Salk Institute for Biological Studies


Andrew  Dillin

Andrew Dillin

Molecular and Cell Biology Laboratory



Andrew Dillin, Pioneer Developmental Chair and a professor in the Molecular and Cell Biology Laboratory, uses the tiny roundworm Ceanorhabditis elegans to study the process of aging by looking at a hormone that is most widely recognized for its role in diabetes among humans: insulin. The insulin signaling pathway in worms is not only almost identical to that found in humans, but Dillin discovered that insulin also controls many physiological aspects in the worm's body, including reproduction and aging. In humans, interfering with insulin/IGF-1 signaling to generate a life-prolonging benefit would lead to type 2 diabetes and possibly cancer. In worms, larval development and reproduction are affected along with longevity.

Some of Dillin's earlier research had hinted at the possibility to genetically manipulate one element of the pathway without disrupting its additional functions, this led him to search for "specificity" factors that may control how and if insulin and IGF-1 impact a wide range of target genes. Recently, he and his team pinpointed a protein specifically responsible for extending lifespan and youthfulness without disrupting the worms' response to some forms of stress, development and fertility controlled by the insulin signaling pathway.

Additionally, Dillin is interested in age-onset neurodegenerative diseases. Like most neurodegenerative diseases, Alzheimer's disease usually appears late in life, raising the question of whether it is a direct and disastrous consequence of aging or if the toxic protein aggregates that cause the disease simply take a long time to form. He discovered that the harmful beta amyloid aggregates accumulate when aging impedes two molecular clean-up crews from getting rid of these toxic species.

"Aging is the single biggest risk factor for most human diseases, ranging from arthritis and cancer to diabetes and neurodegenerative disease. Our goal is to unravel the basic molecular mechanisms that drive the aging process, which will allow us to promote healthy aging for humankind."

Beyond age 65, the number of people with Alzheimer's disease doubles every five years. Centenarians, however, seem to escape most common age-related diseases, including the ravages of Alzheimer's. One of the telltale signs of Alzheimer's disease is the buildup of toxic clumps of beta amyloid plaques in the brain. Beta amyloid production probably occurs in all brains, but healthy cells clear away excess amounts. Brains of people with Alzheimer's disease, by contrast, are unable to control beta amyloid accumulation. The same is true for Alzheimer's mouse models, which are genetically engineered to overproduce beta amyloid.

To determine whether modulating the aging process could influence the onset of Alzheimer's, a team of investigators in Dillin's lab slowed the aging process in an Alzheimer's mouse model by lowering the activity of the IGF-1 signaling pathway– a highly conserved pathway that plays a crucial role in regulating lifespan and youthfulness across many species and is linked to extreme longevity in humans. Mice with reduced IGF-1 signaling live up to 35 percent longer than normal mice, and some very long-lived humans carry mutations in components of the IGF-1 pathway.

Dillin's group then employed a battery of behavioral tests to find out whether it was simply the passage of time or aging per se that determined the onset of the disease. Chronologically old but biologically young animals appeared nearly normal in the tests long after age-matched, normal-aging Alzheimer's mice exhibited severe impairments. When Dillin and his team looked at their brains, however, they found that those of the long-lived mice were riddled with highly compacted plaques.

These results clearly support the emerging theme that the plaques have a protective function and that as mice age, they become less efficient at stashing toxic beta amyloid fibrils in tightly packed aggregates. This work validates the hypothesis that genetic and pharmacologic changes to create a healthy lifespan can greatly reduce the onset of some of the most devastating diseases afflicting mankind.

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