Role of Hypothalamic IKK-beta/NF-kappaB in Nutritional Control of Aging

描述（由申请人提供）：衰老和衰老相关疾病的发展涉及机体氧化应激和炎症的逐步形成，这是一种有害反应，可能是营养和能量失衡的重要结果。相反，许多物种的衰老已被证明是通过热量限制（CR）重新编程的;潜在的反应包括FoxO和SIRT家族对氧化应激的抵消作用。然而，还有一个大问题有待研究：营养如何与衰老过程联系起来，以及什么组织驱动这种联系。在初步研究的支持下，确定了下丘脑IKK 2/NF-：B在响应营养和引起各种全身生理失调中的作用，本研究的长期目标是解决代谢炎症的主开关途径如何的基本问题，包括I：B激酶-2（IKK 2）和下游核转录因子NF-：B，在下丘脑中介导衰老的营养控制。基于本研究建立的小鼠模型，最近获得的初步数据证明：（1）衰老与下丘脑中IKK 2/NF-：B的慢性激活和代谢性炎症的发展相关;（2）热量限制（CR）减少下丘脑中衰老依赖性IKK 2/NF-：B激活和相关的代谢性炎症诱导;（3）基因转移指导的IKK 2/NF-：B在下丘脑的营养感应区域，即下丘脑中基底（MBH）的激活，抑制了几种分子标记物（4）选择性消融MBH中营养感测神经元中的IKK 2减缓衰老和与衰老相关的健康衰退。因此，该项目假设下丘脑中IKK 2/NF-：B的年龄依赖性激活-特别是在营养感测亚区和神经元亚群中-长期促进衰老和衰老相关的生理下降;在该区域和相关神经元中抑制IKK 2/NF-：B可以模拟和增强CR的抗衰老作用，并代表控制衰老相关疾病的策略。将进行以下3个特定目的以检验该假设：1）分析正常和CR调节的衰老过程中下丘脑IKK 2/NF-：B活性; 2）检测IKK 2/NF-：B对下丘脑中CR分子标志物的作用; 3）确定下丘脑IKK 2/NF-：B在营养控制衰老中的作用。这些目的的实验将在一系列建立的小鼠模型中有序地分析衰老相关的分子和生理学，其中IKK 2/NF-：B在下丘脑营养敏感区域或细胞亚群中特异性地被激活或抑制。该项目代表了寻求建立大脑指导的分子和细胞基础，介导营养对衰老的作用的第一个此类项目。该项目的成功完成还可能为防治与衰老有关的疾病提供广泛的新战略。 公共卫生相关性：衰老和与衰老相关的疾病的发展涉及身体的氧化应激和炎症的逐步形成，这是一种可以由来自消耗的食物的卡路里引起的有害反应，相反，衰老已经被证明可以通过卡路里（食物）限制来减缓。由于大脑中的下丘脑是感知身体营养（热量）状况的总部，并且下丘脑中的炎症通路可以响应营养信号并影响下丘脑功能，因此本项目将研究下丘脑中的炎症通路是否以及如何介导营养对衰老的作用。这项研究的成功将推进我们对营养如何参与衰老和衰老相关疾病发展的认识，并为对抗衰老相关疾病提供广泛的新策略。

DESCRIPTION (provided by applicant): The development of aging and aging-related diseases involves body's progressive formation of oxidative stress and inflammation, a deleterious reaction that can be an important outcome of nutritional and energy imbalance. Conversely, aging across many species has been shown to be re-programmed by caloric restriction (CR); the underlying reactions include counteraction against oxidative stress by the FoxO and SIRT families. However, a large question has yet to be investigated: How nutrition connects with the aging process and what tissue(s) drive this connection. With the support of preliminary research that identified the role of hypothalamic IKK2/NF- :B in responding to nutrition and causing various whole-body physiological dysregulations, the long-term goal of this research is to address the fundamental question of how the master-switch pathway of metabolic inflammation, comprising I:B kinase-2 (IKK2) and the downstream nuclear transcription factor, NF-:B, in the hypothalamus mediates nutritional control of aging. Based on the established mouse models of this study, preliminary data were recently obtained to demonstrate: (1) aging is associated with chronic activation of IKK2/NF-:B and development of metabolic inflammation in the hypothalamus; (2) caloric restriction (CR) reduces aging-dependent IKK2/NF-:B activation and the related induction of metabolic inflammation in the hypothalamus; (3) Gene transfer-directed IKK2/NF-:B activation in the nutrition-sensing hypothalamic region, the mediobasal hypothalamus (MBH), suppresses several molecular markers (FoxOs and SIRTs) that underlie the anti-aging effects of CR; (4) Selective ablating IKK2 in nutrition-sensing neurons in the MBH de- accelerates aging and aging-associated health declines. Thus, this project hypothesizes that age-dependent activation of IKK2/NF-:B in the hypothalamus-particularly in the nutrition-sensing subregion and neuronal subpopulations-chronically promotes aging and aging-related physiological declines; suppressing IKK2/NF-:B in this region and in the related neurons can mimic and enhance the anti- aging effects of CR and represent a strategy for controlling aging-related disorders. The following 3 specific Aims will be performed to test this hypothesis are: 1) To profile hypothalamic IKK2/NF-:B activities in the normal and CR-modulated processes of aging; 2) To test the action of IKK2/NF-:B on molecular markers of CR in the hypothalamus; 3) To determine the role of hypothalamic IKK2/NF-:B in nutritional control of aging. The experiments of these Aims will orderly analyze aging-related molecles and physicology in a series of the established mouse models in which IKK2/NF-:B is activated or inhibited specifically in the nutrition-sensing hypothalamic region or cell subpopulations. This project represents the first of its kind in seeking to establish a brain-directed molecular and cellular basis that mediates the nutritional actions on aging. The successful completion of this project may also provide broad new strategies to combat aging-related diseases. PUBLIC HEALTH RELEVANCE: The development of aging and aging-related diseases involves body's progressive formation of oxidative stress and inflammation, a deleterious reaction that can be induced by calories from consumed food, and conversely, aging has been shown to be slowed down by caloric (food) restriction. Because the hypothalamus in the brain is the headquarters for sensing body's nutritional (calorie) status, and because an inflammatory pathway in the hypothalamus can respond to nutritional signals and affect hypothalamic functions, this project will investigate whether and how this inflammatory pathway in the hypothalamus mediates the nutritional actions on aging. Success of this study will advance our knowledge about how nutrition is involved in the development of aging and aging-related diseases, and provide broad new strategies to combat aging-related diseases.