AGING AND HUMAN ENDOCRINE REGULATION

衰老与人体内分泌调节

• 批准号: 6160390
• 负责人: S M HARMAN
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6160390
• 关键词: aging; bioenergetics; body composition; clinical research; cortisol; gender difference; growth hormone releasing hormone; hormone regulation /control mechanism; human old age (65+); human subject; human tissue; muscle strength; neuroendocrine system; peptide hormone; sex hormones; somatotropin

Summary of work: Normal aging is associated with loss of lean body and muscle mass and strength. There are also increases in body fat, deterioration in lipid profiles and glucose intolerance (risk factors for heart diseasse) and reductions in cardiac function and fitness, immune function, and skin thickness. Reductions in sex steroid hormones, testosterone (T) in men and estradiol (E2) in women as well as growth hormone (GH) and its primary messenger, insulin like growth factor I (IGF-I), with age appear to contribute to these changes in body composition. Cortisol, the major steroid secreted by the adrenal gland generally opposes the actions of GH and may increase somewhat with age. Prior studies have shown partial reversal of age-related changes in lean body and fat mass, skin thickness, and certain metabolic variables when rhGH was given to older persons. Work in our laboratory has demonstrated improved muscle strength, lipoprotein patterns, blood pressure, and glucose tolerance in men over 65 years of age treated with GH releasing hormone. Current studies examine the effects of GH and sex steroid hormone replacement, alone and combined, on body composition, skeletal muscle (strength, biochemistry, molecular biology), bone biochemistry, glucose and lipid metabolism, measures of gonadal, immune, renal, and cardiac function, quality of life and psychological and sexual variables in healthy men and women over 65 years of age over a 6 month period. Recently we have added measurements of plasma leptin, a hormone secreted by fat cells which influences satiety and energy metabolism, and of arterial compliance. As of 8/15/97, 109 subjects have entered the study, 95 have completed, 6 have dropped out and 8 are active. Because treatment groups remain masked, analyses to study domains at baseline. We have recently investigated the extent to which plasma leptin levels are independently related to body fat and to endocrine-metabolic correlates of body fat in the elderly. Leptin levels and % total fat were greater in women vs men, and leptin was highly correlated with measures of fat in both sexes. Leptin was related inversely to GH secretion in both women and men, but was not significantly related to age or other hormone or metabolic variables in either sex. Moreover, the gender difference in leptin and its relationships with GH were completely accounted for by the variation in % total fat. These data suggest that in healthy elderly individuals, plasma leptin levels are a function of adiposity per se, but not of age, sex or other endocrine-metabolic factors. We have also examined the relationships of GH and cortisol secretion in our study population using deconvolution analysis, a unique mathematical technique for assessing hormone secretion rates. As part of this effort, we assessed approximate entropy (ApEn), a measure of the orderliness of hormone release. We found that half-life of GH was longer, and mean and integrated GH secretion were greater, in women vs. men. The frequency of cortisol secretory bursts, its production rate, and the total cortisol secretion were also greater in women. The half-life of cortisol and the interval between bursts of cortisol secretion were longer in men. There was no gender difference in ApEn for GH, whereas the ApEn for cortisol secretion was higher (i.e. more disorganized) in women. We observed a direct relationship of cortisol secretion to the mass of GH secreted per burst and hence to GH production rate but no relationhship of cortisol with GH half-life or GH interburst interval. Our findings that in healthy older women vs men cortisol secretion is greater, less orderly, and enhances GH secretion by increasing the GH secretory mass/burst and that cortisol (at normal physiological concentrations) appears to enhance GH secretion provide new insights into hormone physiology in the elderly. The coupling of cortisol to GH secretion suggests that the body may compensate for potential deleterious effects of cortisol on body composition by an increase in GH production. These studies are aimed at understanding (a) the potential clinical utility of interventions with GH and/or sex steroid hormones and (b) the cellular, biochemical, and molecular events responsible for, and resulting from, altered secretion of these hormones with age. Such investigations may lead to novel therapies to delay or ameliorate the deleterious effects of aging on the musculoskeletal system and other systems which contribute to frailty and loss of mobility in the elderly. We propose to continue vigorous recruitment efforts in order to meet the requirements of the study timetable. Analysis of baseline data including MRI and DEXA measurements and measures of cardiac function will continue through FY '98. Treatment data will be analyzed in early to mid-FY '99. New studies are being planned, investigating the effects of an oral GH stimulating agent (GHRP analogue) on bone in osteoporotic women and men and on cardiovascular risk factors and cardiovascular function in older men and women with and without heart disease.

