Back to Methuselah: Weill Cornell scientists find fly gene linked to aging
By Jonathan Weil
By simply switching off one copy of a gene, Weill Cornell Medical College researchers have enabled fruit flies to extend their normal life span by 51 percent -- the equivalent in human terms of extending life 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, or fruit fly, a favorite model for studies into aging and longevity because of its relatively short life span (about two months). What's more, stunted works by encoding a molecule that connects to a receptor lying on the surface of cells -- a receptor that has 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.
Even though this research remains in its infancy, it holds the promise of drugs that could someday "make everyone live longer," Huang said.
His team's findings appeared on the Web in the advance publication of Nature Cell Biology (May 9).
Since the beginnings of recorded history, humans have sought an elixir or potion granting them immortality. But now, with the explosion of research into the human genome, scientists could be finally closing in on the secrets of aging.
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 percent longer than flies bearing the usual two copies of the gene.
Still, other pieces of the longevity puzzle remained. As Huang explained, receptors like GPCR exist to receive chemical signals borne by molecules, called ligands, deep within the cell.
"It's like a lock and key -- the ligand is passing the signal, and the receptor is receiving the signal," said Huang.
He 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," 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."
But would "knocking out" one copy of stunted extend lifespan, as it had with methuselah? To find out, Huang created two mutant fly strains, called sunEM67 and sunY6, in which a copy of the stunted gene was deleted.
The result, Huang said, was "beautiful."
He said, "It was just like we predicted. When we got rid of a copy of stunted, it did increase the life span." With just one copy of the stunted gene, the sunEM67 strain of mutant flies lived 25 percent longer than normal flies, while flies from the sunY6 mutant strain fared even better, gaining an extra 51 percent in total life span.
The mechanisms by which deletions of either methuselah or stunted work to slow aging within the cell remain unclear, although experts like Huang suspect the genes might 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, but we don't know the exact connection between them yet," Huang said.
The next step, he said, "is to try and see whether these systems work in humans, as well."
Originally published in the June 10, 2004 issue of Cornell Chronicle
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