The creation of an extraordinarily long-lived fruit fly by genetics researchers at the University of Rochester has led scientists down an unexpected new path in the fight against diabetes. The mutant fly is serving as a portal for understanding the factors that determine how nutrition and stress set the foundation for metabolic syndrome and diabetes, why diabetes occurs more frequently as people age, and indeed why people live as long as they do.
Dirk Bohmann, Ph.D., and Henri Jasper, Ph.D., are focusing on a cell signaling system that responds to stress and works in tandem with the insulin receptor that is central to diabetes. They recently received $2.5 million from the National Institutes of Health to conduct the next phase of their studies.
Why spend such funds on a fly that lives 40 percent longer than the average fly? Because of its promise for human health. New findings on aging, diabetes, and stress converge on the fly the team created. Later this month Bohmann will discuss the fly's implications for aging and health at a symposium in Sweden sponsored by the Wenner-Gren Foundations and also at the exclusive International Workshop on the Molecular and Developmental Biology of Drosophila, sponsored by the European Molecular Biology Organization, in Crete.
Bohmann and Jasper showed in 2003 that boosting the amount of a molecular signal known as JNK in a fruit fly allows the fly to live 85 days instead of 60, by spurring the fly to defend itself more aggressively against the oxidative stress that accelerates with aging. Such stress comes from the same chemical process that makes cars rust in the Rochester winter: Free-wheeling molecules known as free radicals zing through materials and run roughshod over anything in their way, including vital proteins and DNA. It's a major reason why generally our bodies falter as we age -- we're literally dinged to death by free radicals.
While scientists knew that JNK in a fly cranks up the anti-oxidants, helping to keep the integrity of genes and proteins intact in the same way people hope substances like vitamins C and E might, few had considered that simply boosting the amount of JNK could have such a broad impact on life span.
Then, in another surprise, Jasper and Bohmann showed that JNK targets the same protein as the widely studied insulin receptor, central to human health and to the disease process that underlies diabetes. The finding has opened up an untapped route for possibly interfering with the disease process that underlies diabetes.
"Obesity is on the rise dramatically, and after decades of increasing life span among people in the United States, there is talk that life expectancy is actually expected to fall soon, largely due to the epidemic of obesity and diabetes," said Bohmann. "It's a huge health issue. Many people have this problem -- it's not going away anytime soon.
"This research isn't so much about making people to live to 120 as it is about preventing diseases like diabetes, heart disease, or Alzheimer's. We're trying to identify the mechanisms that cause damage to our body as we age, and prevent them. This has opened a new playing field for people in aging research."
The work was initially supported by the Nathan Shock Center, funded by the National Institute on Aging, and the Upstate Coalition of Aging Research. Now, Bohmann will use $1.4 million in a new five-year study exploring the relationship between JNK and the insulin receptor, while Jasper will use $1.1 million in a four-year study investigating just how much control JNK seems to wield over insulin production.
It's likely, for instance, that JNK counters the effects of the insulin receptor and inhibits the production of insulin, a crucial hormone that converts the food we eat into forms that the body can utilize. JNK detects stress in the environment and not only prepares the body to deal with insults from the environment, but also limits the amount of insulin, preparing the body for stress by slowing its metabolism and limiting its energy output. It might also offer a new way to control insulin production.
Like JNK, the insulin receptor is also involved in determining life span. Caloric restriction -- limiting the calories an organism ingests -- generally increases lifespan in organisms ranging from worms to flies, and maybe humans. Somehow, JNK and the insulin receptor together seem to work in tandem to affect life span.
"We're learning that an organism's life span may not be limited by design," said Bohmann. "It was once thought that people and other organisms could simply live only a certain number of years and that's it. Instead, our genes play a crucial role in determining and adjusting how long we live. Can we control this process more fully? Perhaps it's possible to re-set the body's aging clock and maybe make someone live longer."
It was Bohmann's questions about cancer-causing genes 20 years ago that led him to focus on JNK, a signaling system that plays a role not only in cancer but in many normal body processes. For several years he has worked with Jasper, using fruit flies to try to unravel the molecular signals that enable cancer cells to grow. Jasper earned his doctoral degree under Bohmann's guidance in 2002 and is now an assistant professor of Biology.
Bohmann initially studied cancer in human cells, then switched to studying fruit flies because he felt that making findings important to human health would happen more rapidly using flies, then transferring the findings to people. He notes that the same molecular signals that control how cells divide in fruit flies control how cells divide in people.
"We continue to be amazed at how similar a fruit fly is to a person," says Bohmann. "We can accomplish the same thing in fruit flies that we would only be able to do with a lot more money, taking a lot longer, in other ways. And many of these experiments could never be done in people or even mice. Working first in fruit flies speeds up the process toward finding potential treatments or cures for diseases like cancer."
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