Researchers at USC and Caltech slow aging dramatically in fruit flies with a new technique that shows general promise in pharmaceutical development.
In a triumph for pests, scientists have figured out how to make the fruitfly live longer.
But humans still may get something out of the deal. As reported online in Nature Chemical Biology, the discovery that a single protein caninhibit aging holds implications for human longevity and for treatment ofsome of the world?s most feared diseases.
?This work is important for two reasons,? said study author Richard Roberts,associate professor of chemistry, chemical engineering and biology at theUniversity of Southern California.
?First, it demonstrates that a single inhibitor can dramatically alterlifespan, a very complex trait. It is remarkable that you can alter it witha single genetic change.
?We don?t really need to make fruit flies live longer, but if we understandhow to do this, our approach may have direct application to higherorganisms, such as ourselves.?
Secondly, Roberts said, the method used by his research group to make theinhibiting proteins ?opens the possibility of developing a lot of newtherapeutics.?
The study describes a new method for blocking receptors involved in agingand disease across many species, including humans.
Receptors are proteins that transmit signals across a cell membrane. In thefruit fly, Roberts and his team manufactured short proteins that blocked areceptor involved in fruit fly aging, as previously demonstrated byco-author Seymour Benzer of Caltech.
Flies with a blocked receptor saw their lives extended by a third, with noapparent side effects.
The same blocking strategy should work in all such receptors, known as classB GPCRs (for G protein-coupled receptors). Many GPCRs figure prominently indisease as well as in normal development, Roberts said.
?It is the most targeted family of receptors? by drug manufacturers, Robertssaid, estimating that a quarter of all pharmaceuticals focus on GPCRs.
?This approach should be generally applicable.?
And generally powerful, given that GPCRs are notoriously unstable anddifficult to work with. The Roberts group went around the problem by cuttingoff the unstable part of the receptor and running experiments only on thepart of the receptor that sticks out of the cell.
Though there were no guarantees that inhibiting one part of the receptorwould incapacitate the whole, the strategy succeeded.
Roberts? method builds on his co-discovery, in 1997, of a simple method forbuilding libraries of trillions of short proteins, or peptides.
Unlike DNA, which can be copied and multiplied millions of times withpolymerase chain reaction (PCR), proteins cannot be copied directly.
But Roberts and Jack Szostak of Massachusetts General Hospital thought offusing peptides to the bits of messenger RNA that contained their sequence.
?Essentially, we developed a way to do PCR on proteins,? Roberts said.
The use of RNA-peptide fusions allowed the easy creation and multiplicationof randomly generated peptides. Roberts termed this approach ?IrrationalDesign.?
In the new study, Roberts and his group literally threw trillions ofpeptides at the receptor and saved the ones that stuck.
?We let the molecules themselves decide if they bind, rather than trying todesign them rationally,? he said.
After multiple cycles, the researchers had a group of peptides that stuck tothe receptor and not to any other protein.
Fruit flies genetically altered to produce such peptides lived longer,suggesting that the peptides were interfering with the receptor?s normalfunction.
Why these particular peptides work, and why the receptor they target playssuch an important role in fruit fly aging, remain the bigger and as yetunanswered questions.