A Brown-based research team says an important aging function takes place in the brain, and it plays a powerful role in the rest of the body. Their study appears in the current Science
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Last summer, Epstein worked through the Undergraduate Teaching and Research Assistantships Program in Tatar’s lab, where fruit flies are used as models to study aging. She has continued working in the lab over the past two semesters as part of the independent study requirement for her applied math-biology major. Tatar is Epstein’s former concentration advisor. She was also a teaching assistant in a biology class he co-taught.
Research spearheaded by the Tatar lab appeared in the April 6 issue of the journal Science. Epstein was a co-author of the study, which was the first to demonstrate that insulin influences the body’s aging process by controlling the release of hormones from the brain
Tatar and colleagues studied an insulin-like receptor (InR), which is a gene with function in the brain and other cells. The gene is analogous to those in species found from top to bottom of the animal kingdom.
Fly InR responds to a form of insulin. As a result, brain cells tell a thyroid- or pituitary-like system to release a second hormone called juvenile hormone. This compound circulates in the body, unleashing a chain of other events that trigger reproduction and rapid aging.
The lab bred fruit flies with mutant InR. The researchers believed that the mutation suppressed release of juvenile hormone, arresting the aging process.
Indeed, the breeding experiments produced dwarf females with lifespans extended by up to 85 percent. Dwarf males also resulted, but they were generally frail and most died within 20 days of hatching. Males that survived to 20 days had low subsequent death rates.
To test whether mutant InR did suppress juvenile hormone, the researchers used the compound to treat the long-lived flies. The treatment restored typical life expectancy to the insects.
"Most of my work involved giving these mutant flies doses of methoprene, which is a synthetic juvenile hormone," Epstein said. "We showed that this treatment brought their lifespans back to normal."
The research provided the first evidence of the way this aging mechanism works, said Tatar, lead investigator and assistant professor of ecology and evolutionary biology.
"It appears that aging is hormonally regulated, with a brain-based pathway that affects general hormones that come from a pituitary-like system," he said.
"We concluded that juvenile hormone deficiency, which results from mutation in the insulin-like receptor pathway, is sufficient to extend lifespan. We think that in flies and worms, and probably in humans, insulin-like compounds mediate aging by either retarding growth or by activating specific endocrine tissue to release other hormones."
Scientists may guess which hormones may be involved in human aging, "but we don’t know which brain signals or external environmental signals turn on the aging mechanism," Tatar said. "This aging mechanism is something we don’t understand at all in humans. But we know something is going on. The neurocircuitry in our brains is similar to that of flies."
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he study was a classic case of scientific collaboration. While on the faculty of SUNY Downstate Medical Center, co-author Robert Garofalo, now of Pfizer Global Research and Development, originally isolated the mutant gene in fruit flies. Garofalo studied diabetes, looking into insulin receptor function. To gain a clearer understanding of that function, he and colleagues developed fruit flies with mutations in their insulin receptors. They found that this mutation limited the flies’ growth and rendered them infertile.When Garofalo’s studies were published in 1996, Tatar noticed that the photos of mutant fly ovaries looked very similar to the ovaries of fruit flies in diapause, an infertile hibernation-like state in which insects exhibit prolonged lifespan. Flies go into diapause during food shortages.
Tatar was following other studies of insulin’s role in prolonging lifespan in worms. He proposed a collaboration with Garofalo to determine if the delayed aging induced by mutated insulin-receptors in worms would also hold true in fruit flies with mutated insulin receptors. The study in Science shows that this is indeed the case.
The collaboration bred both research and publication opportunities for undergraduates. In addition to Epstein, another co-author is former undergraduate Andrew Kopelman, who graduated last May.
In fact, Tatar and Kopelman initiated the study in Science as part of Kopelman's senior thesis. Kopelman had designed an experiment to give mutant flies juvenile hormone to test whether this would restore their fertility. It did, suggesting the hormone’s key link in the aging mechanism.
"Andrew had the aha! moment," Tatar said. "He did the experiment and came running over to say it worked. Once we found that the hormone restored fertility, we could guess the rest. (Epstein would later use juvenile hormone to restore normal lifespan in the mutant flies).
"I had a lot of fun working with Andrew. He made the genotypes for the flies used in the experiments, and he did the lifespan assays. This work was the basis for the whole report."
Kopelman, who works in a Boston laboratory, will enter medical school this fall.
Currently working on her senior honors thesis in the lab, Epstein continues the research she began last summer, all of which is related to her contribution to the Science paper. It’s valuable experience to work for an extended period on a research project, she said.
"I enjoy doing biology research," she said. "I am interested in continuing in biology in the areas of computational biology and bioinformatics."
Epstein plans to attend graduate school, but hopes to defer admission for one year.
Meanwhile, the Tatar lab has begun studying how a fly brain makes insulin and how the insulin-signaling pathway regulates hormones that circulate throughout the body.