COLLAGEN CROSSLINKS--BIOMARKERS OF AGING

本研究的目的是筛选一组生化指标， 作为大鼠结缔组织老化潜在标志物的测定 和老鼠。 这些测定将包括酶促测定和 非酶介导的胶原交联变化： 所述测定将包括两个编程事件（根据 酶控制，如赖氨酰氧化酶衍生的合成 交联）和年龄相关的“随机”事件（ 它们似乎不受细胞控制，典型的是 非酶糖基化的化合物的合成 赖氨酸和羟基赖氨酸以及高级美拉德产品）。 年龄- 这些交联的相关变化将在 胶原蛋白来源于皮肤，尾腱，心脏，肺和主动脉， 大鼠和小鼠。 组织含量与 具体的交叉连接和实足年龄将被检查 在动物的一生中，重点是 寿命的后半部分。 多个时间间隔的采样应 提供足够的数据来确定数学 函数最好地描述了特定 评价参数。 以确定是否有任何变化率 的参数可以与寿命，组织从 用能延长寿命的食物喂养的大鼠和小鼠， 分析了 最后，研究将确定是否有任何 与年龄相关的胶原交联含量之间的相关性 组织和高级美拉德产品的水解产物的含量 血液蛋白质如血红蛋白和白蛋白。 年龄在3至30个月之间的大鼠和小鼠将被 由NIA提供。 除了进行横断面研究外， 对这些动物，建议进行纵向研究， 每组一个队列，其中将进行非致死性试验， 每6个月在相同的动物身上进行一次， 寿命 最后，为了获得来自时间点附近的数据， 寿命结束时，建议获得年龄较大的小鼠和大鼠 分别为30个月和24个月;这些组的动物 每隔3个月处死一次。 HPLC方法现在可用于快速，定量 胶原交联的分析。 既往研究已经证明 待分析的交联随着年龄而变化（增加或 在整个生命周期中，不仅是短寿命物种， 例如老鼠，也有长寿的物种，例如猴子， 人类 本研究的具体目标是确定 年龄相关变化与 实际年龄，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.