Age-dependent increases in the oxidative damage of DNA, RNA, and their metabolites in normal and senescence-accelerated mice analyzed by LC–MS/MS: Urinary 8-oxoguanosine as a novel biomarker of aging

Gan, Wei; Nie, Ben; Shi, Fei; Xu, Xinmin; Qian, Jianchang; Takagi, Yasuaki; Hayakawa, Hiroshi; Sekiguchi, Mutsuo; Cai, Jian‐Ping

doi:10.1016/j.freeradbiomed.2012.02.016

Cited by 82 publications

(50 citation statements)

References 39 publications

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“…Athough MDA-modified vimentin was previously identified in the brain cortex of Alzheimer's patients via a proteomic screen of MDA-oxidized proteins (45), astrocytes in the brain demonstrate age-related changes that resemble those of the SASP, including expression of several cytokines, accumulation of proteotoxic aggregates, and elevated levels of vimentin (96). Nonetheless, the accumulation of MDA-modified vimentin detected in SAMP8 mice may also reflect senescence-independent cellular changes in response to DNA-damage signaling constitutively occurring in this mouse strain (97). Based on these data, we propose the detection of secreted MDA-modified vimentin as a product and readout of senescent cells.…”

Section: Discussionmentioning

confidence: 94%

Senescent cells expose and secrete an oxidized form of membrane-bound vimentin as revealed by a natural polyreactive antibody

Frescas

Roux

Aygun‐Sunar

et al. 2017

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

115

103

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Studying the phenomenon of cellular senescence has been hindered by the lack of senescence-specific markers. As such, detection of proteins informally associated with senescence accompanies the use of senescence-associated β-galactosidase as a collection of semiselective markers to monitor the presence of senescent cells. To identify novel biomarkers of senescence, we immunized BALB/c mice with senescent mouse lung fibroblasts and screened for antibodies that recognized senescence-associated cell-surface antigens by FACS analysis and a newly developed cell-based ELISA. The majority of antibodies that we isolated, cloned, and sequenced belonged to the IgM isotype of the innate immune system. In-depth characterization of one of these monoclonal, polyreactive natural antibodies, the IgM clone 9H4, revealed its ability to recognize the intermediate filament vimentin. By using 9H4, we observed that senescent primary human fibroblasts express vimentin on their cell surface, and MS analysis revealed a posttranslational modification on cysteine 328 (C328) by the oxidative adduct malondialdehyde (MDA). Moreover, elevated levels of secreted MDA-modified vimentin were detected in the plasma of aged senescence-accelerated mouse prone 8 mice, which are known to have deregulated reactive oxygen species metabolism and accelerated aging. Based on these findings, we hypothesize that humoral innate immunity may recognize senescent cells by the presence of membrane-bound MDA-vimentin, presumably as part of a senescence eradication mechanism that may become impaired with age and result in senescent cell accumulation.aging | oxidative posttranslational modifications | biomarker | SAMP8 | malondialdehyde

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Section: Discussionmentioning

confidence: 94%

Senescent cells expose and secrete an oxidized form of membrane-bound vimentin as revealed by a natural polyreactive antibody

Frescas

Roux

Aygun‐Sunar

et al. 2017

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

115

103

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“…A complicated and largely uncharacterised suite of naturally occurring mutations plagues SAMP8 strains, culminating in the early onset of age-related morbidity related to oxidative stress and a markedly reduced life span (Bayram et al 2012, Gan et al 2012. This is significantly less than that observed in their accelerated senescence-resistant counterparts, denoted SAMR1, which served as the control strain for this study.…”

Section: Discussionmentioning

confidence: 99%

The senescence-accelerated mouse prone 8 as a model for oxidative stress and impaired DNA repair in the male germ line

Smith¹,

Iuliis²,

Lord³

et al. 2013

Reproduction

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The discovery of a truncated base excision repair pathway in human spermatozoa mediated by OGG1 has raised questions regarding the effect of mutations in critical DNA repair genes on the integrity of the paternal genome. The senescence-accelerated mouse prone 8 (SAMP8) is a mouse model containing a suite of naturally occurring mutations resulting in an accelerated senescence phenotype largely mediated by oxidative stress, which is further enhanced by a mutation in the Ogg1 gene, greatly reducing the ability of the enzyme to excise 8-hydroxy,2 0 -deoxyguanosine (8OHdG) adducts. An analysis of the reproductive phenotype of the SAMP8 males revealed a high level of DNA damage in caudal epididymal spermatozoa as measured by the alkaline Comet assay. Furthermore, these lesions were confirmed to be oxidative in nature, as demonstrated by significant increases in 8OHdG adduct formation in the SAMP8 testicular tissue (P!0.05) as well as in mature spermatozoa (P!0.001) relative to a control strain (SAMR1). Despite this high level of oxidative DNA damage in spermatozoa, reactive oxygen species generation was not elevated and motility of spermatozoa was found to be similar to that for the control strain with the exception of progressive motility, which exhibited a slight but significant decline with advancing age (P!0.05). When challenged with Fenton reagents (H 2 O 2 and Fe 2C ), the SAMP8 spermatozoa demonstrated a highly increased susceptibility to formation of 8OHdG adducts compared with the controls (P!0.001). These data highlight the role of oxidative stress and OGG1-dependent base excision repair mechanisms in defining the genetic integrity of mammalian spermatozoa.

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“…Interestingly, DR mice and rats have a lower concentration of 8oxodG in all tissues compared with controls fed ad libitum, suggesting that an altered metabolic state may protect cells from DNA damage (99). Improved methods of 8oxodG detection have confirmed these discoveries linking DNA damage and aging in different species (99,100).…”

Section: Mitochondrial Quality Control and Homeostasismentioning

confidence: 98%

Signaling Networks Determining Life Span

Riera

Merkwirth

Filho

et al. 2016

Annu. Rev. Biochem.

152

138

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The health of an organism is orchestrated by a multitude of molecular and biochemical networks responsible for ensuring homeostasis within cells and tissues. However, upon aging, a progressive failure in the maintenance of this homeostatic balance occurs in response to a variety of endogenous and environmental stresses, allowing the accumulation of damage, the physiological decline of individual tissues, and susceptibility to diseases. What are the molecular and cellular signaling events that control the aging process and how can this knowledge help design therapeutic strategies to combat age-associated diseases? Here we provide a comprehensive overview of the evolutionarily conserved biological processes that alter the rate of aging and discuss their link to disease prevention and the extension of healthy life span.

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Age-dependent increases in the oxidative damage of DNA, RNA, and their metabolites in normal and senescence-accelerated mice analyzed by LC–MS/MS: Urinary 8-oxoguanosine as a novel biomarker of aging

Cited by 82 publications

References 39 publications

Senescent cells expose and secrete an oxidized form of membrane-bound vimentin as revealed by a natural polyreactive antibody

Senescent cells expose and secrete an oxidized form of membrane-bound vimentin as revealed by a natural polyreactive antibody

The senescence-accelerated mouse prone 8 as a model for oxidative stress and impaired DNA repair in the male germ line

Signaling Networks Determining Life Span

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