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身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家族对氧化应激的对抗。然而，还有一个大问题有待研究：营养是如何与衰老过程联系在一起的，又是什么组织推动了这种联系。在初步研究确定下丘脑IKK2/NF-:B在营养反应和引起各种全身生理失调中的作用的支持下，本研究的长期目标是解决下丘脑代谢炎症的主开关通路，包括I:B激酶-2 （IKK2）和下游核转录因子NF-:B，如何介导衰老的营养控制的基本问题。基于本研究建立的小鼠模型，最近获得的初步数据表明：(1)衰老与下丘脑IKK2/NF-:B的慢性激活和代谢性炎症的发生有关；(2)热量限制（CR）减少衰老依赖性IKK2/NF-:B的激活和下丘脑代谢性炎症的相关诱导；(3)基因转移导向的IKK2/NF-:B在下丘脑营养感应区，即下丘脑中基底（MBH）的激活，抑制了CR抗衰老作用的几个分子标记（FoxOs和sirt）；(4)选择性消融MBH中营养感应神经元中的IKK2加速衰老和衰老相关的健康衰退。因此，该项目假设下丘脑中IKK2/NF-:B的年龄依赖性激活-特别是在营养感应亚区和神经元亚群中-慢性促进衰老和与衰老相关的生理衰退；抑制该区域和相关神经元的IKK2/NF-:B可以模拟和增强CR的抗衰老作用，是控制衰老相关疾病的一种策略。为了验证这一假设，将进行以下3个具体目的：1)分析下丘脑IKK2/NF-:B在正常和cr调节的衰老过程中的活性；2)检测IKK2/NF-:B对下丘脑CR分子标志物的作用；3)探讨下丘脑IKK2/NF-:B在营养调控衰老中的作用。这些Aims的实验将在一系列已建立的小鼠模型中有序地分析IKK2/NF-:B在营养感知下丘脑区域或细胞亚群中特异性激活或抑制的衰老相关分子和生理学。这个项目是同类中第一个寻求建立一个以大脑为导向的分子和细胞基础，介导衰老的营养作用。这一项目的成功完成也可能为防治与衰老有关的疾病提供广泛的新战略。

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.