Diverse effects of somatopause and aging on the skeleton

躯体更年期和衰老对骨骼的多种影响

• 批准号: 9903190
• 负责人: MITCHELL B SCHAFFLER
• 金额: $ 45.07万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903190
• 关键词: Adult; Affect; Age-Related Bone Loss; Aging; Apoptosis; Biology; Biomechanics; Bone Matrix; Bone Resorption; Bone Tissue; Carbonates; Cell Death; Cell Survival; Cells; Cessation of life; Collaborations; Development; Energy Metabolism; Environment; Fracture; Health; Health Care Costs; Homeostasis; Hormonal; Hormonal Change; Impairment; Insulin-Like Growth Factor I; Life; Life Expectancy; Link; Mechanics; Menopause; Metabolic; Metabolic stress; Metabolism; Minerals; Mitochondria; Molecular; Morbidity - disease rate; Morphology; Mus; Osteoblasts; Osteoclasts; Osteocytes; Osteoporosis; Outcome; Outcome Study; Oxidation-Reduction; Physiology; Process; Production; Property; Reactive Oxygen Species; Regulation; Resistance; Risk; Signal Transduction; Skeleton; Somatotropin; Stress; System; Testing; Tissues; age related; aged; bone; bone cell; bone health; bone loss; bone quality; crystallinity; detection of nutrient; flexibility; improved; in vivo; inorganic phosphate; insulin mediators; intercellular communication; mechanical load; mechanical properties; mineralization; mitochondrial dysfunction; normal aging; novel; preservation; response; sex

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.

抽象的： 迄今为止，与年龄相关的骨骼变化被认为是由两个不同的， 潜在的协同原因：i）全身性马匹变化，尤其是somappause， 与年龄相关的生长马及其介体胰岛素样生长的下降 因子1 [IGF-1]和ii）骨细胞活性和 组织特性。这些过程是伴随和重叠的，它们的独特 未建立对年龄相关骨质流失的影响。我们已经开发了 整体分子到全骨方法研究控制的新机制 衰老期间的骨骼完整性。我们建立在Dr.博士之间的长期合作的基础上。 沙夫勒（Schaffler）是骨细胞和骨生物力学专家，以及雅卡尔（Yakar）博士，专家 GH/IGF-1生理学，以及与Pavlov博士的新合作，专家 线粒体。我们专注于骨细胞，占骨细胞> 95％的骨细胞 非常长寿。骨细胞整合了骨骼的激素和机械 环境，产生打开成骨细胞和破骨细胞的关键信号，还 直接影响骨料的特性。在此提案中，我们将研究 在老化骨细胞的生存能力和功能上的种子轴通过 以下目的：1）确定GH/IGF-1影响的细胞机制 骨组织质量； 2）确定GH/IGF-1轴如何控制骨细胞的生存能力 和衰老期间的代谢灵活性。我们的研究链接了衰老的三个标志 “改变细胞间通信”，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，“营养传感放松”，这是 细胞代谢的中心。我们期望揭开明显和重叠的效果 正常衰老和针对骨骼健康的体系。完成学习 将确定GH/IGF-1的形态学和分子机制 轴影响老化骨骼的骨细胞。