Aging of the Heart

心脏的老化

• 批准号: 8415033
• 负责人: Piero Anversa
• 金额: $ 229.96万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415033
• 关键词: Adult; Affect; Age; Aging; Angiotensin II; Animal Model; Animals; Apoptosis; Autologous; Behavior; Birth; Blood Vessels; Cardiac; Cardiac Myocytes; Cell Aging; Cell Count; Cell Cycle; Cell Death; Cell physiology; Cells; Cessation of life; Characteristics; Cicatrix; Conflict (Psychology); Coronary; Coronary Vessels; DNA Damage; Data; Defect; Diffuse; Disease; Elderly; Endothelial Cells; Equilibrium; Etiology; Feasibility Studies; Female; Fibroblasts; Fibrosis; Functional disorder; Future; Gender; Growth; Harvest; Health; Heart; Heart failure; Human; In Vitro; Lead; Life; Live Birth; Longevity; Microcirculation; Mothers; Muscle Cells; Myocardial; Myocardium; Myopathy; Natural regeneration; Organ; Organism; Oxidative Stress; Pathologic; Performance; Phenotype; Process; Program Research Project Grants; Property; Proto-Oncogene Protein c-kit; Protocols documentation; Receptor, Angiotensin, Type 1; Relaxation; Research; Role; Sarcomeres; Sex Characteristics; Smooth Muscle Myocytes; Stem cells; Stretching; Structure; Supporting Cell; Telomerase; Telomere Shortening; Testing; Time; Vascular Endothelial Cell; Ventricular Dysfunction; Ventricular Function; Woman; aged; cell age; cell growth; conditioning; gap junction channel; heart function; human female; human male; interstitial; male; mechanical behavior; men; novel strategies; postnatal; prevent; public health relevance; senescence; stem cell therapy; telomere; young mother

DESCRIPTION (provided by applicant): Currently, we have little understanding of the etiology of myocardial aging. Rarely, studies in animals and humans have considered aging as an independent process and time as the major cause of the aging myopathy. Only occasionally cardiac aging in humans has been characterized independently from concomitant pathologic states. Aging has been interpreted as a variable, which cooperates with a variety of diseases, to define the old, poorly functional heart. This Program Project Grant (PPG) aims at the: a) Definition of myocardial aging; b) Identification of the determinants of the cardiac senescent phenotype; and c) Recognition whether the aging myopathy conditions health and life span. The major hypothesis to be tested is that aging of cardiac stem cells (CSCs) affects the size and properties of the myocyte, vascular, and fibroblast progeny which, in turn, conditions the structure and function of the heart. Aged CSCs may generate a smaller number of senescent myocytes with defects in electrical and mechanical behavior, and a larger number of fibroblasts which, together, underlie diastolic dysfunction and the old cardiac phenotype. This PPG has five objectives: a) To determine whether the adult heart is a self-autonomous organ regulated by the orderly organization and growth of CSCs; b) To determine whether telomeric shortening in CSCs with aging leads to time-dependent changes in the growth properties of CSCs and characteristics of the differentiated progeny; c) To determine whether old CSCs with short telomeres generate functionally-defective myocytes together with enhanced formation of fibroblasts; d) To determine whether accumulation of fibroblasts and myocytes with impaired contractile performance promotes diastolic dysfunction, typically present in the senescent heart; and e) To determine whether strategies preventing the aging myopathy, or reversing myocardial aging can be developed to extend health and life span in the elderly. The common theme of this PPG is understanding the control of CSC growth and commitment, the etiology of CSC senescence and death, and the impact that old CSCs have on the properties of the differentiated progeny The telomere-telomerase axis is viewed as the key regulator of CSC replication, senescence and death, conditioning myocyte, coronary vasculature, and organ aging. Alterations in the turnover rate of cardiomyocytes, vascular cells, and fibroblasts define the aging myopathy. CSCs with preserved function are present in the old heart, and repopulating protocols with CSCs possessing intact telomeres may replace defective myocytes with new, mechanically efficient cells, and restore the coronary vasculature and microvasculature reversing the senescent phenotype, ultimately, prolonging health and life span of the organ and organism. To fulfill these objectives, the role of CSCs in myocardial aging of small (Projects 1 and 2) and large (Project 3) animals and humans (Project 4) will be investigated in an integrated manner to identify the variables that lead to ventricular dysfunction in the old heart.

描述(申请人提供)：目前，我们对心肌老化的病因知之甚少。很少有动物和人类的研究认为衰老是一个独立的过程，时间是衰老肌病的主要原因。只有偶尔，人类心脏老化的特征是独立于伴随的病理状态。衰老被解释为一个变量，它与各种疾病协同作用，定义老年、功能不佳的心脏。该计划项目赠款(PPG)旨在：a)心肌老化的定义；b)确定心脏衰老表型的决定因素；以及c)识别衰老肌病是否会影响健康和寿命。需要检验的主要假设是，心脏干细胞(CSCs)的老化影响心肌细胞、血管和成纤维细胞后代的大小和性质，进而调节心脏的结构和功能。衰老的CSCs可能会产生较少数量的衰老心肌细胞，具有电和机械行为缺陷，以及大量的成纤维细胞，共同构成舒张期功能障碍和陈旧心脏表型的基础。该PPG有五个目标：a)确定成人心脏是否是受CSCs有序组织和生长调节的自我自治器官；b)确定CSCs中端粒缩短是否会导致CSCs生长特性和分化后代特征的随时间变化；c)确定端粒较短的老年CSCs是否会产生功能缺陷的肌细胞并促进成纤维细胞的形成；d)确定CSCs中收缩性能受损的成纤维细胞和肌细胞的积累是否会促进舒张性功能障碍，这种功能通常存在于衰老的心脏中；以及e)确定是否可以制定预防衰老肌病或逆转心肌衰老的策略，以延长老年人的健康和寿命。这个PPG的共同主题是了解CSC生长和承诺的控制，CSC衰老和死亡的病因，以及旧CSC对分化后代特性的影响。端粒-端粒酶轴被认为是CSC复制、衰老和死亡、调节心肌细胞、冠脉血管和器官老化的关键调节因子。心肌细胞、血管细胞和成纤维细胞周转率的改变定义为老年性肌病。在陈旧的心脏中存在着功能完好的CSCs，用端粒完整的CSCs进行再填充，可以用新的、机械有效的细胞取代有缺陷的心肌细胞，恢复冠脉血管和微血管系统，逆转衰老的表型，最终延长器官和生物体的健康和寿命。为了实现这些目标，将以综合的方式研究CSCs在小(项目1和2)和大(项目3)动物和人类(项目4)心肌老化中的作用，以确定导致旧心脏心功能不全的变量。