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 在一系列物种中，生育时高龄的母亲会降低后代的寿命和健康， 包括人类然而，控制母体年龄对后代影响的机制尚不清楚。 随着年龄的增长，线粒体容易受损和功能障碍，并且是母系遗传的，这表明它们可能 在代际母亲对后代健康的影响中发挥作用。我们的研究表明， 与年轻人相比，母亲的寿命更短，繁殖能力更低，健康状况更差，行为也会改变， 母亲的后代我们发现，这些变化与每个细胞的线粒体DNA含量更高，线粒体更多， 线粒体变大，线粒体膜间面积减少，氧化电位降低，ATP含量降低， 以及活性氧（ROS）水平的改变。我们的研究结果和关于衰老中线粒体的文献导致了 我们假设高龄产妇的线粒体功能障碍会导致功能障碍性的 线粒体在后代通过补偿性生物合成和减少自噬在发展过程中。这 破坏后代线粒体功能和细胞核通讯，导致加速 后代衰老本项目的目的是了解线粒体机制，通过该机制，孕产妇 年龄决定后代的衰老。在这项研究中，我们将：（1）确定母体线粒体机制， 触发母体年龄效应;（2）确定导致mtDNA积累的发育机制， 老年母亲后代中受损的线粒体;（3）确定涉及的后代线粒体机制 在负面的母亲年龄的影响，并确定这些机制是否是ROS依赖。这项工作将 使用qPCR和RNA-Seq来定量mtDNA和对代谢、信号传导和 动力学;成像以量化线粒体超微结构和线粒体自噬，以及药理学和RNAi 操纵母体和后代线粒体以测试机制。我们会用生化呼吸测定法， 和成像方法来测量线粒体效率。其他生物化学和成像方法 将用于量化ROS和细胞损伤。我们将使用寿命表实验来测量寿命， 生殖反应的母亲年龄或机械测试。将对雌性和雄性后代进行研究。 我们的研究系统是轮虫臂尾轮虫manjavacas-一种短命的，水生的，微观的无脊椎动物， 作为研究母体年龄效应的模型具有独特的优势。我们的方法将识别出 高龄产妇导致线粒体DNA积累和线粒体受损的机制， 改变后代的线粒体动力学、结构和功能;并降低后代的适应性。如果 成功，这项研究将通过揭示后代加速衰老的驱动因素来推进这一领域， 母亲年龄的影响，并通过确定机制的基础上，一个鲜为人知的原因，个体间 健康和寿命的可变性。我们的发现将对理解与年龄相关的变化产生影响 在女性生育力和确定治疗年龄相关功能障碍的潜在目标。