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Researchers from the Moscow Institute of Physics and Technology, Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Institute of Biology of Komi Science Centre of the Ural Branch of the Russian Academy of Sciences, and Insilico Medicine, USA, determined which genes are affected by mutation that extends lifespan of fruit flies. Comparing gene activity of long-living fly strains to the control insects helped reveal mechanisms of aging and identify drug targets associated with aging-related diseases. The study was published in Scientific Reports.



"Gene activity controls all functions of a cell and, ultimately, the organism as a whole," said Alexey Moskalev, head of the Aging and Lifespan Genetics Lab at MIPT and the first author of the study. "We can better understand the biology behind longevity if we identify which genes are more active and which ones are less active at different ages in long-living strains of animals as compared to the short-living ones."



Biogerontologists use animals with short lifespans to test their hypotheses before moving on to conducting long-term experiments on mammals. Fruit fly (Drosophila melanogaster) is a very convenient model organism as its genome is well studied and it contains genes correlated to 40% of human diseases, and the fruit flies' lifespan is only a couple of months. Drosophila breeding and genome editing are well-established technologies. Apart from that, fruit flies have two sexes, unlike creatures such as nematodes.



The authors of the study used a specially bred strain of Drosophila with E(z) gene partially suppressed. This gene affects the activity of other genes. Such mutant flies have remarkably longer lifespans than control specimens and exhibit a higher tolerance to adverse conditions. Which specific genes are affected by the mutation, however, has been, until now, unclear.



The Russian researchers confirmed the positive effect of the mutation, with the average lifespan of Drosophila extended by 22-23%. As part of the experiment, the flies were starved, poisoned with paraquat, and exposed to scorching temperatures of 35 °C (95 °F). The mutant Drosophila displayed higher tolerance to all of these factors. Apart from that, the mutation had an unexpected effect on the flies' fertility.



"It is known that in Drosophila, lifespan extension induced by mutation is often associated with reduced reproduction. But in our case, we saw an increase in mutant female fecundity across all age groups", Alexey Moskalev said in his comment on the study results.



Having confirmed the positive effects of the mutation, the researchers analyzed the product of all active genes within a cell (transcriptome analysis) to compare gene activity of mutant Drosophila and control specimens. They discovered 239 genes with the amount of gene product significantly different for the long- and short-living related groups. Among other things, these genes are involved in metabolism.



"We discovered that the mutation triggers a global alteration of metabolism. It affects carbohydrate metabolism, lipid metabolism, and nucleotide metabolism, as well as immune response genes activity and protein synthesis", Moskalev added.



The authors of the study plan to extend the lifespan of fruit flies even further by exposing them to combinations of various chemical and physical factors. The ultimate goal is to extend maximum species lifespan or the longest lifespan recorded for a specimen of the species.



Reference: Moskalev et al. 2019. Transcriptome Analysis of Long-lived Drosophila melanogaster E(z) Mutants Sheds Light on the Molecular Mechanisms of Longevity. Scientific Reports. DOI: https://doi.org/10.1038/s41598-019-45714-x.



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