Aging Systems in Geriatrics: the Male Gonadal Axis

老年病学中的衰老系统：男性性腺轴

• 批准号: 7882844
• 负责人: JOHANNES D VELDHUIS
• 金额: $ 41.09万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7882844
• 关键词: Acute; Address; Affect; Age; Aging; Albumins; Anabolism; Androgens; Area; Automobile Driving; Back; Blood - brain barrier anatomy; Blood Circulation; Blood Glucose; Brain; Chronic; Chronic Disease; Clinical; Comorbidity; Corticotropin; Country; Data; Dose; Elderly; Estradiol; Estrogen Receptors; Failure; Feedback; Frequencies; Geriatrics; Gland; Goals; Gonadal Steroid Hormones; Gonadal structure; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Grant; Health Care Costs; Hormones; Human; Hydrocortisone; Hypogonadism; Hypothalamic structure; Impairment; Individual; Inflammatory; Institute of Medicine (U.S.); Institutionalization; Insulin-Like Growth Factor I; Investigation; Knowledge; Left; Life Style; Luteinizing Hormone; Mediating; Medical; Metabolic Control; Methodology; Modeling; Muscle; Myocardial Infarction; Neurosecretory Systems; Operative Surgical Procedures; Outcome; Pain; Pattern; Pharmaceutical Preparations; Physiologic pulse; Physiological Adaptation; Pituitary Gland; Prevention strategy; Process; Production; Quality of life; Recombinants; Regulation; Risk; Safety; Signal Transduction; Sleep Deprivation; Slide; Somatostatin; Somatotropin-Releasing Hormone; Steroid Receptors; Stress; Supplementation; System; Systems Analysis; Testis; Testosterone; Therapeutic; Time; Trauma; World Health Organization; abdominal fat; age effect; age related; aged; analytical method; analytical tool; base; bone; disability; falls; feeding; frailty; ghrelin; in vivo; innovation; leydig interstitial cell; male; men; novel; older men; public health relevance; response; stressor; tool

DESCRIPTION (provided by applicant): The systemic availability of testosterone (Te) in healthy men declines by 35-50% by age 75 compared with age 25 yr. Illness, trauma, surgery, inanition, pain, stress, medications and institutionalization further reduce Te availability in elderly subjects. However, the primary cause of progressive age-related androgen depletion is not known. The issue is significant, because impoverished anabolism accentuates physical frailty, exacerbates comorbidity, reduces quality of life and expands health-care costs. Studies accomplished to date suggest that multiple (rather than single) mechanisms mediate Te depletion in older men, viz.: (i) decreased release of hypothalamic gonadotropin-releasing hormone (GnRH), which drives pituitary luteinizing hormone (LH) secretion; (ii) impaired Leydig-cell responsiveness to LH pulses; and reduced feedback by Te onto GnRH and LH secretion. The last issue is central to understanding how aging disrupts the male GnRH-LH-Te axis, because the axis operates as a counterbalanced feedforward and feedback system. Accordingly, the first major objective of this proposal is to determine the basis of feedback failure using a novel clinical paradigm and analytical methodology just developed under R21 AG23777-02. Hypothesis I. Age disrupts androgen and estrogen receptor-mediated negative feedback on GnRH outflow and/or pituitary LH secretion, as quantified under a selective hypothalamic vis-¿-vis pituitary feedback clamp. In addition to the age-associated decline in Te availability, superimposed acute illness and chronic disease further suppress the GnRH-LH-Te axis at any age. The mechanisms mediating inhibitory effects are unknown. Stress concomitantly alters the anabolic GH-IGF-I and catabolic ACTH-cortisol axes. These observations raise the question, How does aging impact stress adaptations among all 3 of Te, GH and cortisol? This fundamental issue will be addressed under the second major objective, stated as a hypothesis. Hypothesis II. Experimentally controlled metabolic, inflammatory and lifestyle (sleep-deprivation) stressors will inhibit GnRH-LH-Te secretion to a greater extent in older than young men, and unmask concomitant age-related failure of stress adaptations of the GH-IGF-I and ACTH-cortisol axes. Unraveling the bases of androgen depletion in the aging male should spark new preventive strategies to obviate failure of anabolic drive, and thus preserve quality of life and function in older individuals. PUBLIC HEALTH RELEVANCE: Aging results in thinner bones, weaker muscles, more abdominal fat, higher blood glucose, greater risk of a heart attack, reduced sexual energy, forgetfulness and increased medical disability. Certain outcomes are related to lower male sex hormones, which fall by about 50% between the ages of 25 and 75 years. Why or how the decline occurs is not known. This grant studies mechanisms in the brain, pituitary (master) gland and testis (male gonad), which begin to fail in aging men under stress.

描述（由申请人提供）：与 25 岁时相比，健康男性 75 岁时睾酮 (Te) 的全身利用率下降 35-50%。疾病、创伤、手术、营养不良、疼痛、压力、药物和收容进一步降低了老年受试者的 Te 可用性。然而，与年龄相关的雄激素进行性耗竭的主要原因尚不清楚。这个问题很重要，因为合成代谢不良会加剧身体虚弱，加剧合并症，降低生活质量并增加医疗费用。 迄今为止完成的研究表明，多种（而不是单一）机制介导老年男性的 Te 消耗，即：（i）下丘脑促性腺激素释放激素（GnRH）的释放减少，该激素驱动垂体黄体生成素（LH）分泌； (ii) Leydig 细胞对 LH 脉冲的反应受损；并减少 Te 对 GnRH 和 LH 分泌的反馈。最后一个问题对于理解衰老如何破坏男性 GnRH-LH-Te 轴至关重要，因为该轴作为平衡的前馈和反馈系统发挥作用。因此，该提案的第一个主要目标是使用刚刚在 R21 AG23777-02 下开发的新型临床范例和分析方法来确定反馈失败的基础。假设 I.年龄破坏雄激素和雌激素受体介导的 GnRH 流出和/或垂体 LH 分泌的负反馈，如在选择性下丘脑相对垂体反馈钳下量化的。 除了与年龄相关的 Te 可用性下降之外，急性疾病和慢性疾病的叠加进一步抑制了任何年龄的 GnRH-LH-Te 轴。介导抑制作用的机制尚不清楚。压力会同时改变合成代谢 GH-IGF-I 和分解代谢 ACTH-皮质醇轴。这些观察结果提出了一个问题：衰老如何影响 Te、GH 和皮质醇这三种物质的压力适应？这个基本问题将在作为假设的第二个主要目标下得到解决。假设二。 实验控制的代谢、炎症和生活方式（睡眠剥夺）压力源将比年轻男性更大程度地抑制老年男性的 GnRH-LH-Te 分泌，并揭示与年龄相关的 GH-IGF-I 和 ACTH-皮质醇轴应激适应失败。 解开老年男性雄激素消耗的基础应该会激发新的预防策略，以避免合成代谢驱动力的失败，从而保持老年人的生活质量和功能。 公共健康相关性：衰老会导致骨骼变薄、肌肉变弱、腹部脂肪增多、血糖升高、心脏病发作的风险增加、性能力下降、健忘和医疗残疾增加。某些结果与男性性激素降低有关，男性性激素在 25 岁至 75 岁之间下降约 50%。下降的原因或方式尚不清楚。这笔资助研究了大脑、垂体（主）腺和睾丸（男性性腺）的机制，这些机制在老年男性在压力下开始失效。