Inflammation and Aging: Cytokines, Bone Loss, and Fracture in Older Men

衰老的炎症假说的核心是这样一种断言，即衰老是损伤的累积， 这是由于免疫反应系统的慢性活动造成的。促炎因子生产过剩 细胞因子与许多老年人常见的慢性疾病有关，包括心血管疾病 疾病、虚弱、认知衰退、痴呆症和总死亡率。有证据表明促炎细胞因子 然而，尽管动物和体外数据支持这种情况，但并不存在导致骨折的因素 协会。骨折是骨质疏松症最具破坏性的后果。初步分析来自 健康、老龄化和身体成分(Health ABC)研究表明，较高可溶性细胞因子受体 水平与骨丢失速度加快和骨折风险增加有关。然而，Health ABC 数据仅基于40名老年男性的骨折，而且没有对发生的脊椎进行系统的评估 骨折，最常见的骨质疏松性骨折。男性骨质疏松性骨折(MROS)研究是第一次 美国老年男性骨骼健康综合研究骨质疏松症是一项重要的公共健康 这是一个问题，因为大约30%的60岁以上的男性会经历骨折。目前的提案将扩大 关于这些初步数据，重点是促炎细胞因子与脊椎和非脊柱的关系 老年男性的骨折。此外，我们还将测量骨整合蛋白，一种抗炎细胞因子， 在破骨细胞形成中起关键作用。这些复杂的过程背后可能存在的机制 炎症是否会导致骨折还不得而知。一个主要的问题是，是否有直接影响 炎性细胞因子在骨丢失和骨折中的作用，或者这是性激素减少的作用 导致不受限制的细胞因子产生和增加骨转换和骨折的水平。同样，我们 将解决这种关联是否受到可修改因素的影响，如定期体力活动和 腹型肥胖，似乎与炎性细胞因子的调节和产生有关。 拟议的研究是以一种新颖而系统的方法来解决这些问题的独特之处 明确了细胞因子和骨折风险之间的联系。使用数据、CT扫描和存储的标本 在MRO中，促炎细胞因子可溶性受体(TNFa-SRI和sRII)、IL-6SR和抗炎 细胞因子，OPG，将在经历过非脊柱事件和 脊椎骨折和截至2006年7月未经历过骨折的男性的随机样本(2：1比率)。 我们将在相同的病例和对照中使用性类固醇激素和骨转换的信息，即 可从其他辅助助学金中获得。此外，我们将研究体力活动的影响和 腹部脂肪组织分布对细胞因子水平和骨折风险的影响。理解生物学 这些协会的机制可导致制定和测试预防性干预措施。

The inflammation hypothesis of aging centers on the assertion that aging is the accumulation of damage, which results from chronic activity of immune response systems. Overproduction of pro-inflammatory cytokines has been linked to a number of chronic conditions common in older adults including cardiovascular disease, frailty, cognitive decline, dementia, and overall mortality. Evidence that pro-inflammatory cytokines contribute to fracture, however, does not exist despite animal and in-vitro data supporting such an association. Fractures are the most devastating consequence of osteoporosis. Preliminary analyses from the Health, Aging and Body Composition (Health ABC) study suggest that higher soluble cytokine receptor levels are associated with faster rates of bone loss and an increased risk of fracture. However, Health ABC data are based on only 40 fractures in older men and there is no systematic assessment of incident vertebral fracture, the most common osteoporotic fracture. The Osteoporotic Fractures in Men (MrOS) study is the first comprehensive study of aging men's skeletal health in the U.S. Osteoporosis is an important public health problem since about 30% of men over age 60 will experience a fracture. The current proposal will expand on these preliminary data and focus on the relationship of pro-inflammatory cytokines and vertebral and nonspine fracture in older men. In addition, we will measure osteoprotegrin, an anti-inflammatory cytokine that plays a key role in osteoclastgenesis. The mechanisms that may underlie these complex processes where inflammation may lead to fractures are unknown. A major question is whether there is a direct effect of inflammatory cytokines on bone loss and fracture, or is this a function of reduced sex steroid hormones levels leading to unrestrained cytokine production and increased bone turnover and fracture. Likewise, we will address whether the association is affected by modifiable factors such as regular physical activity and abdominal adiposity, which appear to be involved in the regulation and production of inflammatory cytokines. The proposed study is uniquely positioned to address these questions in a novel yet systematic approach for defining the connection between cytokines and fracture risk. Using data, CT scans and stored specimens from MrOS, levels of pro-inflammatory cytokine soluble receptors (TNFa-sRI and sRII, IL-6SR and the antiinflammatory cytokine, OPG, will be compared between men who experienced incident non-spine and vertebral fracture and a random sample (2:1 ratio) of men who did not experience fracture as of July 2006. We will use information on sex steroid hormones and bone turnover in the same cases and controls which is available from other ancillary grants. In addition, we will examine the influence of physical activity and abdominal adipose tissue distribution on cytokine levels and fracture risk. Understanding the biological mechanisms for these associations could lead to the development and testing of preventive interventions.