Stress, Glucocorticoid and Leydig Cell Aging

描述（由申请人提供）：应激是一种广泛存在的疾病，其特征在于糖皮质激素活性过多。糖皮质激素过载的损害作用在包括生殖系统在内的许多器官中是明显的。在大脑中，应激水平的糖皮质激素加速海马老化过程。这种加速的一个迹象是神经退化。这一发现导致了更普遍的建议，即压力加速了身体其他组织和器官的衰老过程，包括男性生殖系统。压力和衰老似乎对Leydig细胞有抑制作用，Leydig细胞是类固醇激素睾酮的主要来源。应激介导的糖皮质激素水平增加抑制类固醇生成酶的表达，导致睾酮分泌速率降低，其模式类似于Leydig细胞老化的正常过程。我们假设，由于11 β-羟基类固醇脱氢酶（11 β-HSD）导致糖皮质激素代谢下降，老年间质细胞对糖皮质激素的抑制作用更敏感，并且慢性应激介导的糖皮质激素水平增加可能加速间质细胞老化。染色体端粒的长度随着所有细胞的衰老而缩短。慢性应激已被证明会增加组织中活性氧（ROS）的产生，导致较低的端粒酶活性和较短的端粒。在本申请中，将研究以下三个具体目的。1)我们将明确年龄相关的糖皮质激素活性变化及其对睾丸功能的影响。我们将通过评估血清糖皮质激素水平、间质细胞110 -HSD酶活性和糖皮质激素受体（GR）数量来检验男性生殖系统中糖皮质激素活性水平在衰老过程中增加的假设。2)我们将测试的假设，慢性应激加速与睾丸间质细胞老化相关的退行性变化。这将通过观察在20天的过程中一小时的应激方案后的间质细胞老化来进行。3)最后，我们将测量压力后Leydig细胞中的ROS水平和端粒酶活性，并询问端粒是否因慢性压力而缩短。基于在其他组织中所显示的结果，我们预期应激诱导的间质细胞端粒长度下降将成为男性生殖衰老的潜在事件。

DESCRIPTION (provided by applicant): Stress is a widespread condition, and is characterized by an over abundance of glucocorticoid activity. Damaging effects of glucocoroticoid overload are evident in many organs including the reproductive system. In the brain, stress-levels of glucocorticoid accelerate hippocampal aging process. One sign of this acceleration is neurodegeneration. This finding has led to the more general proposal that stress accelerates the aging process in other tissues and organs of the body, including the male reproductive system. Stress and aging appear to have inhibitory effects on Leydig cells, which are the primary source of the steroid hormone testosterone. Stress-mediated increases in glucocorticoid levels inhibit steroidogenic enzyme expression resulting in decreased rates of testosterone secretion, following a pattern that is similar to the normal process of Leydig cell aging. We hypothesize that old Leydig, cells are more susceptible to the inhibitory effects of glucocorticoid due to declines in glucocorticoid metabolism by the 11 P -hydroxysteroid dehydrogenase enzyme (11 P -HSD), and chronic stress-mediated increases in glucocorticoid levels may accelerate Leydig cell aging. The lengths of the telomeres of chromosomes shorten as all cells age. Chronic stress has been shown to increase the generation of reactive oxygen species (ROS) in tissues, resulting in a lower telomerase activity, and shorter telomeres. In the present application, the following three Specific Aims will be investigated. 1) We will define age-related changes in glucocorticoid activity and their consequences for testis function. We will test the hypothesis that levels of glucocorticoid activity in the male reproductive system increase during aging by evaluation of the levels of serum glucocorticoid, Leydig cell 110 -HSD enzyme activity and glucocorticoid receptor (GR) numbers. 2) We will test the hypothesis that chronic stress accelerates the degenerative changes associated with Leydig cell aging. This will be approached by observation of Leydig cell aging after a regimen of one-hour of stress over the course of twenty days. 3) Finally, we will measure ROS levels and telomerase activity in Leydig cells after stress and ask whether telomeres are shortened as a result of chronic stress. Based on results shown in other tissues, we expect that stressed-induced declines in Leydig cell telomere length will become established as an underlying event of male reproductive aging.