Project 3: Developmental programming-aging interactions in primate metabolism

摘要 随着人类年龄的增长，影响营养利用和储存的变化往往会导致健康并发症，导致 肥胖、糖尿病(DM)、心血管疾病(CVD)和肝脏并发症。这些健康 当个体暴露于母亲肥胖(MO)时，并发症更突出，发病更早 或在胎儿自身发育过程中营养减少，导致胎儿宫内生长受限(IUGR)。这个 狒狒是一种具有良好特性的非人灵长类动物(NHP)模型，用于研究人类血脂异常和其他 代谢异常，如胰岛素抵抗和糖尿病。与年龄相关的合并症在狒狒身上发展为 在人类身上。我们培育出了一种独特的群体正常生活史(NLC)，IUGR和MO狒狒。我们的 科学前提是：1。衰老相关的代谢变化可以在生命早期被察觉。2.互动 发育规划和衰老是新陈代谢控制和能量的主要决定因素 管理层。3.规范数据和干预措施产生的成果，涉及方案拟订和 NHP模型中的衰老对于将研究结果转换到人类以开发治疗方法是必不可少的 延长健康范围。我们假设：特征分子信号可以预测新陈代谢 围产期计划(MO、IUGR和皮质醇替代干预(CRI))引起的变化 加速与年龄相关的代谢并发症。我们有三个目标来解决这个假设：目标1： 从青壮年到中年(6-148岁；人类)狒狒的NLC老化特征 相当于18-90岁)。我们将使用集成的基因组学方法与细胞和生理 量化肝脏、骨骼肌和血液中与衰老相关的正常变化的测量。目标2： 确定宫内压力如何影响新陈代谢衰老。我们将测量目标1中描述的参数 在IUGR和MO狒狒身上。目标3：确定CRI是否改变了代谢变化的轨迹 随着年龄增长而发生。我们将用皮质醇对NLC狒狒进行为期4年的治疗，以确定CRI是否导致 与年龄相关的代谢功能障碍。项目3与我们的研究结果和其他机构的整合是协同的 系统(项目1-大脑；项目2-心脏和血管)，以实现U19的目标，得出一个全面的 使用我们独特的狒狒模型开发和预测与年龄相关的健康并发症的模型， 确定可预测的分子特征，并探索延缓代谢衰老的干预措施。项目3是 通过将代谢挑战、生理测量和细胞生物能量学与 综合组学分析构建在正常衰老过程中发生变化的详细分子网络 代谢组织，并受到宫内应激和皮质醇替代干预的影响。

ABSTRACT As humans age, changes affecting nutrient utilization and storage often result in health complications, leading to obesity, diabetes mellitus (DM), cardiovascular disease (CVD) and hepatic complications. These health complications are more prominent with earlier onset when individuals were exposed to maternal obesity (MO) or reduced nutrients during their own fetal development resulting in intra-uterine growth restriction (IUGR). The baboon is a well-characterized nonhuman primate (NHP) model to study human dyslipidemia and other metabolic abnormalities such as insulin resistance and DM. Age-related co-morbidities develop in baboons as in humans. We have developed a unique colony normal life course (NLC), IUGR and MO baboons. Our scientific premises are: 1. Aging-related metabolic changes can be detected early in life. 2. Interactions between developmental programming and aging are major determinants of metabolic control and energy management. 3. Normative data and results from interventions addressing mechanisms of programming and aging in NHP models are essential for translation of research findings to humans to develop therapies to extend health span. We hypothesize that: Characteristic molecular signatures are predictive of metabolic changes caused by perinatal programming (MO, IUGR, and cortisol replacement intervention (CRI) accelerates age-related metabolic complications. We have 3 aims to address this hypothesis: Aim 1: Characterize NLC aging in baboons ranging from young adult to middle-age adult (6-148 years; human equivalent 18-90 years). We will use integrated omic approaches with cellular and physiological measurements to quantify normal aging-related changes in liver, skeletal muscle, and blood. Aim 2: Determine how in utero stresses impact metabolic aging. We will measure parameters described in Aim 1 in IUGR and MO baboons. Aim 3: Determine whether CRI alters the trajectory of metabolic changes that occur with age. We will administer cortisol to NLC baboons for 4 years to determine whether CRI results in age-related metabolic dysfunction. Project 3 is synergistic with integration of our findings and other organ systems (Project 1 – brain; Project 2 – heart and vessels) towards the U19 goal of deriving a comprehensive model for development and prediction of age-related health complications using our unique baboon models, identify predictive molecular signatures, and explore interventions to delay metabolic aging. Project 3 is innovative by integrating metabolic challenges, physiological measures, and cell bioenergetics with comprehensive omic analyses to construct detailed molecular networks that change in normal aging in metabolic tissues and are impacted by in utero stress and cortisol replacement intervention.