Hypothalamic Glucoregulation in Aging Rodents by fMRI

在美国，老龄化是发病率、死亡率和医疗费用的重要原因，并与糖尿病和动脉粥样硬化有关。记录饮食限制(DR)抗衰老作用的证据在各种实验动物中都存在。在不同年龄的小鼠、大鼠和非人类灵长类动物中，使用各种DR方案的慢性降低血糖水平也得到了明确的证明。事实上，有研究表明，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，众所周知，下丘脑在进食和饮水等过程中扮演着极其关键的角色，它与血糖调节密切相关。然而，DR后降糖抗衰老作用的体内特异性和机制仍不清楚。我们的总体长期目标是了解DR后血糖下降的下丘脑机制(S)，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使用功能磁共振成像(FMRI)在体内监测下丘脑葡萄糖代谢随年龄的变化以及它们在DR中的逆转。中心假设是，衰老改变了下丘脑的糖调节，而DR延缓了这种与年龄相关的变化。我们在早期研究中获得的数据显示，DR在一天中和大鼠的整个生命周期中都能降低血糖水平。这项拟议研究的基本原理是，一旦通过功能磁共振获得饮食限制大鼠下丘脑反应的知识，随后就可以确定导致这一反应的机制。我们为开展这项拟议的项目做好了独一无二的充分准备，因为我们团队的研究已经就DR对大鼠的影响产生了新的观察结果，并成功地展示了在人类和大鼠服用葡萄糖后的体内下丘脑fMRI反应(反映基础血流量、血容量和与潜在神经活动相关的血氧变化的信号强度变化)。中心假说将被检验，这项应用的目标将通过追求以下特定目标来实现：(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，以及DR是否逆转它；以及(B)确定是否可以在小鼠身上检测到这些与年龄相关的变化，以便能够在未来使用转基因模型。建议的工作具有新颖性和创新性。并有望证明，随着年龄的增长，腹膜内注射葡萄糖引起的正常fMRI下丘脑反应有显著变化。这些结果将对我们理解DR中的糖调节产生重大影响。此外，它们将在未来研究DR在转基因小鼠模型中的作用方面具有极其重要的价值。最后，这项拟议的研究有望为老龄化研究做出根本性的新贡献，并最终有望减少与老龄化相关的并发症。

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.