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

衰老的炎症假说的核心是衰老是损伤的积累， 这是由免疫反应系统的慢性活动引起的。促炎因子过度产生 细胞因子与老年人常见的许多慢性疾病有关， 疾病、虚弱、认知能力下降、痴呆和总体死亡率。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样的观点， 协会骨折是骨质疏松症最具破坏性的后果。初步分析， 健康、衰老和身体组成（健康ABC）研究表明，较高的可溶性细胞因子受体 水平与更快的骨质流失率和骨折风险增加有关。健康ABC 数据仅基于40例老年男性骨折，没有系统的评估事件椎骨 骨折，最常见的腰椎骨折。男性骨质疏松性骨折（MrOS）研究是第一个 美国老年男性骨骼健康的综合研究骨质疏松症是一个重要的公共健康问题 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 这些初步的数据，并集中在促炎细胞因子和脊椎和非脊椎的关系， 老年人骨折此外，我们将测量骨保护素，一种抗炎细胞因子， 在破骨细胞生成中起关键作用。这些复杂过程背后的机制， 炎症可能导致骨折是未知的。一个主要的问题是， 炎性细胞因子对骨丢失和骨折的影响，或者这是性类固醇激素减少的一个功能 导致不受限制的细胞因子产生和增加的骨转换和骨折。同样我们 将讨论这种关联是否受到可改变因素的影响，如定期的身体活动， 腹部肥胖，这似乎是参与调节和生产的炎症细胞因子。 拟议的研究是唯一的定位，以解决这些问题，在一个新的但系统的方法， 确定细胞因子和骨折风险之间的联系。利用数据、CT扫描和储存的标本 从MrOS，促炎细胞因子可溶性受体（TNF α-sRI和sRII，IL-6SR和TNF α-β）的水平 将在经历非脊柱事件的男性和经历非脊柱事件的男性之间比较细胞因子OPG 椎骨骨折和随机抽样（2：1比例）的男性谁没有经历骨折截至2006年7月。 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， 其他辅助赠款。此外，我们还将研究体育活动的影响， 腹部脂肪组织分布对细胞因子水平和骨折风险的影响。了解生物学 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.