Protein tricks body into starvation mode
New work suggests that a hormone that makes the body think it’s starving could prolong life about as long as severely cutting calories does but without the denial.
A hormone called fibroblast growth factor-21, or FGF21, lengthened the lives of mice that had been genetically engineered to constantly produce large amounts of the protein, researchers at the University of Texas Southwestern Medical Center at Dallas report online October 15 in eLife. The hormone is normally made by the liver during fasting and may tap into some of the same life-extending biochemical processes as does caloric restriction, a proven longevity booster.
Caloric restriction — usually defined as cutting calorie intake to 75 to 80 percent of the amount needed to maintain normal body weight, while still maintaining good nutrition — has been shown lengthen life in a wide variety of species, such as fruit flies and dogs. Minimal calorie consumption turns on many different biological processes that slow aging, says Cynthia Kenyon, a developmental biologist at the University of California, San Francisco. The hormone in the study somehow interferes with a chain reaction anchored by insulin-like growth factor-1 (IGF-1), a process that is also shut down by caloric restriction and thought to be responsible for many of its life-extending effects.
In the study, researchers led by UT Southwestern’s David Mangelsdorf and Steven Kliewer genetically engineered mice to constantly make five to 10 times as much FGF21 as normal. These engineered mice lived 30 to 40 percent longer than normal mice on a standard diet. Female mice benefitted from the hormone even more than males; about a third of the FGF21-producing female mice still were alive at 44 months old. Average survival for normal mice in the study was about 28 months.
Hormone-producing mice were leaner than normal mice despite eating slightly more. They also had improved health measures, such as greater sensitivity to insulin and lower triglyceride levels. The mice tended to burned fat instead of sugar for energy, the researchers found. But the news was not all good. Higher levels of FGF21 were associated with low bone density and female infertility. Both drawbacks are part of the body’s normal response to starvation and could pose problems if the hormone is used to treat people, says Mangelsdorf, a Howard Hughes Medical Institute investigator. The researchers have already begun testing whether the hormone can extend longevity in mice if its production is delayed until adulthood.
Exactly how the hormone works is still under investigation, Mangelsdorf says. The researchers know FGF21 is made in the liver and indirectly affects that organ’s function, but they aren’t sure where else in the body it works. It is also not clear how the hormone prolongs life. It does not affect the same biological processes as caloric restriction, except for the IGF-1 pathway in the liver, yet has many of the same benefits.
But the hormone must be doing something more than simply shutting down IGF-1, says Luigi Fontana, a physician and gerontologist at Washington University in St. Louis. People who have mutations that inactivate IGF-1 are dwarves who generally don’t get cancer, but they don’t live much longer than anyone else, so the longevity benefit of the hormone may be due to some other action. Anti-aging properties of the hormone probably depend upon multiple different effects, and turning off only one biological process won’t work, Fontana says. “Many biologists are looking for the magic bullet,” he says, “but maybe there isn’t one.”
Y. Zhang et al. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. eLife. Vol. 1, October 15, 2012, p. e00065. DOI: 10.7554/eLife.00065
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