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.