Age-associated DNA damage is accelerated in the senescence-accelerated mice

Hosokawa, Masanori; Fujisawa, Hitoshi; Ax, Susanne; Zahn-Daimler, Gertrud; Ζahn, Rudolf K.

doi:10.1016/s0047-6374(00)00158-5

Cited by 33 publications

(11 citation statements)

References 18 publications

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“…Uryvaeva et al (1999) have shown an accelerated accumulation of micronuclear aberrations with age in the liver cells of SAMP mice as compared to the SAMR strain. The ageassociated incidence of somatic Hprt mutations in splenic lymphocytes, as well as DNA damage (mainly DNA single strand breaks) in six organs, are also accelerated in SAMP-1 mice as compared to the SAMR-1 (Odagiri et al, 1998;Hosokawa et al, 2000).…”

Section: Discussionmentioning

confidence: 96%

Body weight is not always a good predictor of longevity in mice

Anisimov

Arbeev

Popovich

et al. 2004

Experimental Gerontology

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There have been some observations that low body weight and a low level of some hormones (e.g. IGF-1) during the first half of life are predictors of longer life in mice. However, contradictions in the available data on the biomarkers of aging and predictors of longevity have shown that the research in these fields has become a controversial pursuit. In our study we addressed the following questions: (i) Can particular physiological parameters (body weight, food intake, estrus function, body temperature, incidence of chromosome aberrations in bone marrow cells) measured at the age of 3 and 12 months be a predictor of longevity and the rate of tumor development in five strains of mice? (ii) Can a heavy body weight at the age of 3 and 12 months be a predictor of longevity and high tumor risk in five strains of mice? Mice of five strains-CBA, SHR, SAMR, SAMP and transgenic HER-2/neu (FVB/N)-were under observation from the age of 2 -3 months until natural death. Body weight and temperature, food consumption, and estrous cycle were longitudinally studied in all animals. Tumors discovered at autopsy were studied morphologically. We calculated the life span's parameters (mean, maximum, mortality rate, mortality rate doubling time) as well as their correlation with other parameters studied. The longest living CBA mice have the lowest body weight at the ages of 3 and 12 months, the lowest food consumption, body temperature, incidence of chromosome aberrations and spontaneous tumor incidence. In comparison with all other mouse strains they also have the latest disturbances in estrus function and highest body weight gain. The shortest living transgenic HER-2/neu mice have the lowest weight at the ages of 12 months, the lowest body weight gain, maximal body temperature, the most rapid disturbances in estrus function and the highest incidence of chromosome aberrations and tumor incidence in comparison to all other mouse strains. Our findings have shown that heavier body weight at the age of 12 months is a predictor of longevity in female CBA and SAMP mice but not in SHR, SAMR and HER-2/neu mice. Excessive body weight at the ages of 3 or 12 months is not a predictor of increased tumor risk in the strains studied. In general, the existence and direction of a significant correlation between body weight and life span depends upon the animals' age and genotype. q

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Section: Discussionmentioning

confidence: 96%

Body weight is not always a good predictor of longevity in mice

Anisimov

Arbeev

Popovich

et al. 2004

Experimental Gerontology

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“…Short-living BDF1, SAMP6/Tan and A/J mice showed a significant agerelated increase in spontaneous frequencies of micronucleated reticulocytes whereas long-living ddY, CD-1, B6C3F1, SAMR1, and MS/Ae did not show significant age-related differences in mean frequencies of spontaneous micronuclei [234]. Long-live mutant Ames dwarf mice and knockout p66 she(/( mice were less vulnerable to oxidative damage than wild-type controls [228,235], whereas senescence-prone strain, SAMP, had increased production of ROS [207], DNA damages and somatic mutation as compared with senescence-resistant SAMR strain [236]. MGMT-overexpressed mice are more resistant to alkylating agents [199,237], whereas deficient in DNA repair MGMT (/( and Parp (/( mice are more susceptible to effect of alkylating chemicals and ionizing radiation [218,238].…”

Section: Effect Of Genetic Modifications Of Aging On Carcinogenesismentioning

confidence: 87%

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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“…SAMP strains show markedly shorter average life span compared with SAMR. The SAMP1 mice exhibited increased chromosome aberration (74), mutation of hprt genes (74), and the strong correlation of DNA damage and aging process (75). Therefore, we used SAMP1 and SAMR1 for our experiments.…”

Section: Animals and Tissue Preparationmentioning

confidence: 99%

Senescence-Dependent MutSα Dysfunction Attenuates Mismatch Repair

Chang¹,

Jin

Yoon

et al. 2008

Molecular Cancer Research

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DNA damage and mutations in the genome increase with age. To determine the potential mechanisms of senescence-dependent increases in genomic instability, we analyzed DNA mismatch repair (MMR) efficiency in young and senescent human colonic fibroblast and human embryonic lung fibroblast. It was found that MMR activity is significantly reduced in senescent cells. Western blot and immunohistochemistry analysis revealed that hMSH2 and MSH6 protein (MutSA complex), which is a known key component in the MMR pathway, is markedly down-regulated in senescent cells. Moreover, the addition of purified MutSA to extracts from senescent cells led to the restoration of MMR activity. Semiquantitative reverse transcription-PCR analysis exhibited that MSH2 mRNA level is reduced in senescent cells. In addition, a decrease in E2F transcriptional activity in senescent cells was found to be crucial for MSH2 suppression. E2F1 small interfering RNA expression reduced hMSH2 expression and MMR activity in young human primary fibroblast cells. Importantly, expression of E2F1 in quiescent cells restored the MSH2 expression as well as MMR activity, whereas E2F1-infected senescent cells exhibited no restoration of MSH2 expression and MMR activity. These results indicate that the suppression of E2F1 transcriptional activity in senescent cells lead to stable repression of MSH2, followed by a induction of MutSA dysfunction, which results in a reduced cellular MMR capacity in senescent cells. (Mol Cancer Res 2008;6(6):978 -89)

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Age-associated DNA damage is accelerated in the senescence-accelerated mice

Cited by 33 publications

References 18 publications

Body weight is not always a good predictor of longevity in mice

Body weight is not always a good predictor of longevity in mice

The relationship between aging and carcinogenesis: a critical appraisal

Senescence-Dependent MutSα Dysfunction Attenuates Mismatch Repair

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