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Worms, Longevity and Diabetes 

By Sean Henahan, Access Excellence 

Boston, MA (August 15 1997)- A gene responsible for the longevity of the geneticists favorite worm, Caenorhabditis elegans, could also help explain the molecular mechanisms of aging in humans and might lead to new therapies for diabetes. 

Depending on environmental conditions, C. elegans might lead a brief and trim life focused on reproduction, or a long, sleepy and chubby life focused on energy conserving survival. Numerous factors- too many other worms in the neighborhood, not enough food, or cold weather- can cause this worm to switch from its normal state to a state of hibernation known as the 'dauer' state (dauer, from the German for enduring). 

Researchers at Harvard Medical School have now cloned and sequenced the gene that helps determine this transition to the dauer state. The gene, called daf-2, bears a remarkable resemblance to the human gene that encodes the insulin receptor,a key metabolic protein. This finding has implications for evolutionary genetics, longevity researchers and diabetes researchers. 

On the evolutionary front, the finding suggests that  the key elements of glucose metabolism in humans may date back as far as 800 million years ago, when mammals and worms parted ways on the evolutionary road. 

The researchers found that, as with the human insulin receptor, the worm gene regulates metabolism. Worms with a defective gene shift their metabolism towards storage of fat rather than burning energy for fast reproduction. A mutation identical to one found in the worm gene has been observed in the same location on the insulin receptor gene of an obese human patient with an atypical form of diabetes. Related research has shown that another gene, age-1, which acts together with daf-2, also controls worm lifespan and matches a human gene. 

"The match between daf-2 and the human insulin receptor is striking," saysGary Ruvkun, PhD "because it brings together what we thought were two separate jigsaw puzzles into one that is much more complete. Both research fields -- the insulin-based system for control of human metabolism and the genetic pathways that control worm metabolism -- are well studied. But the newly discovered similarities between daf-2 and the human insulin receptor may help to solve outstanding mysteries about how human insulin regulates metabolism and why this regulation fails in diabetes, which affects about 5 percent of the general population." 

The researchers demonstrated that this insulin-like signaling in worms also controls the animals' entry into the dauer state. In this hibernating state, worms store up fat and can survive much longer than their normal 10-day lifespan. The human equivalent would be to take a nap and wake up 300 years later. 

"Many animals hibernate, some for extended periods of time, and the genes that allow animals to survive longer periods of metabolic shutdown may help them withstand tough periods of drought or cold in which food supplies are scarce. While humans don't hibernate, there have been reports that very-low-calorie diets cause dramatic increases in longevity in some mammals. The increase in worm lifespan associated with this hibernation state may be very similar to the increase in mammalian longevity caused by reduced food intake. 

"In fact," Ruvkun continues, "the same mutations that allow people to survive famines might underlie the prevalence of diabetes in certain populations. For example, almost half of the Pima Indians in Arizona, who have high levels of obesity, develop diabetes. What was once a beneficial mutation, allowing people to store enough fat to survive and reproduce, could now be a cause of disease when food is plentiful." 

Ruvkun beleives that variations in the human counterparts of other genes in the worm's insulin-like pathway may be responsible for the variations in diabetes prevalence among several human populations. Ruvkun and colleague Shoshanna Gottlieb have identified a gene that allows worms to survive normally in the absence of their insulin signals. This is one of several observations that could lead to new treatments for diabetes. 

The research appears in the August 15, 1997  issue of  Science. 

Related information on the Internet
AE: C. Elegans Genome 
C. Elegans World 
AE: Mystery of Aging

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