Ron DePinho has found that genetic activity that puts caps on the ends of chromosomes (background) helps maintain the fitness of mammals. Photo by Kris Snibbe.

A few years ago, researchers thought they had found a way to slow aging. As we get older, the ends of the chromosomes that carry our genes start to erode. If scientists could find a way to repair these loose ends -- to literally knit the raveled sleeve of life -- then it might be possible to manipulate a person's life span.

A protein in the body, called telomerase, can place natural caps, called telomeres, on chromosomes to replace the loss of life's loose ends. Adding extra copies of genes needed to make telomerase can keep cells active beyond the point where they usually stop dividing and die.

Further study, however, revealed a paradox. Telomerase is found in abundance in cancer cells, which also keep dividing beyond normal limits. Using telomeres to prolong life, therefore, might lead to cancer. The erosion of chromosomes could be a natural mechanism to prevent the immortal replication of cells that characterizes tumor growth.

By tracking six generations of mice without the ability to make telomeres, Harvard Medical School investigators have cleared up some of the mystery surrounding this puzzling relationship.

"Loss of telomeres is not a direct cause of aging," says Ronald DePinho, professor of medicine and genetics. "However, it does contribute to an important aspect of aging, the capacity to handle stress born of infections, surgery, chemotherapy and other physical insults to the body." Older people whose chromosomes are shortened by the loss of telomeres are less able to cope with, or survive, such stresses.

But, turning the paradox around, this fraying of genetic material should also result in a decrease in cancer. With no way to repair the end of chromosomes, cells would die instead of multiplying indefinitely into tumors. While many tumors contain cells with an abundance of telomerase, noncancerous cells next to them show unprotected, eroding chromosomes.

"To our surprise, we found that cancer occurs whether telomeres are in good repair or not," DePinho says. "They can be friend or foe, depending on the genetic makeup of a cell. If chromosomes become damaged during reproduction, daughter cells may not receive a gene crucial to tumor suppression, and the disease will occur whether telomeres are abundant or not. We are working with this new information to determine how we can guide the development of new treatments for all types of cancers."

DePinho, who also holds the title of American Cancer Society Professor, did these experiments with research associate Leonard Rudolph and other colleagues at the Harvard-affiliated Dana Farber Cancer Institute in Boston. Their report was published March 5 in the journal Cell.

Media Extends Life

DePinho points out that it was the media, not scientists, who originated the idea that telomeres might extend life or prevent cancer. One national magazine hailed the idea as "miraculous."

What scientists actually found is that telomeres preserve the integrity of chromosomes so that genetic information is passed from one generation to the next. Twenty-three pairs of chromosomes in the nucleus of every human cell carry all the genetic information that makes us what we are and what our progeny will be. These chromosomes are copied and passed on to daughters and sons.

However, this process does not copy the very ends of the chromosomes. These ends consist of repeated telomeres, so with each replication, the telomere string becomes shorter. Various research teams have shown that telomeres decrease as people age; the older you get the more unraveled your chromosome sleeves become. The human limit seems to be about 50 divisions.

When the news media read about these results, they put two and two together and got 22. It seemed reasonable enough: making more telomeres could slow the human biological clock. In the case of cancer cells, accelerated telomerase activity would speed up the clock and cause them to die quickly. The problem with that reasoning: no one had actually proved that telomere length had anything to do with causing cancer or aging.

Later, geneticists isolated a gene that plays a major role in making telomerase, a protein crucial for stitching telomere caps onto chromosome ends. To the press, controlling telomerase activity provided an obvious means for fighting aging and cancer. To DePinho and others, it provided an obvious way to determine just what happens as telomere strings get shorter.

Impaired Survival

DePinho, Rudolph, and their colleagues genetically engineered mice so they lacked the telomerase gene, then bred them for six generations. At each generation, their telomeres shortened. The researchers then compared these mice with others having normal telomere genes.

After six generations, it was found that telomerase-deficient mice do not exhibit all the signs of accelerated aging. They show no greater incidences of thinning bones, blocked arteries, cataracts, or diabetes than normal mice.

"We conclude that telomere loss is not the reason why mice or humans age," DePinho says emphatically. "But the loss does affect fitness in the face of stress."

By the third generation, telomerase-deficient mice developed gray hair, baldness, and skin ulcerations similar to those of bed-ridden elderly people. By the sixth generation, the animals went gray at a considerably younger age. Worse than skin and hair problems, however, these mice demonstrated an impaired wound-healing, or tissue-regeneration, ability.

"Elderly people can have good mental health, their hearts beat fine, they walk and climb stairs and handle most routine daily functions," DePinho explains. "But they have a diminished capacity to respond to the acute stresses of major surgery, massive infections, and chemotherapeutic treatments."

Young mice, even with very short telomeres don't have such a problem, but old telomere-depleted mice do. "The two are associated, but that doesn't mean one causes the other," DePinho notes.

DePinho and his colleagues are continuing their studies of what mice can tell them about telomeres and aging, and about what effect chromosome caps have or don't have on cancer. For example, would it be possible to reduce stress responses in elderly mice by countering the effects of reduced telomeres? How might telomerase activity be manipulated to produce the early death of cancer cells? If you increase the activity of telomerase to help elders deal with stress, will you make cancer cells more deadly?

"Mice aren't little people," DePinho comments. "We can't apply what happens to them directly to us. But the lessons we've learned from them have taught us a great deal. We've learned that telomere function won't reverse aging, but it can helps us to maintain overall fitness. Other findings have changed our view of some fundamental aspects of cancer."