Stem cells and aging

有许多途径和过程似乎控制着衰老的速度和我们对与年龄相关的疾病的易感性，如神经退行性变、动脉粥样硬化和癌症。一个日益受到牵连的新兴过程是成体干细胞的枯竭、衰竭或与年龄相关的功能障碍。干细胞衰老的原因或方式背后的机制还没有得到广泛的研究。我们的重点是细胞内代谢和干细胞老化之间的联系。我们的假设是，控制干细胞和祖细胞内的代谢和细胞内的活性氧物种(ROS)是干细胞维持的关键组成部分。此外，我们假设许多与干细胞调控有关的基因也会影响这些细胞的潜在新陈代谢。 我们最近在Polycomb调控因子Bmi1和细胞内代谢之间建立了一个有趣的联系(Liu等人，《自然》，2009)。以前的工作已经证明，Bmi1的缺失会导致干细胞自我更新几乎完全失败。因此，Bmi1的活性以及由此延伸的Polycomb表观遗传调控，是维持造血和神经干细胞间隔所必需的。我们的结果还表明，Bmi1在调节线粒体功能和ROS动态平衡方面具有重要作用。特别是，在缺乏Bmi1的情况下，ROS水平增加，并足以激活DNA损伤反应(DDR)途径。 我们还探讨了干细胞生物学的其他调节因子与新陈代谢之间的联系。我们的兴趣之一是Wnt信号通路和新陈代谢之间的联系。我们最近的数据表明，Wnt信号在哺乳动物蛋白代谢中发挥着重要作用，特别是在肝脏对饥饿的反应中(Liu等人，2011年)。 我们目前的努力是使用更多的遗传模型来探索线粒体功能和干细胞功能之间的关系。

There are many pathways and processes that appear to regulate the rate of aging and our susceptibility to age-related diseases such as neurodegeneration, atherosclerosis and cancer. One emerging process that has been increasingly implicated is the depletion, exhaustion or age-related dysfunction of adult stem cells. The mechanism behind why or how stem cells age has not been extensively studied. We have focused on the connection between intracellular metabolism and stem cell aging. Our hypothesis is that the control of metabolism and intracellular reactive oxygen species (ROS) within stem and progenitor cells is a key component of stem cell maintainence. Furthermore, we hypothesize that many of the genes implicated in stem cell regulation will also influnce the underlying metabolism of these cells. We have recently made an interesting connection between the Polycomb regulator Bmi1 and intracellular metabolism (Liu et al., Nature, 2009). Previous work has demonstrated that the absence of Bmi1 leads to a near total failure of stem cell self-renewal. Thus, Bmi1 activity and by extension Polycomb epigenetic regulation, is required to maintain both the hematopoietic an neural stem cell compartment. Our results also suggested that Bmi1 has important functions in regulating mitochondrial function as well as ROS homeostasis. In particular, in the absence of Bmi1, levels of ROS increase and are sufficient to activate the DNA damage response (DDR) pathways. We have also probed the connection between other regulators of stem cell biology and metabolism. One of our interests has been the connection between the Wnt signaling pathway and metabolism. Our recent data suggest that Wnt signaling plays an important role in mammalain metabolism particularly in the response of the liver to starvation (Liu et al, 2011). Our current efforts are to use additional genetic models to probe the relationship between mitochondrial function and stem cell function.