Ponce de León's early 16th century search for the fountain of youth is among the most familiar quests for longevity, but it wasn't the last. For ages, people have tried unproven pills, potions, and techniques in pursuit of a longer life.
"Aging research has sometimes missed the mark," says Andrew Dillin, a biologist at the Salk Institute for Biological Studies. But his lab isn't trying to discover a biological fountain of youth: He wants to modify the aging process to slow or prevent aging-related diseases like Alzheimer's. "Recently, we've started to get a handle on the mechanisms of aging, and we're starting to have a common language with the rest of the scientific world."
While he's always had a passion for science, Dillin didn't set out to study aging, or even biology—he preferred chemistry. But, a graduate school lab rotation sparked an interest in yeast genetics. "I simply fell in love with genetics, the genetic approach, and I had a patient teacher," he says.
By the time he finished graduate school, Dillin was eager to address a big biological question. Then he heard that University of California, San Francisco, biologist Cynthia Kenyon had shown that altering a single gene in the nematode Caenorhabditis elegans doubled its life span. That presented the big question Dillin had been looking for: Why do cells age? He joined Kenyon's lab for a postdoctoral fellowship and has studied aging ever since. "I was fascinated that a single gene could regulate a process as complex as aging," Dillin says.
To date there are only three known ways to increase longevity in worms, mice, and fruit flies. You can simply reduce dietary intake. You can lower the number of signals from the hormone insulin/insulin growth factor-1(IGF-1), which regulates metabolism and growth. Or you can reduce energy production from the cell's engine, the mitochondria. In Kenyon's lab, Dillin's research set the foundation for two of the three pathways: insulin signaling and longevity and mitochondrial function and longevity. Specifically, he found that insulin signaling begins to affect aging during adulthood and continues through relatively advanced ages. By altering mitochondrial function, Dillin also found that decreased energy production reduced a worm's body size and activity level and extended its adult life span.
Recently, his lab at the Salk Institute discovered that the nematode gene pha-4 (called Foxa in mammals) is essential for the increased longevity seen in mice and other animals kept on near-starvation diets. "If we [turn the gene on] in worms on a normal diet, we can trick them into thinking that they are diet restricted," he says. "We're now working on discovering the molecular sensors of dietary restriction and the critical tissues and cells that respond to dietary restriction that allow a long and healthy life span."
This work on aging has pulled Dillin from classic genetics toward biochemical research. He considers it a natural progression from there to uncovering the cause of late-onset neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's. All these illnesses are linked to faulty proteins created as we age. "In the back of my mind, I've always been interested in the proteins, and how the cell decides what is a good protein," Dillin says.
The single greatest risk factor for many of these neurodegenerative diseases is age, and Dillin has surmised that known cellular pathways associated with aging may interfere with protein folding. He discovered that reduced insulin/IGF-1 signaling suppressed the toxic effects of human beta-amyloid—the protein linked to Alzheimer's disease—in worms. Even more intriguing, his lab found that the insulin/IGF-1 signaling pathways regulate two key proteins that influence how the cell handles toxic jumbles of proteins called aggregates: One protein breaks them up, while the other sequesters them in even bigger clumps. This is a known problem with Alzheimer's disease.
"Every cell has to deal with proteins that aggregate," Dillin says, noting that people with these serious neurodegenerative diseases are fine for decades and then their cells can no longer handle the aggregates of proteins. "There is something in young people that keeps them resistant to protein aggregation. There is a balance between how much flawed protein is being generated and how well you can deal with it. It is our hypothesis that the genetic pathways that we have found that regulate longevity do so by protecting the proteome from mismanagement."
Dillin suggests that a principal cause of aging and aging-related diseases is a person's declining ability to manage these protein clumps in their cells. His group is working to understand how the two proteins they discovered confer their protective effects. They are also looking for other aggregation and disaggregation pathways that are conserved in worms and mice in the hopes of finding clues that one day will help patients with neurodegenerative disease.
"In order for a human to live for a long time, they must keep their proteome in order," Dillin says. "A bad protein is like having a bad kid in class—it takes resources and energy away from the students who are behaving. Making a bad protein upsets the entire system."