Exercise, Age-Related Memory Decline, and Hippocampal Function.

描述(申请人提供)：在美国，寿命的延长、发病率和死亡率的降低导致了越来越多的老年人，这是在讨论公共政策时经常提到的人口统计学“定时炸弹”。根据人口普查局的数据，65岁及以上的人口将在未来25年内翻一番。此外，这些老年人将比他们的前辈过着更健康的生活。虽然健康寿命的延长是不可否认的社会益处，但它也带来了一个重大的社会问题：与衰老相关的认知能力下降的流行病。迫切需要制定干预措施来解决这一日益严重的问题。与衰老相关的认知功能障碍不是弥漫性的；相反，它针对特定的大脑区域，特别是额叶和海马体结构。海马区独立但相互关联的亚区不同地容易受到致病机制的影响，包括正常的衰老过程。一系列体内和死后的研究都集中在齿状回(DG)上，因为DG是衰老过程中不同的目标海马区。与致病过程一样，任何改善大脑功能的干预都是有区域选择性的。其中一种干预是体育锻炼，它已被证明可以改善额叶和海马区的功能。使用功能磁共振成像(FMRI)的高分辨率变体，我们已经证明有氧训练对人类和小鼠的DG功能都有选择性的好处。此外，DG功能的改善与词表学习任务的表现改善有关，但与传统上被认为是额叶依赖的任务的表现无关。然而，这项研究的人类部分有明显的缺陷：它很小(N=11)，缺乏对照组，只招募年轻的受试者(20-45岁)，并且只使用有限的神经心理测试组件。这项建议的总体目标是使用fMRI的高分辨率变体来测试有氧训练将在年轻(20-35岁)和老年(50-65岁)的样本中诱导DG功能改善的假设，并随机分配到活跃训练条件或等待名单对照组。我们将使用更全面的神经心理测试来检验DG功能的变化与选定的认知能力之间的关系。结合正常衰老不同地针对DG的观察，这项研究计划将确定，体育锻炼是改善随着年龄增长而出现的潜伏的认知下滑的有效方法。因此，这一应用的潜在意义是巨大的。 与公共健康相关：根据美国人口普查局的数据，美国65岁及以上的人口预计将在未来25年内翻一番，这颗“人口定时炸弹”将带来与老龄化相关的认知能力下降的流行病，给个人及其家庭、医疗保健系统和整个社会带来负担。迫切需要了解认知衰退的病理生理学，然后开发干预措施来解决这个日益严重的问题，在这一应用中，我们建议在年轻人和老年人的样本中测试有氧运动训练对认知功能的影响。此外，由于最近的证据表明，1)认知老化对海马齿状回(DG)有不同的靶点，2)运动改善DG功能，因此我们还使用fMRI来检验运动诱导的认知功能改善是否通过增加DG的脑血流量来调节。

DESCRIPTION (provided by applicant): In the US, increased length of life and reduced morbidity and mortality have resulted in a growing number of older adults, the demographic "time bomb" often referred to in discussions of public policy. According to the Census Bureau, the population aged 65 and over will double in size within the next 25 years. Moreover, these older adults will live healthier lives than their predecessors. While this increased length of a healthy life is an undeniable societal benefit, it brings with it a major societal problem: an epidemic of aging-related cognitive decline. The need to develop interventions to address this growing problem is urgent. Aging-related cognitive dysfunction is not diffuse; rather it targets selected brain areas, in particular the frontal lobes and the hippocampal formation. The separate but interconnected subregions of the hippocampus are differentially vulnerable to pathogenic mechanisms, including the normal aging process. A range of in vivo and post-mortem studies have converged on the dentate gyrus (DG) as the hippocampal subregion differentially targeted by the aging process. As with pathogenic processes, any intervention that improves brain function does so with regional selectivity. One such intervention is physical exercise, which has been shown to improve both frontal lobe and hippocampal function. Using a high-resolution variant of functional magnetic resonance imaging (fMRI), we have demonstrated that aerobic training selectively benefitted DG function both humans and mice. In addition, improvement in DG function was associated with improved performance on a word list learning task but not in tasks conventionally thought to be frontal lobe dependent. The human part of the study had significant shortcomings, however: it was small (N = 11), lacked a control group, enrolled only young subjects (age 20-45 years), and employed only a limited neuropsychological testing battery. The overall goal of this proposal is to use the high-resolution variant of fMRI to test the hypothesis that aerobic training will induce improvements in DG function in a sample of younger (age 20-35) and older (50-65) adults, assigned randomly to an active training condition or wait list control group. We will use more comprehensive neuropsychological testing to examine the relationship between changes in DG function and selected cognitive capacities. Taken together with the observation that normal aging differentially targets the DG, this research program will establish that physical exercise is an effective approach for ameliorating the insidious cognitive slide that occurs in all of us as we age. Thus, the potential significance of this application is substantial. PUBLIC HEALTH RELEVANCE: According to the US Census Bureau, the United States population aged 65 and over is expected to double in size within the next 25 years, and this "demographic time bomb" will bring with it an epidemic of aging-related cognitive decline, imposing burdens on individuals and their families and on the healthcare system and society as a whole. The need to understand the pathophysiology of cognitive decline and then develop interventions to address this growing problem is urgent and in this application, we propose to test the impact of aerobic exercise training on cognitive function in a sample of young and older adults. In addition, because recent evidence suggests that 1) the dentate gyrus (DG) of the hippocampal formation is differentially targeted by cognitive aging and 2) that exercise improves DG function, we also use fMRI to test whether exercise-induced improvement in cognitive function is mediated by increased cerebral blood volume to the DG.