Sci. Aging Knowl. Environ., 2 March 2005
Will Humans Join the Club?
Changes in insulin-signaling genes might extend human longevity
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2005/9/nf17
Most people don't crawl through the dirt or hover over rotten fruit, but a new study reveals one thing we might have in common with the worms and flies that do. Women with particular alterations in insulin-signaling genes live longer than normal, suggesting that similar pathways influence aging in humans, nematodes, and fruit flies. But some researchers express reservations about the results.
The hormones insulin and insulin-like growth factor 1 (IGF-1) control metabolism and growth in mammals. Numerous studies suggest that the molecules also influence the pace of deterioration. For instance, flies and worms with snags in a pathway that resembles the mammalian ones sparked by insulin and IGF-1 live longer than normal. The same might hold true for mammals. Rodents that lack insulin's receptor protein in fat tissue eat copiously without gaining weight and survive unusually long (see "Lasting Without Fasting"). And mice with a half-portion of IGF-1's receptor also gain extra time (see "One for All"). Humans with the same genetic alterations found in long-lived dwarf mice might enjoy unusual longevity, but these individuals are rare and the data aren't conclusive (see "Power to the People"), and assessments of IGF-1 quantities in centenarians have produced conflicting findings.
To investigate the connection between insulin-like signaling and aging in humans, Heemst and colleagues examined the genes of 1200 participants in the Leiden 85-Plus Study, in which researchers followed people aged 85 or older for up to 14 years. Previous studies had suggested that specific alterations in genes that produce proteins in the insulin and IGF-1 pathways either amplified or dampened pathway signals. Individuals who carried certain variants predicted to reduce signaling weren't as tall as individuals who didn't carry those gene versions, but they tended to live longer. For instance, women with one version of growth hormone, a molecule that stimulates production of IGF-1, were 20% less likely to die at any given age than were women with different versions. However, men with signal-blunting mutations were no better off. Together, the results suggest that women live longer when insulin-like signaling is quenched. That finding matches observations of sex differences in the longevity of long-lived dwarf mice. Growth hormone and IGF-1 can help reinvigorate tissues, and the researchers speculate that for men, those benefits outweigh any potential gains from reductions in insulin-related signaling.
"This is one of the first studies that definitively shows that [alterations] in insulin signaling contribute to longevity," says Holly Brown-Borg, a physiologist at the University of North Dakota in Grand Forks. "It's really exciting because there isn't that much evidence in humans yet." But other researchers want stronger evidence. For instance, the different gene flavors might result in shorter stature by accelerating osteoporosis rather than stalling growth, suggesting that those gene versions might be detrimental, says epidemiologist Michael Browner of the California Pacific Medical Center in San Francisco. To convince him that the gene differences alter longevity, he'd like to see more data on other groups of subjects. "It's potentially interesting, but it needs to be confirmed," he says. For now, we'll have to wait to find out if we can keep company with worms and flies.
March 2, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150