Researchers have long known that they can make mice live longer by making them superskinny. Now, a genetic modification that makes the brain less responsive to insulin increases the life span of mice while making them fat as well. The results suggest that the brain can regulate life span independently of the body's ability to respond to insulin.
Drastically restricting the number of calories mice eat can extend their lives by as much as 50%. Researchers have suspected that the key to this increase in life span is the body's response to insulin, a protein that shuttles sugar from the bloodstream into cells. Diabetics, for example, have high levels of sugar in their blood because their tissues respond weakly to insulin, a condition called insulin-resistance. The half-starved mice are skinny, use insulin efficiently, and have low amounts of insulin in their tissues, suggesting a slowed-down metabolism.
Conversely, genetically modifying mice to reduce the amount of insulin in fat tissue also produces long-lived, lean mice--presumably by slowing metabolism as well. A protein called insulin receptor substrate-2 (Irs2) resides on cell surfaces in many tissues, including the brain, and allows the cells to respond to insulin. Morris White, a molecular biologist at Harvard Medical School in Boston, Massachusetts, and colleagues wanted to know whether interfering with this protein could extend life.
To find out, the team deleted one of the two copies of the gene from the chromosomes of mice. At 22 months, the modified mice were slightly heavier than the normal mice. In addition, the modified mice lived about 17% longer than the normal animals and used insulin as efficiently. Next, the team deleted one copy of the gene only in the neurons. These mice were about 15% heavier than the normal mice but used insulin inefficiently, hallmarks of a prediabetic condition called metabolic syndrome, the researchers report this week in Science. In spite of this metabolic disadvantage, the mice lacking half of their Irs2 in their brains outlived their leaner peers by about 18%. That suggests that life span is controlled not by the rate of metabolism in other tissue but by the brain and its ability to regulate response to insulin.
"It's kind of a mixed bag of a mouse," says geneticist Leonard Guarente of the Massachusetts Institute of Technology in Cambridge, who was not involved with the work. "They live longer but get a metabolic profile that's bad." The genetically modified mice's traits contrast so starkly with those of calorie-restricted animals that there must be at least two ways to extend the lives of the mice, he says.
Molecular biologist Cynthia Kenyon of the University of California, San Francisco, says the result goes against the accepted view of longevity researchers, who have "a real strong prejudice that you have to [use insulin efficiently] to live longer." She adds that cutting Irs2 signaling in humans might increase life span, but Guarente warns that side effects could include diabetes.