Sci. Aging Knowl. Environ., 5 February 2003
Lasting Without Fasting
Zapping insulin signaling in fat helps well-fed mice persist
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/sageke;2003/5/nw21
Key Words: obesity metabolism adiposity
Like the svelte cheerleader whom every socially conscious girl envies, mice with crippled insulin signaling in fat tissue eat all they want yet avoid getting chubby. Although the cheerleader will probably have blimped out by her 20th reunion, the rodents remain impressive throughout their lives: They live substantially longer than usual, according to a new study. The research suggests that maintaining glucose control late in life enhances longevity, and that fat reduction might partly explain how calorie restriction stalls aging.
Mutations that muffle invertebrate versions of the insulin/insulin-like growth factor-1 (IGF-1) pathway can dramatically extend life-span. In mammals, the pathway is split into two--one controlled by insulin and the other by IGF-1. The IGF-1 pathway appears to modulate aging: Mice with a half-dose of the IGF-1 receptor protein survive unusually long (see "One for All"). Moreover, rodents on a calorie-restricted diet and certain dwarf mice outlast controls and harbor less IGF-1 and insulin (see Genetically Altered Mice: Ames dwarf, Laron, Little, and Snell dwarf mice). But crippling insulin signaling causes diabetes and early death, which leaves the contribution of insulin to mammalian aging unclear.
Previously, diabetes researcher Ronald Kahn of Harvard University and colleagues engineered mice to lack the insulin receptor protein in fat tissue. The protein triggers the tissue to sop up excess glucose and store it as fat. The mice--known as FIRKO mice, for fat-specific insulin receptor knockout--carry considerably less blubber than normal animals do and don't lose the ability to regulate blood-sugar concentrations, as occurs in diabetes. Now, the team has found that FIRKO mice live nearly 20% longer than normal. Although the FIRKO mice were leaner than usual, they didn't skimp on food: They ate even more than control mice did relative to their body weight. The animals seem to speed metabolism and burn the excess calories rather than storing them as fat, says Kahn.
The altered animals might explain how calorie restriction works, Kahn suggests, because mice on this austere diet also carry reduced amounts of fat and maintain control of blood-sugar concentrations with age. "It's not what's coming in by mouth" that influences life-span, says Kahn; "it's how it gets stored." But reduced fat storage can't account for all of calorie restriction's life extension, says diabetes researcher Nir Barzilai of Albert Einstein College of Medicine in New York City. The FIRKO mice don't live nearly as long as calorie-restricted animals do, even though they are just as lean, suggesting that "there's another substantial factor" involved, he says.
The study "is bound to become influential," says pathologist Richard Miller of the University of Michigan, Ann Arbor. The results "will justify greater attention to insulin- and glucose-control mechanisms" in studies of long-lived rodents, he says. Miller notes that some scientists have argued that dwarf mice live longer because they eat less, but the new study provides added evidence that longevity can be uncoupled from the amount of food consumed. That's good news, because as a longevity treatment, starvation isn't likely to win any popularity contests.
--R. John Davenport; suggested by Arlan Richardson
February 5, 2003
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Citation: R. J. Davenport, Lasting Without Fasting. Science's SAGE KE (5 February 2003), http://sageke.sciencemag.org/cgi/content/full/sageke;2003/5/nw21
Science of Aging Knowledge Environment. ISSN 1539-6150