COLLAGEN CROSSLINKS: BIOMARKERS OF AGING

本研究的目的是筛选出一组生化的 作为大鼠结缔组织衰老潜在标记物的检测 还有老鼠。这些检测将包括酶促和 非酶介导的胶原交联物的变化 是，检测将包括两个程序化事件(在 酶促控制，如赖氨酰氧化酶的合成 交叉链接)和与年龄相关的“随机”事件( 它们似乎不受细胞控制，典型的例子是 非酶糖基化等化合物的合成 赖氨酸和羟赖氨酸以及先进的美拉德产品)。年龄- 这些交联链中的相关变化将在 胶原蛋白来源于皮肤、尾腱、心脏、肺和主动脉 老鼠和老鼠。不同组织含量之间的关系 具体的交叉连接和年代顺序将被检查 在动物的一生中，重点是 生命的后半生。按多个间隔进行采样应 提供足够的数据来确定 函数最好地描述了特定对象的变化率 评估的参数。以确定是否有任何 参数中的一部分可以与长寿相关，来自 喂食延长寿命的饲料的大鼠和小鼠也将 分析过了。最后，这项研究将确定是否有 与年龄相关的胶原蛋白交联度的相关性 水解物的组织和高级美拉德产品含量 血液中的蛋白质，如血红蛋白和白蛋白。 年龄从3个月到30个月的大鼠和小鼠 由NIA提供。除了进行横断面研究 对于这些动物，建议对其进行纵向研究 每组一组，其中非致命性测试将是 在相同的动物身上每6个月进行一次 寿命。最后，为了从附近的时间点获取数据 在寿命结束时，建议获得衰老的小鼠和大鼠 分别为30个月和24个月；这两组动物 将每隔3个月牺牲一次。 高效液相色谱方法学现可用于快速、定量 胶原蛋白的交联度分析。之前的研究记录了 待分析的交联度随年龄变化(增加或 减少)在整个生命周期中，不仅是短暂的物种 如老鼠，但也有长寿物种，如猴子和 人类。这项研究的具体目标是确定 年龄相关变化和年龄变化之间的确切关系 时间顺序的年龄，并确定这些变化的速度 参数可以用来预测寿命。

The purpose of this study is to screen a panel of biochemical assays as potential markers of aging in connective tissue in rats and mice. These assays will include both enzymatically and nonenzymatically mediated changes in collagen crosslinking: that is, the assays will encompass both programmed events (under enzymatic control, such as the synthesis of lysyl oxidase-derived crosslinks) and age-related "random" events (the mechanisms of which do not appear to be under cellular control, as typified by synthesis of such compounds as nonenzymatically glycosylated lysine and hydroxylysine and advanced Maillard products). Age- associated changes in these crosslinks will be measured in collagen derived from skin, tail tendon, heart, lungs and aorta of rats and mice. The relationship between tissue content of specific crosslinks and chronological age will be examined throughout the lifetime of the animals, with emphasis on the second half of the lifespan. Sampling at multiple intervals should provide sufficient data for determining what mathematical function best describes the rate of change of the specific parameters evaluated. To determine if the rate of change of any of the parameters can be correlated with longevity, tissues from rats and mice fed diets that extend their lifespan will also be analyzed. Finally, the study will determine if there are any correlations between age-related collagen crosslink content of tissues and advanced Maillard product content of hydrolysates of blood proteins such as hemoglobin and albumin. Rats and mice ranging in age from 3 to 30 months are to be provided by NIA. In addition to performing cross-sectional studies on these animals, it is proposed to perform a longitudinal study on one cohort from each group, in which nonlethal assays will be performed on the same animals every 6 months throughout their lifespans. Finally, in order to obtain data from time points near the end of the lifespan, it is proposed to obtain mice and rats aged 30 months and 24 months, respectively; animals from these groups will be sacrificed at 3 month intervals. HPLC methodologies are now available for rapid, quantitative analysis of collagen crosslinks. Previous studies have documented that the crosslinks to be analyzed change with age (increase or decrease) throughout the lifespan not only of short-lived species such as rats, but also of long-lived species such as monkeys and humans. The specific goals of this study are determining the precise relationship between age-associated changes and chronological age, and determining if the rate of change of these parameters can be used to predict longevity.