May 27, 1999 Researchers at UC San Francisco have determined that signals from the reproductive system influence the lifespan of the nematode roundworm C. elegans, a phenomenon that could offer insight into the impact of reproductive development on aging in humans.
In the May 27 issue of Nature, they report 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. And the explanation is not due to the failure of the animals to produce progeny - which researchers have speculated causes wear on the body, and thus aging - because animals that fail to have progeny for other reasons age normally.
Instead, the lifespan of the animal appears to be sensitive to the balance between signals from the germ line and somatic tissue. The authors speculate that this system allows the animal to coordinate its rate of aging with the development of its reproductive system, so that it produces progeny when it is still youthful.
The authors also report in the Nature paper that the reproductive signals act by modulating the activity of two genes - DAF-16 and DAF-2 - in a hormone signaling pathway whose components resemble those of the insulin and IGF-1 hormone systems in humans. The researchers previously discovered that these genes regulate aging in C. elegans.
As the pathway closely resembles the insulin/IGF pathways in humans, researchers suspect that lifespan may be regulated in a similar way in higher organisms, including humans. (Many basic biological processes, such as cell growth and tissue formation, are known to occur similarly in nematodes and humans.) The signals identified in the microscopic nematode have not been characterized, but the researchers suspect that at least one may be a small peptide hormone similar to insulin or IGF-1.
In work that laid the groundwork for the current finding, the investigators determined that 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. In the current study, the researchers' findings suggest that germ cell signals decrease lifespan by down-regulating, or inhibiting, DAF-16, while somatic gonad signals increase life span by repressing the activity of DAF-2.
Just as DAF-16 and DAF-2 normally counteract each other to produce a consistent lifespan in C. elegans, the signals from the reproductive system normally counteract each other by modulating these two opposing proteins in the IGF/insulin-like pathway.
In addition to regulating the lifespan of adult animals, the DAF-2/DAF-16 pathway allows young worms to enter a hibernation-like state if food is limited. The new findings, said the senior author of the study, Cynthia Kenyon, PhD, the Herbert Boyer Professor of Biochemistry and Biophysics at UCSF, indicate that lifespan is not a fixed and immutable process but instead a very plastic one, subject to change by hormonal signals. These new findings imply that the roundworm's insulin/IGF-1 system integrates multiple signals to define the rate of aging of the animal.
"We suspect," she said, "that the DAF-2/DAF-16 system acts as a master regulator to regulate development and aging in response to environmental signals, such as food, as well as internal signals that reflect the state of the reproductive system."
External factors affecting the rate at which reproductive cells develop could, in turn, influence the aging of the individual animal.
"If something were to happen to an individual animal to cause some of its germ cells to develop more slowly than normal, such as a mutation that slows down the development of the germ cells, the number of germ line signals might diminish. As a result, the activity of DAF-16 would go up, which would keep the animals young for a long time," said the lead author of the study, Honor Hsin, a researcher in Kenyon's lab.
Likewise, Hsin said, if something happened during the development of a new species of animal to change the rate of development of the germ line, the rate of aging of the whole species might be slowed down over the course of millions of years so that it wouldn't age too fast for the germ line.
"Our finding demonstrates an inherent relationship between the reproductive state of C. elegans and its lifespan, which may have implications for the co-evolution of reproductive capability and longevity," said Kenyon. "The germ cells can effectively rule the life span of this animal."
While the model proposed by the researchers is compelling in its symmetry, it took the team months to isolate the specific contributions of the biochemical signals, and to determine the genetic controls they modulate. They did so by developing various models of C. elegans.
First, they killed the germ cells of a group of nematodes but left the somatic gonads in tact. These animals remained active and healthy longer than normal and live approximately 60 percent longer. This told them that a germ cell signals somehow decreases lifespan.
They then determined what gene the germ cell signal targets to exact its toll, the suspicion being that it acted on either the DAF-16 or DAF-2 gene, or both. They did so by deleting both the DAF-16 gene and the germ cells from a group of nematodes. Lifespan was not increased. The finding suggested that DAF-16 activity was needed in order for animals missing their germ lines to have long lifespans. In other words, the finding suggested that the germ line signal inhibits DAF-16.
Next, they deducted that the germ cell signal doesn't act on DAF-2. When they deleted germ cells in animals in which the DAF-2 gene was defective, the nematodes lived twice as long as the already long-lived animals missing DAF-2, which is four times as long as normal. The researchers reasoned that if the germ cells worked through DAF-2, their absence would not have mattered, because the mutants lack the DAF-2 receptor anyway.
"The idea is you get even more DAF-16 activity if you kill both the germ cells and disrupt DAF-2," said Kenyon. "This shows that the germ cells operate independently of DAF-2. If either DAF-2 or germ cells are defective, DAF-16 levels rise and the animals live longer. If both are missing, DAF-16 levels rise even more, and the animals live even longer."
The bigger challenge was teasing out the role and mode of operation of the somatic gonads. The researchers knew that the reproductive tissue surrounding the germ cells had some role, because when they killed both the germ cells and the surrounding tissue the roundworms lived a normal lifespan. This was a very important finding, because it showed that just having progeny did not shorten the lifespan of the animal. Thus, contrary to the predictions of some theorists, there was no tradeoff between having progeny and living longer.
Instead, it indicated that that somatic gonad also produced signals that regulated lifespan. If the somatic gonads had no effect, the animals would have lived a longer than normal lifespan, given that the germ cell signal's lifespan-repressing action would have been missing.
The researchers could not tease out the unique impact of the somatic gonads, however, because killing the somatic gonads required killing the germ cells, as well, since the germ cells are embedded in the somatic tissue and cannot develop in their absence. The investigators' solution was to try to reveal the somatic gonad's unique role by again manipulating DAF-16 and DAF-2 genes, which they did.
The authors also made another interesting finding: Their observations suggested that there may be more than one site on the DAF-2 gene to which signals that regulate lifespan can attach. One site appears to bind to hormones regulated by environmental signals, and the other appears to bind to hormones regulated by the activity of the somatic gonad. This suggests that at least two different hormones can affect lifespan by regulating DAF-2 activity.
The overall conclusion remains the same, however, Kenyon said: Like a rheostat, germ cell signals act on DAF-16, somatic gonad signals act on DAF-2, and their presence or absence is reflected in the down-regulation or up-regulation of the activity of the DAF-2 and DAF-16 proteins, which either increase or decrease life span. This fine balance could be affected by circumstances that affect the development of the reproductive system.
"Now we want to identify the signals that are produced by the reproductive system and to find out how their production is regulated." Ultimately the researchers would like to find out if the reproductive system's impact is universal for other organisms. "We'd like to look at mice and fruit flies," said Kenyon.
Ultimately, of course, they'd like to look in humans.
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