Investigation into Heart Aging

 描述(申请人提供)：老年人心脏功能减退。80岁时，左心室收缩功能不到20岁时的一半。衰老，即使是没有明显心血管疾病的表面上健康的人，也与心脏结构受损有关，并包括心脏储备功能。衰老是公认的心脏病风险因素。例如，心脏病的患病率随着年龄的增长而增加。事实上，老年人心脏病的死亡率比年轻人高。Klotho是最近发现的一种抗衰老基因。Klotho基因的突变加速了小鼠的衰老进程，缩短了小鼠的寿命，而Klotho基因的过度表达则减缓了小鼠的衰老进程，延长了小鼠的寿命。Klotho主要在肾脏表达，并分泌到血液中。在人类中，老年人口中循环中的klotho水平下降。这项应用的目的是在动物模型中调查klotho缺乏是否会导致听力损害，并评估klotho的体内表达或klotho蛋白的补充是否可以预防或减轻与衰老相关的心脏损害。中心假说是，Klotho基因缺陷损害心肌细胞收缩功能，上调胶原合成，从而损害心脏功能，并导致心脏重构(纤维化)。这项研究的理论基础是，如果klotho缺乏导致心脏损害，那么在体内上调klotho基因表达或补充klotho蛋白可能是一种新的治疗干预方法，以预防或减轻与衰老相关的心脏损害和衰竭。这一目标将通过几种新方法的结合实现两个连贯的具体目标来实现。两个具体的目标是：(1)确定Klotho缺乏是否会导致心力衰竭和重塑，并探讨其潜在的分子机制。(2)研究肾脏特异性表达Klotho基因或补充Klotho蛋白是否能减轻衰老相关的心脏损伤。这项拟议的工作具有创新性和重大意义，因为它利用最先进的方法来解决与衰老相关的心脏损伤，这一问题影响了大量人口，但仍未得到充分研究。这些结果将揭示新的分子途径，介导与衰老相关的心力衰竭和重塑的发病机制。该项目的完成可能为衰老相关心脏损伤的治疗策略提供新的见解。

 DESCRIPTION (provided by applicant): The heart function declines in the aged population. At age 80 years, LV contractile function is less than half of what it was at age 20 years. Aging, even in apparently healthy individuals without overt cardiovascular disease, is associated with damaged heart structure and comprised cardiac reserve function. Aging is a recognized risk factor for heart diseases. For instance, the prevalence of heart disease increases with age. Indeed, the mortality from heart diseases is higher in the aged than in the young population. Klotho is a recently-discovered anti- aging gene. Mutation of klotho gene expedites the aging process and shortens the life-span while over- expression of klotho slows the aging process and extends the life-span in mice. Klotho is predominately expressed in kidneys and secreted into the blood. In humans, the level of circulating klotho declines in the aged population. The objective of this application is to investigate, in animal models, if klotho deficiency causes hear damage and assess if in vivo expression of klotho or supplement of klotho protein prevents or attenuates aging-associated heart damage. The central hypothesis is that klotho gene deficiency impairs cardiomyocyte contractile function and upregulates collagen synthesis thereby impairing heart function and causing heart remodeling (fibrosis), respectively. The rationale for the proposed research is that if klotho deficiency causes heart damage, then, in vivo upregulation of klotho gene expression or supplement of klotho protein may be a novel approach for therapeutic intervention to prevent or attenuate aging-related heart damage and failure. This objective will be achieved by pursuing two coherent specific aims using a combination of several novel approaches. The two specific aims are: (1) Determine if klotho deficiency causes heart failure and remodeling and investigate the underlying molecular mechanisms. (2) Investigate if kidney-specific expression of klotho gene or supplement of klotho protein attenuates aging-associated heart damage. The proposed work is innovative and significant because it utilizes state-of-the-art approaches to address aging-associated heart damage which affects a large population but remains poorly explored. The results will reveal novel molecular pathways that mediate the pathogenesis of aging-related heart failure and remodeling. Completion of this project may provide new insights into therapeutic strategies for aging-related heart damage.