Aging Fitness & Failure: Mechanisms of Diastolic Dysfunction

描述（由申请人提供）：长期缺乏身体活动会给我们的老龄化人口带来大量的流动性、死亡率和成本。这项竞争性更新的前一个资助期的主要发现是，久坐的衰老会导致心脏明显萎缩和僵硬。相比之下，大师运动员的心脏顺应性与年轻对照组没有区别。因此，长期的运动训练可以防止心脏硬化，而心脏硬化以前被认为是衰老不可避免的结果。然而，即使是长时间和高强度的运动训练（一年底每周4-6小时）也未能恢复这些健康老年人的心脏顺应性。该项目的总体目标是确定久坐衰老导致心脏硬化的机制，确定其在衰老过程中发生的时间，并确定维持心脏顺应性的持续运动训练的最小剂量。我们的假设是：假设1a：久坐的生活方式会导致心脏在一生中逐渐萎缩和硬化。具体目标1a：通过心脏力学、松弛、形态学和结构组成（脂质含量和纤维化）的综合侵入性和非侵入性测量，研究年龄在25至75岁之间50年久坐不动的个体的横截面。假设1b：如果开始得足够早，并持续一段时间，足够的运动量可以防止这种硬化过程；这个数字低于成为一名有竞争力的大师赛运动员的要求。特定目标1b：确定持续以两种不同剂量进行训练的健康个体：30分钟，5次或更多x/周；或30分钟，每周2-3次，持续至少25年。将进行与目标1相同的结构和功能评估。假设2：心肌顺应性对衰老的慢性可塑性依赖于代谢的长期变化，从而导致心肌甘油三酯和/或晚期糖基化终产物（AGEs）的积累。具体目标2：到：a)在目标#1a和1b的所有受试者中使用MRS测量心肌甘油三酯沉积，包括广泛的久坐老化和终身健康水平；b)测量糖化血红蛋白作为蛋白糖化的指标；c)进行延迟增强MRI对比，并测量血浆纤维化标志物。假设3：在先前久坐不动的老年人通过运动训练改善心脏顺应性之前，AGE交联必须被打破。在减少与久坐衰老相关的心脏僵硬方面，AGE交联抑制剂与运动训练的结合将优于单独的干预。具体目标3：在平行动物和人类研究中，研究一种使用ALT- 711的新型干预措施，ALT- 711是AGEs交联的特异性破坏者，可以单独使用，也可以与运动训练结合使用。总结一下——这些实验将提供新的和重要的信息，关于心脏如何随着年龄的增长而硬化，以及是否有规律的体育锻炼可以预防它

DESCRIPTION (provided by applicant): Chronic physical inactivity carries with it substantial mobidity, mortality and cost for our aging population. The key finding of the previous funding period for this competitive renewal was that sedentary aging leads to marked atrophy and stiffening of the heart. In contrast, Masters athletes had cardiac compliance that was indistinguishable from young controls. Thus life long exercise training prevented the stiffening of the heart that previously had been considered to be an inevitable consequence of aging. Yet even prolonged and intense exercise training (up to 4-6 hours/week at the end of a year) failed to restore cardiac compliance in these healthy seniors. The global objective of this program is to determine the mechanism(s) of cardiac stiffening with sedentary aging, ascertain when in the aging process it occurs, and identify the minimal dose of sustained exercise training that preserves cardiac compliance over time. Our hypotheses are: Hypothesis 1a: A sedentary lifestyle leads to progressive atrophy and stiffening of the heart over a lifetime. Specific Aim 1a: To examine a cross-section of sedentary individuals over 5 decades from age 25 to 75 with comprehensive invasive and non-invasive measures of cardiac mechanics, relaxation, morphology and structural composition (lipid content and fibrosis). Hypothesis 1b: A sufficient amount of exercise exists that will prevent this stiffening process, if started early enough, and sustained over time; this amount is below that required to be a competitive Masters athlete. Specific Aim 1b: To identify healthy individuals who have consistently trained at 2 different doses: 30 min, 5 or more x/wk; or 30 min, 2-3 x/wk for at least 25 yrs. The same structural and functional assessment will be performed as in aim 1. Hypothesis 2: Chronic plasticity of myocardial compliance in response to aging is dependent on long term changes in metabolism, leading to accumulation of myocardial triglyceride and/or advanced glycation end products (AGEs). Specific Aim 2: to: a) measure myocardial triglyceride deposition using MRS in all the subjects from aim #1a and 1b encompassing a broad range of sedentary aging, and lifelong fitness levels; b) measure hemoglobin A1C as an index of protein glycation; c) perform delayed enhancement contrast MRI, and measure plasma markers of fibrosis. Hypothesis 3: AGE crosslinks must be broken before an improvement in cardiac compliance can occur with exercise training in previously sedentary seniors. The combination of an AGE crosslink breaker with exercise training will be superior to either intervention alone in reducing the cardiac stiffness associated with sedentary aging when initiated later in life. Specific Aim 3: To examine a novel intervention using ALT- 711 a specific breaker of the crosslinks of AGEs in parallel animal and human studies both alone and in combination with exercise training. Lay summary - these experiments will provide new and important information regarding how the heart stiffens with age, and whether regular physical activity can prevent it