Relief of oxidative stress by ascorbic acid delays cellular senescence of normal human and Werner syndrome fibroblast cells

Kashino, Genro; Kodama, Seiji; Nakayama, Yasuichi; Suzuki, Keiji; Fukase, Kazuaki; Goto, Makoto; Watanabe, Masami

doi:10.1016/s0891-5849(03)00326-5

Cited by 79 publications

(50 citation statements)

References 33 publications

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“…Ascorbic acid is a major physiological antioxidant that replenishes GSH levels, prevents high-caloric-diet-induced dyslipidemia (30) and also influences the outcome of several agerelated disorders, such as diabetes mellitus, obesity, and atherosclerosis (31). It is known that ascorbate delays replicative senescence of WS fibroblasts in vitro (32). Therefore, we investigated the role of ascorbate in the disease progression of our mouse model.…”

Section: Resultsmentioning

confidence: 99%

Vitamin C restores healthy aging in a mouse model for Werner syndrome

et al. 2009

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Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN homologue exhibit many phenotypic features of WS, including a prooxidant status and a shorter mean life span compared to wild-type animals. Here, we show that Wrn mutant mice also develop premature liver sinusoidal endothelial defenestration along with inflammation and metabolic syndrome. Vitamin C supplementation rescued the shorter mean life span of Wrn mutant mice and reversed several age-related abnormalities in adipose tissues and liver endothelial defenestration, genomic integrity, and inflammatory status. At the molecular level, phosphorylation of age-related stress markers like Akt kinase-specific substrates and the transcription factor NF-κB, as well as protein kinase Cδ and Hif-1α transcription factor levels, which are increased in the liver of Wrn mutants, were normalized by vitamin C. Vitamin C also increased the transcriptional regulator of lipid metabolism PPARα. Finally, microarray and gene set enrichment analyses on liver tissues revealed that vitamin C decreased genes normally up-regulated in human WS fibroblasts and cancers, and it increased genes involved in tissue injury response and adipocyte dedifferentiation in obese mice. Vitamin C did not have such effect on wild-type mice. These results indicate that vitamin C supplementation could be beneficial for patients with WS.

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Section: Resultsmentioning

confidence: 99%

Vitamin C restores healthy aging in a mouse model for Werner syndrome

et al. 2009

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“…Several studies have shown that ascorbic acid should be used in the more stable and less cytotoxic phosphoric ester magnesium salt, phosphorylated at the 2, 3-enediol moiety (Chepda et al 2001;Kashino et al 2003;Yokoo et al 2004). These studies showed that adding APM at 130-450 lM (33-115 mg/l) conferred a lifespan extension that was not observed using ascorbic acid alone.…”

Section: Resultsmentioning

confidence: 99%

Telomere dynamics during replicative senescence are not directly modulated by conditions of oxidative stress in IMR90 fibroblast cells

et al. 2009

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The replicative lifespan of many cell types is determined by the length of telomeres in the initiating cell population. In 20% oxygen, IMR90 cells have a shorter replicative lifespan compared to that achieved in conditions that lower the levels of oxidative stress. We sought to address the role of telomere dynamics in determining the replicative lifespan of IMR90 cells. We analysed clonal populations cultured in parallel in 3 and 20% oxygen. We observed that, at senescence, telomere length was shorter in 3% oxygen and this was proportional to the lifespan extension. We observed no detectable difference in the rate of telomere erosion in the two culture conditions, however as the cells approached senescence the growth rate of the cultures slowed with a commensurate increase in the rate of telomere erosion. We conclude that, in 20% oxygen senescence of IMR90 is telomere-independent, but telomere-dependent in 3% oxygen.

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“…Readers are directed to some recent reviews on intervention studies in overall aging and lifespan extension. A list of interventional strategies ranging from antioxidant administration to CR that have been attempted to modulate life span in various organisms and in human cells, ex vivo, and their ability to extend life span is provided in Table 1 (18,33,88,137,148,149,167,172,183,209,227,321,387,392,395). A few of these interventions, in the context of immune aging are discussed below.…”

Section: Ponnappan and Ponnappanmentioning

confidence: 99%

Aging and Immune Function: Molecular Mechanisms to Interventions

Ponnappan

2011

Antioxidants & Redox Signaling

290

266

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The immune system of an organism is an essential component of the defense mechanism aimed at combating pathogenic stress. Age-associated immune dysfunction, also dubbed ''immune senescence,'' manifests as increased susceptibility to infections, increased onset and progression of autoimmune diseases, and onset of neoplasia. Over the years, extensive research has generated consensus in terms of the phenotypic and functional defects within the immune system in various organisms, including humans. Indeed, age-associated alterations such as thymic involution, T cell repertoire skewing, decreased ability to activate naïve T cells and to generate robust memory responses, have been shown to have a causative role in immune decline. Further, understanding the molecular mechanisms underlying the generation of proteotoxic stress, DNA damage response, modulation of ubiquitin proteasome pathway, and regulation of transcription factor NFkB activation, in immune decline, have paved the way to delineating signaling pathways that cross-talk and impact immune senescence. Given the role of the immune system in combating infections, its effectiveness with age may well be a marker of health and a predictor of longevity. It is therefore believed that a better understanding of the mechanisms underlying immune senescence will lead to an effective interventional strategy aimed at improving the health span of individuals. Antioxid. Redox Signal. 14, 1551-1585.

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Relief of oxidative stress by ascorbic acid delays cellular senescence of normal human and Werner syndrome fibroblast cells

Cited by 79 publications

References 33 publications

Vitamin C restores healthy aging in a mouse model for Werner syndrome

Vitamin C restores healthy aging in a mouse model for Werner syndrome

Telomere dynamics during replicative senescence are not directly modulated by conditions of oxidative stress in IMR90 fibroblast cells

Aging and Immune Function: Molecular Mechanisms to Interventions

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