Dec. 17, 1999 The microscopic roundworm is at it again, offering dramatic insights into the factors that regulate aging, at least in C. elegans. This time, UCSF researchers report that lessening the nematode's ability to perceive its environment - presumably through smell or taste -- increases its lifespan by more than a third.
Instead of living for two-plus weeks, the animals live three or four weeks -- the equivalent of a jump of from, say, 90 to 130 years in humans -- and remain youthful during this time.
The finding, reported in the December 16 issue of Nature, does not mean that people should start pinching their noses. What it does suggest, the researchers say, is that chemical signals from the environment, perhaps pheromones or the smell or taste of something in their food, influence the nematode's rate of aging, probably by acting on a hormone signaling system.
As many fundamental biological processes have been conserved between the worm and higher species, it is possible, the researchers say, that environmental signals also influence the lifespan of mammals, including humans.
While the chemical signals affecting the roundworm's lifespan have not been identified, the researchers say they most likely provide information that's crucial to the survival of the organism. They could, for instance, be pheromones that reflect population density, or compounds that originate from organic material, reflecting food availability.
"A lot of people think lifespan is something that's fixed within the individual organism, but this study suggests that the rate of the aging process is something that can be influenced by external factors, and that something as simple as signals in the environment can have a big effect on it," says Cynthia Kenyon, PhD, the Herbert Boyer Professor of Biochemistry and Biophysics at UC San Francisco and the senior author of the study. "It might be advantageous for worms to have different lifespans under different conditions, such as the presence of other worms in the environment or the food supply."
The finding fits nicely with a study reported last spring in Nature1 by Kenyon's laboratory that showed that signals from the reproductive system influence the lifespan of the roundworm. The researchers reported that signals from germ cells - the sperm and egg in humans - shorten lifespan, while signals from the somatic gonads - the part of the reproductive tissue that surrounds the germ cells - lengthen lifespan, sending equal but opposite signals. If the cells that give rise to the germ line are removed, the animals remain youthful longer, and live much longer than normal.
The reproductive signals, they determined at the time, act by modulating the activity of two genes - DAF-16 and DAF-2, which make up a hormone signaling pathway resembling the insulin and IGF-1 hormone systems in humans. When the DAF-2 receptor receives a signal from its insulin/IGF-like hormone, it inhibits the activity of the DAF-16 gene, which normally signals cells to continue to live long and productively. When the DAF-2 gene is mutated, DAF-16's activity increases, and the animal remains active and youthful much longer than normal and lives more than twice as long. The researchers' findings suggested that germ cell signals decrease lifespan by down-regulating, or inhibiting, DAF-16, while somatic gonad signals extend lifespan by regulating the activity of the DAF-2 receptor.
Regulation of lifespan by the reproductive system could be beneficial to the roundworm, Kenyon says. If, for instance, an event, such as a mutation, were to occur in an individual animal to cause some of its germ cells to develop more slowly than normal, the number of germ line signals might diminish, and, as a result the activity of the DAF-16 gene would go up. The action would keep the animal young enough to have progeny when the germline did mature.
The two studies suggest that the roundworm is affected by signals from two very different origins -- from the environment and from its own reproductive system -- both of which would seem to be particularly relevant to its survival.
The current study also indicates that the environmental signals may act through the same DAF-2/DAF-16 hormone-signaling pathway as the reproductive signals. And this finding suggests, says Kenyon, that the hormone system acts as a central regulator of lifespan, integrating signals from various places to control development and aging in response to environmental signals, such as food, as well as internal signals that reflect the state of the reproductive system.
Moreover, the study provides evidence that the environmental signals may actually influence the reproductive system's impact on lifespan, suggesting, says Kenyon, that the two systems are linked through a very complex, coordinated control mechanism.
The researchers conducted their study by mutating various genes in the head and tail that are needed for the animals to smell and taste correctly - either genes that make cilia, the tips of the sensory neurons that respond to substances in the environment, or genes that are required for the act of smelling and tasting. The altered worms could still smell and taste, but not as well as normal. Depending on the genes targeted, the roundworms lost some degree of sensory perception. The researchers ultimately focused much of their research on two of the numerous mutated genes studied, daf-10 and osm-5.
Whether humans have a hormone signaling system that regulates lifespan remains to be seen, says Kenyon, but the fact that the human insulin and IGF-1 hormone signaling pathway closely resembles the roundworm's offers a point of inquiry. If there is such hormonal regulation, external factors may well influence it, she says. And if so, she says, it's possible that these hormones could be altered by therapeutic intervention.
Regardless, she says, "We're really getting the sense from these model organisms that lifespan is something that can be changed. And it looks like there are a lot of potential ways that these little worms can change their own."
The co-author of the study was Javier Apfeld, PhD, a predoctoral fellow in Kenyon's lab.
The study was funded by the National Institute of Aging.
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