The goal of the project is to elucidate, in the model organism Caenorhabditis elegans, a biochemical process that contributes to organismal aging. Except for oxidants, the chemical or physical processes which have the capacity to disturb biological homeostasis and promote aging have not been characterized in detail. We propose that electrophilic products of lipid peroxidation, such as 4-hydroxynonenal (4-HNE), exert such an effect. We have found that expression of CeGSTP2-2, a glutathione transferase able to metabolize 4-HNE, correlates inversely with life span among natural genetic variants and among long-lived mutants, and that its expression is regulated by insulin-like growth factor signaling. By genetic manipulation of C. elegans, we have further shown that the level of CeGSTP2-2 and life span extension not only correlate, but are causally linked. The aim of the proposal is to define the mechanisms underlying that relationship. Specifically: (1) The hypothesis will be tested that life-span extension by CeGSTP2-2 is mediated by 4-HNE or similar aldehydes, rather than by unrelated substrates of CeGSTP2-2. (2) The functional significance of the very limited tissue distribution of CeGSTP2-2 will be defined. (3) The mechanism of inducibility of CeGSTP2-2 will be characterized, with special emphasis on regulation by insulin-like growth factor signaling. (4) By analysis of epistasis, the hypothesis will be tested that CeGSTP2-2 is not only a downstream effector counteracting the stochastic damage by electrophiles which leads to aging, but that it also modulates high-level signaling pathways that regulate aging. The project will combine biochemical techniques centered on electrophile metabolism with powerful genetic approaches available for C. elegans. The synergism of these two methods is expected to yield new insights into a fundamental mechanism that contributes to the aging process. Public Health Relevance: The focus of the proposed work is to define a basic mechanism which contributes to aging, a topic central to the mission of the National Institute on Aging. Closely similar pathways have been found to underlie aging in diverse species, and it is likely that the chemical processes that determine life span are also conserved. Therefore, understanding the process in the roundworm (in which experiments are much easier and faster) will help to shed light on human aging. The type of damage to be studied here could become the target of future interventions designed to slow aging and deter age-associated diseases.

R01AG028088

2007-02-01

2012-10-31