Aging Fitness & Failure: Mechanisms of Diastolic Dysfunction

描述(申请人提供)：长期缺乏体力活动会导致我们老龄化人口的发病率、死亡率和成本。这一竞争性更新的前一个资助期的关键发现是，久坐衰老会导致心脏明显萎缩和僵硬。相比之下，大师赛运动员的心脏顺应性与年轻对照组几乎没有区别。因此，终身运动训练防止了心脏僵硬，而以前人们认为心脏僵硬是衰老的必然结果。然而，即使是长时间和高强度的运动训练(一年结束时每周高达4-6小时)也无法恢复这些健康老年人的心脏顺应性。该计划的全球目标是确定心脏僵硬与静坐衰老的机制(S)，确定在衰老过程中何时发生，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：久坐的生活方式会导致终生心脏进行性萎缩和僵硬。具体目标1a：对年龄从25岁到75岁的50岁以上久坐不动的人进行全面的有创和无创心脏力学、松弛、形态和结构成分(脂质含量和纤维化)测量。假设1b：有足够的运动量可以防止这种僵硬的过程，如果开始得足够早，并随着时间的推移而持续；这个量低于成为一名竞技大师赛运动员所需的量。具体目标1b：确定持续进行两种不同剂量训练的健康个体：30分钟，5次/周或30分钟，2-3次/周，至少25年。将进行与目标1相同的结构和功能评估。假设2：随着年龄的增长，心肌顺应性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/或晚期糖基化终末产物(AGEs)的积累。具体目标2：a)使用MRS测量目标1a和1b中所有受试者的心肌甘油三酯沉积，包括广泛的久坐不动老化和终身健康水平；b)测量作为蛋白质糖基化指标的血红蛋白A1C；c)进行延迟增强磁共振成像，并测量血浆纤维化标记物。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，年龄的交叉连接必须被打破。老年交联剂与运动训练相结合，在减少与晚年开始的久坐衰老相关的心脏僵硬方面，将优于单独进行干预。具体目标3：检验一种使用ALT-711的新干预方法，ALT-711是一种在平行的动物和人类研究中单独和结合运动训练的AGEs交叉链的特定断裂器。这些实验将提供新的和重要的信息，关于心脏是如何随着年龄的增长而变硬的，以及定期的体育锻炼是否可以防止心脏僵硬

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