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: 8062247
• 负责人: JOHANNES D VELDHUIS
• 金额: $ 38.85万
• 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/8062247
• 关键词: Acute; Address; Affect; Age; Aging; Albumins; Anabolism; Androgen Receptor; Androgens; Area; Automobile Driving; Back; Blood - brain barrier anatomy; Blood Circulation; Blood Glucose; Brain; CRH gene; 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; Grant; Health Care Costs; 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; SHBG gene; Safety; Signal Transduction; Sleep Deprivation; Slide; Somatostatin; Somatotropin-Releasing Hormone; Steroid Receptors; Stress; Supplementation; System; Systems Analysis; Testis; Testosterone; Therapeutic; Time; Trauma; United States National Institutes of Health; 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、药物和收容进一步减少。然而，与年龄相关的雄激素逐渐减少的主要原因尚不清楚，因为合成代谢不足会加剧身体虚弱。 (i) 下丘脑促性腺激素释放激素 (GnRH) 的释放减少，该激素可驱动垂体促黄体生成素 (LH) 分泌；(ii) 间质细胞对 LH 脉冲的反应性受损，并减少 Te 对 GnRH 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，该提案的首要目标是确定反馈的基础。使用刚刚在 R21 AG23777-02 下开发的新型临床范式和分析方法失败了。年龄会破坏雄激素和雌激素受体介导的 GnRH 流出和/或垂体负反馈。 LH 分泌，在选择性下丘脑 vis-¿ -vis 垂体反馈钳除了与年龄相关的 Te 可用性下降外，叠加的急性疾病和慢性疾病会进一步抑制任何年龄的 GnRH-LH-Te 轴，介导压力同时改变合成代谢的机制尚不清楚。 GH-IGF-I 和分解代谢 ACTH-皮质醇轴提出了一个问题：衰老如何影响 Te、GH 和皮质醇这三种物质之间的压力适应？该问题将在第二个主要目标下得到解决，作为假设 II，实验控制的代谢、炎症和生活方式（睡眠剥夺）压力会比年轻男性更大程度地抑制 GnRH-LH-Te 分泌。揭示与年龄相关的 GH-IGF-I 和 ACTH-皮质醇轴应激适应障碍，揭示老年男性雄激素耗竭的基础。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、肌肉无力、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水平降低有关。 25 岁至 75 岁之间大约有 50% 的人出现这种下降，目前尚不清楚这种下降的原因或方式。对于处于压力下的老年男性来说，这种方法开始失效。