Saturday, June 9, 2007

Super Fruit Fly may Harbor Hope for Human Longevity

Researchers at USC and Caltech have spectacularly slowed aging in fruit flies with a new technique that shows general promise in pharmaceutical development.

In a triumph for pests, scientists have found out how to make the fruit fly live longer. But the development may still have something for humans. As reported online in Nature Chemical Biology, the discovery that a single protein can slow down aging holds implications for humans’ prolonged existence and for treatment of some of the world’s most dreaded diseases. “This work is important for two reasons,” said study author Richard Roberts, associate professor of chemistry, chemical engineering and biology at the University of Southern California. “First, it demonstrates that a single inhibitor can dramatically alter lifespan, a very complex trait. It is remarkable that you can alter it with a single genetic change. We don’t really need to make fruit flies live longer, but if we understand how to do this, our approach may have direct application to higher organisms, such as ourselves,” he added. Secondly, Roberts said, the method used by his research team to make the inhibiting proteins “opens the prospect of developing a lot of new therapeutics.” The study describes a new method for blocking receptors involved in aging and disease across many species, including humans. Receptors are proteins that send out signals across a cell membrane. In the fruit fly, Roberts and his team manufactured short proteins that blocked a receptor involved in fruit fly aging, as earlier demonstrated by co-author Seymour Benzer of Caltech.

The results were spectacular. Flies with a blocked receptor saw their lives extended by a third, with no noticeable side effects.

The same blocking strategy should work in all such receptors, known as class B GPCRs (for G protein-coupled receptors). Many GPCRs figure prominently in disease as well as in normal development, Roberts said. “It is the most targeted family of receptors” by drug manufacturers, Roberts said, estimating that a quarter of all pharmaceuticals focus on GPCRs. “This approach should be generally applicable,” he added. And generally powerful, given that GPCRs are extremely unstable and difficult to work with. The Roberts group went around the problem by disconnecting the unstable part of the receptor and running experiments only on the part of the receptor that sticks out of the cell. Though there were no guarantees that inhibiting one part of the receptor would harm the whole, the strategy succeeded. Roberts’ method builds on his co-discovery, in 1997, of a simple method for building libraries of trillions of short proteins, or peptides. In the new study, Roberts and his group literally threw trillions of peptides at the receptor and saved the ones that stuck. “We let the molecules themselves decide if they bind, rather than trying to design them rationally,” he said. After multiple cycles, the researchers had a group of peptides that fixed to the receptor and not to any other protein. Fruit flies genetically transformed to produce such peptides lived longer, suggesting that the peptides were interfering with the receptor’s normal function. However the questions that have been left unanswered are why these particular peptides work, and why the receptor they target plays such an important role in fruit fly aging.


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