Using Kenyon's discovery of the IGF pathway as his springboard, Dillin has begun investigating whether downregulating the IGF pathway can keep an animal healthy as it lives longer. A postdoc in his lab, Ehud Cohen, combined a worm model of Alzheimer's—in which Aβ proteins accumulate in the roundworm's body wall—with the long-lived, IGF-downregulated worms. The onset of toxicity was delayed in the worms. “I thought the protected worms would actually have fewer plaques than the unprotected worms. That's what any neurologist would tell you,” Dillin says. “But they actually had more.”

The longer-lived worms accumulated plaques, but the plaques seemed far less toxic than those in the regular IGF worms. “It was a really striking result, because it was so clear that it wasn't just time—there was something inherent about remaining youthful,” Dillin says.

When they moved the Alzheimer's research to mice, Dillin and Cohen, now at the Hebrew University Medical School in Jerusalem, found even more striking results. In research published in Cell on December 11, 2009, they created an Alzheimer's mouse model with downregulated IGF signaling and compared those animals with mice engineered to have Alzheimer's with a normal lifespan. Just like the worms, mice with downregulated IGF still had A_ aggregating in their brains—with as many plaques as their Alzheimer's addled counterparts—but they were almost completely asymptomatic.

The results confounded the group for the better part of a year. But they eventually found that the longer-lived mice had plaques that were far denser and in a conformation that likely eliminated much of the misfolded proteins' toxicity. Rather than destructive, the plaques in these mice were actually protective, amassing the dangerous protein in such a way as to inactivate it. Something about muting the IGF pathway, Dillin believes, allows for continued protein surveillance and protection from mechanisms that have gone awry.

“This is the first study to show that you've not only extended an animal's lifespan but also actually improved its quality of life,” Dillin says. The transgenic mice were living longer, and they were eluding a disease they had been genetically programmed to develop. Dillin is investigating the mechanisms involved and is looking at other neural conditions as well, including Parkinson's and Lou Gehrig's diseases.

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