Aging is a pleiotropic process involving genetic and environmental factors. Recently it has been demonstrated that dietary constituents may affect senescence. In the present study, adult (3 month-old) mice were fed diets supplemented with ubiquinone (coenzyme Q(10)), alpha-lipoic acid, melatonin or alpha-tocopherol for a six-month period to determine if antioxidants may reverse or inhibit the progression of certain age-associated changes in cerebral mitochondrial electron transport chain (ETS) enzyme activities. The control consisted of a group of mice maintained on a basal diet for the same period. The activity of cytochrome c oxidase (Complex IV) increased with age but melatonin supplementation restored the activity to levels of 3 month-old animals. The activity of succinate dehydrogenase (Complex II) showed no age-related changes. However, this enzyme complex was elevated, in animals supplemented with coenzyme Q(10), alpha-lipoic acid and alpha-tocopherol, above corresponding values obtained with basal diet. NADH-ubiquinone oxidoreductase (Complex I) and ubiquinol:ferricytochrome-c oxidoreductase (Complex III) activities remained unchanged.

The basal levels of expression of mRNA of cytokines, interleukin-6 (IL-6) and tumor necrosis factor (TNF-alpha), in the cerebral cortex of 5 and 26 month-old male B6C3F1 mice have been compared. In addition, the responsivity of animals of differing age to an inflammatory stimulus (lipopolysaccharide, LPS) has been studied. Basal levels of both of these cytokine mRNAs were elevated in aged animals relative to the younger group. However LPS administration led to a robust increase in cytokine mRNA levels in the younger animals but in aged mice, there was either an unchanged (IL-6) or a depressed (TNF-alpha) response. Administration of dietary melatonin (200 ppm) to aged mice for 6 weeks prior to sacrifice, resulted in reduction of basal levels of cytokine mRNA to values found in the younger animals. Furthermore, following administration of LPS to melatonin fed animals, cerebral cytokine mRNA levels were significantly elevated rather than being unchanged or depressed. Taken together these findings reflect a trend in the cortices of melatonin-treated aged mice, to more closely approximate the status of younger mice. For comparative purposes, parallel studies were carried out using an immunologically active organ (spleen) and a non-neural organ with a low rate of cell turnover (heart muscle). In both these tissues, basal levels of cytokine mRNAs of animals of either age were very low, and there was a marked positive response to LPS. Dietary melatonin had no effect on the responses of TNF-alpha mRNA to LPS but attenuated the reaction of splenic IL-6 mRNA, thus bringing the response closer to that of the younger mice.

The potential utility of dietary supplementation in order to prevent some of the oxidative and inflammatory changes occurring in the brain with age, has been studied. The cerebral cortex of 27-month-old male B6C3F1 mice had elevated levels of nitric oxide synthase 1 (EC 1.14.13.39) (nNOS) and peptide nitrotyrosine relative to cortices of younger (4-month-old) animals. After 25-month-old mice received basal diet together with 300 mg/l acetyl L-carnitine in the drinking water for 8 weeks, these levels were fully restored to those found in younger animals. A partial restoration was found when old animals received basal diet supplemented with 200 ppm melatonin in the diet. Levels of mRNA (messenger RNA) for nNOS were unchanged following these treatments implying translational regulation of nNOS activity. Behavioral indices indicative of exploratory behavior were also depressed in aged animals. Dietary supplementation with melatonin or acetyl L-carnitine partially reversed these changes. These findings suggest that dietary supplementation cannot merely arrest but indeed reverse some age-related increases in markers of oxidative and inflammatory events occurring with the cortex.