The deleterious effects of both acute and chronic ethanol consumption are enhanced in aging organisms; however, little is known of the biochemical mechanisms involved. Our previous studies have demonstrated that a glutathione deficiency is a general phenomenon of senescent organisms and its correction leads to increased longevity. Since glutathione is known to protect against ethanol toxicity by detoxifying reactive products of ethanol metabolism such as acetaldehyde, peroxides and free radicals, we hypothesize that many of the adverse effects of ethanol are enhanced in aging due to a relative glutathione deficiency. Further, correction of this deficiency will also reduce the aging impairments. The objectives of this proposed study are to test this hypothesis by elucidating the effects of aging on specific components of ethanol metabolism as well as biochemical and physiological responses to ethanol administration in the aging C57BL/6 mouse model. The metabolic systems selected for study include alcohol dehydrogenase, aldehyde dehydrogenase and the microsomal ethanol-oxidizing system. The biochemical and physiological responses to ethanol that will be analyzed include fatty liver development, lipid peroxidation, loss of motor activity and hypothermia. Changes observed in these parameters will be correlated with endogenous GSH status and chronological age. Finally, once specific aging changes have been identified, we plan to determine the effects of altering glutathione levels in vivo on these parameters. These results should provide important information on the effect of aging and GSH deficiency on several important ethanol-induced physiological and biochemical impairments as well as the major enzyme systems involved in ethanol metabolism. Ultimately, this research should provide essential information regarding the sensitivity of elderly individuals to alcohol and potential mechanisms for prevention of ethanol-related morbidity and mortality.
| Vogt, B L; Richie Jr, J P (1993) Fasting-induced depletion of glutathione in the aging mouse. Biochem Pharmacol 46:257-63 |
