Role of IGF-1 In Diastolic Dysfunction of Aging

14.功能性衰老：导致组织、系统或器官功能障碍的年龄相关变化的遗传、生理、细胞和生化机制。 衰老与以延长的舒张期为特征的心脏性能下降有关。这种舒张功能障碍导致65岁以上人群充血性心力衰竭的发病率增加。尽管一种提出的衰老舒张功能障碍的潜在机制是细胞内心脏钙处理的改变，但最近的证据表明，与年龄相关的生长激素（GH）分泌或胰岛素样生长因子-1（IGF-1）的脉动性下降， GH的调节剂，也可能参与其中。为了评价GH和IGF- 1衰老对舒张功能的作用，将使用年龄模拟GH缺乏大鼠模型。将接受GH治疗并随后停用GH的侏儒大鼠与持续补充GH的侏儒大鼠和杂合的盐水治疗侏儒大鼠进行比较，以评估舒张功能 在完整心脏（超声心动图）、心肌细胞（力学和Ca 2+瞬变）中，以及在钙调节蛋白水平（即，SERCA 2，受磷蛋白）。 我们推测，年龄介导的GH（或IGF-1）分泌减少改变了生长激素水平。 钙调节蛋白参与心肌舒张，这是舒张功能的基础。 衰老功能障碍。这项研究将为将来研究IGF-1信号如何调节衰老心肌的编程和基因表达提供基础。

14. Functional Senescence: Genetic, physiological, cellular and biochemical mechanisms that underlie age-related changes leading to dysfunction in tissues, systems, or organs. Aging is associated with diminished cardiac performance characterized by a prolonged relaxation phase. This impairment in relaxation, diastolic dysfunction, contributes to the increased incidence of congestive heart failure in people older than 65. Although one proposed mechanism underlying diastolic dysfunction of aging is an alteration in intracellular cardiac calcium handling, recent evidence suggests that an age-related decline in the pulsatility of growth hormone (GH) secretion or Insulin-Like Growth Factor-1 (IGF-1), the mediator of GH, may also be involved. To evaluate the role of GH and IGF- 1 senescence on diastolic function, an age-simulated GH deficient rat model will be used. Dwarf rats treated and subsequently withdrawn from GH will be compared to dwarfs continuously repleted with GH and to heterozygous, saline-treated dwarfs in order to assess diastolic function in the intact heart (echocardiography), cardiomyocyte (mechanics and Ca 2+ transients), and at the calcium regulatory protein level (i.e., SERCA2, phospholamban). We hypothesize that age-mediated reductions in the phasic secretion of GH (or IGF-1) alter the calcium regulatory proteins involved in myocardial relaxation and that this underlies diastolic dysfunction of aging. This study will provide the groundwork for future studies examining how IGF-1 signaling may modulate the programming and gene expression of the senescent myocardium.