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

描述(申请人提供)：衰老和衰老相关疾病的发展涉及身体逐渐形成氧化应激和炎症，这是一种有害的反应，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由热量限制(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。然而，一个大问题还有待研究：营养与衰老过程是如何联系的，是什么组织(S)推动了这种联系。在初步研究的支持下，确定了下丘脑IKK2/NF-：B在营养反应和引起各种全身生理失调中的作用，本研究的长期目标是解决下丘脑中代谢炎症的主开关途径，包括I：B激酶-2(IKK2)和下游核转录因子NF-：B如何介导营养调控衰老的基本问题。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展有关；(2)热量限制(CR)减少了衰老依赖的IKK2/NF-：B的激活和相关的下丘脑代谢性炎症的诱导；(3)基因转移指导的下丘脑营养感知区域-下丘脑(MBH)的IKK2/NF-：B的激活抑制了几个分子标志物(Foxos和SIRTs)的抗衰老作用；(4)选择性消融MBH内营养感觉神经元中的IKK2可减缓衰老，并使衰老相关的健康状况下降。因此，本项目假设在下丘脑，特别是在营养感受区和神经元亚群中，随着年龄的增长，IKK2/NF-：B的激活会慢性地促进衰老和衰老相关的生理衰退；在该区域和相关神经元中抑制IKK2/NF-：B可以模拟和增强CR的抗衰老作用，并代表了控制衰老相关疾病的一种策略。为了验证这一假说，我们将采取以下三个具体目标：1)分析正常和CR调节的衰老过程中下丘脑IKK2/NF-：B的活性；2)检测IKK2/NF-：B对下丘脑CR分子标志物的作用；3)确定下丘脑IKK2/NF-：B在营养控制衰老中的作用。这些AIMS的实验将有序地分析一系列已建立的小鼠模型中与衰老相关的分子和生理学，在这些模型中，IKK2/NF-：B在营养感知下丘脑区域或细胞亚群中被特异性地激活或抑制。该项目是寻求建立大脑导向的分子和细胞基础的第一个此类项目，该分子和细胞基础调节衰老的营养作用。该项目的成功完成还可能为抗击衰老相关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逐渐形成氧化应激和炎症，这是一种有害的反应，可由摄入的食物中的卡路里引起，反过来，已证明限制卡路里(食物)可减缓衰老。由于大脑中的下丘脑是感知身体营养(卡路里)状态的总部，而且下丘脑中的炎症通路可以对营养信号做出反应并影响下丘脑功能，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。这项研究的成功将促进我们对营养如何参与衰老和衰老相关疾病的发展的了解，并为抗击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.