Modulation of immune senescence by androgen treatment in aged male macaques

雄激素治疗对老年雄性猕猴免疫衰老的调节

• 批准号: 8582384
• 负责人: Ilhem Messaoudi
• 金额: $ 24.69万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8582384
• 关键词: Address; Affect; Age; Aged, 80 and over; Aging; Aging-Related Process; Androgens; Andropause; Animal Model; Animals; Antibodies; Attenuated; Autopsy; B Cell Proliferation; B-Lymphocyte Subsets; B-Lymphocytes; Bacterial Infections; Biological Markers; Biopsy; Bone Density; Bone Marrow; Bronchoalveolar Lavage; Cardiovascular Diseases; Cells; Circadian Rhythms; Clinical; Cognition; Cognitive; Collaborations; Diabetes Mellitus; Elderly; Endocrine; Female; Frequencies; Funding; Goals; Gonadal Steroid Hormones; Homeostasis; Hormones; Hour; Human; Hypogonadism; Immune; Immune response; Immune system; Immunity; Immunoglobulin G; Infection; Inflammatory; Influenza vaccination; Interleukin-6; Kinetics; Laboratories; Link; Lung; Lymphocyte; Lymphopoiesis; Macaca; Macaca mulatta; Measures; Memory; Modified Vaccinia Virus Ankara; Morbidity - disease rate; Mucous Membrane; Osteoporosis; Output; Pattern; Performance; Peripheral; Physiological; Physiological Processes; Placebos; Plasma; Population; Predisposition; Primates; Production; Resources; Severities; Sleep Wake Cycle; Supplementation; T cell response; T memory cell; T-Lymphocyte; TNF gene; Testing; Testosterone; Thymus Gland; Tissues; United States National Institutes of Health; Vaccination; Vaccines; Viral; Virus Diseases; age related; aged; bone; bone mass; cost effective; cytokine; dehydroepiandrosterone; design; fitness; immune function; immunoregulation; improved; influenza virus vaccine; innovation; juvenile animal; lymph nodes; male; meetings; men; mortality; multidisciplinary; muscle form; news; nonhuman primate; novel; novel therapeutic intervention; older men; prototype; public health relevance; research study; response; sarcopenia; seasonal influenza; senescence

DESCRIPTION (provided by applicant): Aging results in a progressive decline in immune function, which leads to increased morbidity and mortality related to infections. In men, increasing age also results in significant perturbations in the levels of circulating androgens (testosterone and dehydroepiandrosterone (DHEA)), which has been linked to sarcopenia, osteoporosis, cardiovascular disease and diabetes. Since sex steroid levels modulate immune function, it is likely that the age-related decline in androgen levels will also affect immune senescence. Although ~70% of men over the age of 80 meet the clinical definition of hypogonadism, there is controversy over treating this population. Nevertheless, the number of testosterone prescriptions has increased dramatically in the US reaching 5.6 million in 2011. Thus, it is critical that we gain a better understanding of the pleiotropic effects of androgen supplementation in aged men. Dr. Urbanski (co-PI) has developed a novel paradigm of androgen replacement in which testosterone and DHEA are administered to mimic the natural circadian rhythm of these hormones. This approach can restore both testosterone and DHEA levels to "youthful" 24-hour rhythms in aged male rhesus macaques. We propose to use this highly innovative paradigm to test the hypothesis that physiological testosterone supplementation, designed to mimic the circulating 24- hour pattern of young animals, will ameliorate major biomarkers of immune senescence and improve T cell responses to vaccination. We will first determine the impact of physiological androgen supplementation on the severity of immune senescence by assessing: 1) the frequency of naive and memory T and B cell subsets; 2) thymic output; 3) plasma levels of key inflammatory cytokines; and inflammatory cytokine production by 4) T cells and 5) innate immune cells. We will then characterize the impact of physiological androgen supplementation on the anti-viral immune response following vaccination with modified vaccinia ankara as well as the seasonal influenza vaccine by measuring: 1) kinetics and magnitude of T and B cell proliferation; 2) frequency of responding T cells; and 3) IgG antibody titer. Finally, we will examine the impact of androgen supplementation on the homeostasis of tissue resident lymphocytes by determining 1) T and B cell subset distribution in bone marrow, lymph nodes, bronchoalveolar lavage, and gut biopsies; and 2) the cytokine milieu of these tissues. These studies will be carried out in close collaboration with Dr. Urbanski's laboratory and leverage a funded NIH R01 study (R01 AG-036670) that is investigating the impact of androgen supplementation on cognitive performance and circadian sleep-wake cycles in aged male macaques. By studying the same animals, we will be able to carry out secondary analyses to uncover additional correlations between immunity and neuro- endocrine function in the aged primate. These efforts have the potential to provide a new therapeutic approach to improve immunity in the growing elderly population.

描述（由申请人提供）：衰老导致免疫功能的逐渐下降，从而导致与感染相关的发病率和死亡率增加。在男性中，年龄的增长还会导致循环中的雄激素（睾酮和脱氢表雄酮（DHEA））水平显著紊乱，这与肌肉减少症、骨质疏松症、心血管疾病和糖尿病有关。由于性类固醇水平调节免疫功能，很可能与年龄相关的雄激素水平下降也会影响免疫衰老。尽管约70%的80岁以上男性符合性腺功能减退的临床定义，但对这一人群的治疗存在争议。然而，2011年，美国开具睾酮处方的数量急剧增加，达到560万。因此，我们有必要更好地了解老年男性补充雄激素的多效性。Urbanski博士（co-PI）开发了一种新的雄激素替代范例，其中睾酮和脱氢表雄酮被管理来模拟这些激素的自然昼夜节律。这种方法可以使老年雄性恒河猴的睾丸激素和脱氢表雄酮水平恢复到“年轻”的24小时节律。我们建议使用这种高度创新的范式来验证这样一种假设，即生理睾酮补充，旨在模仿年轻动物的循环24小时模式，将改善免疫衰老的主要生物标志物，并改善T细胞对疫苗接种的反应。我们将首先通过评估来确定生理性雄激素补充对免疫衰老严重程度的影响：1)初始和记忆T细胞和B细胞亚群的频率；2)胸腺输出；3)血浆关键炎症因子水平；T细胞和先天免疫细胞产生炎性细胞因子。然后，我们将通过测量以下指标来描述生理性雄激素补充对接种改性安卡拉牛苗和季节性流感疫苗后抗病毒免疫反应的影响：1)T细胞和B细胞增殖的动力学和幅度；2)应答T细胞频率；3) IgG抗体滴度。最后，我们将通过确定1)骨髓、淋巴结、支气管肺泡灌洗和肠道活检中的T细胞和B细胞亚群分布来检验雄激素补充对组织常驻淋巴细胞稳态的影响；2)这些组织的细胞因子环境。这些研究将与Urbanski博士的实验室密切合作进行，并利用NIH资助的R01研究（R01 AG-036670），该研究正在调查雄激素补充对老年雄性猕猴认知表现和昼夜睡眠-觉醒周期的影响。通过研究相同的动物，我们将能够进行二次分析，以揭示老年灵长类动物免疫和神经内分泌功能之间的额外相关性。这些努力有可能为提高日益增长的老年人口的免疫力提供一种新的治疗方法。