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

描述（由申请人提供）：在美国，寿命的延长和发病率和死亡率的降低导致老年人数量的增加，这是公共政策讨论中经常提到的人口“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生活得更健康。虽然健康寿命的延长是一个不可否认的社会效益，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。迫切需要制定干预措施来解决这一日益严重的问题。衰老相关的认知功能障碍不是弥漫性的；相反，它针对的是选定的大脑区域，特别是额叶和海马体。海马体中分离但相互联系的亚区对致病机制的易感性不同，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）作为海马亚区不同的目标老化过程。与致病过程一样，任何改善大脑功能的干预都具有区域选择性。其中一种干预措施是体育锻炼，它已被证明可以改善额叶和海马的功能。使用高分辨率的功能性磁共振成像（fMRI），我们已经证明有氧训练选择性地有益于人类和小鼠的DG功能。此外，DG功能的改善与单词列表学习任务的表现改善有关，但与通常认为依赖额叶的任务无关。然而，该研究的人类部分有明显的缺点：研究规模小（N = 11），缺乏对照组，只招募了年轻受试者（20-45岁），并且只使用了有限的神经心理学测试。本提案的总体目标是使用高分辨率的功能磁共振成像来验证有氧训练将诱导年轻（20-35岁）和老年（50-65岁）成年人改善DG功能的假设，这些成年人被随机分配到积极训练条件组或等候名单对照组。我们将使用更全面的神经心理学测试来检查DG功能变化与选择的认知能力之间的关系。结合对正常衰老对DG的不同影响的观察，本研究项目将确立体育锻炼是一种有效的方法，可以改善随着年龄增长而发生在我们所有人身上的潜在认知衰退。因此，这个应用程序的潜在意义是巨大的。

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.