Stress, Glucocorticoid and Leydig Cell Aging

描述(申请人提供)：应激是一种普遍的情况，其特征是糖皮质激素活性过高。糖皮质激素超负荷的损害效应在包括生殖系统在内的许多器官中都很明显。在大脑中，糖皮质激素的压力水平加速了海马体的衰老过程。这种加速的一个迹象是神经退化。这一发现导致了一种更普遍的观点，即压力会加速身体其他组织和器官的衰老过程，包括男性生殖系统。压力和衰老似乎对睾丸间质细胞有抑制作用，而间质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的增加抑制类固醇生成酶的表达，导致睾酮分泌率下降，遵循与间质细胞衰老的正常过程类似的模式。我们推测，由于11 P-羟基类固醇脱氢酶(11 P-HSD)对糖皮质激素代谢的抑制作用，老年间质细胞更容易受到糖皮质激素的抑制作用，而慢性应激介导的糖皮质激素水平的升高可能加速间质细胞的衰老。染色体的端粒长度随着所有细胞的衰老而缩短。已有研究表明，慢性应激会增加组织中活性氧物种(ROS)的生成，导致端粒酶活性降低，端粒变短。在本申请中，将调查以下三个具体目标。1)我们将定义与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、Leydig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随着年龄的增长而增加的假设。2)我们将检验这一假说，即慢性应激加速了与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后间质细胞的老化来实现。3)最后，我们将检测应激后间质细胞的ROS水平和端粒酶活性，并询问端粒是否因慢性应激而缩短。根据在其他组织中显示的结果，我们预计应激诱导的间质细胞端粒长度下降将被确立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.