Scientists report that fruit flies inhibited from producing the protein Sirt4 are short-lived, while flies modified to make extra Sirt4 are live longer. Flies lacking Sirt4 show increased sensitivity to starvation, decreased fertility and activity, and an inability to use energy stores in their bodies, add the researchers, who say their work suggests that increasing Sirt4 activity may be an important approach for treating age-related metabolic decline and disorders, such as diabetes and obesity.

Their study (“Sirt4 Is a Mitochondrial Regulator of Metabolism and Lifespan in Drosophila melanogaster”) is published in the Proceedings of the National Academy of Sciences (PNAS).

“Sirtuins are an evolutionarily conserved family of NAD+-dependent deacylases that control metabolism, stress response, genomic stability, and longevity. Here, we show the sole mitochondrial sirtuin in Drosophila melanogaster, Sirt4, regulates energy homeostasis and longevity. Sirt4 knockout flies have a short lifespan, with increased sensitivity to starvation and decreased fertility and activity. In contrast, flies overexpressing Sirt4 either ubiquitously or specifically in the fat body are long-lived. Despite rapid starvation, Sirt4 knockout flies paradoxically maintain elevated levels of energy reserves, including lipids, glycogen, and trehalose, while fasting, suggesting an inability to properly catabolize stored energy,” write the investigators.

“Metabolomic analysis indicates several specific pathways are affected in Sirt4 knockout flies, including glycolysis, branched-chain amino acid metabolism, and impaired catabolism of fatty acids with chain length C18 or greater. Together, these phenotypes point to a role for Sirt4 in mediating the organismal response to fasting and ensuring metabolic homeostasis and longevity.” 

“We show that Sirt4 is responsible for regulating both lifespan and metabolism in an organism, and specifically that it coordinates the metabolic response to fasting,” said lead author Jason Wood, Ph.D., a researcher in Brown University's department of molecular biology, cell biology and biochemistry. “We also demonstrate that overexpressing the gene for Sirt4 can extend the lifespan of the fly.”

In the study, flies modified to produce extra Sirt4 saw their healthy lifespans extended by 20%. Removing the ability of flies to produce Sirt4 cut their healthy lives by 20%. Also, without Sirt4 in their cells, flies when removed from food died rapidly, even when nutrients and fats were still present in their bodies.

Sirtuins are known to regulate aspects of longevity, metabolism, genome stability, diabetes, and neurodegeneration. Sirt4 is found in mitochondria.

Human cells contain seven different sirtuins, including three mitochondrial sirtuins—Sirt3, Sirt4, and Sirt5. Fruit fly cells contain just one mitochondrial sirtuin, Sirt 4. Increasing or decreasing expression of Sirt4 in living flies allowed the researchers to discover what function Sirt4 played in the insects and possibly in humans.

“We show for the first time that increasing the activity of a mitochondrial sirtuin can extend lifespan,” Dr. Wood said. “No previous research has found that increasing the activity of a mitochondrial sirtuin such as Sirt4 extends the healthy lifespan of a living organism.”

The study also shows Sirt4 may be a gene responsible for the metabolic action of fasting, particularly the gene vital to regulating when an organism switches from carbs to fat. A creature that lacks the gene starves to death much more rapidly than normal under poor nutritional conditions.

According to Stephen Helfand, Ph.D., a professor of biology at Brown and senior author of the study, “Without Sirt4, the fly cannot access many of the nutrients and stored fats when fasting.”

Researchers know that temporary fasting in a living organism is valuable in resetting its metabolism. Such findings gave rise to what are called “near-starvation” diets to improve health and extend lifespan.

But scientists don't know how that fasting-to-reverse-aging mechanism works. Sirtuins likely play a role, Dr. Helfand said. “We want to understand more about the role of sirtuins and their involvement in pathways of calorie restriction. We think Sirt4 is an attractive target to help improve diseases of metabolism and possibly extend healthy life. In living flies, we saw that it worked, but we're not sure how.”

Studies in mammalian cells and tissues have produced conflicting results on how mitochondrial sirtuins affect overall metabolism in mammals, Dr. Helfand added. The fruit fly has just one mitochondrial sirtuin, offering a “clear, focused ability to disrupt that one protein,” he said. “This provides us with a direct approach for assessing the major functions of mitochondrial sirtuins.”