Senior Scholar Award in Aging
Fred E. Regnier, Ph.D, co-PI
Purdue University
Arlan G. Richardson, Ph.D, co-PI
University of Texas Health Science Center - San Antonio

A Novel Proteomic Approach to Identifying, Sequencing, and Quantifying Oxidatively Damaged Proteins in Tissues of Aged Animals

One of the most widely accepted theories in aging research is the free radical or oxidative stress theory of aging, which states that a steady-state accumulation of oxidative damage in cells and tissues leads to aging. Over the past two decades, it has been shown that oxidative damage to cells increases with age in a wide range of organisms, including humans, as would be predicted from the oxidative stress theory of aging. In addition, manipulations that retard aging and increase lifespan have been shown to retard/reduce the age-related accumulation of oxidative damage. Therefore, oxidation appears to be an important factor in the mechanism underlying the aging process.

A major deficiency in the oxidative stress theory of aging is that it does not allow one to explain at the molecular/biochemical level how increased oxidative damage can bring about aging. The general argument, which is not particularly informative, is that the increased levels of oxidative damage lead to reduced physiological function, which leads to aging. However, there is no model for how reduced function can arise from increased oxidative damage. The experiments described in this grant represent the first attempt to identify those physiological processes that are altered by oxidative damage and that potentially could be important in aging.

Research over the past two decades has shown that oxidative damage occurs in lipid, DNA, and protein molecules in cells/tissues and that oxidative damage to these three classes of molecules increase significantly with age. In our research, we will focus on protein oxidation because it has been shown that global protein oxidation increases with age in organisms ranging from houseflies to humans and because proteins play an essential role in cellular metabolism and function. For example, all metabolic pathways occur because of the action of specific proteins, termed enzymes. Therefore, oxidative damage to a protein could alter its ability to catalyze a chemical reaction in a cell, and therefore, to conduct a specific function. We hypothesize that that certain proteins, and therefore, specific reactions/metabolic pathways, are more vulnerable to the age-related increase in oxidation than other proteins and that the changes in these reactions/pathways play a major role in aging.

In this grant, we will employ the latest and most advanced technology in proteomics to identify the proteins that become oxidatively damaged and determine how aging alters the specific sites of oxidative damage in these proteins. Data from these studies will allow investigators for the first time to begin the identification of metabolic pathways that are compromised by oxidative damage. This information will allow researchers to identify molecular targets that can be used to test new anti-aging therapies.

Contact Dr. Regnier.

Contact Dr. Richardson.