Genome instability: Cancer or aging?

Vijg, Jan; Dollé, Martijn E.T.

doi:10.1016/j.mad.2007.05.004

Cited by 18 publications

(8 citation statements)

References 17 publications

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“…The prevailing view is that radiation- or spontaneously-induced genomic instability plays a major role in multi-stage carcinogenesis and the functional decline of tissues in aging [76]. There is good evidence from animal and human studies to show that high-LET alpha-emitters such as plutonium and Thorotrast induce genomic instability, the latter through the inactivation of DNA mismatch repair [77,78].…”

Section: Comparison Of Aging and Radiation Effectsmentioning

confidence: 99%

Ionizing radiation and aging: rejuvenating an old idea

Richardson

2009

Aging

119

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This paper reviews the contemporary evidence that radiation can accelerate aging, degenerative health effects and mortality. Around the 1960s, the idea that ionizing radiation caused premature aging was dismissed as the radiation-induced health effects appeared to be virtually confined to neoplasms. More recently, radiation has become associated with a much wider spectrum of age-related diseases, including cardiovascular disease; although some diseases of old age, such as diabetes, are notably absent as a radiation risk. On the basis of recent research, is there a stronger case today to be made linking radiation and aging? Comparison is made between the now-known biological mechanisms of aging and those of radiation, including oxidative stress, chromosomal damage, apoptosis, stem cell exhaustion and inflammation. The association between radiation effects and the free-radical theory of aging as the causative hypothesis seems to be more compelling than that between radiation and the nutrient-sensing TOR pathway. Premature aging has been assessed by biomarkers in calorie restriction studies; yet, biomarkers such as telomere erosion and p16INK4a are ambiguous for radiation-induced aging. Some animal studies suggest low dose radiation may even demonstrate hormesis health benefits. Regardless, there is virtually no support for a life span extending hypothesis for A-bomb survivors and other exposed subjects.

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Section: Comparison Of Aging and Radiation Effectsmentioning

confidence: 99%

Ionizing radiation and aging: rejuvenating an old idea

Richardson

2009

Aging

119

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“…Despite the fact that one seems to exclude the other, sufficient information has now accumulated to implicate common processes behind both aging and cancer [37-41]. Both tissue renewal, lack of which causes degeneration due to natural loss of damaged or worn-out differentiated cells, and tumorigenesis depend on the presence of cells capable of proliferation.…”

Section: Stem Cells and The Aging-cancer Relationshipmentioning

confidence: 99%

Genome instability, cancer and aging

Maslov

Vijg

2009

Biochimica et Biophysica Acta (BBA) - General Subjects

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110

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DNA damage-driven genome instability underlies the diversity of life forms generated by the evolutionary process but is detrimental to the somatic cells of individual organisms. The cellular response to DNA damage can be roughly divided in two parts. First, when damage is severe, programmed cell death may occur or, alternatively, temporary or permanent cell cycle arrest. This protects against cancer but can have negative effects on the long term, e.g., by depleting stem cell reservoirs. Second, damage can be repaired through one or more of the many sophisticated genome maintenance pathways. However, erroneous DNA repair and incomplete restoration of chromatin after damage is resolved, produce mutations and epimutations, respectively, both of which have been shown to accumulate with age. An increased burden of mutations and/or epimutations in aged tissues increases cancer risk and adversely affects gene transcriptional regulation, leading to progressive decline in organ function. Cellular degeneration and uncontrolled cell proliferation are both major hallmarks of aging. Despite the fact that one seems to exclude the other, they both may be driven by a common mechanism. Here, we review age related changes in the mammalian genome and their possible functional consequences, with special emphasis on genome instability in stem/progenitor cells.

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“…Replicative or cellular senescence-associated permanent cell growth arrest of normal human cells serves as a major barrier to tumor formation (1)(2)(3)(4)(5)(6)(7). The cell growth arrest limits the ability of normal cells to proliferate and preserves genomic integrity by preventing cells with short telomeres from entering the cell cycle (2,3,7).…”

Section: Introductionmentioning

confidence: 99%

“…The cell growth arrest limits the ability of normal cells to proliferate and preserves genomic integrity by preventing cells with short telomeres from entering the cell cycle (2,3,7).…”

Section: Introductionmentioning

confidence: 99%

Expression of an IFN-Inducible Cellular Senescence Gene, IFI16, Is Up-Regulated by p53

Song

Alimirah

Panchanathan

et al. 2008

Molecular Cancer Research

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IFN-inducible IFI16 protein (encoded by IFI16 gene at 1q23.1) is the human member of the IFN-inducible structurally related p200 family proteins. Increased expression of the IFI16 protein, a positive modulator of p53-mediated transcription, in normal old human diploid fibroblasts (HDF) is associated with cellular senescence-mediated cell growth arrest. However, the underlying mechanisms that contribute to transcriptional activation of the IFI16 gene in old HDFs remain to be elucidated. Here, we reported that functional activation of p53 in normal young HDFs and p53-null Saos2 cell line resulted in transcriptional activation of the IFI16 gene. We identified a potential p53 DNA-binding site (indicated as IFI16-p53-BS) in the 5 ¶-regulatory region of the IFI16 gene. Importantly, p53 bound to IFI16-p53-BS in a sequence-specific manner in gel-mobility shift assays. Furthermore, p53 associated with the 5 ¶-regulatory region of the IFI16 gene in chromatin immunoprecipitation assays. Interestingly, p53 associated with the regulatory region of the IFI16 gene only on treatment of cells with DNA-damaging agents or in the old, but not in the young, HDFs. Importantly, our promoter-reporter assays, which were coupled with site-directed mutagenesis of IFI16-p53-BS, showed that p53 activates transcription of the IFI16 gene in HDFs through the p53 DNA-binding site. Together, our observations provide support for the idea that up-regulation of IFI16 expression by p53 and functional interactions between IFI16 protein and p53 contribute to cellular senescence.

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Genome instability: Cancer or aging?

Cited by 18 publications

References 17 publications

Ionizing radiation and aging: rejuvenating an old idea

Ionizing radiation and aging: rejuvenating an old idea

Genome instability, cancer and aging

Expression of an IFN-Inducible Cellular Senescence Gene, IFI16, Is Up-Regulated by p53

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