Mutation frequency and specificity with age in liver, bladder and brain of lacI transgenic mice.
Mutation frequency and specificity were determined as a function of age in nuclear DNA from liver, bladder, and brain of Big Blue lacI transgenic mice aged 1.5-25 months. Mutations accumulated with age in liver and accumulated more rapidly in bladder. In the brain a small initial increase in mutation frequency was observed in young animals; however, no further increase was observed in adult mice. To investigate the origin of mutations, the mutational spectra for each tissue and age were determined. DNA sequence analysis of mutant lacI transgenes revealed no significant changes in mutational specificity in any tissue at any age. The spectra of mutations found in aging animals were identical to those in younger animals, suggesting that they originated from a common set of DNA lesions manifested during DNA replication. The data also indicated that there were no significant age-related mutational changes due to oxidative damage, or errors resulting from either changes in the fidelity of DNA polymerase or the efficiency of DNA repair. Hence, no evidence was found to support hypotheses that predict that oxidative damage or accumulation of errors in nuclear DNA contributes significantly to the aging process, at least in these three somatic tissues.
Stuart
G R
GR
Centre for Environmental Health, University of Victoria, Victoria, British Columbia V8W 3N5, Canada. gstuart@uvic.ca
Oda
Y
Y
de Boer
J G
JG
Glickman
B W
BW
D000375:Aging / Q000235:genetics* / Q000502:physiology; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics*; D001921:Brain / Q000502:physiology; D029968:Escherichia coli Proteins; D056968:Lac Repressors; D008099:Liver / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D012097:Repressor Proteins / Q000235:genetics*; D001743:Urinary Bladder / Q000502:physiology
D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D056968:Lac Repressors; D012097:Repressor Proteins