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: 9812866
• 负责人: Kristopher Burkewitz
• 金额: $ 24.9万
• 依托单位: VANDERBILT UNIVERSITY
• 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 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9812866
• 关键词: 5' -AMP-activated protein kinase; ATF6 gene; Address; Age; Age of Onset; Aging; Animals; Automobile Driving; Behavior; Biological; Biological Process; CREB1 gene; Caenorhabditis elegans; Cardiovascular Diseases; Cells; Cellular Metabolic Process; Cellular biology; Clinical; 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; Link; Longevity; Malignant Neoplasms; Mammalian Cell; Mediating; Mediator of activation protein; Membrane; Metabolic; Metabolism; Microscopy; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Morphology; Neurodegenerative Disorders; Nuclear; Onset of illness; Organelles; Osteoporosis; Output; Pathology; Pathway interactions; Patients; Phase; Physiology; Play; Protein Kinase; Proteins; Public Health; Regulation; Reproduction; Resolution; Risk Factors; Role; Shapes; Signal Transduction; Site; Stroke; System; Testing; Therapeutic; Training; Transcription Coactivator; Transgenic Organisms; Translating; age related; aged; design; detection of nutrient; differential expression; functional decline; gene therapy; healthy aging; improved; in vivo; in vivo monitoring; insight; lipid metabolism; metabolomics; mitochondrial metabolism; novel; prevent; proteostasis; response; sensor; side effect; targeted treatment; 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.

项目概要/摘要 老年性疾病包括癌症、神经退行性疾病、糖尿病、心血管疾病、中风、 骨质疏松症正在给公众健康带来负担，而且这种负担很快就会变得难以克服。加剧 这个问题，合并症在老年人中很常见。应对这一问题的理想治疗策略 危机的目标是统一危险因素，但患者年龄是所有这些疾病唯一共同的危险因素。 幸运的是，越来越清楚的是，衰老的生物过程是可塑的，因此衰老的速度和速度 老龄化质量可能会得到改善。遗传和营养干预导致实际或感知的能量- 耗竭是促进健康衰老的强大而保守的机制。不幸的是这些干预措施 例如分子低能传感器AMPK的激活，也会带来临床上不可接受的副作用，例如 由于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 足以实现健康老龄化的下游机制。通过 C 长寿的遗传模型。 通过激活 AMPK 在线虫中，我们证明能量消耗的负面副作用可以是 与健康老龄化的积极影响无关。使用公正的系统级方法，我们发现 长寿特异性机制涉及线粒体动力学的下游调节 代谢功能，我们现在证明线粒体动力学的调节是 AMPK 的因果关系 长寿。新数据表明，扰乱介导体内平衡的未折叠蛋白反应（UPR） 内质网 (ER) 的一部分，与 AMPK 通路相互作用，通过一种机制延长寿命 这也需要线粒体重塑。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，这些数据提出了一种新的范式 衰老：内质网/线粒体对寿命的调节是通过综合代谢机制实现的。身体的 线粒体网络的变化是衰老的标志，但细胞器动力学的机制如何 与长寿有关尚不清楚。通过基因灭活线粒体重塑的介质 （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 与低能量长寿有关。通过新颖的转基因技术和高分辨率显微镜训练 目标 2，我将检验以下假设：UPRER 扰动会促进线粒体形态的改变 细胞器之间的信号传递。最后在 R00 阶段，Aim 3 将建立在开发的工具和见解的基础上 目标 1 和 2 确定线虫中 ER 线粒体间细胞器的遗传机制 沟通可以直接延长健康寿命并保护代谢稳态。采取 总之，该提案的目标是确定进化上如何保守的能量传感途径 协调调节细胞器间信号传导和代谢功能以促进长寿。