Dec. 11, 2001 Two University of Colorado at Boulder researchers working with GenoPlex Inc. in Denver have identified a biological switch that controls lifespan in tiny worms, a finding that could have applications for mammals, including people.
The switch, known as DAF-16, is a protein that can either lengthen or shorten the lifespan in the eyelash-sized roundworm, C. elegans, said CU-Boulder psychology Professor Thomas Johnson. Johnson, who is a fellow in the university’s Institute for Behavioral Genetics, or IBG, said DAF-16 is a critical part of a complex signaling pathway that involves insulin and glucose.
IBG Research Associate and principal author Samuel Henderson and Johnson are publishing a paper Dec. 11 on the topic in the prestigious journal Current Biology. Henderson and Johnson both are associated with GenoPlex.
The key to DAF-16 is whether it penetrates the nucleus of cells, said Henderson. "When it does penetrate the nucleus, it appears to turn on a switch to lengthen roundworm lives."
The switch, which is controlled by food availability, temperature and stress, likely has a homologue, or similar protein, in mammals, including humans, said Johnson. Insulin released with glucose in humans goes up and stores more fat when they consume sugar, inhibiting DAF-16 to enter the nucleus of the cells. It is likely that the same process occurs in other animals, he said.
Henderson has identified a molecule that embodies a trade off, said Johnson. "If DAF-16 is ‘on,’ it triggers less reproduction, more efficient cell repair and longer lives. On the other hand, if DAF-16 is ‘off,’ the result is more reproduction, worse cell repair and a shortened lifespan," he said.
Johnson authored a milestone paper in 1990 in Science magazine showing that mutating a single gene in roundworms could double their lifespan -- the first researcher discovered the lifespan of an animal could be increased by genetic mutation. Since then, researchers around the world have been tinkering with proteins and genes of C. elegans in attempts to understand how lifespan can be increased.
The increased longevity, said Johnson, is due to the ability of C. elegans to resist environmental ‘insults.’ The mutated C. roundworm species from Johnson’s early work have been linked to oxygen metabolism. Just as metal rusts when it is exposed to certain oxygen compounds, so do living cells, he said.
"The longer lived species of C. elegans have a higher resistance to free radicals and environmental stress," said Johnson.
When DAF-16 is located in the cytoplasm of cells outside of the nucleus, it is in the "off" mode, said Henderson. It is only when the cell is seeking more food that DAF-16 enters the cell nucleus, triggering a cascade of biochemical events that lead to a longer lifespan.
There is a good possibility scientists could develop a pharmaceutical intervention that would trigger translocation of DAF-16 into the cell nucleus of a variety of animals, including humans, said Henderson. This would cause organisms to lower their reproduction level and fight off the negative impacts of free radicals.
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