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

项目3：总结/摘要Nathan K. LeBrasseur，M.S.，博士 作为马约诊所专科中心人类项目（项目1和2）的机械补充 根据性别差异卓越研究（SCORE），该项目将测试中心假设， 卵巢切除术（OVX）诱导的雌性小鼠内分泌紊乱加速并加剧了 与年龄相关的衰老细胞，反过来，损害身体和认知的临床相关措施 性能我们的假设是建立在我们最近的工作，证明了细胞的因果作用， 衰老是衰老的标志，在多种与年龄相关的病症的发生中。我们的初步数据 支持我们假设，并证明衰老细胞介导功能下降，在特定组织中， 与身体和认知能力相关的基因，在雌性小鼠中比雄性小鼠更丰富， 高龄我们将通过两个具体目标来检验我们的中心假设，这两个目标将（1）确定 OVX和长期雌激素替代对小鼠健康的影响程度;以及（2）确定 OVX和长期雌激素替代影响的程度， 多种组织中的衰老细胞。我们的方法将利用一种新的小鼠转基因报告系统， 使定量，时间和诱导可视化，跟踪和分离p16 Ink 4a的独特能力。 阳性衰老细胞。在六个月大时，小鼠将经历OVX或假手术，并开始连续的 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，和 3)OVX +安慰剂]。然后，我们将在五个临床相关领域测量健康跨度的轨迹： 身体成分、身体表现、心血管功能、代谢稳态和认知功能 在12个月、18个月和24个月大时发挥功能。我们将在这些时间点系统地量化衰老细胞 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， 雌激素替代治疗可以延缓和减轻卵巢切除的功能性后果。我们预测 OVX的有害作用和雌激素的治疗作用将被反映，如果不是在此之前， 负责同步功能参数的组织中的衰老细胞负荷。如项目1， 对于女性，我们进一步预测，系统性衰老细胞负荷的循环标志物将与女性的衰老相关。 小鼠的身体和认知健康的临床相关测量。该项目将使系统 卵巢切除和雌激素替代对健康寿命综合评价的远期影响 重要的是，这将揭示衰老和内分泌干扰是否会对人类产生协同有害影响。 衰老的基本生物学在人类无法达到的分辨率水平上。

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.