Mutational fingerprints of aging

Abstract

Using a lacZ plasmid transgenic mouse model, spectra of spontaneous point mutations were determined in brain, heart, liver, spleen and small intestine in young and old mice. While similar at a young age, the mutation spectra among these organs were significantly different in old age. In brain and heart G:C-->A:T transitions at CpG sites were the predominant mutation, suggesting that oxidative damage is not a major mutagenic event in these tissues. Other base changes, especially those affecting A:T base pairs, positively correlated with increasing proliferative activity of the different tissues. A relatively high percentage of base changes at A:T base pairs and compound mutants were found in both spleen and spontaneous lymphoma, suggesting a possible role of the hypermutation process in splenocytes in carcinogenesis. The similar mutant spectra observed at a young age may reflect a common mutation mechanism for all tissues that could be driven by the rapid cell division that takes place during development. However, the spectra of the young tissues did not resemble that of the most proliferative aged tissue, implying that replicative history per se is not the underlying causal factor of age-related organ-specific differences in mutation spectra. Rather, differences in organ function, possibly in association with replicative history, may explain the divergence in mutation spectra during aging.

Figure 1

Point mutational spectra of the lacZ reporter gene in brain, heart, liver, spleen and small intestine from young (3.5 months) and old (32 months) mice. Bars represent the frequency of each type of point mutation as indicated. The black areas in the G:C→A:T bars indicate the fraction of such mutations that had occurred at CpG sites and the gray areas in the Del (–1) bars indicate the fraction of such mutations that had occurred at reiterated sites, i.e. a sequence of three or more of the same nucleotide. Corrections for recurrent mutations were made.

Figure 2

Point mutational spectra of the lacZ reporter gene in spontaneous lymphomas found in old mice. See legend to Figure 1 for an explanation of the bars. Mutational spectra are expressed as percentages to omit inaccuracies in correcting mutant frequencies for frequent recurrent mutations leading to a small number of unique plasmids analyzed for some lymphomas (Table 1).

Figure 3

Point mutational spectra of mock-recovered plasmids grown in E.coli C. See legend to Figure 1 for an explanation of the bars. Mutational spectra are expressed as percentages, since thus far there is no evidence that they represent a real background, i.e. find their origin in the rescue process (see text).