Aging Fitness & Failure: Mechanisms of Diastolic Dysfunction

描述（由申请人提供）：长期缺乏身体活动对我们的老龄化人口来说具有相当大的流动性、死亡率和成本。上一个资助期的关键发现是，久坐不动的衰老会导致心脏明显萎缩和硬化。相比之下，大师赛运动员的心脏顺应性与年轻的对照组没有区别。因此，终身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的必然结果。然而，即使是长时间和高强度的运动训练（在一年结束时高达4-6小时/周）也未能恢复这些健康老年人的心脏顺应性。该计划的总体目标是确定久坐老化的心脏僵硬机制，确定在老化过程中何时发生，并确定随着时间的推移保持心脏顺应性的最小剂量的持续运动训练。我们的假设是：假设1a：久坐不动的生活方式导致心脏在一生中进行性萎缩和硬化。具体目标1a：研究年龄在25 - 75岁之间、超过50年的久坐个体的横截面，对心脏力学、舒张、形态和结构组成（脂质含量和纤维化）进行全面的有创和无创测量。假设1b：足够的运动量存在，将防止这种僵硬的过程，如果开始得足够早，并持续一段时间;这一数额低于所需的是一个有竞争力的大师运动员。具体目标1b：确定持续接受2种不同剂量训练的健康个体：30分钟，5次或更多次/周;或30分钟，2-3次/周，持续至少25年。将进行与目标1相同的结构和功能评估。假设二：心肌顺应性对衰老的慢性可塑性依赖于代谢的长期变化，导致心肌甘油三酯和/或晚期糖基化终产物（AGEs）的积累。具体目标二：收件人：a）使用MRS测量来自目标#1a和1B的所有受试者的心肌甘油三酯沉积，包括广泛的久坐老化和终身健康水平; B）测量血红蛋白A1 C作为蛋白质糖化的指标; c）进行延迟增强对比MRI，并测量纤维化的血浆标志物。假设三：在以前久坐的老年人通过运动训练改善心脏顺应性之前，必须打破AGE交联。AGE交联破坏剂与运动训练的组合在降低与生活后期开始的久坐老化相关的心脏僵硬度方面优于任何一种单独干预的上级。具体目标3：在动物和人体平行研究中，单独使用ALT- 711（AGEs交联的特异性破坏剂）以及与运动训练联合使用，检查一种新的干预措施。这些实验将提供新的重要信息，关于心脏如何随着年龄的增长而变硬，以及定期的身体活动是否可以预防它。

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