postmitotic tissues, but changes have occurred in old chromatin that have affected the ability of repair enzymes to efficiently process these adducts.