Discovery of gut-brain regulatory pathway in flies offers insight into human aging

Biologists at Brown University have discovered how a neuropeptide hormone produced in the gut of flies can control their lifespan.

The results, published in the Proceedings of the National Academy of Sciences (PNAS), also have implications for humans, the researchers say, especially as new diabetes and obesity drugs based on gut hormones from the same family as the fly hormone become more widespread .

Over the past two decades, study author Marc Tatar, a biology professor affiliated with the Center for the Biology of Aging at Brown University, has studied how the hormones insulin and insulin-like growth factors ( IGF) control the aging of flies.

“We know that reducing insulin and IGF signaling slows aging and extends lifespan in flies,” Tatar said.

Tatar approaches the study of aging from the perspectives of ecology and evolutionary biology, part of the interdisciplinary approach taken by the Center for the Biology of Aging. Researchers in Tatar’s lab studied an insulin-regulating hormone called neuropeptide F (NPF) in flies, which is produced in the gut and secreted into the circulation in response to diet.

For the study, they found a way to use genetic tools to reduce the ability of the flies’ guts to secrete NPF and therefore reduce insulin secretion. Next, they mapped NPF production in flies, from the gut to the brain to pituitary-like tissue, and linked it all to diet.

They found that suppressing intestinal NPF extended the flies’ longevity, as did blocking NPF receptors in the brain that control another hormone called juvenile hormone. The researchers concluded that intestinal NPF modulates aging in flies through the integration of nutrient sensing, insulin signaling, and juvenile hormone production.

“We showed how all these things work together to control lifespan,” Tatar said.

The researchers are conducting additional experiments to understand what happens when they increase the secretion of NPF, and therefore insulin, in flies.

“Based on this research reported in PNASwe believe that overproduction of intestinal NPF in flies will have a negative effect on aging and reduce lifespan,” Tatar said.

As small and simple as flies may seem, Tatar said they actually have many of the same genes as humans, and there are analogous hormones in humans that are involved in similar processes and pathways. Understanding the mechanisms of aging in flies can also help explain what happens in humans.

Humans do not produce NPF or juvenile hormone. However, humans produce insulin and secrete intestinal hormones that regulate insulin production, such as pancreatic polypeptide Y (PPY) and glucagon-like peptide-1 (GLP-1). GLP-1 belongs to the same family of hormones as NPF: they are both called incretins because they can increase insulin secretion.

There has been an explosion of research into GLP-1 agonists, which mimic incretin GLP-1 in humans and trigger the release of insulin in the pancreas.

Tatar’s research team concluded that given how insulin-increasing drugs, such as GLP-1 agonists, are used to treat diabetes and obesity, and given what They discovered in the files on the relationship between insulin and aging, perhaps it is time to consider how they might impact human aging.

“The fly is a great model for humans, but we need to advance research from flies to mice and establish studies looking at GLP1 agonists and aging,” Tatar said. “It will take years, but it’s important.”