Turning a Daf Ear to Stress
Authors: Davenport R. John 
Published: August 2003

NOVATO, CALIFORNIA
--In the life-extension Olympics, nematodes have bragging rights. Unlike the oldest rodents, which can survive only about 50% longer than normal, some mutant worms have doubled life-spans. Many observations have hinted that mammals can benefit from perturbations in the same genes that confer exceptionally long life on worms, but no one had directly tested that idea before. Now, a study presented here 25 September 2002 at the Buck Institute Symposium on Neuroendocrine Systems and Lifespan Determination reveals that a life-extending worm mutation helps mice fight stress. Unfortunately for the resilient mice, the mutation also elicits the beginning stages of diabetes.

Some long-lived nematodes harbor mutations that quench a molecular cascade that resembles the insulin and insulin-like growth factor-1 (IGF-1) pathways in mammals. One such mutation is in the
daf-2
gene, which encodes the cell surface receptor that transmits the worm's hormonal signal. Some studies suggest that crippling the IGF-1 pathway could delay the demise of rodents as well: Dwarf mice with mutations that stem the production of growth hormone--which sparks the production of IGF-1--have extended life-spans (see
Bartke Viewpoint
). But the effects of insulin and IGF-1 on mammalian longevity remain fuzzy, because other hormone pathways are perturbed in the dwarf mice and because insulin and IGF-1 modulate so many processes, such as metabolism and bone and muscle growth.

To elucidate the similarities between the putative aging pathways in worms and mammals, Shirasawa and colleagues engineered mice to carry a mutation in the insulin-receptor gene that is equivalent to the life-extending mutation in
daf-2
. Animals carrying two altered copies of the insulin receptor died shortly after birth from a diabetes-like imbalance in fat metabolism; those with only one altered copy survived, although these rodents carried elevated concentrations of insulin in their blood, which is an early sign of diabetes. The animals didn't develop the full-blown disease, however: Their blood glucose concentrations remained normal.

Long-lived
daf-2
mutant worms withstand stress better than normal worms do, so the team investigated whether the mutant mice had similar powers. In 80% oxygen--an environment that inflicts oxidative damage on tissues--mice with the
daf-2
-like mutation survived longer than control animals did. The altered mice also held up unusually well to bleomycin, a chemical that normally induces an age-related disease called lung fibrosis. Compared with controls, the lungs of the chemically treated mutants carried few inflammatory cells and high concentrations of superoxide dismutase (SOD), an enzyme that defuses potentially damaging oxygen-containing compounds. Curiously, amounts of inflammation-stimulating compounds called interleukins rose in the lungs of the mutants; why these animals show fewer signs of inflammation despite having elevated quantities of interleukin isn't clear.

"It's an important study," says physiologist Andrzej Bartke of Southern Illinois University in Springfield. It strengthens the idea that "controlling insulin signaling may be critical in controlling aging" in mice and perhaps humans, he says. If researchers can tinker with the pathway without interfering with insulin's many beneficial contributions, perhaps worms won't be the only ones bragging.

--R. John Davenport

T. Shirasawa, Insulin signal pathways and resistance for oxidative stress in mammals. Buck Institute Symposium 2002: Neuroendocrine Systems and Lifespan Determination, 24 to 27 September 2002, Novato, California.
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