Sci. Aging Knowl. Environ., 11 December 2002
One for All
Worm and fly longevity pathway controls mouse aging, too
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/sageke;2002/49/nf15
Mice have officially joined the club. A genetic manipulation that extends the lives of nematodes and fruit flies also delays death in the furry scurriers, according to a new study. Previous research hinted that similar antiaging mechanisms function in mammals and their spineless cronies, but this result provides the clearest indication yet that the same longevity pathway operates in three diverse species. The finding confirms that information about aging gleaned from worms and flies applies to rodents and brings the knowledge one step closer to people.
"It's wonderful," says nematode geneticist Cynthia Kenyon of the University of California, San Francisco. "It shows quite clearly that [the longevity pathway] is conserved in mammals, and that's really powerful. If it's true in worms and flies and mice, the chance that it's not true in humans is small."
The Golden Path
Nine years ago, Kenyon's research team discovered worm mutants that live twice as long as normal. The mutation interrupts a pathway that resembles the insulin and insulin-like growth factor-1 (IGF-1) pathways, which regulate metabolism and growth in mammals. Blocking the fruit fly version of the insulin/IGF-1-like receptor--which activates the pathway--extends the insect's life-span as well. Studies on mice have suggested that the IGF-1 pathway controls longevity in rodents (see Bartke Viewpoint); for example, two lines of dwarf mice with defects in the growth hormone (GH) pathway, which triggers production of IGF-1, live longer than normal (see Ames dwarf and Snell dwarf mice). The amounts of other hormones, such as thyroid-stimulating hormone and prolactin, also plummet in the Ames and Snell dwarves, raising questions about what change is responsible for life extension. Other lines with glitches only in the GH pathway also live long (see Laron and Little mice), suggesting that the IGF-1 pathway is the crucial determinant of life-span. But the receptor protein in worms and flies has two counterparts in mammals--the insulin receptor and the IGF-1 receptor (IGF-1R)--and no one had measured life-span in animals with a stutter specifically in the IGF-1 pathway.
To resolve the pathway's role in mouse longevity, Martin Holzenberger, a geneticist at the National Institute of Health and Medical Research (INSERM) in Paris, France, and colleagues engineered animals that lack one or both copies of the gene for IGF-1R. Animals without the gene died immediately after birth. Mice toting one IGF-1R gene--which produce half the usual amount of IGF-1R--not only survived to adulthood, but they lived 26% longer than their normal littermates did. Boy mice got shortchanged. Males with half-strength IGF-1R lived only 16% longer than normal males did, whereas mutant females enjoyed a 33% life extension.
Many genetic changes that prolong life harm organisms in other ways. Snell and Ames dwarf mice are puny, and neither sex is fertile. Some long-lived worms and flies are also stunted and sterile. But mice with one copy of IGF-1R seemed robust. They grew normally, and females produced the same-sized litters, starting at the same age, as did controls. The altered rodents had normal body temperature, a measure of metabolic rate, and they ran around their cages as much as control animals did, suggesting that the mutants didn't sacrifice vigor to delay death. The mice also consumed a normal amount of food, indicating that they weren't living longer by eating less, a regimen that extends the life-span of numerous species (see Weindruch Classic Paper and Genes/Interventions Database entries: nematodes, mice, rats, spiders, flies, yeast, and dogs). The animals weren't completely healthy, however. Male mice showed early signs of diabetes; after a glucose injection, their blood sugar concentrations remained high for an abnormally long period of time. The significance of this defect isn't clear, says Holzenberger, but it might explain why males don't display the same degree of life extension as do females.
One theory of aging posits that organisms deteriorate because oxidative damage accumulates (see "The Two Faces of Oxygen"). Supporting the idea, many long-lived variants of worms, flies, and mice shrug off compounds that cause oxidative damage. To gauge their mutants' response to such stress, Holzenberger's team injected animals with paraquat, a herbicide that spurs formation of reactive oxygen species, molecules that attack proteins, DNA, and membranes. The mutant mice survived the treatment hours longer than did controls. In addition, the team exposed cells derived from the mutant animals to hydrogen peroxide, another destructive chemical. A higher percentage of cells with reduced amounts of IGF-1R survived the insult than did cells plucked from normal mice.
No one knows yet whether the enhanced resistance to oxidative stress is enough to boost longevity. "That's the $100,000 question," says physiologist Arlan Richardson of the University of Texas, San Antonio. "They've shown that the animals are more resistant, but how does that translate into animals living longer?"
Holzenberger can't answer that question yet, but to take the first step in that direction, he and his colleagues investigated how quantities of molecules controlled by IGF-1R changed in the mutant animals. Cells from the altered mice carried low concentrations of the activated form of p66shc. A 1999 study showed that a mutation in the p66shc gene extends mouse life-span and renders the animals resistant to oxidative stress. The new result will feed interest in p66shc, says physiologist Andrzej Bartke of Southern Illinois University Medical School in Springfield, and it suggests that the loss of IGF-1R might fight off oxidative stress by squelching p66shc.
That idea is intriguing, says Kenyon. The stress resistance of the p66shc mouse mutants likely stems from changes in a family of proteins related to daf-16, a worm protein targeted by the insulin/IGF-1-like pathway (see "Stay Mellow, Stay Young"). "This brings it all together and suggests that the same regulatory network is controlling life-span in all animals," Kenyon adds.
Tightening the Link
Some questions about the study remain, however. Richardson notes that the mutant and normal mice died much earlier than do most lab mice; the long-lived mutants, for example, survive less than 25 months on average, 5 months shorter than a typical experimental mouse. One reason might be that the animals in the study weren't isolated from pathogens, and he wonders whether the results would change if the mice were reared in a cleaner environment. He'd also like to know more about why the animals die, and whether they actually incur less oxidative damage.
Nevertheless, the work "really puts the focus on IGF-1" as a key to life-span in mammals, says Bartke. Further studies on the mice should clarify the similarities between rodents and lower organisms, says evolutionary biologist Marc Tatar of Brown University in Providence, Rhode Island. For instance, obstructing the activity of daf-2--the worm version of the receptor protein--only during adulthood extends life-span (see Sonntag and Ramsey Perspective). Tatar wants to know whether the same is true in mice, or whether amounts of IGF-1R must be slashed during early development as well. And daf-2 needs to be blocked only in neurons to extend worm life; Holzenberger plans to generate mice with reduced amounts of IGF-1R in specific tissues. "That would be very exciting," says Bartke. "It would test even more rigorously the parallels between mammals and invertebrates."
The results are making splashes beyond the ivory tower. Kenyon, along with biologist Lenny Guarente of the Massachusetts Institute of Technology in Cambridge, founded the biotech company Elixir Pharmaceuticals on the premise that work on worms will reveal secrets of human aging (see "'Gero-Tech' Sprouts, But Will It Bloom?"). The solid connection between worms, flies, and mice "is great news for Elixir," she says--as well as for other companies taking a similar tack. Whether the link will reveal an antiaging tonic for any species awaits further study, but we might at least find out whether humans belong to the same club as worms, flies, and mice.
December 11, 2002
R. John Davenport is an associate editor of SAGE KE. He's stopping his daily injections of IGF-1 immediately.
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Citation: R. J. Davenport, One for All. Science's SAGE KE (11 December 2002), http://sageke.sciencemag.org/cgi/content/full/sageke;2002/49/nf15
Science of Aging Knowledge Environment. ISSN 1539-6150