Enhanced glycogenesis is involved in cellular senescence via GSK3/GS modulation
Enhanced glycogenesis is involved in cellular senescence via GSK3/GS modulation
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DOI：
10.1111/j.1474-9726.2008.00436.x
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发表时间：
2008-12-01
期刊：
影响因子：
7.8
通讯作者：
Yoon, Gyesoon
中科院分区：
文献类型：
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作者：
Seo, Yong-Hak;Jung, Hyun-Jung;Yoon, Gyesoon
糖原生物发生及其对生理刺激的反应通常与年龄相关疾病有关。然而，它们与细胞衰老和老化的直接关系尚未明确阐明。在这里，我们报告了糖原生成增强在细胞衰老中的重要作用。糖原积累、糖原合成酶 (GS) 激活和糖原合成酶激酶 3 (GSK3) 失活通常发生在多种细胞衰老模型中，包括衰老 F344 大鼠的肝组织。 GSK3 抑制剂（SB415286 和 LiCl）的亚细胞毒性浓度足以诱导细胞衰老并增加糖生成。有趣的是，SB415286 诱导的糖原生成是不可逆的，活性氧水平的增加和衰老表型的增加也是不可逆的。使用 siRNA 或显性失活突变体 (GSK3 beta-K85A) 阻断 GSK3 活性也能有效诱导衰老表型，并且 GS 敲除可显着减弱应激诱导的衰老表型。总而言之，这些结果清楚地表明，糖原生成增强不仅很常见，而且与细胞衰老和衰老直接相关，表明 GSK3 和 GS 作为衰老的新型调节剂，并为衰老和衰老相关发病机制的代谢背景提供了新的见解。
Glycogen biogenesis and its response to physiological stimuli have often been implicated in age-related diseases. However, their direct relationships to cell senescence and aging have not been clearly elucidated. Here, we report the central involvement of enhanced glycogenesis in cellular senescence. Glycogen accumulation, glycogen synthase (GS) activation, and glycogen synthase kinase 3 (GSK3) inactivation commonly occurred in diverse cellular senescence models, including the liver tissues of aging F344 rats. Subcytotoxic concentrations of GSK3 inhibitors (SB415286 and LiCl) were sufficient to induce cellular senescence with increased glycogenesis. Interestingly, the SB415286-induced glycogenesis was irreversible, as were increased levels of reactive oxygen species and gain of senescence phenotypes. Blocking GSK3 activity using siRNA or dominant negative mutant (GSK3 beta-K85A) also effectively induced senescence phenotypes, and GS knock-down significantly attenuated the stress-induced senescence phenotypes. Taken together, these results clearly demonstrate that augmented glycogenesis is not only common, but is also directly linked to cellular senescence and aging, suggesting GSK3 and GS as novel modulators of senescence, and providing new insight into the metabolic backgrounds of aging and aging-related pathogenesis.