Mutational fingerprints of aging

Dollé, Martijn E.T.; Snyder, Wendy K.; Dunson, David B.; Vijg, Jan

doi:10.1093/nar/30.2.545

Cited by 85 publications

(49 citation statements)

References 24 publications

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“…has reported recently mutational spectra of the small intestine and the heart as determined by using a mouse model with chromosomally integrated lacZ reporter gene (48,49). Interestingly, the nuclear DNA spectrum of the small intestine (proliferative tissue) was similar to the mtDNA spectrum of buccal cells in that it was comprised predominantly of point mutations.…”

Section: Epithelial Mutational Hotspot: Clonal Expansion Via Randommentioning

confidence: 95%

Clonally expanded mtDNA point mutations are abundant in individual cells of human tissues

Nekhaeva

Bodyak

Kraytsberg

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

192

113

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Using single-cell sequence analysis, we discovered that a high proportion of cells in tissues as diverse as buccal epithelium and heart muscle contain high proportions of clonal mutant mtDNA expanded from single initial mutant mtDNA molecules. We demonstrate that intracellular clonal expansion of somatic point mutations is a common event in normal human tissues. This finding implies efficient homogenization of mitochondrial genomes within individual cells. Significant qualitative differences observed between the spectra of clonally expanded mutations in proliferating epithelial cells and postmitotic cardiomyocytes suggest, however, that either the processes generating these mutations or mechanisms driving them to homoplasmy are likely to be fundamentally different between the two tissues. Furthermore, the ability of somatic mtDNA mutations to expand (required for their phenotypic expression), as well as their apparently high incidence, reinforces the possibility that these mutations may be involved actively in various physiological processes such as aging and degenerative disease. The abundance of clonally expanded point mutations in individual cells of normal tissues also suggests that the recently discovered accumulation of mtDNA mutations in tumors may be explained by processes that are similar or identical to those operating in the normal tissue. somatic mutation ͉ clonal expansion ͉ single cell ͉ aging ͉ cancer

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Section: Epithelial Mutational Hotspot: Clonal Expansion Via Randommentioning

confidence: 95%

Clonally expanded mtDNA point mutations are abundant in individual cells of human tissues

Nekhaeva

Bodyak

Kraytsberg

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

192

113

View full text Add to dashboard Cite

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“…Thus, caretaker tumor suppressors restrain the development of cancer by suppressing the development of mutations. Since mutations not only cause cancer, but have also been proposed to independently contribute to aging, genes that encode caretaker tumor suppressor functions are straightforward longevity assurance genes (Martin, 1966;Dolle et al, 2002;Vijg and Dolle, 2002;Hasty et al, 2003).…”

Section: Tumor Suppressor Mechanismsmentioning

confidence: 99%

Aging, tumor suppression and cancer: high wire-act!

Campisi

2005

Mechanisms of Ageing and Development

155

120

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Evolutionary theory holds that aging is a consequence of the declining force of natural selection with age. We discuss here the evidence that among the causes of aging in complex multicellular organisms, such as mammals, is the antagonistically pleiotropic effects of the cellular responses that protect the organism from cancer. Cancer is relatively rare in young mammals, owing in large measure to the activity of tumor suppressor mechanisms. These mechanisms either protect the genome from damage and/or mutations, or they elicit cellular responsesapoptosis or senescence-that eliminate or prevent the proliferation of somatic cells at risk for neoplastic transformation. We focus here on the senescence response, reviewing its causes, regulation and effects. In addition, we describe recent data that support the idea that both senescence and apoptosis may indeed be the double-edged swords predicted by the evolutionary hypothesis of antagonistic pleiotropyprotecting organisms from cancer early in life, but promoting aging phenotypes, including late life cancer, in older organisms. # 2004 Published by Elsevier Ireland Ltd.

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“…The character of these changes could vary in different tissues and might cause uneven tissue aging. Recently, Dolle et al [75] using a lacZ plasmid transgenic mouse model, determined spectra of spontaneous point mutations in different organs in young and old mice. While similar at a young age, the mutation spectra among these organs were significantly different in old age.…”

Section: Aging and Multi-stage Carcinogenesismentioning

confidence: 99%

The relationship between aging and carcinogenesis: a critical appraisal

Anisimov

2003

Critical Reviews in Oncology/Hematology

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The incidence of cancer increases with age in humans and in laboratory animals alike. There are different patterns of age-related distribution of tumors in different organs and tissues. Aging may increase or decrease the susceptibility of various tissues to initiation of carcinogenesis and usually facilitates promotion and progression of carcinogenesis. Aging may predispose to cancer by several mechanisms: (1) tissue accumulation of cells in late stages of carcinogenesis; (2) alterations in homeostasis, in particular, alterations in immune and endocrine system and (3) telomere instability linking aging and increased cancer risk. Increased susceptibility to the effects of tumor promoters is found both in aged animals and aged humans, as predicted by the multistage model of carcinogenesis. Available evidence supporting the relevance of replicative senescence of human cells and telomere biology to human cancer seems quite strong, however, the evidence linking cellular senescence to human aging is controversial and required additional stuidies. Data on the acceleration of aging by carcinogenic agents as well as on increased cancer risk in patients with

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Mutational fingerprints of aging

Cited by 85 publications

References 24 publications

Clonally expanded mtDNA point mutations are abundant in individual cells of human tissues

Clonally expanded mtDNA point mutations are abundant in individual cells of human tissues

Aging, tumor suppression and cancer: high wire-act!

The relationship between aging and carcinogenesis: a critical appraisal

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