Mitochondrial mechanisms of maternal age effects on offspring health and lifespan

母亲年龄影响后代健康和寿命的线粒体机制

• 批准号: 10418989
• 负责人: Kristin Gribble
• 金额: $ 34.75万
• 依托单位: MARINE BIOLOGICAL LABORATORY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10418989
• 关键词: Age; Aging; Animals; Area; Autophagocytosis; Behavior; Biochemical; Biogenesis; Biological Models; Caring; Cells; Communication; Complex; Development; Disease; Embryo; Embryonic Development; Etiology; Female; Fertility; Functional disorder; Gene Expression; Genes; Health; Homeostasis; Human; Image; Incidence; Inherited; Invertebrates; Investments; Literature; Longevity; Maternal Age; Measures; Metabolic; Metabolism; Microscopic; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Mothers; Nerve Degeneration; Nuclear; Outcome; Oxidation-Reduction; Oxidative Phosphorylation; Pharmacologic Substance; Pharmacology; Phenotype; Play; Population; Production; Public Health; RNA Interference; Reactive Oxygen Species; Reproduction; Research; Resistance; Role; Signal Transduction; Source; Stress; Structure; System; Testing; Time; Work; advanced maternal age; age effect; age related; aged; cell injury; cell motility; comparative; early onset; experimental study; female fertility; fitness; healthspan; imaging approach; improved; innovation; inter-individual variation; intergenerational; male; mitochondrial dysfunction; mitochondrial metabolism; negative affect; offspring; postnatal; reproductive; response; targeted treatment; transcriptome sequencing; young mother

7. PROJECT SUMMARY Advanced maternal age at the time of reproduction decreases offspring lifespan and health in a range of species, including humans. The mechanisms controlling maternal age effects on offspring are unknown, however. Mitochondria are prone to damage and dysfunction with age and are maternally inherited, suggesting they may play a role in intergenerational maternal effects on offspring health. Our work shows that offspring from older mothers have shorter lifespan, lower reproduction, decreased health, and altered behavior relative to young- mother offspring. We found that these changes are associated with higher mtDNA per cell, more mitochondria, larger mitochondria, decreased mitochondrial intermembrane area, lower oxidative potential, lower ATP content, and altered reactive oxygen species (ROS) levels. Our results and the literature on mitochondria in aging led to our hypothesis that mitochondrial dysfunction in advanced maternal age causes accumulation of dysfunctional mitochondria in offspring through compensatory biogenesis and decreased autophagy during development. This disrupts offspring mitochondrial function and mitochondrial-nuclear communication, leading to accelerated offspring aging. The objective of this project is to understand the mitochondrial mechanisms by which maternal age determines offspring aging. In this study, we will: (1) identify the maternal mitochondrial mechanisms that trigger maternal age effects; (2) identify the developmental mechanisms causing accumulation of mtDNA and damaged mitochondria in old-mother offspring; and (3) identify the offspring mitochondrial mechanisms involved in negative maternal age effects and determine if these mechanisms are ROS-dependent. This work will be accomplished using qPCR and RNA-Seq to quantify mtDNA and controls on metabolism, signaling, and dynamics; imaging to quantify mitochondrial ultrastructure and mitophagy, and pharmacological and RNAi manipulation of maternal and offspring mitochondria to test mechanisms. We will use biochemical, respirometry, and imaging approaches to measure mitochondrial efficiency. Additional biochemical and imaging approaches will be used to quantify ROS and cellular damage. We will use lifetable experiments to measure lifespan and reproduction in response to maternal age or mechanistic tests. Studies will be on both female and male offspring. Our study system is the rotifer Brachionus manjavacas—a short-lived, aquatic, microscopic invertebrate with unique advantages as a model for investigating maternal age effects. Our approach will identify the cellular mechanisms by which advanced maternal age causes accumulation of mtDNA and damaged mitochondria in offspring; changes offspring mitochondrial dynamics, structure, and function; and decreases offspring fitness. If successful, this research will advance the field by revealing drivers of accelerated aging in offspring due to maternal age effects and by identifying mechanisms underlying a poorly understood cause of interindividual variability in healthspan and lifespan. Our findings will have implications for understanding age-related changes in female fertility and for identifying potential targets for treatment of age-related dysfunction.

7。项目摘要 繁殖时的高级遗产年龄在一系列物种中下降后代的寿命和健康， 包括人类。但是，控制母校年龄对后代的影响的机制尚不清楚。 线粒体容易随着年龄的增长而造成伤害和功能障碍，并且主要是遗传的，这表明它们可能 在代际母校对后代健康的影响中发挥作用。我们的工作表明，年龄较大的后代 母亲的寿命较短，繁殖降低，健康状况降低和相对于年轻人的行为改变 母亲后代。我们发现这些变化与每个细胞较高的mtDNA有关，线粒体更多， 较大的线粒体，改善了线粒体膜间面积，较低的氧化潜力，较低的ATP含量， 并改变活性氧（ROS）水平。我们的结果和关于衰老中线粒体的文献导致 我们的假设是，高级产妇年龄的线粒体功能障碍会导致功能失调的积累 通过补偿生物发生和开发过程中的自噬改善了后代的线粒体。这 破坏后代线粒体功能和线粒体核交流，导致加速 后代衰老。该项目的目的是了解母体的线粒体机制 年龄决定后代衰老。在这项研究中，我们将：（1）确定母体线粒体机制 触发母校的年龄影响； （2）确定导致mtDNA加速的发展机制 老母子后代的线粒体受损； （3）确定涉及的后代线粒体机制 在负生物年龄效应中，并确定这些机制是否依赖于ROS。这项工作将是 使用QPCR和RNA-Seq量化MTDNA并对其进行代谢，信号传导和对照 动力学;成像以量化线粒体超微结构和线粒体，以及药物和RNAi 操纵母体和后代线粒体以测试机制。我们将使用生化，呼吸法， 以及测量线粒体效率的成像方法。其他生化和成像方法 将用于量化ROS和细胞损伤。我们将使用寿命实验来测量寿命和 响应产妇年龄或机械测试的繁殖。研究将对男性和男性后代进行。 我们的研究系统是Rotifer Brachionus manjavacas，一种短暂的，水生的，微观的无脊椎动物， 独特的优势作为研究母校年龄效应的模型。我们的方法将识别细胞 高级产妇年龄会导致mtDNA积累和线粒体损坏的机制 后代；改变后代线粒体动力学，结构和功能；并降低后代健身。如果 成功的这项研究将通过揭示由于 孕产妇的年龄影响并通过识别个人间个体原因的基本机制 健康范围和寿命的可变性。我们的发现将对了解与年龄相关的变化有影响 在女性生育能力和确定与年龄相关功能障碍的潜在靶标。