Andrew Dillin has found a way to manipulate the IGF pathway to sequester misfolded proteins.

Mix amyloid plaques with longevity and you get mice that not only live longer, but healthier too.

Andrew Dillin wants to increase the human health span—not just years, but healthy years. He believes the secret to preventing many age-related neurotoxic diseases—including Alzheimer's, Parkinson's, and Lou Gehrig's diseases—lies in the body's ability to recognize and sequester improperly folded proteins.

Dillin, an HHMI investigator at the Salk Institute for Biological Studies, has been building a strong case for his misfolded-protein theory. A few years ago, he showed that there are mechanisms in immature worms that can inactivate misfolded, toxic proteins; as the animals age, however, that surveillance system degrades until the aggregation of those proteins leads to disease. Now, he and his colleagues have linked that finding to mice engineered to exhibit Alzheimer's disease. [Prions are a different set of proteins that misfold with different results—see “A Silver Lining.”]

Amyloid beta, or Aβ, is a misfolded protein that accumulates in the brains of Alzheimer's patients and creates dense plaques that are a hallmark of the disease. When Dillin genetically reprograms mice to have a longer lifespan, they seem to retain the youthful ability to isolate, compartmentalize, and pack away Aβ proteins. The result: plaques that appear similar to those of Alzheimer's but are denser and seemingly benign. Somehow, the surveillance mechanism identifies and secludes the dangerous proteins in a way that older brains cannot.

He began to take a hard look at aging during his postdoc at the University of California, San Francisco. From 1999 to 2002, he studied the genetics of aging in the lab of Cynthia Kenyon, who in 1993 discovered that changing a single gene could double a roundworm's lifespan. Changing the gene, called daf-2, downregulated the insulin/insulin growth factor (IGF) pathway, which is found in organisms from the tiny worm to the largest mammals.

The IGF pathway is one of three genetic pathways known to affect aging. Dillin had a hand in discovering the other two. One, involved in mitochondrial signaling, he discovered in 2002 during his time in Kenyon's lab. “If you reduce mitochondrial function you can increase lifespan,” he says. “If you go down too far, it kills the animal, but at a certain level you get a positive response.” In his own lab, Dillin discovered the genetic determinant responsible for longevity induced by caloric restriction—another long-known but little-understood cause of increased lifespan—and found that a different signaling pathway, acting on the roundworm gene pha-4 (FoxA in mammals), was responsible.

Dillin contends these three distinct pathways have at least one thing in common: “We think that all these pathways, when they are downregulated, trick the system to turn on the protein surveillance machinery much more highly, to really take care of the proteome,” he says.

Photo: Lou Mora

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