Project 3 - Effects of Ovariectomy on the Biology of Physical and Cognitive Aging in Mice

项目 3 - 卵巢切除术对小鼠身体和认知衰老生物学的影响

基本信息

批准号：
10414015
负责人：
Nathan K LeBrasseur
金额：
$ 37.02万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10414015
关键词：
Acute Adipose tissue Affect Age Age-Months Aging Alzheimer&apos s Disease Anxiety Area Arteries Arthritis Bilateral Biology Biology of Aging Blood Circulation Blood Vessels Body Composition Body Weight Brain Brain region CDKN2A gene Cardiovascular Physiology Cardiovascular system Cell Aging Cells Centers of Research Excellence Cerebellum Chronic Disease Chronic Obstructive Pulmonary Disease Clinic Cognitive Cognitive aging Complement Coronary Arteriosclerosis Data Disease Doctor of Philosophy Echocardiography Elderly Endocrine disruption Estrogen Replacements Estrogen Therapy Estrogens Exhibits Female Foundations Functional disorder Glucose Growth Health Hippocampus (Brain)Homeostasis Human Hypothalamic structure Impaired cognition Impairment Learning Left Life Link Long-Term Effects Malignant Neoplasms Mammalian Oviducts Measures Mediating Memory Menopause Metabolic Metabolism Methods Mouse Strains Mus Muscle Operative Surgical Procedures Organ Osteoporosis Outcome Ovarian hormone Ovariectomy Ovary Performance Phenotype Physical Function Physical Performance Physical activity Placebo Control Placebos Play Pre-Clinical Model Premenopause Process Prophylactic treatment Proteins Reporter Reporting Research Design Resolution Risk Risk Factors Role Salpingo-Oophorectomy Sex Differences Skeletal Muscle Specialized Center System Tamoxifen Testing Therapeutic Effect Tissues Transgenic Mice Transgenic Organisms Uterus Ventricular Woman Women&apos s Group Work age related cell injury circulating biomarkers clinically relevant cognitive function cognitive performance executive function exercise capacity experience experimental group functional decline healthspan healthy aging improved insight insulin sensitivity male multiple chronic conditions muscle strength novel premature senescence sex sham surgery treadmill

项目摘要

PROJECT 3: SUMMARY/ABSTRACT Nathan K. LeBrasseur, M.S., Ph.D. As a mechanistic complement to the human projects (Projects 1 and 2) in the Mayo Clinic Specialized Center of Research Excellence (SCORE) on Sex Differences, this Project will test the central hypothesis that ovariectomy (OVX)-induced endocrine disruption in female mice hastens and exacerbates the accumulation of age-related senescent cells and, in turn, compromises clinically-relevant measures of physical and cognitive performance. Our hypothesis is founded on our recent work demonstrating the causal role of cellular senescence, a hallmark of aging, in the genesis of multiple age-related conditions. Our preliminary data support our hypothesis and demonstrate that senescent cells mediate functional decline and, in specific tissues relevant to physical and cognitive performance, are more abundant in female compared to male mice of advanced age. We will test our central hypothesis through two specific aims, which will (1) determine the degree to which OVX and long-term estrogen replacement impacts healthspan in mice; and (2) determine the extent to which OVX and long-term estrogen replacement affects the accumulation and abundance of senescent cells in multiple tissues. Our approach will leverage a novel transgenic reporter system in mice that enables the unique ability to quantitatively, temporally, and inducibly visualize, track, and isolate p16Ink4a- positive senescent cells. At six months of age, mice will undergo OVX or sham surgery and begin continuous estrogen or placebo treatment [three experimental groups: 1) sham surgery + placebo, 2) OVX + estrogen, and 3) OVX + placebo]. We will then measure the trajectory of healthspan across five clinically-relevant domains: body composition, physical performance, cardiovascular function, metabolic homeostasis, and cognitive function at 12, 18, and 24 months of age. We will systematically quantify senescent cells at these timepoints across tissues, and test their association with measures of healthspan. We anticipate that OVX mice will exhibit accelerated and more severe deficits in the five healthspan domains compared to sham-operated mice, and that estrogen replacement will both delay and mitigate functional consequences of OVX. We predict that the deleterious effects of OVX and therapeutic effects of estrogen will be reflected, if not preceded, by senescent cell burden in tissues responsible for synchronizing functional parameters. As in Project 1 for women, we further anticipate that circulating markers of systemic senescent cell burden will correlate with the clinically-relevant measures of physical and cognitive health in mice. This Project will enable systematic exploration of the long-term effects of OVX and estrogen replacement on integrated measures of healthspan and importantly, will reveal whether aging and endocrine disruption exert synergistically detrimental effects on the fundamental biology of aging at a level of resolution not achievable in humans.

项目 3：摘要/摘要 Nathan K. LeBrasseur，硕士、博士作为梅奥诊所专业中心人类项目（项目 1 和 2）的机械补充关于性别差异的卓越研究（SCORE），该项目将测试以下中心假设：卵巢切除术（OVX）引起的雌性小鼠内分泌干扰加速并加剧了与年龄相关的衰老细胞，进而损害临床相关的身体和认知测量表现。我们的假设是基于我们最近的工作，证明了细胞的因果作用衰老是衰老的一个标志，是多种与年龄相关的疾病的起源。我们的初步数据支持我们的假设并证明衰老细胞介导功能衰退，并且在特定组织中与身体和认知表现相关，与雄性小鼠相比，雌性小鼠的含量更高高龄。我们将通过两个具体目标来检验我们的中心假设，这将（1）确定 OVX 和长期雌激素替代对小鼠健康寿命的影响程度； (2) 确定 OVX 和长期雌激素替代对雌激素积累和丰度的影响程度多个组织中的衰老细胞。我们的方法将利用小鼠的新型转基因报告系统具有定量、暂时和诱导地可视化、跟踪和分离 p16Ink4a 的独特能力阳性衰老细胞。六个月大时，小鼠将接受 OVX 或假手术并开始连续雌激素或安慰剂治疗[三个实验组：1) 假手术 + 安慰剂，2) OVX + 雌激素，以及 3) OVX+安慰剂]。然后，我们将测量五个临床相关领域的健康寿命轨迹：身体成分、身体表现、心血管功能、代谢稳态和认知 12、18 和 24 个月龄时发挥功能。我们将在这些时间点系统地量化衰老细胞跨组织，并测试它们与健康寿命指标的关联。我们预计 OVX 小鼠将与假手术小鼠相比，在五个健康跨度领域表现出加速和更严重的缺陷，雌激素替代疗法将延迟并减轻 OVX 的功能后果。我们预测 OVX 的有害作用和雌激素的治疗作用将通过以下方式反映出来（如果不是先于此）负责同步功能参数的组织中的衰老细胞负担。如项目 1 所示女性，我们进一步预计，系统性衰老细胞负担的循环标志物将与小鼠身体和认知健康的临床相关测量。该项目将实现系统化探索 OVX 和雌激素替代对健康寿命综合指标的长期影响重要的是，将揭示衰老和内分泌干扰是否对人体产生协同有害影响衰老的基本生物学，其分辨率水平在人类中无法实现。