How the "longevity gene" works
Geneticists have revealed the secret of longevity of mutant flies
Scientists from the Moscow Institute of Physics and Technology, the Institute of Molecular Biology named after Engelhardt RAS, the Institute of Biology of Komi NC UrO RAS and Insilico Medicine (USA) have established which genes are affected by a mutation that prolongs the life of fruit flies. A comparison of the gene activity of long-lived flies and a control group of insects clarifies the mechanisms of aging and identifies targets for drugs against age-related diseases. The study was published in the journal Scientific Reports (Moskalyov et al., Transcriptome Analysis of Long-lived Drosophila melanogaster E(z) Mutants Sheds Light on the Molecular Mechanisms of Longevity).
"The activity of genes controls all the functions of the cell and ultimately the organism as a whole," explains the head of the study Alexey Moskalev, Head of the Laboratory of Life Expectancy and Aging Genetics at MIPT. "If we establish which genes are more and which are less active at different ages in long–lived animal lines compared to short-lived ones, we can better understand the biology of longevity."
Before setting up long-term experiments on mammals, biogerontologists test their hypotheses on animals with a short lifespan. Fruit flies are a convenient model, because their genome is well studied and contains 40% of the genes of human diseases, and the life expectancy is only a couple of months. The technologies of breeding these insects and editing their genome are well developed. In addition, fruit flies have two sexes, unlike, for example, nematodes.
The authors of the work used a specially bred line, or "breed", of fruit flies, in which one of the two copies of the gene called E(z) is turned off. This gene is able to regulate the activity of other genes. Such mutant flies live much longer than their counterparts and demonstrate greater resistance to adverse conditions. But exactly which genes are affected by the mutation, it was still unclear.
Russian scientists have confirmed the beneficial effect of mutation: it increased the life expectancy of fruit flies by an average of 22-23%.
The effect of a heterozygous mutation in E(z) on the life expectancy of males (a) and females (b). M, Max – an increase in average and maximum life expectancy, respectively. Drawings from an article in Scientific Reports – VM.
During the experiment, the flies were starved, poisoned with paraquat and subjected to 35-degree heat. Drosophila mutants have demonstrated increased resistance to all these factors. Moreover, an unexpected effect of mutation on reproduction was discovered.
"It is known that an increase in the life expectancy of fruit flies due to mutations is often accompanied by a decrease in reproductive ability. However, in our case, on the contrary, there was an increase in the fertility of mutant females in all age groups," commented Alexey Moskalev on the results of the study.
Having confirmed the positive effect of the mutation, the scientists compared the activity of genes in ordinary fruit flies and in mutants. To do this, the method of sequencing the products of all active cell genes (transcriptome) was used. 239 genes were found, the number of products of which significantly differed in long- and short-lived closely related groups. These genes affect, among other things, metabolism.
"We found out that the mutation causes a global restructuring of the body's metabolism. It affects the metabolism of carbohydrates, fats and nucleotides, as well as the activity of immune genes and the regulation of protein biosynthesis," Moskalev added.
In the future, the authors of the study will attempt to further increase the life expectancy of fruit flies using combinations of various factors of chemical and physical nature. Ultimately, the goal is to exceed the so-called species life span limit, that is, the maximum documented life span of individuals of a given species.
The work was carried out with the support of the Russian Science Foundation
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