Cellular senescence impairs circadian expression of clock genes in vitro and in vivo
Cellular senescence impairs circadian expression of clock genes in vitro and in vivo
复制标题
DOI：
10.1161/01.res.0000204504.25798.a8
复制
发表时间：
2006-03-03
影响因子：
20.1
通讯作者：
Komuro, I
中科院分区：
文献类型：
--
作者：
Kunieda, T;Minamino, T;Komuro, I
昼夜节律由一组时钟基因调节，这些基因形成转录反馈回路，并以24小时为周期产生昼夜振荡。衰老改变了广泛的生理、内分泌和行为节律。虽然最近的证据表明，细胞老化有助于各种年龄相关的疾病，其对昼夜节律的影响还没有得到检查。我们在这里报告，细胞衰老损害昼夜节律在体外和体内。与年轻细胞相比，在血清刺激的衰老细胞中时钟基因的昼夜节律表达明显减弱。端粒酶的引入完全阻止了与衰老相关的时钟基因表达的减少。血清刺激激活cAMP反应元件结合蛋白，但在衰老细胞中，这一信号通路的激活明显减弱。用该途径的激活剂治疗有效地恢复了衰老细胞受损的时钟基因表达。当年轻细胞被植入年轻小鼠或老年小鼠时，植入的细胞被受体的昼夜节律有效地携带。相反，植入的衰老细胞的夹带明显受损。这些结果表明，衰老降低了细胞将昼夜节律信号传递到其生物钟的能力，并且调节生物钟基因表达可能是治疗与年龄相关的昼夜节律性损伤的新策略。
Circadian rhythms are regulated by a set of clock genes that form transcriptional feedback loops and generate circadian oscillation with a 24-hour cycle. Aging alters a broad spectrum of physiological, endocrine, and behavioral rhythms. Although recent evidence suggests that cellular aging contributes to various age-associated diseases, its effects on the circadian rhythms have not been examined. We report here that cellular senescence impairs circadian rhythmicity both in vitro and in vivo. Circadian expression of clock genes in serum- stimulated senescent cells was significantly weaker compared with that in young cells. Introduction of telomerase completely prevented this reduction of clock gene expression associated with senescence. Stimulation by serum activated the cAMP response element- binding protein, but the activation of this signaling pathway was significantly weaker in senescent cells. Treatment with activators of this pathway effectively restored the impaired clock gene expression of senescent cells. When young cells were implanted into young mice or old mice, the implanted cells were effectively entrained by the circadian rhythm of the recipients. In contrast, the entrainment of implanted senescent cells was markedly impaired. These results suggest that senescence decreases the ability of cells to transmit circadian signals to their clocks and that regulation of clock gene expression may be a novel strategy for the treatment of age- associated impairment of circadian rhythmicity.