Stem cells and aging

有许多途径和过程似乎调节着衰老的速度和我们对年龄相关疾病（如神经变性、动脉粥样硬化和癌症）的易感性。一个日益涉及的新兴过程是成体干细胞的耗竭、衰竭或与年龄相关的功能障碍。干细胞为何或如何衰老背后的机制尚未得到广泛研究。我们专注于细胞内代谢和干细胞衰老之间的联系。我们的假设是，干细胞和祖细胞内代谢和细胞内活性氧（ROS）的控制是干细胞维持的关键组成部分。此外，我们假设许多涉及干细胞调控的基因也会影响这些细胞的潜在代谢。

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.