Hormetic efficacy of rutin to promote longevity in Drosophila melanogaster

Hormetins are compounds that mediate hormesis by being beneficial at low doses but detrimental at high doses. Recent studies have highlighted that many compounds that extended lifespan in model organisms did so by mediating hormesis. Rutin is a glycosylate conjugate of quercetin and rutinose and is abundant in citrus fruits and buckwheat seeds. Rutin possess ROS scavenging, anti-cancer, cardio-protective, skin-regenerative and neuro-protective properties. Drosophila melanogaster is an attractive model organism for longevity studies owing to its homology of organ and cellular-pathways with mammals. In this study, we aimed to understand the effect of rutin on extending longevity in Drosophila melanogaster. Male and female flies were administered with a range of rutin doses (100-800 A mu M) to analyse whether rutin mediated lifespan-extension by hormesis. Effect of rutin on physiological parameters like food intake, fecundity, climbing activity, development and resistance to various stresses was also studied. Lifespan assays showed that rutin at 200 and 400 A mu M significantly extended median lifespan in both male and female flies beyond which flies exhibited drastically reduced longevity. Increase in survival at 400 A mu M was associated with reduced food intake and fecundity. Flies exhibited improved climbing capability with both 200 and 400 A mu M rutin. Flies fed with 100 and 200 A mu M rutin exhibited enhanced survival upon exposure to oxidative stress with 400 A mu M rutin exhibiting no improvement in median lifespan following oxidative stress. Analysis of endogenous peroxide upon treatment with rutin (100-400 A mu M) with or without 5% H2O2 showed elevated levels of endogenous peroxide with 400 A mu M rutin whereas no increase in hydrogen peroxide level was observed with rutin at 100 and 200 A mu M. Finally, gene expression studies in male flies revealed that rutin treatment at 200 and/or 400 A mu M elevated transcript levels of dFoxO, MnSod, Cat, dTsc1, dTsc2, Thor, dAtg1, dAtg5 and dAtg7 and reduced transcript levels of dTor. Collectively, rutin at 200 and 400 A mu M improved longevity in flies; 200 A mu M rutin acted as a mild stressor to prolong lifespan in flies by mediating hormesis whereas 400 A mu M, being a high dose for best positive effects.