Role of Mitochondrial Homeostasis in Animal Aging

项目摘要 线粒体功能障碍长期以来与衰老和许多年龄发病性疾病有关。 因此，确定可以应用于老年动物以改善线粒体稳态的干预措施， 对于延长健康寿命的目标是非常可取的。线粒体自噬（mitochondrial autophagy） 一种自噬质量控制机制，可以去除功能失调的线粒体。最近，我们发现 Parkin是一种E3泛素连接酶，其功能是促进线粒体自噬， 果蝇衰老最近的证据表明，帕金与线粒体分裂/融合相互作用， 机械介导功能失调的线粒体的周转。事实上，我们已经证明， 帕金效应与线粒体动力学向增加的裂变的转变有关。此外，委员会认为， 我们现在已经发现，上调Drp 1，一种与发动蛋白相关的蛋白， 裂变，在中年的一段有限的时间内，足以延长寿命和健康。而且我们 显示了果蝇p62（一种据报道介导线粒体自噬自噬衔接子）在中年时的上调 也减缓了生物体的衰老在描述衰老过程中线粒体动力学的变化时，我们发现， 向线粒体融合的中年转变与功能失调的线粒体的积累有关。 值得注意的是，我们已经发现，在中年时，短期诱导Drp 1， 形态和功能恢复到年轻状态。 近年来，已经确定了一些增加哺乳动物寿命的药物。然而，在这方面， 任何药物的长期治疗都可能导致有害的副作用。因此，有利的是 确定介导抗衰老作用的细胞机制和/或确定 可以引起这些细胞变化。在这里，我们表明，喂养假定的抗衰老药物二甲双胍， 有限的时间段，激活Drp 1和诱导体内线粒体分裂。 在这里，我们建议通过探索三个具体目标来建立这些突破性的发现： 1)为了研究中年转向线粒体分裂促进健康的机制， 2）研究中年诱导p62促进健康衰老的机制，3） 研究包括二甲双胍在内的进化上保守的抗衰老干预措施之间的关系， 线粒体动力学和线粒体自噬。 本文提出的工作将为分子和细胞机制提供基本的见解 衰老的迹象同时，我们的研究可能提供新的治疗方法，可以应用于 在中年至晚年的有限时间内，延缓衰老和相关疾病的发生和发展。

Project Summary Mitochondrial dysfunction has long been implicated in aging and numerous age-onset diseases. Therefore, identifying interventions that can be applied in aged animals to improve mitochondrial homeostasis would be highly desirable towards the goal of prolonging healthspan. Mitochondrial autophagy (mitophagy) is an autophagic quality control mechanism that removes dysfunctional mitochondria. Recently, we identified novel roles for Parkin, an E3 ubiquitin ligase that functions to promote mitophagy, in the modulation of Drosophila aging. Recent evidence indicates that Parkin interacts with the mitochondrial fission/fusion machinery to mediate the turnover of dysfunctional mitochondria. Indeed, we have shown that the anti-aging effects of Parkin are associated with a shift in mitochondrial dynamics towards increased fission. Moreover, we have now discovered that up-regulating Drp1, a Dynamin-related protein that catalyzes mitochondrial fission, for a limited period of time in mid-life is sufficient to prolong lifespan and healthspan. Furthermore, we show that up-regulation of Drosophila p62, an autophagy adaptor reported to mediate mitophagy, in mid-life also slows organismal aging. In characterizing alterations in mitochondrial dynamics during aging, we find that a mid-life shift towards mitochondrial fusion is linked to the accumulation of dysfunctional mitochondria. Remarkably, we have discovered that short-term induction of Drp1, in mid-life, restores mitochondrial morphology and function to a youthful state. In recent years, a number of drugs that increase lifespan in mammals have been identified. However, long-term treatment with any drug can cause deleterious side effects. Therefore, it would be advantageous to identify the cellular mechanisms that mediate the anti-aging effects and/or identify transient interventions that can induce these cellular changes. Here, we show that feeding the putative anti-aging drug metformin, for a limited period of time to aged flies, activates Drp1 and induces mitochondrial fission in vivo. Here, we propose to build upon these groundbreaking discoveries by exploring three specific aims: 1) To examine the mechanisms by which a mid-life shift towards mitochondrial fission promotes healthy aging, 2) To examine the mechanisms by which mid-life induction of p62 promotes healthy aging, and 3) To examine the relationships between evolutionarily conserved anti-aging interventions including metformin, mitochondrial dynamics and mitophagy. The work proposed herein will provide fundamental insights into the molecular and cellular mechanisms of aging. At the same time, our studies may provide new therapeutic approaches, that can be applied for a limited period of time in mid- to late-life, to delay the onset and progression of aging and associated diseases.