Circadian-Regulated Aging Physiologies

项目摘要 昼夜节律调节，或行为和生物功能的24小时振荡，是一个保守的特征， 存在于从植物到脊椎动物的各种生物体中的生物学。虽然一个广泛观察到的特征， 衰老是昼夜调节的丧失，昼夜调节过程是否是驱动衰老的主要因素 仍然未知。昼夜节律调节的丧失通常被认为是病理性的。在人类中， 昼夜节律调节与肥胖、糖尿病和感染的高发病率有关。在本提案中，我们 目前的证据从果蝇模型黑腹果蝇，一种特定类型的昼夜节律失调， 不是病理性的，而是延缓衰老，延长寿命。因为对果蝇的研究提供了 关于免疫和代谢等生物功能的昼夜节律调节的信息， 在脊椎动物中复制，果蝇是一个有用的模型系统。 核心生物钟由转录激活因子和转录抑制因子组成， 24-在单细胞和多细胞生物体中基因表达和生物功能的小时振荡。 我们发现果蝇中保守的转录抑制因子Timeless（Tim）或Period（Per）的缺失 通过独立于经典长寿途径（如胰岛素）的机制显著延长寿命 信号，但由于上调保守的代谢过程，称为线粒体解偶联， 解偶联蛋白UCP 4C在肠中的表达增加。我们的研究进一步表明， 降低ROS水平和抑制肠道中与年龄相关的干细胞扩增的衰老机制。 这些发现表明昼夜节律调节、线粒体代谢、干细胞 生物学和寿命。 在这个建议中，我们将在果蝇中使用强大的遗传和细胞生物学方法， 研究昼夜节律调节在细胞，组织， 具体和生物体水平。昼夜节律调节的高度保守性和这种基本的 细胞代谢方面，线粒体解偶联，提出了令人兴奋的可能性，这些机制 在脊椎动物中是保守的。我们将研究损失的机制， Per介导的昼夜节律调节和上调的线粒体解偶联导致寿命延长， 三种方法：1）我们将确定昼夜节律失调的细胞和分子机制 和线粒体解偶联，抑制年龄相关的肠干细胞扩增; 2）我们将确定 肠道中的线粒体解偶联是否会影响其他组织的衰老;以及3）我们将确定 功能窗口和其他组织特异性位置，其中昼夜节律失调和线粒体 解偶联延长生物体寿命。由于昼夜节律调节和衰老都是由进化调节的， 保守的分子机制，我们希望我们的工作将与人类健康有关。

PROJECT SUMMARY Circadian regulation, or 24-hour oscillations in behavior and biological function, is a conserved feature of biology that is present in diverse organisms from plants to vertebrates. While a widely-observed feature of aging is loss of circadian regulation, whether circadian-regulated processes are major factors that drive aging remains unknown. Loss of circadian regulation is typically thought to be pathological. In humans, loss of circadian regulation is associated with higher rates of obesity, diabetes, and infection. In this proposal, we present evidence from the fly model Drosophila melanogaster that a specific type of circadian dysregulation is not pathological but delays aging and extends lifespan. Because studies in Drosophila have provided crucial information about circadian regulation of biological functions such as immunity and metabolism, findings that have been replicated in vertebrates, Drosophila is well established as a useful model system. The core circadian clock consists of transcriptional activators and transcriptional inhibitors that cause 24-hour oscillations in gene expression and biological functions in both single cells and multicellular organisms. We found that loss of the conserved transcriptional inhibitors Timeless (Tim) or Period (Per) in Drosophila significantly extends lifespan by a mechanism independent of canonical longevity pathways such as insulin signaling, but due to upregulation of a conserved metabolic process called mitochondrial uncoupling via increased expression of the uncoupling protein UCP4C in the intestine. Our studies further implicate an anti- aging mechanism of lowering ROS levels and suppressing age-related stem cell expansion in the intestine. These findings suggest novel connections between circadian regulation, mitochondrial metabolism, stem cell biology, and lifespan. In this proposal, we will use the powerful genetic and cell biological methods in Drosophila to investigate the mechanisms by which circadian regulation modulates animal lifespan on the cellular, tissue- specific, and organism levels. The highly-conserved nature of both circadian regulation and this fundamental aspect of cellular metabolism, mitochondrial uncoupling, raise the exciting possibility that these mechanisms underlying lifespan extension are conserved in vertebrates. We will investigate the mechanisms by which loss of Per-mediated circadian regulation and upregulated mitochondrial uncoupling lead to lifespan extension in three ways: 1) we will determine the cellular and molecular mechanisms underlying circadian dysregulation and mitochondrial uncoupling that suppress age-related intestinal stem cell expansion; 2) we will determine whether mitochondrial uncoupling in the gut impacts the aging of other tissues; and 3) we will determine the functional window and other tissue-specific locations in which circadian dysregulation and mitochondrial uncoupling extend organism lifespan. As both circadian regulation and aging are regulated by evolutionarily conserved molecular mechanisms, we expect our work will have relevance for human health.