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Role of AGE/RAGE signaling as a driver of pathological aging in the brain

Project Description:

A major goal of aging research is to prevent or limit the natural decline of physiological functions that occurs with time. Age-related reductions in the ability to learn, remember, sleep well, and perform physical tasks can drastically decrease an individual’s independence and negatively affect their quality of life. The goal of this project to evaluate whether the accumulation of advanced glycation end products (AGEs) and their receptor (RAGE) directly cause these impairments in adult (12-months) and advanced age (24-months). It is widely accepted that sugar-modified molecules accumulate in aged tissue and targeting their production and signaling has been a focus of many neurodegenerative disease researchers. However, there are still gaps in our scientific understanding of the effects of these in the healthy aging system. Recent evidence suggests that reducing AGEs can increase the lifespan and motor function of C. elegans worms. We hypothesize that systemic knockout of RAGE will enhance longevity as well as behavioral and physiological signs of aging by attenuating the response to and release of maladaptive oxidative stress and inflammatory markers. The major goal is to better understand the role of advanced glycation end products on regulating healthspan or the period of healthy life. Our aims are designed to 1) determine if RAGE knockout mice will have altered cognitive function, 2) assess the effects of RAGE knockout on longevity and hallmarks of aging in these mice, and 3) measure changes in AGE accumulation and oxi-inflammatory signaling in RAGE knockout mice. Successful completion will allow us to better understand how glycation contributes to the aging process and may present a paradigm shift in our understanding of both the AGE/RAGE signaling cascade and the potential of therapeutically targeting RAGE signaling.

Contact Information:

Photo of James A. Stewart

Dr. James A. Stewart, Jr.
Associate Professor of Pharmacology
   and Research Associate Professor in the Research Institute of Pharmaceutical Sciences
Faser Hall 307

Associated Personnel:

Cody Porter
Graduate Student/Research Assistant

Sherilyn Hulugalla
Graduate Student/Research Assistant

Miguel DeLeon (Ashpole Lab)
Graduate Student/Research Assistant