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For the first time: Longevity modulated without disrupting life-sustaining function

eir larval development and reproduction were disrupted.

"So, the central question became whether we would be able to genetically manipulate one element of the pathway without disrupting its additional functions," said Dillin. "In this regard, we thought that the life extending function of this pathway would be elusive, whereas the developmental and reproductive functions would be more amenable. We were delighted to find that Smk-1 proved to be specific for the one function we thought the most elusive," he added.

Some of Dillin's earlier research had hinted at the possibility that "specificity" factors may control how and whether insulin and IGF-1 impact a target gene. Identifying those factors one by one would allow scientists to separate the different functions of insulin/IGF-1 signaling and to manipulate them individually without wreaking havoc on the organism's normal functioning.

Together with the lab of another Salk scientist, Tony Hunter, Ph.D., Dillin's team identified a protein in the worm Caenorhabditis elegans that allowed them to do just that. The protein is encoded by the Smk-1 gene. "Smk-1 is the first known gene that regulates longevity without affecting other vital functions of the insulin signaling pathway," said Wolff.

Under favorable conditions, a still unidentified molecule binds to DAF-2, the worms' equivalent of the insulin/IGF-1 receptor, which is located at the cell's surface. A cascade of signaling molecules relays the information deep into the cell till it reaches a protein called DAF-16. Known as a transcription factor, DAF-16 encodes a DNA-binding protein that turns on other genes but when DAF-2 is active, it is unable to enter the cell's nucleus to activate its target genes.

When environmental conditions turn harsh as a result of overcrowding and scarce nutrients, for example, DAF-2 signaling shuts down. No longer marooned outside the nucleus, DAF-16 crosses into the nucleus, and triggers all the
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Source:Salk Institute


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