Diverse effects of somatopause and aging on the skeleton

摘要： 到目前为止，与年龄相关的骨骼变化被认为是由两种截然不同的和 潜在的协同作用原因：i)全身激素变化，特别是躯体更年期， 生长激素[GH]及其介体胰岛素样生长的年龄相关性下降 因子-1[IGF-1]和II)骨细胞活性的“固有”累积或暂时变化 组织属性。这些过程是相伴和重叠的，它们各自不同 对与年龄相关的骨丢失的影响尚未确定。我们已经开发出一种 从分子到骨骼的综合方法研究新的调控机制 老化过程中的骨骼完整性。我们建立在两国之间长期合作的基础上。 Schaffler博士，骨细胞和骨生物力学专家，以及Yakar博士， GH/IGF-1生理学，以及与巴甫洛夫博士的新合作，巴甫洛夫博士是 线粒体。我们专注于骨细胞，它占骨细胞的95%，是 非常长寿。骨细胞整合了骨骼的荷尔蒙和机械 环境，产生启动成骨细胞和破骨细胞的关键信号，还 直接影响骨材料的性能。在这项提案中，我们将研究 促生长轴对衰老骨细胞活性和功能的影响 目的如下：1)确定GH/IGF-1影响的细胞机制 骨组织质量；2)确定GH/IGF-1轴控制骨细胞活性的方式 和衰老过程中的代谢灵活性。我们的研究将衰老的三个特征联系在一起 “细胞间通讯改变”，这是组织完整性的核心，“线粒体” “功能障碍”，这是细胞生存的核心，以及“放松营养感应”，这是 细胞代谢的中枢。我们期待着解开截然不同和重叠的影响 正常衰老和更年期，特别是对骨骼健康的影响。完成我们的学业 将决定GH/IGF-1的形态和分子机制 AXIS影响老化骨骼的骨细胞。

ABSTRACT: To date age-related changes in bone are thought to result from two distinct and potentially synergistic causes: i) systemic hormonal changes, particularly somatopause, the age-related declines in growth hormone [GH] and its mediator insulin-like growth factor-1 [IGF-1] and ii) “intrinsic” cumulative or temporal changes in bone cell activity and tissue properties. These processes are concomitant and overlapping, and their distinct effects on age-related bone loss were not established. We have developed an integrative molecular-to whole bone approach to study novel mechanisms controlling bone integrity during aging. We build on a long-standing collaboration between Dr. Schaffler, an expert in osteocytes and bone biomechanics, and Dr. Yakar, an expert in GH/IGF-1 physiology, and a new collaboration with Dr. Pavlov, an expert in mitochondria. We focus on osteocytes, which comprise > 95% of bone cells and are extremely long-lived. Osteocytes integrate the bone's hormonal and mechanical environment, produce the key signals that turn on osteoblasts and osteoclasts, and also directly influence bone material properties. In this proposal we will study the effects of the somatotropic axis on the viability and function of the aging osteocytes via the following aims: 1) Determine the cellular mechanisms by which GH/IGF-1 affect bone tissue quality; 2) Determine how GH/IGF-1 axis controls osteocyte viability and metabolic flexibility during aging. Our studies link three hallmarks of aging “altered intercellular communication”, which is central to tissue integrity, “mitochondrial dysfunction”, which is central to cell survival, and “deregulated nutrient sensing”, which is central to cellular metabolism. We expect unraveling the distinct and overlapping effects of normal aging and somatopause specifically on bone health. Completion of our studies will determine the morphological and the molecular mechanisms by which the GH/IGF-1 axis affects osteocytes of the aging skeleton.