Targeting mechanisms of inter-organelle communication to promote healthy aging

细胞器间通讯的靶向机制促进健康衰老

• 批准号: 9242811
• 负责人: Kristopher Burkewitz
• 金额: $ 12.78万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242811
• 关键词: 5' -AMP-activated protein kinase; Address; Adverse effects; Age; Age of Onset; Aging; Animals; Automobile Driving; Behavior; Biological; Biological Process; CREB1 gene; Caenorhabditis elegans; Cardiovascular Diseases; Cells; Cellular Metabolic Process; Cellular biology; Communication; Comorbidity; Coupled; Data; Defect; Diabetes Mellitus; Dietary Intervention; Disease; Elderly; Endoplasmic Reticulum; Fertility; Gene Expression; Genes; Genetic; Genetic Models; Goals; Growth; Health; Homeostasis; Immunity; Individual; Intervention; Knowledge; Life; Link; Longevity; Malignant Neoplasms; Mammalian Cell; Mediating; Mediator of activation protein; Membrane; Metabolic; Metabolism; Microscopy; Mitochondria; Modeling; Molecular; Monitor; Morbidity - disease rate; Morphology; Neurodegenerative Disorders; Nuclear; Organelles; Osteoporosis; Output; Pathology; Pathway interactions; Patients; Phase; Physiology; Play; Proteins; Public Health; Regulation; Reproduction; Resolution; Risk Factors; Role; Shapes; Signal Transduction; Site; Stroke; System; Testing; Therapeutic; Training; Transcription Coactivator; Transgenic Organisms; Translating; abstracting; age related; aged; design; detection of nutrient; differential expression; functional decline; gene therapy; healthy aging; improved; in vivo; insight; lipid metabolism; metabolomics; mitochondrial metabolism; novel; prevent; response; sensor; therapeutic development; tool; transcription factor

Project Summary/Abstract Age-onset diseases including cancer, neurodegenerative disease, diabetes, cardiovascular disease, stroke, and osteoporosis are generating a public health burden that is quickly becoming insurmountable. Exacerbating this problem, co-morbidities are common among the elderly. The ideal therapeutic strategy to confront this crisis is to target a unifying risk factor, but patient age is the only risk factor common to all these diseases. Fortunately, it is increasingly clear that the biological processes of aging are malleable, thus the rate and quality of aging may be improved. Genetic and nutritional interventions causing real or perceived energy- depletion are robust, conserved mechanisms to promote healthier aging. Unfortunately these interventions, e.g. activation of the molecular low-energy sensor AMPK, also carry clinically unacceptable side effects, such as suppressed immunity and fertility. Translating these findings into therapeutics thus requires identification of downstream mechanisms that are sufficient for healthier aging. Through a genetic model of longevity in C. elegans via activation of AMPK, we demonstrated that the negative side-effects of energy-depletion can be uncoupled from the positive effects on healthy aging. Using unbiased, systems-level approaches, we found that the longevity-specific mechanism involves downstream regulation of mitochondrial dynamics and metabolic functions, and we now demonstrate that regulation of mitochondrial dynamics is causal to AMPK longevity. New data indicate that perturbing the unfolded protein response (UPR), which mediates homeostasis of the endoplasmic reticulum (ER), interacts with the AMPK pathway to extend lifespan through a mechanism that also requires mitochondrial remodeling. Given recent studies showing that the ER physically interacts with mitochondria to regulate organelle morphology and metabolic signaling, these data suggest a new paradigm in aging: ER/mitochondrial regulation of longevity occurs through an integrated metabolic mechanism. Physical changes in mitochondrial networks are a hallmark of aging, but how organelle dynamics are mechanistically involved in longevity is unknown. By genetically inactivating mediators of mitochondrial remodeling (fission/fusion), Aim 1 will define how mitochondrial dynamics drive the changes in mitochondrial metabolism associated with low-energy longevity. Through novel transgenics and training in high-resolution microscopy in Aim 2, I will test the hypothesis that UPRER perturbations promote altered mitochondrial morphology and signaling between organelles. Finally in the R00 phase, Aim 3 will build on the tools and insights developed in Aims 1 and 2 to identify genetic mechanisms in C. elegans by which ER-mitochondrial inter-organelle communication can be directly targeted to extend healthy lifespan and protect metabolic homeostasis. Taken together, the goal of this proposal is to identify how evolutionarily conserved energy-sensing pathways coordinately modulate inter-organelle signaling and metabolic function to promote longevity.

项目总结/摘要 包括癌症、神经退行性疾病、糖尿病、心血管疾病、中风、 和骨质疏松症正在产生一种公共卫生负担，这种负担正迅速变得难以克服。加剧 这个问题，合并症在老年人中很常见。面对这种情况的理想治疗策略 危机是针对一个统一的风险因素，但病人的年龄是唯一共同的风险因素，所有这些疾病。 幸运的是，越来越清楚的是，衰老的生物过程是可塑性的，因此， 可以改善老化的质量。遗传和营养干预导致真实的或感知的能量- 消耗是促进更健康衰老的稳健、保守的机制。不幸的是，这些干预措施， 例如分子低能传感器AMPK的激活也带来临床上不可接受的副作用，例如 免疫力和生育能力受到抑制因此，将这些发现转化为治疗方法需要确定 这些下游机制足以让老年人更健康。通过C. 通过激活AMPK，我们证明了能量消耗的负面副作用可以被 与健康老龄化的积极影响脱钩。使用无偏的系统级方法，我们发现 长寿特异性机制涉及线粒体动力学的下游调节， 我们现在证明线粒体动力学的调节是AMPK的因果关系， 中心blog新的数据表明，干扰介导体内平衡的未折叠蛋白反应（UPR） 与AMPK通路相互作用，通过一种机制延长寿命。 也需要线粒体重塑鉴于最近的研究表明，ER与 线粒体调节细胞器形态和代谢信号，这些数据表明了一种新的范式， 衰老：ER/线粒体对寿命的调节是通过一个综合的代谢机制发生的。物理 线粒体网络的变化是衰老的标志，但细胞器动力学如何在机械上 与长寿有关的因素是未知的。通过基因失活线粒体重塑介质 （裂变/融合），目标1将定义线粒体动力学如何驱动线粒体代谢的变化 与低能量寿命有关。通过新的转基因技术和高分辨率显微镜的培训， 目的2，我将检验UPRER扰动促进线粒体形态改变的假设， 细胞器之间的信号传递最后，在R 00阶段，Aim 3将建立在 目的1和2是为了确定C.通过内质网-线粒体间细胞器 交流可以直接针对延长健康寿命和保护代谢稳态。采取 总之，这个提议的目标是确定进化上保守的能量感应途径是如何 协调调节细胞器间信号传导和代谢功能以促进长寿。