Mar. 5, 1999 BOSTON -- Mice lacking a gene for making telomeres -- chromosomal elements with a conjectured but controversial role in aging and cancer -- were found to go gray, lose hair faster, and recover less easily from the stress of surgery and chemotherapy than normal animals. They also developed tumors more often and died earlier, a team of Dana-Farber Cancer Institute (DFCI) researchers report in the March 5 Cell.
"Until now no one has shown the phenotypic effect of telomere loss on the aging organism," says Lenhard Rudolph, research associate in medicine at DFCI and Harvard Medical School (HMS), and lead author of the study. Telomeres -- nubs of protein and nucleic acids poised at either end of DNA strands -- are produced during embryonic development. They crumble away as cells mature and divide, suggesting telomere erosion might somehow control aging. But the process had been studied only in cultured cells.
By knocking out one of the genes for a telomere-making complex, telomerase, Ron DePinho, the American Cancer Society professor at DFCI, and his colleagues created successive generations of mice, each with shorter telomeres. Surprisingly, symptoms were not observed in the telomere-deprived newborns. For example, third generation mice displayed symptoms only after they had reached the age of 18 months. Even the most telomere-deficient sixth generation mice had to go through a waiting period, albeit shorter, before symptoms appeared.
In this and other respects, the mouse findings confirm but, intriguingly, confound expectations about the role of telomeres in aging and cancer. While telomere shortening is clearly important, it is not sufficient to bring about the depredations of age. "Something else in the aging organism cooperates with telomere dysfunction to compromise fitness," says DePinho, who is also a professor of medicine (genetics) at HMS. What else that is remains unclear. "That's one of the central questions in biology? What is the basis for organismal aging? Is it free radical damage that accumulates? Is it general mitochondrial dysfunction? Or are there other mechanisms?"
The experiments also demonstrate the widely held belief that telomeres are associated with cancer -- but not in the way researchers were expecting. Previously, tumor cells had been observed to display an excess of telomerase activity suggesting telomerase might be involved in the cell becoming immortal. But the new findings indicate a lack of telomerase can also lead to cancer. "These experiments have been to a certain extent mind-bending. No one would have anticipated that you could have gotten an increase in cancer from a lack of telomerase," DePinho says.
However, there is a possible explanation. Normally, telomeres keep chromosomal tips from unraveling or sticking to other chromosomes. Deprived of these protective shields, chromosomes might fuse, break, or undergo other changes that could lead to the loss or gain of genes and, in turn, to cancer. "So the studies teach us that if we lose telomerase function in normal cells, that might also set the stage for the initiation of cancer in aged individuals," DePinho says.
One of the goals fueling telomerase research is the hope that it might lead to new cancer treatments. Anti-telomerase compounds are being developed that could prevent aspiring cancer cells from making new telomeres and thus dividing endlessly. Rather than dashing such hopes, DePinho believes the real lesson of the new experiments is that cancer cells can turn all kinds of situations to their advantage. Some cancer cells may require telomerase while others thrive in its absence.
"We have learned that there are many roads to cancer. But if we throw up good roadblocks we can diminish the rate of cancer formation. So it's a numbers game," he says. "In a situation where many aspiring cells are moving towards cancer, by knocking out telomerase we may have a reasonable chance of decreasing the ratio of tumor formation," he says.
Earlier research had shown DePinho that the telomere story was not a simple one. For example, soon after cancer cells were shown to express telomerase, DePinho and his colleagues found that mice lacking the complete telomere-making complex could develop cancers. But how often they did so in comparison to normal mice was not known. Nor had anyone looked systematically at the effects of telomere loss on aging animals.
Previous observations had shown that while sixth generation knockout mice show some slight abnormalities even at birth, third generation newborns appear perfectly normal. Tracking the third generation mice, Rudolph found that 18-month-olds display an unusually high incidence of skin ulcerations in addition to graying hair and hair loss -- signs that organs with high proliferative rates were slowing down or undergoing cell death.
More significantly, when exposed to a blood-cell depleting agent, normal adults showed signs of recovering their blood cell supply after about a week whereas most of the older knockouts did not repopulate. In fact, many died. The knockouts also took longer to heal from minor wounds. Sixth generation adults ran into the same trouble, but sooner. Interestingly, young animals -- normal and knockout -- did not appear to be affected by the interventions.
Knowing more about such stress responses could help explain why surgery and chemotherapy take a greater toll on older people, the researchers say. Similarly, the finding that many telomere-deficient adult mice developed tumors could yield insight into why people are more likely to develop cancers as they age.
But just as telomere loss may mean different things to aspiring cancer cells, it may yield several different outcomes in other kinds of diseased cells. "The consequences of the loss of telomere function, and especially whether or not it facilitates or inhibits cancer, may be context dependent," DePinho says. "The bottomline is that it is really complex. Telomeres are definitely important -- they impact on life span, organismal fitness, and cancer incidence. But what this story tells us is that there's tremendous complexity."
This work was funded by the National Institutes of Health.
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