Beyond Methuselah: Weill Cornell Scientists Identify a Fly Gene Linked to Aging — Discovery Could Lead to Drugs That Extend Human Life

Manipulation of the "stunted" Gene Increased Flies' Lifespans by 51%, Next Step Is to Determine How the Gene Works in Humans

May 21, 2004

New York, NY

By simply switching off one copy of a gene, Weill Cornell Medical College researchers have enabled fruit flies to live 51% longer the equivalent in human terms of extending average lifespan to the ripe old age of 113.

The gene, called stunted, is one of only a few such longevity genes to be discovered in the Drosophila fly, a favorite model for studies into aging and longevity. What's more, stunted works by encoding a molecule that connects to a receptor lying on the surface of cells a receptor that's long been a favorite target for pharmaceutical research.

That's why we're so excited, because this receptor, called the G-protein coupled receptor (GPCR), is such a fantastic target for drug development, explained lead researcher Dr. Xin-Yun Huang, Professor of Physiology and Biophysics at Weill Cornell Medical College, in New York City.

Even though this research remains in its infancy, it holds the promise of drugs that could someday make everyone live longer, Dr. Huang said.

His team's findings appear in the May 9th advance online publication of Nature Cell Biology.

Since the beginnings of recorded history, humans have sought an elixir, potion, or Holy Grail granting them immortality. But now, with the explosion of research into the human genome, scientists may be finally closing in on the secrets of aging.

Those secrets lie deep within each of our cells and the cells of all living things on Earth. Because of its relatively short lifespan (about two months), the Drosophila fruit fly has long been a preferred subject for research into longevity.

In 1998, scientists identified a gene that directs the function of a specific G-protein coupled receptor lying on the surface of fly cells. They discovered that if they disabled one copy of that gene aptly dubbed methuselah flies lived an average 35% longer than flies bearing the usual two copies of the gene.

Still, other pieces of the longevity puzzle remained. As Dr. Huang explains, receptors like GPCR exist to receive chemical signals borne by molecules deep within the cell called ligands.

It's like a lock and key the ligand is passing the signal, and the receptor is receiving the signal, he explained.

Dr. Huang theorized that if the methuselah gene encoding for a receptor played a role in aging, maybe genes controlling ligands aimed at that receptor might influence aging, too.

To find out, his team analyzed masses of fly cells, looking for chemical clues that would identify ligands that lock into methuselah-controlled GPCRs.

In this case we found two, Dr. Huang said. And the good news is that, although it's two ligands, they are actually produced by the same gene.

The Weill Cornell researchers named that gene stunted and designated its two newly-identified ligands as Sun A and Sun B.

Now came the final, crucial test would deleting, or knocking out, one copy of stunted extend lifespan, as it had with methuselah? To find out, Dr. Huang said, we created two mutant fly strains, called sunEM67 and sunY6, in which a copy of the stunted gene is deleted.

The result, he said, was beautiful.

It was just like we predicted. When we got rid of a copy of stunted,it did increase the lifespan, Dr. Huang said. With just one copy of the stunted gene,the sunEM67 strain of mutant flies lived 25% longer than normal flies, while flies from the sunY6 mutant strain fared even better, gaining an extra 51% in total lifespan.

The mechanisms by which deletions of either methuselah or stunted work to slow aging within the cell remain unclear, although experts like Dr. Huang suspect they may help cells fight off oxidative stress damage to cells caused by rogue molecules called free radicals. There's a correlation between resistance to stress and aging, Dr. Huang said, but we don't know the exact connection between them yet.

Whatever the underlying mechanism, the discovery of stunted provides researchers studying cellular aging with the vital missing half of the GPCR-ligand puzzle, at least as it pertains to flies.

Our next step, Dr. Huang says, is to try and see whether these systems work in humans, as well.

The Weill Cornell researcher remains cautiously optimistic. We already know that humans have these ligands, Dr. Huang pointed out, but we don't know whether humans have the receptors. So we are trying to identify them, using the Human Genome. We're basically looking at all the GPCRs, and finding out which one matches with our ligands.

Of course, the ultimate aim of all this research is therapies that might help our cells and, by extension, our bodies live longer, healthier lives. While an immortality pill may seem far-fetched, Dr. Huang is heartened by the fact that drug companies are already very familiar with G-protein coupled receptors.

Of all the drugs on the market, more than 60% work on GPCRs, either to block or activate these receptors, he said. They are already the most successful target in all drug development.

Collaborating on the research were Svetlana Cvejic, Zheng Zhu, and Sarah J. Felice, all of Weill Cornell's Department of Physiology and Biophysics, and Yemiliya Berman, of the Department of Pharmacology at New York University School of Medicine, in New York.

The study was funded by grants from the National Institutes of Health.