Department of Investigative Pathology, Nagasaki University, Japan.
Aging Cell. 2010 Jun;9(3):372-82. doi: 10.1111/j.1474-9726.2010.00563.x. Epub 2010 Mar 6.
The FoxO transcription factors may be involved in the antiaging effect of calorie restriction (CR) in mammals. To test the hypothesis, we used FoxO1 knockout heterozygotic (HT) mice, in which the FoxO1 mRNA level was reduced by 50%, or less, of that in wild-type (WT) mouse tissues. The WT and HT mice were fed ad libitum (AL) or 30% CR diets from 12 weeks of age. Aging- and CR-related changes in body weight, food intake, blood glucose, and insulin concentrations were similar between the WT and HT mice in the lifespan study. The response to oxidative stress, induced by intraperitoneal injection of 3-nitropropionic acid (3-NPA), was evaluated in the liver and hippocampus at 6 months of age. Several of the selected FoxO1-target genes for cell cycle arrest, DNA repair, apoptosis, and stress resistance were up-regulated in the WT-CR tissues after 3-NPA injection, while the effect was mostly diminished in the HT-CR tissues. Of these gene products, we focused on the nuclear p21 protein level in the liver and confirmed its up-regulation only in the WT-CR mice in response to oxidative stress. The lifespan did not differ significantly between the WT and HT mice in AL or CR conditions. However, the antineoplastic effect of CR, as indicated by reduced incidence of tumors at death in the WT-CR mice, was mostly abrogated in the HT-CR mice. The present results suggest a role for FoxO1 in the antineoplastic effect of CR through the induction of genes responsible for protection against oxidative and genotoxic stress.
FoxO 转录因子可能参与了哺乳动物热量限制 (CR) 的抗衰老作用。为了验证这一假说，我们使用 FoxO1 敲除杂合子 (HT) 小鼠，其中 FoxO1 mRNA 水平降低到野生型 (WT) 小鼠组织的 50%或更低。WT 和 HT 小鼠从 12 周龄起分别自由进食 (AL) 或 30% CR 饮食。在寿命研究中，WT 和 HT 小鼠的体重、食物摄入量、血糖和胰岛素浓度的衰老和 CR 相关变化相似。在 6 个月大时，通过腹腔注射 3-硝基丙酸 (3-NPA) 评估了肝脏和海马中的氧化应激反应。在 WT-CR 组织中，有几个与细胞周期停滞、DNA 修复、细胞凋亡和应激抵抗相关的 FoxO1 靶基因在 3-NPA 注射后上调，而 HT-CR 组织中的这种作用大部分减弱。在这些基因产物中，我们关注肝脏中的核 p21 蛋白水平，并在 WT-CR 小鼠中证实了其在氧化应激下的上调。WT 和 HT 小鼠在 AL 或 CR 条件下的寿命没有显著差异。然而，CR 的抗肿瘤作用，如 WT-CR 小鼠死亡时肿瘤发生率降低所表明的那样，在 HT-CR 小鼠中大部分被消除。这些结果表明，FoxO1 通过诱导对氧化和遗传毒性应激具有保护作用的基因，在 CR 的抗肿瘤作用中发挥作用。
