Mitochondrial biogenesis, genetics and cell loss in mammalian aging

哺乳动物衰老过程中的线粒体生物发生、遗传学和细胞损失

基本信息

批准号：
9285634
负责人：
JUDD M. AIKEN
金额：
$ 39.23万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9285634
关键词：
5&apos -AMP-activated protein kinase Adult Affect Age Age-Years Aging Agonist American Animals Apoptosis Atrophic Bezafibrate Biogenesis Caloric Restriction Cell Death Cells Cessation of life Chronic Creatine Data Deletion Mutation Dominant-Negative Mutation Electron Transport Etiology Event Fiber Frequencies Gene Expression Genes Genetic Genome Human Individual Intervention Length Link Longevity Measurement Measures Metformin Mitochondria Mitochondrial DNA Molecular Morphology Muscle Muscle Cells Muscle Fibers Muscle function Muscular Atrophy Mutation Necrosis Outcome Pathway interactions Peroxisome Proliferator-Activated Receptors Pharmacology Protein Kinase Public Health RNA Interference Rattus Replication Error Role Skeletal Muscle Specific qualifier value Structure Testing Time Tissues Up-Regulation aged analog base dosage frailty guanidinopropionic acid loss of function mitochondrial DNA mutation mitochondrial genome muscle aging mutant pleiotropism prevent quadriceps muscle rosiglitazone transcription factor translation factor treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Mitochondrial biogenesis is a target of many aging interventions. While the induction of mitochondrial biogenesis is generally thought to be beneficial, our data indicate that activating mitochondrial biogenesis at old age drives the intracellular accumulation of mitochondrial DNA (mtDNA) deletion mutations and results in an 18% loss of muscle fibers and a 1,200% increase in electron transport chain (ETC) deficient muscle fiber segments. These effects were antagonistically pleiotropic; they were not observed in treated young rats. Based on our data, up-regulation of mitochondrial biogenesis in aged humans may cause significant skeletal muscle damage. These studies will clarify the role of mitochondrial biogenesis in mtDNA deletion mutation accumulation and evaluate the old-age specific effects of compounds that stimulate mitochondrial biogenesis in skeletal muscle. Project outcomes: · Specify the cellular pathways and ages at which inducing mitochondrial biogenesis increases mtDNA deletion mutation frequency, ETC deficiencies and fiber loss. · Infer the causality of mitochondrial biogenesis in fiber loss by specifying the order of events and time required between mitochondrial biogenesis, mtDNA deletion mutation accumulation and cell death. · Determine whether other AMPK or peroxisome proliferator-activated receptor agonists, which target mitochondrial biogenesis, also induce deletion mutation accumulation and cell death when initiated at old ages. · Downregulate mitochondrial biogenesis in old rats to prevent ETC deficiencies and fiber loss. By understanding the mechanisms and impacts of inducing mitochondrial biogenesis at old ages, we will specify targets and treatment strategies that mitigate the antagonistic effects.

项目概要/摘要线粒体生物发生是许多衰老干预措施的目标。生物发生通常被认为是有益的，我们的数据表明，激活线粒体生物发生衰老会导致细胞内线粒体 DNA (mtDNA) 缺失突变的积累，并导致肌纤维损失 18%，电子传递链 (ETC) 缺陷肌纤维增加 1,200% 这些作用是拮抗的多效性；在治疗的年轻大鼠中没有观察到这些作用。根据我们的数据，老年人线粒体生物发生的上调可能会导致骨骼肌显着增加这些研究将阐明线粒体生物发生在 mtDNA 缺失突变中的作用。积累并评估刺激线粒体生物发生的化合物的老年特异性效应在骨骼肌中。项目成果： · 明确诱导线粒体生物发生增加 mtDNA 的细胞途径和年龄缺失突变频率、ETC 缺陷和纤维损失。 · 通过指定事件的顺序和时间来推断线粒体生物发生与纤维损失的因果关系线粒体生物发生、mtDNA 缺失突变积累和细胞死亡之间所需的。 · 确定其他 AMPK 或过氧化物酶体增殖物激活受体激动剂是否靶向线粒体生物发生，在老年时启动时也会诱导缺失突变积累和细胞死亡年龄。 · 下调老年大鼠线粒体生物发生，以防止 ETC 缺乏和纤维损失。通过了解老年时诱导线粒体生物发生的机制和影响，我们将指定减轻拮抗作用的目标和治疗策略。