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.

项目摘要/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、 骨质疏松症正在产生一种公共卫生负担，这一负担正在迅速变得无法克服。加剧 这个问题，在老年人中是很常见的。面对这一问题的理想治疗策略 危机是针对一个统一的危险因素，但患者年龄是所有这些疾病共同的唯一危险因素。 幸运的是，越来越清楚的是，衰老的生物过程是可塑性的，因此， 老化质量可能会得到改善。基因和营养干预导致实际或感知的能量- 耗竭是促进更健康衰老的强大、保守的机制。不幸的是，这些干预， 例如激活分子低能量传感器AMPK，也会带来临床上不可接受的副作用，如 因为它抑制了免疫力和生育力。因此，将这些发现转化为治疗学需要确定 下游机制足以促进更健康的衰老。通过建立长寿的遗传模型。 通过激活AMPK，我们证明了能量耗竭的负面副作用可以是 脱钩对健康衰老的积极影响。使用不偏不倚的系统级方法，我们发现 长寿特有的机制涉及线粒体动力学的下游调节和 代谢功能，我们现在证明线粒体动力学的调节是AMPK的原因 长寿。新数据表明，干扰介导动态平衡的未折叠蛋白反应(UPR) 内质网(ER)，与AMPK途径相互作用，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内质网在物理上与 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 衰老：内质网/线粒体对长寿的调节是通过一种综合的代谢机制进行的。物理 线粒体网络的变化是衰老的标志，但细胞器动力学是如何机械地 与长寿有关的因素尚不清楚。通过基因失活线粒体重塑的介体 (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。通过新的转基因技术和高分辨率显微镜培训 目的2，我将检验UPRER扰动促进线粒体形态改变和 细胞器之间的信号。最后，在R00阶段，AIM 3将建立在 目的1和2鉴定线虫内质网-线粒体细胞器间的遗传机制 沟通可以直接针对延长健康寿命和保护代谢动态平衡。已被占用 总之，这项提议的目标是确定进化上如何保守的能量感应通路 协调调节细胞器间信号和代谢功能，促进长寿。