Akt, cellular senescence, and lifespan

寿命和能量代谢之间的耦合是有据可查的，热量限制是 可以延长多种生物的寿命。线虫和蝇的遗传学研究 显示通过PI 3 K及其下游效应物丝氨酸/苏氨酸的胰岛素信号传导受损， 激酶Akt与能量代谢下降和寿命延长有关。In C.埃莱甘斯 决定寿命的胰岛素信号传导的最远端效应物是叉头转录因子， 16，其通过磷酸化被Akt灭活。因此，Akt活性的降低增加了β-16活性。 从而延长寿命。Akt的另一个保守下游效应子，雷帕霉素的靶点 (TOR)最近，在线虫和苍蝇的寿命的调节涉及。但 PISK/Akt信号通路对哺乳动物寿命的贡献尚未被彻底研究。 特别是，没有现存的遗传证据支持这一途径在哺乳动物寿命中的作用。 这可能部分是由于该途径与一系列过程的关联，包括细胞凋亡， 葡萄糖代谢和分化，这使得评估其在调节哺乳动物细胞中的作用变得复杂。 中心blog我们的长期目标是确定Akt是否可以调节寿命和对氧化应激的敏感性。 老鼠的压力小鼠具有由不同基因编码的三种Akt同种型（akt 1、akt 2和akt 3）。我们 我建议利用我们的研究中产生的基因工程Akt缺陷小鼠的可用性， 实验室这些动物缺乏单独或组合的akt基因。他们提供了极好 用于检查Akt活性和单个Akt同种型对 长寿和氧化应激依赖性衰老和衰老。在细胞水平上，我们将扩展我们的 来自Akt（敲除）KO小鼠的细胞表现出较低的基础水平， 细胞内活性氧（ROS）比野生型对应物，而细胞表达 激活的Akt产生更高的ROS水平。这些变化与以下方面的相应变化相关联： 能量代谢和氧气消耗。我们将阐明Akt活性 调节细胞内ROS丰度和Akt在细胞衰老调节中的作用。在 在生物体水平上，我们将确定是否部分消融Akt活性所造成的个体损失， 同种型，单独或组合，足以延长正常寿命，并赋予抗氧化性， 老鼠的压力

The coupling between lifespan and energy metabolism is well documented, and caloric restriction was shown to extend the lifespan of a wide spectrum of organisms. Genetics studies in nematodes and flies showed that impaired insulin signaling through PI3K and its downstream effector, the serine/threonine kinase, Akt, is associated with a decline in energy metabolism and an extended lifespan. In C. elegans, the most distal effector of insulin signaling that determines lifespan is the forkhead transcription factor, DAF- 16, which is inactivated by Akt via phosphorylation. Thus, reduced Akt activity increases DAF-16 activity and thereby increases lifespan. Another conserved downstream effector of Akt, the target of rapamycin (TOR), was recently implicated in the regulation of lifespan both in nematodes and flies. However, the contribution of the PISK/Akt signaling pathway to longevity in mammals has not been thoroughly explored. In particular, there is no extant genetic evidence supporting a role for this pathway in mammalian lifespan. This may be due, in part, to the association of this pathway with an array of processes including, apoptosis, glucose metabolism, and differentiation, which complicate evaluating its role in modulating mammalian longevity. Our long-term goal is to determine whether Akt can regulate lifespan and sensitivityto oxidative stress in mice. The mouse has three Akt isoforms encoded by distinct genes (aktl, akt2, and akt3). We propose to take advantage of the availability of genetically engineered Akt-deficient mice generated in our laboratory. These animals lack individual akt genes, alone and in combination. They provide excellent genetic models for examination of the contributions of Akt activity and individual Akt isoforms to longevity and oxidative-stress-dependent aging and senescence. At the cellular level, we will expand on our initial observations that cells derived from Akt (knockout) KO mice exhibit lower basal levels of intracellular reactive oxygen species (ROS) than their wild-type counterparts, whereas cells expressing activated Akt generate higher ROS levels. These changes are associated with corresponding changes in both energy metabolism and oxygen consumption. We will elucidate the mechanisms whereby Akt activity regulates intracellular ROS abundance and the role of Akt in the regulation of cellular senescence. At the organism level, we will determine whether partial ablation of Akt activity caused by the loss of individual isoforms, alone or in combination, is sufficient to extend normal lifespan and confer resistance to oxidative stress in the mouse.