Hypothalamic Glucoregulation in Aging Rodents by fMRI

在美国，衰老是发病率、死亡率和医疗保健费用的一个重要原因，并与糖尿病和动脉粥样硬化有关。证据表明，饮食限制（DR）的抗衰老作用存在于各种各样的实验动物。长期降低不同年龄的小鼠、大鼠和非人类灵长类动物的血糖水平，并使用各种DR方案也得到了清楚的证明。事实上，已经有人提出降低血糖可能是DR延缓衰老机制的一个重要组成部分。此外，下丘脑在进食和饮水等过程中所起的极其重要的作用以及它在血糖调节中的密切参与是众所周知的。然而，DR后降低血糖抗衰老作用的体内特异性和机制尚不清楚。我们的总体长期目标是了解DR后血糖降低的下丘脑机制，并根据所获得的知识开发有效的预防和治疗抗衰老策略。这一特殊应用的目的是利用功能磁共振成像（fMRI）监测下丘脑葡萄糖代谢随衰老的体内变化及其与DR的逆转。中心假设是衰老改变了下丘脑的血糖调节，而DR延缓了这种与年龄相关的变化。在我们早期的研究中获得的数据表明，DR在大鼠的一生中降低了全天的血糖水平。这项研究的基本原理是，一旦通过功能磁共振成像获得了限制饮食的大鼠下丘脑反应的知识，就可以随后确定产生这种反应的机制。我们已经为这个项目做好了充分的准备，因为我们团队的研究已经在大鼠中产生了关于DR影响的新观察结果，并且已经成功地证明了人类和大鼠在葡萄糖给药后体内下丘脑fMRI反应（信号强度变化反映了基础血流量、血容量和与潜在神经活动相关的血氧变化）。中心假设将被检验，本应用的目标将通过追求以下具体目标来实现：(a)确定大鼠下丘脑的葡萄糖代谢是否随着年龄的增长而改变，DR是否会逆转这一变化；(b)确定这些与年龄相关的变化是否可以在小鼠中检测到，以便将来能够使用转基因模型。提议的工作是新颖和创新的。并有望证明，随着年龄的增长，在正常的fMRI下丘脑反应中，腹膜内葡萄糖给药会引起显著的变化。这些结果将对我们对DR中血糖调节的理解产生重大影响，并且对未来研究DR在转基因小鼠模型中的作用具有重要价值。最后，该研究有望对衰老研究做出根本性的新贡献，并最终有望减少与衰老相关的并发症。

Aging is a significant cause of morbidity, mortality, and health-care costs in the United States and has associations with diabetes and atherosclerosis. Evidence documenting the anti-aging effect of dietary restriction (DR) exists in a wide variety of laboratory animals. Chronically lowered plasma glucose levels in mice, rats and non-human primates of different ages and using a variety of DR regimens have also been clearly demonstrated. Indeed, it has been suggested that lowered plasma glucose may be an important component of the mechanism by which DR retards aging. Further, the extremely crucial role that the hypothalamus plays in processes like feeding and drinking and its intimate involvement in glucoregulation are well known. However, the in vivo specificity and mechanism responsible for the anti-aging action of decreased plasma glucose following DR still remains unknown. Our overall long-term goal is to understand the hypothalamic mechanism(s) accountable for the decreased plasma glucose following DR and the development of effective preventive and therapeutic anti-aging strategies from the knowledge so gained. The objective of this particular application is to monitor in vivo alterations in glucose metabolism of the hypothalamus with aging and their reversal with DR, using functional magnetic resonance imaging (fMRI). The central hypothesis is that aging alters hypothalamic glucoregulation and that DR retards this age-associated change. Data obtained in our earlier study showed that DR lowers plasma glucose levels throughout the course of the day and over the lifespan of rats. The rationale that underlies the proposed research is that, once knowledge of the hypothalamic response is obtained in diet restricted rats with fMRI, the mechanism that is responsible for this can be subsequently determined. We are uniquely well prepared to undertake the proposed project, as our team's research has already yielded novel observations concerning the effects of DR in rats and has also been successful in demonstrating the in vivo hypothalamic fMRI response (signal intensity change which is a reflection of changes in basal blood flow, blood volume, and blood oxygenation associated with underlying neural activity) following glucose administration in both humans and rats. The central hypothesis will be tested and the objective of this application accomplished by pursuing the following specific aims: (a) To determine if glucose metabolism in the rat hypothalamus is altered with aging and whether DR reverses it; and (b) To determine if these age-related changes can be detected in mice so as to be able to use transgenic models in the future. The proposed work is novel and innovative. and is expected to demonstrate that there are significant alterations with aging, in the normal fMRI hypothalamic response induced by intraperitoneal glucose administration. Such outcomes will have a significant impact on our understanding of glucoregulation in DR. Further, they will be extremely valuable in investigating the effects of DR in transgenic models of mice in the future. Finally, the proposed research is expected to make fundamental new contributions to aging research and can eventually be expected to reduce the complications associated with aging.