Mutational fingerprints of aging
Open accessAbstract
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.
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Even apparently normal tissues harbor cells with potentially oncogenic mutations.
“In addition, even apparently normal tissues harbor cells with potentially oncogenic mutations, and the incidence of mutant cells increases with age (Jonason et al., 1996; Dolle et al., 2002).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Dolle et al., 2002
The Introduction describes somatic mutations in mouse tissues and says they are thought to play a major causal role in cancer. The Results and Discussion find mutations in non-tumor tissues and similarities between mutations in old spleen and lymphoma, but the study measured mutations in a neutral lacZ reporter, not mutations shown to be oncogenic. Its finding therefore supports the general point, but not the implication that the detected cells carried potentially oncogenic mutations. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe incidence of mutant cells increases with age.
“In addition, even apparently normal tissues harbor cells with potentially oncogenic mutations, and the incidence of mutant cells increases with age (Jonason et al., 1996; Dolle et al., 2002).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Dolle et al., 2002
The Results and Discussion report higher point-mutation frequencies on average in older mice, with increases in four of five organs examined. The study measured mutations in a lacZ reporter in mice, not the incidence of mutant cells generally, and found no significant increase in brain. (LLM, conf=0.86)
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- Authors
- Dolle, M. E. T.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2002-01-15
- Volume
- 30
- Issue
- 2
- Pages
- 545-549
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC99828
- OpenAlex
- W2117178083
- Cited by
- 87
- References
- 27
- Citations by year
- 2024: 1 · 2023: 2 · 2021: 1 · 2020: 4 · 2019: 1 · 2018: 3 · 2017: 5 · 2016: 3 · 2015: 4 · 2014: 6 · 2013: 3 · 2012: 2
- FWCI
- 2.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nucleic Acids Research (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (7r01ca075653-03)
- National Institute on Aging (AG13319-05, 1PO1AG17242-01, P01AG017242, P30AG013319)
- National Cancer Institute (1R01CA75653-03)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Keywords
- mutation spectrum, aging, oxidative damage, tissue-specific mutagenesis, compound mutations, lymphoma, splenocytes, hypermutation, carcinogenesis, cell proliferation
- MeSH terms
- Aging, Animals, Base Sequence, Brain, Cell Division, DNA Damage, DNA Mutational Analysis, Intestine, Small, Lac Operon, Liver, Lymphoma, Male, Mice, Inbred C57BL, Mice, Transgenic, Myocardium, Organ Specificity, Spleen, DNA Fingerprinting, Mutagenesis, Point Mutation, Genes, Reporter, Oxidative Stress, CpG Islands, Models, Animal, Mice
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