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.项目总结 在一系列物种中，生育时较高的产妇年龄会降低后代的寿命和健康， 包括人类。然而，控制母亲年龄对后代影响的机制尚不清楚。 线粒体容易随着年龄的增长而受损和功能障碍，并且是母系遗传的，这表明它们可能 在代际母体对后代健康的影响中发挥作用。我们的研究表明，年长的后代 与年轻母亲相比，母亲的寿命更短，生育率更低，健康状况更差，行为也发生了变化。 母子。我们发现，这些变化与每个细胞线粒体DNA的增加，线粒体的增加， 线粒体变大，线粒体膜间面积减小，氧化电位降低，ATP含量降低， 并改变了活性氧(ROS)水平。我们的结果和关于线粒体衰老的文献导致了 我们的假设是，高龄产妇线粒体功能障碍会导致功能障碍的积累 线粒体在后代中的代偿生物发生和减少自噬在发育过程中。这 破坏后代线粒体功能和线粒体-核通讯，导致加速 后代衰老。该项目的目标是了解母体线粒体的机制 年龄决定后代的衰老。在本研究中，我们将：(1)确定母体线粒体的机制 触发母亲年龄效应；(2)确定导致线粒体DNA积累的发育机制和 老母亲后代的线粒体受损；以及(3)确定涉及的后代线粒体机制 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来量化mtDNA以及对新陈代谢、信号和 动力学；线粒体超微结构和有丝分裂定量的成像；药理学和RNAi 操纵母体和子代线粒体以测试机制。我们将使用生化，呼吸测定法， 以及测量线粒体效率的成像方法。其他生化和成像方法 将被用来量化ROS和细胞损伤。我们将使用寿命实验来测量寿命和 对母亲年龄或机械测试作出反应的生殖。研究将在雌性和雄性后代身上进行。 我们的研究系统是轮虫Brachionus Manjavacas-一种短暂的、水生的、微小的无脊椎动物， 作为研究母亲年龄影响的模型，它具有独特的优势。我们的方法将识别细胞 高龄孕妇线粒体DNA积聚和线粒体损伤的机制 后代；改变后代线粒体的动力学、结构和功能；并降低后代的适合度。如果 这项研究的成功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，以及通过确定个体间原因知之甚少的潜在机制 健康寿命和寿命的变异性。我们的发现将对理解与年龄相关的变化有所启示 在女性生育力方面，并确定治疗年龄相关功能障碍的潜在目标。