The neurotransmitter dopamine ( DA) is known to be involved in a multitude of physiological processes. We investigated sexually dimorphic effects of disruptions in DA homeostasis and its relationship to senescence using three different Drosophila melanogaster mutants namely Catsup ( Catsup 26) with elevated DA levels, and pale ( ple 2), Punch ( Pu Z22) with depleted DA levels. In all genotypes including controls, DA levels were significantly lower in old (45-50-day-old) flies compared with young (3-5-day-old) in both sexes. Interestingly, females had lower DA content than males at young age whereas this difference was not observed in old age, suggesting that males had a larger decline in DA levels with age. Females, in general, were longer lived compared with males in all genotypes except ple 2 mutants with depleted DA levels. This phenotype was abolished in the ple2 rescue flies. Interestingly, females also demonstrated marked age-related decline in circadian locomotor activity compared with males. Old Catsup 26 males with elevated DA levels accumulated significantly lower levels of lipid peroxidation product 4-hydroxy 2-nonenal (4- HNE) compared with age-matched wild type, ple 2 and Pu Z22 mutant males. In Catsup 26 revertant lines this phenomenon was absent. We also observed a sexually dimorphic response in the expression levels of key stress and aging associated and/or related transcription factor genes across genotypes with elevated or depleted DA levels which was reverted to wild type levels in specific rescue lines. Taken together, our results reveal a novel sexually dimorphic involvement of DA in senescence characteristics of D. melanogaster. [ABSTRACT FROM AUTHOR]