Project 3: Developmental programming-aging interactions in primate metabolism

摘要 随着人类年龄的增长，影响营养素利用和储存的变化往往会导致健康并发症， 肥胖、糖尿病（DM）、心血管疾病（CVD）和肝脏并发症。这些健康 当个体暴露于母体肥胖（MO）时，并发症更突出， 或在其自身胎儿发育期间营养减少，导致子宫内生长受限（IUGR）。的 狒狒是研究人类血脂异常和其他血脂异常的非人灵长类动物（NHP）模型， 代谢异常，如胰岛素抵抗和DM。狒狒会出现与乳腺癌相关的并发症， 在人类身上。我们已经开发了一个独特的群体正常生命过程（NLC），IUGR和MO狒狒。我们 科学前提是：1。衰老相关的代谢变化可以在生命早期发现。2.相互作用 是代谢控制和能量的主要决定因素 管理3.涉及方案拟订机制的干预措施的规范性数据和成果， NHP模型中的衰老对于将研究结果转化为人类以开发治疗方法至关重要， 延长健康寿命。我们假设：特征性的分子标记是代谢性疾病的预测因子。 围产期程序（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： 表征狒狒中的NLC老化，范围从青年到中年（6-148岁;人类 相当于18-90岁）。我们将使用整合的组学方法与细胞和生理 测量以量化肝脏、骨骼肌和血液中的正常衰老相关变化。目标二： 确定子宫内压力如何影响代谢老化。我们将测量目标1中描述的参数 在IUGR和MO狒狒中。目的3：确定CRI是否改变代谢变化的轨迹， 随着年龄的增长而发生。我们将对NLC狒狒给予皮质醇4年，以确定CRI是否会导致 与年龄相关的代谢功能障碍项目3是协同与整合我们的研究结果和其他机构 系统（项目1 -大脑;项目2 -心脏和血管），以实现U19的目标， 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， 识别预测性分子特征，并探索延缓代谢性衰老的干预措施。项目3是 通过整合代谢挑战，生理措施和细胞生物能量学， 全面的组学分析，以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，并受到子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.