工作总结：正常的衰老与瘦体质的丧失有关， 肌肉质量和力量。 也会增加身体脂肪， 血脂谱恶化和葡萄糖耐受不良（ 心脏病）和心脏功能和健康下降，免疫 功能和皮肤厚度。性类固醇激素减少， 男性的睾酮（T）和女性的雌二醇（E2）以及生长 激素（GH）及其主要信使胰岛素样生长因子I （IGF-I），随着年龄的增长，似乎有助于身体的这些变化 混合物.皮质醇，肾上腺分泌的主要类固醇 通常反对GH的作用，并且可能随着年龄的增长而有所增加。 先前的研究表明，部分逆转与年龄相关的变化，在瘦 身体和脂肪量，皮肤厚度和某些代谢变量， rhGH用于老年人。我们实验室的工作证明 改善肌肉力量，脂蛋白模式，血压，和 65岁以上男性接受GH释放治疗后的葡萄糖耐量 激素. 目前的研究检查生长激素和性类固醇激素的影响， 替代，单独和联合，对身体组成，骨骼肌 （强度、生物化学、分子生物学）、骨生物化学、葡萄糖 和脂质代谢，测量性腺，免疫，肾脏和心脏 功能、生活质量以及心理和性变量， 年龄超过65岁的健康男性和女性，为期6个月。最近 我们增加了对血浆瘦素的测量，瘦素是一种由脂肪分泌的激素， 影响饱腹感和能量代谢的细胞， 合规截至1997年8月15日，109名受试者进入研究，95名受试者 完成后，6人退出，8人在职。 因为治疗组 保持设盲，在基线时分析研究领域。 我们最近 研究了血浆瘦素水平在多大程度上独立于 与体脂肪和体脂肪的内分泌代谢相关性相关， 老人女性的瘦素水平和总脂肪百分比高于男性， 瘦素与男性和女性的脂肪含量高度相关。 瘦素与生长激素分泌呈负相关，但 与年龄或其他激素或代谢无显著相关 在任何性别的变量。 此外，瘦素和 其与生长激素的关系完全由变异来解释 以%总脂肪计。 这些数据表明，在健康的老年人中， 血浆瘦素水平是肥胖本身的函数，而不是年龄的函数， 性别或其他内分泌代谢因素。我们亦研究了 GH和皮质醇分泌的关系在我们的研究人群中使用 反卷积分析，一种独特的数学技术，用于评估 激素分泌率 作为这项工作的一部分，我们评估了大约 熵（ApEn），一种衡量激素释放有序性的指标。 我们发现 GH的半衰期较长，平均和综合GH分泌 更大的，在女性vs.男性。 皮质醇分泌爆发的频率， 其生产率和总皮质醇分泌也更大， 妇女 皮质醇的半衰期和皮质醇爆发之间的间隔 男性的皮质醇分泌时间较长。 没有性别差异 GH的ApEn，而皮质醇分泌的ApEn更高（即更多）。 无组织）在妇女。 我们观察到皮质醇与 分泌量与每次爆发分泌的GH质量之比，从而与GH产量之比 皮质醇与GH半衰期或GH爆发间期无相关性 interval. 我们的研究发现，在健康的老年妇女与男性皮质醇 分泌更多，不那么有序，并通过以下方式增强GH分泌： 增加GH分泌质量/爆发和皮质醇（正常 生理浓度）似乎增强GH分泌提供了新的 对老年人激素生理学的深入了解。 皮质醇偶联 生长激素分泌表明，身体可能会补偿潜在的 皮质醇通过增加GH对身体组成的有害影响 生产 这些研究旨在了解（a）潜在的临床 用GH和/或性类固醇激素干预的效用和（B） 细胞、生物化学和分子事件， 随着年龄的增长，这些激素的分泌发生了变化。 这种调查 可能导致新的治疗方法来延迟或改善有害作用 肌肉骨骼系统和其他系统的老化 老年人的虚弱和行动能力的丧失。我们建议继续 积极招聘，以符合 学习时间表。 基线数据分析，包括MRI和DEXA 心脏功能的测量和测量将持续到财年 '98. 治疗数据将在1999财政年度早期至中期进行分析。 新研究 正在计划，调查口服生长激素刺激的影响， 药物（GHRP类似物）对骨质疏松症女性和男性的骨作用， 老年男性的心血管危险因素和心血管功能， 患有和不患有心脏病的女性。