Womb to Tomb: Developmental Programming and Aging Interactions in Primates

摘要 具体目标/意义。在我们充分表征的狒狒非人灵长类动物（NHP）模型中， 发展规划和老龄化，我们使用分类组和纵向，生命过程的方法 评估交互式编程老化机制。发展规划可以定义为 在关键发育时间窗口中对挑战的反应，改变生命过程表型。 前提/假设。1.衰老的前因存在于大脑的早期-下丘脑-垂体- 肾上腺（HHPA）轴（HHPAA），大脑和行为;心血管系统（CVS）;和代谢。2. 编程-老化相互作用是生命过程HHPA、大脑、行为、CVS和 代谢健康跨度。3.比较规范性、生命过程观察性对照数据与来自三个 改变衰老轨迹的干预措施提供了对关键衰老机制和细胞途径的见解， 翻译成人类所需的信息，以预测与年龄相关的机制， 降低健康寿命。研究结果使人类衰老的标志物和有益的干预措施的发展成为可能。 项目- 1. HHPAA，大脑和行为。2：CVS功能。3：新陈代谢。核心- A：管理; B： 动物; C：基因组学; D：MRI; E：样本和数据管理。Synergy：所有组件研究全部96 动物体内MRI和系绳研究和体外组织学，细胞培养和分子方法。我们 研究分为4组的96只狒狒，6-17岁（相当于人类约18- 68岁; 24- 68岁）时的雄性和雌性相等。 68%的生命周期）。组：1. 48例正常生命过程对照（NLC）; 2. 16个IUGR后代（F1）， 中度营养不良的母亲; 3. 16 F1肥胖，营养过剩的母亲; 4。在16在12- 17我们钳 血浆皮质醇恢复到正常水平。比较NLC和干预措施的衰老机制， 生命过程的信息，整个动物和细胞机制修改编程老化的相互作用。 新的初步数据。我们提出了新的证据，增加皮质醇和加速大脑，CVS， IUGR中的代谢老化。对PAR-16-143复杂集成多组件项目的响应 老龄化研究（U19）。我们解决了要求“大规模纵向观察研究. 多种结果与分子，遗传，机械数据和干预.动物模型老化- 相关的条件.多个端点来阐明机制。调查人员来自多个机构 并在老龄化研究和规划以及完成大型NIH P01 R24 P51我们在全球范围内共享资源。创新生命过程NHP研究是罕见的。我们 为这些研究建立了我们自己的定制设施。我们现在1.进行活检不 安乐死，使得能够在这些群组上进一步应用; 2.将联合收割机U19体内和体外数据与 组织学和分子学数据来自我们广泛的胎儿（130个胎儿）和出生后档案（120个成人出生 到25岁）来产生一个新的从子宫到坟墓的机械编程和衰老框架。

ABSTRACT Specific aims/significance. In our well-characterized baboon nonhuman primate (NHP) models of developmental programming and aging we use both categorical group and longitudinal, life course approaches to evaluate interactive programming-aging mechanisms. Developmental programming can be defined as responses to challenges in critical developmental time windows that alter life course phenotype. Premises/hypotheses. 1. Aging antecedents are present early in the hippocampal-hypothalamo-pituitary- adrenal (HHPA) axis (HHPAA), brain, and behavior; cardiovascular system (CVS); and metabolism. 2. Programming-aging interactions are major determinants of life course HHPA, brain, behavior, CVS, and metabolic health span. 3. Comparing normative, life course observational control data with data from three interventions that alter aging trajectory provides insights into key aging mechanisms and cellular pathways and information needed for translation to humans to anticipate age-related mechanisms that either increase or decrease health span. Findings enable development of markers and beneficial interventions in human aging. Projects - 1. HHPAA, Brain, and Behavior. 2: CVS Function. 3: Metabolism. Cores - A: Administrative; B: Animal; C: Genomics; D: MRI; E: Samples and Data Management. Synergy: All components study all 96 animals with in vivo MRI and tether studies and in vitro histological, cell culture, and molecular approaches. We study 96 baboons in 4 groups, equal males and females at 6–17 years (y) (human equivalent ~18–68y; 24– 68% of the life course). Groups: 1. 48 normal life course controls (NLC); 2. 16 IUGR offspring (F1) of moderately undernourished mothers; 3. 16 F1 of obese, over-nourished mothers; 4. In 16 at 12–17y we clamp plasma cortisol to normal 5y levels. Comparison of aging mechanisms in NLC and interventions provides information on life course whole animal and cellular mechanisms modified by programming-aging interactions. New preliminary data. We present new evidence of increased cortisol and accelerated brain, CVS, and metabolic aging in IUGR. Responsiveness to PAR-16-143 Complex Integrated Multi-Component Projects in Aging Research (U19). We address requested “Large-scale longitudinal observational studies… integration of multiple outcomes with molecular, genetic, mechanistic data and interventions… animal models for aging- related conditions… multiple endpoints to elucidate mechanisms.” Investigators are from multiple institutions and have worked and published together in aging research and programming and in completing large NIH P01s, R24s, P51s. We share resources worldwide. Innovation. Life course NHP studies are rare. We assembled unique cohorts and built our own custom facility for these studies. We now 1. perform biopsies not euthanasia, enabling further applications on these cohorts; 2. combine U19 in vivo and in vitro data with histological and molecular data from our extensive fetal (130 fetuses) and postnatal archives (120 adults birth to 25y) to produce a new mechanistic programming and aging framework from womb to tomb.