Age-related changes in murine CNS mRNA gene expression are modulated by dietary melatonin





Bondy, S. C. , Sharman, K. G., Yuan-Wen Ge, Y-W., Debomoy K. Lahiri, Sharman, E. H.

Department of Community and Environmental Medicine, University of California, Irvine, CA 92697-1825



The profile of gene expression is not constant throughout the life cycle. Gene array analysis has been used to quantitatively estimate the extent to which genes are expressed in the cerebral cortex of both young (4-month) and old (27 month) B6C3F1 male mice. A stringent degree of significance was obtained using an Affymetrix program and six different comparisons. Out of 12423 mRNA levels, only 25 changed significantly with age. Nine of these genes coded for inflammatory proteins, all of which were elevated in aged, relative to younger mice.

Melatonin (200 ppm) was included in the diet of aged animals for 8 weeks. Such supplementation with melatonin is able to elevate levels of melatonin in both serum and cortical tissue. This treatment reversed 13 of the 25 genes altered with age. Levels of 8 of the 9 inflammatory genes elevated with age, were reduced by melatonin. In no case did melatonin potentiate age-related changes in gene expression.

Concentrations of mRNAs for inflammatory cytokines interleukin-6 (IL-6) and TNFa, were not present in the microarray in sufficient amounts for quantitation. These were therefore assayed by Northern blotting. Both mRNA species were greatly elevated with age but lost their ability to respond to an exogenous inflammogen, lipopolysaccharide (LPS). Dietary melatonin reversed this age-related increase in basal levels of IL-6 and TNFa mRNAs. Melatonin also restored the ability of these mRNAs to be expressed more in the presence of LPS.

The restoration of a more youthful gene profile to brains of aged animals by melatonin treatment, to a large extent, involves reversal of age-induced elevation of basal inflammatory parameters. Supported by NIH Grants AG16794 and ES 7992.




Key words: Brain, melatonin, inflammation, cytokines, mRNA, neurodegeneration







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