Jan. 18, 2002 The raw material for each generation -- the pool of stem cells that gives rise to eggs and sperm -- also controls the rate of aging into adulthood, UCSF scientists have found in research on the roundworm C. elegans. The unsuspected role may find parallels in other organisms including humans, they suggest.
The finding shows for the first time that genes act in the adult animal to control its rate of aging. The stem cells, it seems, can modify lifespan even as aging is proceeding.
The key stem cells, the scientists found, are not those that actually become egg or sperm, but their sister cells from the same stem cell pool, known as "proliferating germline stem cells," that divide continuously in the animal’s reproductive tissues.
"Now we know that these proliferating stem cells are master control cells, sitting at the top of the paths that affect both reproduction and aging," said Cynthia Kenyon, PhD, the Herbert Boyer Professor of Biochemistry and Biophysics at UCSF.
The research, coupled with other findings, indicates that the pool of egg and sperm precursor stem cells affects lifespan by influencing a steroid hormone. If a hormone is found to affect human aging as well, it could make a likely target for drugs to prolong life, the researchers speculate.
The dual stem cell influence over both reproduction and aging suggests that the relationship may have evolved to assure animals reproduce while they are still young, according to the scientists.
Their study is reported in the January 18 issue of the journal Science.
Lead author is Nuno Arantes-Oliveira, a graduate student in Kenyon’s lab.
In the last few years, Kenyon’s research group has identified several genes in C. elegans that dramatically affect aging, and has zeroed in on the reproductive system as one source of signals that control the lifespan.
Three years ago the lab reported that signals from the germline – the source of sperm and eggs – shorten lifespan, while signals from the somatic gonads – the part of the reproductive tissue that surrounds the germ cells – lengthen lifespan, with the two systems able to send equal but opposite signals. They showed that removing the precursor egg and sperm cells increased lifespan, but not because of sterility which some researchers had speculated would boost longevity.
The new research identified both the location of the key germline stem cells and the timing of their effect by studying how removing germline stem cells in worms of different ages affected the animals’ longevity. The scientists found that the worms lived longer whether the germline stem cells were lost during development or in early adulthood.
The germline stem cells produce the sperm and egg cells. When they divide, they also produce more stem cells, and so they remain a source of new germ cells throughout the life of the animal. Their role in controlling longevity was unexpected.
Earlier research in the Kenyon lab had shown that a protein known as DAF-16 is a crucial player in the route by which the reproductive system controls lifespan. DAF-16 is a transcription factor – a protein that activates genes in response to other signals. The new study shows that DAF-16 is specifically required in the adult worm to allow germline stem cells to modify lifespan.
"To my knowledge, this is first gene that has been found to affect aging through its action in the adult," Arantes-Oliveira said. "It suggests there are genes that really function actively to regulate the aging process; it’s not just as a consequence of a change in development."
A second lifespan protein the group had discovered earlier, known as DAF-12, acts in the cells of animals as a receptor for a hormone. The germline stems cells, the researchers conclude, affect aging through their influence on a steroid hormone. They now want to find out more precisely how the germline stem cells affect hormone action.
"We’re now searching for the missing pieces," Kenyon explains. "We’re looking for other proteins that may be involved in this surprising level of control over lifespan. We particularly want to know more about this steroid hormone. What is it? Do humans have it?"
Overall, the research reveals a refined system of control over lifespan in C. elegans, both through the ability of the somatic gonads to increase longevity, and the newfound capacity of the proliferating germline stem cells to shorten life.
Collaborators in the research and coauthors on the paper are Javier Apfeld, PhD, a graduate student in the Kenyon lab when the research was carried out; and Andrew Dillin, PhD, a postdoctoral fellow at UCSF in biochemistry and biophsyics.
The research was supported by the National Institutes of Health, a Howard Hughes Medical Institute predoctoral fellowship, the Portuguese Foundation of Science and Technology , the Gulbenkian Foundation and the Damon Runyon-Walter Winchell Foundation.
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