While the E(z) mutant strain of Drosophila melanogaster doesn’t quite live to the biblical old age of 969 years old, it does have an increased lifespan and greater stress resistance than its wild-type brethren. This tiny insect is often used as a model for human genetics and now a team of investigators, led by scientists at the Engelhardt Institute of Molecular Biology in the Russian Academy of Sciences, studying this long-lived mutant has determined which genes are affected by a mutation that extends the 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.

Findings from the new study were published recently in Scientific Reports through an article titled “Transcriptome Analysis of Long-lived Drosophila melanogaster E(z) Mutants Sheds Light on the Molecular Mechanisms of Longevity.”

Drosophila 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. Moreover, scientists will often use animals with short lifespans to test their hypotheses before moving on to conducting long-term experiments on mammals.

“Gene activity controls all functions of a cell and, ultimately, the organism as a whole,” explained lead investigator Alexey Moskalev, PhD, head of the Aging and Lifespan Genetics Lab at Moscow Institute of Physics and Technology. “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.”

In the current study, the researchers used a specially bred strain of Drosophila with the 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 unclear—until now.

“Using genome-wide transcriptome analysis, we demonstrated that lifespan extension, increase of resistance to hyperthermia, oxidative stress and endoplasmic reticulum stress, and fecundity enhancement in E(z) heterozygous mutants are accompanied by changes in the expression level of 239 genes (p < 0.05),” the authors wrote. “Our results demonstrated sex-specific effects of E(z) mutation on gene expression, which, however, did not lead to differences in lifespan extension in both sexes. We observed that a mutation in an E(z) gene leads to perturbations in gene expression, most of which participate in metabolism, such as carbohydrate metabolism, lipid metabolism, drug metabolism, nucleotide metabolism.”

The research team 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,” Moskalev commented.

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 concluded.

The study authors 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.

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