|Worms, Longevity and Diabetes
By Sean Henahan, Access Excellence
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
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.