Apr. 6, 2001 PROVIDENCE, R.I. — Scientists have provided the first evidence of a hormone-based aging mechanism they suggest may promote long life in species ranging from roundworms to humans. The mechanism begins in the brain with a mutant gene that suppresses the release of hormones that prompt rapid aging.
“This is the first evidence of the way this aging mechanism works,” said lead investigator Marc Tatar, of Brown University. “It appears that aging is hormonally regulated, with a brain-based pathway that affects general hormones that come from a pituitary-like system.”
The researchers studied a gene with function in the brain and other cells, called an insulin-like receptor (InR). The gene is analogous to those in species 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 researchers bred fruit flies with mutant InR. They believed the mutation suppressed the release of juvenile hormone, arresting the aging process. Indeed, the breeding experiment produced dwarf females with life spans extended by up to 85 percent. Dwarf males also resulted, but they were generally frail and most died by 20 days. Males that survived to 20 days had low subsequent death rates.
To test whether mutant InR had suppressed juvenile hormone, the researchers administered juvenile hormone to treat the long-lived flies. The treatment restored typical life expectancy to the insects.
In the brain, an important aging function is taking place, which plays a powerful role in the rest of the body, the scientists said. Their study appears in the current issue of Science.
“We concluded that juvenile hormone deficiency, which results from mutation in the insulin-like receptor pathway, is sufficient to extend lifespan,” said Tatar, assistant professor of ecology and evolutionary biology. “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,” he 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.”
Aging is much easier to study in flies than in humans, Tatar said. As cold-blooded creatures, flies have a much greater range of adaptability to environmental signals such as light, temperature or food. These all may trigger reproduction and rapid aging.
“Our brains function in a narrow range of physiological states and perhaps cannot adapt to signals that in cold-blooded organisms may prompt long-lived states,” he said. “Humans don't adapt to environments. We adapt environments to us.”
The research serves as a model for further studies in other species such as mice, where scientists already breed all sorts of genetic possibilities, Tatar said. He and colleagues are currently studying how a fly brain makes insulin and how the insulin-signaling pathway regulates hormones that circulate throughout the body.
“We’d also like to study how juvenile hormone regulates body aging,” Tatar said. “What does it do to tissues and cells, for example? Does it increase a fly’s resistance to stress or change a fly’s immune resistance?”
Co-author Robert Garofalo, now of Pfizer Global Research and Development, originally isolated the mutant gene in fruit flies, while on the faculty of SUNY Downstate Medical Center. Garofalo had studied diabetes by looking into insulin receptor 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.
The other authors are former Brown undergraduate Andrew Kopelman; current Brown undergraduate Diana Epstein; post-doctoral researcher Meng-Ping Tu, who conducted the research as a graduate student at the University of Massachusetts; and faculty member Chich-Ming Yin, University of Massachusetts.
The research was funded by a grant from the National Institute of Aging and a New Scholar Award from the Ellison Medical Foundation.
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