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. 项目概要 繁殖时的高龄母亲会降低一系列物种的后代寿命和健康状况， 然而，控制母亲年龄对人类影响的机制尚不清楚。 线粒体随着年龄的增长容易受到损伤和功能障碍，并且是母系遗传的，这表明它们可能 我们的工作表明，母亲对后代健康的代际影响发挥着重要作用。 母亲的寿命较短、繁殖能力较低、健康状况较差，而且行为方式也与年轻人相比。 我们发现这些变化与每个细胞更高的线粒体DNA、更多的线粒体有关， 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， 我们的研究结果和有关衰老过程中线粒体的文献导致了活性氧（ROS）水平的改变。 我们的假设是，高龄产妇的线粒体功能障碍会导致功能失调的积累 后代中的线粒体通过代偿性生物发生和发育过程中自噬的减少来实现。 扰乱后代线粒体功能和线粒体-核通讯，导致加速 该项目的目的是了解母体衰老的线粒体机制。 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。 触发母亲年龄效应；(2) 确定导致 mtDNA 积累的发育机制和 年老母亲后代线粒体受损；(3) 确定所涉及的后代线粒体机制 母亲年龄的负面影响，并确定这些机制是否依赖于 ROS。 使用 qPCR 和 RNA-Seq 来量化 mtDNA 并控制代谢、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 我们将使用生物化学、呼吸测量法来操纵母体和后代线粒体来测试机制。 和成像方法来测量线粒体效率其他生化和成像方法。 将用于量化 ROS 和细胞损伤。我们将使用生命实验来测量寿命和细胞损伤。 生殖对母亲年龄或机制测试的影响将针对女性和男性后代进行。 我们的研究系统是轮虫 Brachionus manjavacas——一种短命的水生微生物无脊椎动物， 作为研究母亲年龄影响的模型的独特优势我们的方法将识别细胞。 高龄产妇导致 mtDNA 积累和线粒体受损的机制 后代；改变后代线粒体动力学、结构和功能并降低后代适应性。 这项研究取得成功，将通过揭示后代加速衰老的驱动因素来推动该领域的发展 母亲年龄的影响，并通过确定个体之间的原因知之甚少的机制 我们的研究结果将对理解与年龄相关的变化产生影响。 女性生育力和确定治疗年龄相关功能障碍的潜在目标。