Role of cellular senescence in cardiovascular aging

老龄化是心血管疾病(CVD)的主要风险因素，到2030年，40%的美国人将 发生某种形式的脑血管病，对社会造成巨大的经济和人员伤亡。仍有许多未知之处 为什么心血管功能障碍会随着年龄的增长而增加。心血管衰老的一个潜在原因是细胞 衰老。这种复杂的应激反应可能是有益的，也可能是有害的，这取决于生理上的 背景。反应的两个特征是：1)细胞增殖永久停止；2)发展 一种衰老相关分泌表型(SASP)--转录上调和分泌 大量的炎性细胞因子、趋化因子、生长因子和蛋白酶。衰老细胞随时间延长而增加 AGE在许多组织中存在，包括心血管系统，SASP与多种 与年龄相关的病理，包括心脏和血管功能障碍。衰老的细胞随着年龄的增长而积累 小鼠和人类的心脏和血管系统，但尚不清楚细胞衰老是否是原因或 心血管老化的后果。我们开发了一种新的老鼠模型，允许可视化 以及体内衰老细胞的消除和它们从组织中的分离，使研究 有或没有衰老细胞的综合系统的功能--如心脏和血管系统。我们 建议检验衰老细胞，特别是SASP是一种重要的 驱动简历老化的机械性过程。为了验证这一假设，我们将制定三个具体目标。 目标1：确定衰老细胞在环境中导致心血管系统功能障碍的程度 实验衰老和自然衰老。这个目标将决定衰老的时间和地点。 细胞在心血管系统中产生，使用急性模型，以及自然衰老的小鼠。我们将雇佣我们的员工 新的小鼠模型，3MR小鼠，在其中我们可以消除细胞来对比有和没有CV功能 衰老细胞；目标2：确定衰老细胞的细胞和分子机制 对心血管组织产生负面影响。这一目标将决定简历中关键细胞类型的敏感度 包括成纤维细胞、内皮细胞和血管平滑肌细胞 动脉和完整的心脏。我们将确定衰老细胞的分泌因子如何影响细胞的功能。 使用共培养和遗传策略的其他细胞类型；目标3：确定新的治疗靶点 人类中与年龄相关的CV功能障碍。已经建立了特定的蛋白质和基因表达特征 对于目标1和目标2中由于衰老而导致的不同细胞类型，在这个最终目标中，我们将使用一种新的 翻译模型-从人类内皮细胞活检来验证我们关于衰老的预测 不同年龄的人类。 总体而言，我们的计划将为衰老作为年龄的主要调节因素的作用提供新的见解- 相关的心血管疾病，并可能提供新的机会目标，以抗击这一毁灭性的疾病。

Aging is the primary risk factor for cardiovascular disease (CVD), and by 2030, 40% of Americans will have some form of CVD incurring a huge economic and human toll on society. Much remains unknown about why cardiovascular dysfunction increases with age. One potential cause of cardiovascular aging is cellular senescence. This complex stress response can be beneficial or detrimental, depending on the physiological context. Two hallmarks of the response are: 1) a permanent arrest of cell proliferation; and 2) development of a senescence-associated secretory phenotype (SASP) -- the transcriptional upregulation and secretion of numerous inflammatory cytokines, chemokines, growth factors and proteases. Senescent cells increase with age in many tissues, including the cardiovascular (CV) system, and the SASP is associated with a variety of age-related pathologies, including cardiac and vascular dysfunction. Senescent cells accumulate with age in the hearts and vasculature of mice and humans, but it is not known if cellular senescence is a cause or consequence of cardiovascular aging. We developed a novel mouse model that permits the visualization and elimination of senescent cells in vivo and their isolation from tissues, making it possible to study the function of integrated systems -- such as the heart and vasculature -- with and without senescent cells. We propose to test the novel hypothesis that senescent cells, and particularly the SASP, are an important mechanistic process driving CV aging. To test this hypothesis, we will develop three specific aims. Aim 1: Determine the extent to which senescent cells cause CV system dysfunction in settings of both experimental senescence and natural aging. This aim will determine when and where senescent cells arise in the cardiovasculature, using an acute model, as well as naturally aged mice. We will employ our novel mouse model, the 3MR mouse in which we can eliminate cells to contrast CV function with and without senescent cells; Aim 2: Determine the cellular and molecular mechanisms by which senescent cells negatively impact cardiovascular tissue. This aim will determine the sensitivity of critical cell types in the CV to senescence, including fibroblasts, endothelial cells, and vascular smooth muscle cells isolated from both arteries and intact hearts. We will determine how secreted factors from senescent cells influence function of other cell types using co-cultures and genetic strategies; Aim 3: To identify novel therapeutic targets for age-related CV dysfunction in humans. Having established specific protein and gene expression signatures for different cell types as a result of senescence in aims 1 and 2, in this final aim we will use a novel translational model – biopsies of endothelial cells from humans to validate our predictions about senescence in different aged humans. Overall our program will provide novel insights into the role of senescence as a major mediator of age- related CVD, and potentially provide new targets of opportunity to combat this devastating disorder.