Age-dependent Attenuation of Antioxidant Responses

University Of Louisville, Louisville KY

Investigators

Abstract

Our hypothesis is that there is an age-dependent attenuation of signaling through anti-oxidant or electrophile response elements (A/EpREs). The anti-oxidant response is a transcriptional response that involves binding of transcription factors, Nrf-2 and a small maf to the A/EpRE. This element is important for both the basal and inducible expression of enzymes involved in glutathione synthesis, oxidative stress responses and detoxication of xenobiotic compounds. Aging and senescence is known to be characterized by glutathione deficiency and an inability to maintain intracellular glutathione in response to environmental challenge. Compounds that reduce glutathione levels are more toxic in aged animals relative to young animals. A diminished response to environmental stress renders the organism more susceptible to cellular damage or disease leading to death. We believe that these age-related increases in toxicity are due to an inability of the animal to respond to environmental stress caused by attenuation of signaling through A/EpREs. To test my hypothesis I propose the following aims. Specific aim 1. We will test the hypothesis that the reduced ability of aged animals to maintain glutathione levels in response to environmental stress is associated with a reduced level and induction of - glutamylcysteine synthetase activity. Specific Aim 2. We will test the hypothesis that in aged animals, genes whose expression is controlled by A/EpRE show a diminished response to a prototypical A/EpRE inducer, t-butyl hydroxyanisole. Specific Aim 3. We will test the hypothesis that the age-related attenuation of responses from A/EpRE elements is related to a reduction or alteration of transcription factor binding to A/EpRE elements. The goal of this proposal is to obtain preliminary data to demonstrate the effects of aging on this key signaling pathway in response to environmental challenge. The long term goal of the project is to define age-dependent repressors of detoxification of toxic chemicals.