Title

Lipid peroxidation product 4-hydroxynonenal: A molecular determinant of oxidative damage and a marker of aging in Drosophila melanogaster

Date of Completion

January 2006

Keywords

Biology, Molecular|Biology, Genetics

Degree

Ph.D.

Abstract

The oxidative stress hypothesis predicts that the accumulation of oxidative damage to a variety of macromolecules is the molecular trigger driving the process of aging. Although an inverse relationship between oxidative damage and life span has been established in several different species, the precise relationship between oxidative damage and aging is not fully understood. This study presents data that characterizes Oxidative Damage and shows a relationship between the accumulation of Oxidative Damage and aging. We have developed an enzyme-linked immunosorbent assay using commercially available reagents for measuring 4-hydroxy-2-nonenal in proteins, a marker for oxidative damage to lipids, and present data in flies to show that 4-hydroxy-2-nonenal-adducts accumulate in an age dependent manner. With immunohistology, we also find the primary site of 4-hydroxy-2-nonenal accumulation is the periceribral fat body, where induction of dFOXO was recently shown to retard aging. When subjected to environmental interventions that shorten life span, such as elevated ambient temperature, the chronological accumulation of 4-hydroxy-2-nonenal-adduct is accelerated. Conversely interventions that extend life span, such as lower ambient temperature or low calorie diets, slow the accumulation of 4-hydroxy-2-nonenal-adduct. These data provide a strong link among caloric restriction, aging and oxidative damage, supporting reactive oxygen species as a major contributor to the aging process. ^