In our prior studies (Orr et al., 2005) we achieved a 30-50% increase in the life span of Drosophila by manipulating glutathione (GSH) production in neuronal tissues, through over-expression of glutamate-cysteine ligase (GCL), a key enzyme in glutathione biosynthesis. In the present study, we identified gene response patterns from which plausible mechanisms responsible for the observed effects on life span might be inferred. Functional clustering analysis of the transcriptome data revealed that biological processes affected by GCLc in young flies (10 days) were generally related to cell morphogenesis and differentiation, while those in older flies were associated with nucleosome organization and detoxification processes. Notably, in older flies there was considerable reduction in the expression of genes related to humoral immunity in the GCLc over-expressors and this was observed in flies of the same chronological age (∼40 days old flies) and in flies of equivalent physiological age (10% dead for both experimentals and controls). Our study demonstrates that most of the GSH-mediated processes and targets are relatively distinct in young and old flies. Nevertheless there exists a restricted number of related processes affected by GCLc in both young and old flies and prominent among them are those associated with proteolysis and metabolism.