Telomere Tales

The protective caps at the ends of chromosomes shrink as we age. Researchers don't yet know whether that erosion causes--or merely accompanies--the diseases that hit us when we're old, but they hope that learning more about telomeres could provide new ways to keep our bodies young.

The ancient Greeks believed that the three Fates ordained how long people lived. Sisters Clotho and Lachesis spun and measured the thread of life, and Atropos snipped it with her scissors, ending one person's journey on Earth. For a long time scientists believed something similar: that the length of our lives was meted out in our telomeres--the protective caps at the ends of the threadlike chromosomes that carry our genes.

But life is never as simple as legend, and most researchers have abandoned the telomere theory of aging. They haven't given up on telomeres, though. Scientists are now testing whether degradation of these termini heralds the maladies associated with growing old, such as heart disease, dementia, and cancer. Understanding the association between telomeres and disease could lead to better treatments for cancer or new ways to stay healthy as we mature.

Starting in the early 1990s, many researchers thought that telomeres might serve as a sort of biological clock. When normal human cells are grown in culture, their telomeres shorten each time the cells divide. At some point, the cells stop reproducing--a phenomenon that scientists thought might be linked to the stubby telomeres. This notion was supported by the discovery that the stalled cells could be revived by the addition of telomerase, a protein that restores the lost chromosome tips. If the same process occurred in living organisms--chromosome shrinkage putting the brakes on cell division--perhaps telomeres might serve as a chronometer that governs how long organisms live.

But that theory was too simple to explain aging in whole organisms. In humans, for example, some cells make telomerase and others don’t, so the chromosome caps shrink in some tissues but not all of them--not a very satisfying way to account for overall aging. Mice produce telomerase in all their tissues; their telomeres remain lengthy, yet these critters grow old along with the rest of us.

For these and other reasons, many researchers abandoned the idea that telomere length dictated the life span of complex organisms. "The only place that's ever worked is in cells growing in a lab," says molecular cell geneticist Elizabeth Blackburn of the University of California, San Francisco (UCSF). Although the long, luxurious telomeres that people are born with do get trimmed with time, adds cell biologist Peter Hornsby of the University of Texas Health Science Center at San Antonio, "there's no evidence that people die of shortened telomeres. They die with them but not of them."

Withered telomeres might not kill people as directly as Atropos with her shears, but they might have an indirect effect on aging by hastening the deterioration of tissues in which cells divide frequently. The strongest evidence comes from rare genetic disorders that compromise telomere integrity. For example, people with a particular form of dyskeratosis congenita have half the normal complement of telomerase. These individuals die in their 40s or 50s from a failure to replenish their blood cells properly. The disappearing telomeres disable the precursor cells in bone marrow that generate immune cells. So patients with this disorder usually die of infections. "Those cases told us why it's important to have the full amount of telomerase: The immune system can't keep churning out the cells you need to fight off infection," says Blackburn.

Another rare genetic disease, ataxia-telangiectasia, also causes telomeres to fray. The defect causes the most damage to the body's stem cells, the master cells that divide continuously to fabricate a variety of tissues. This loss of stem cells cripples the body's ability to regenerate tissues--a condition that might drive much age-related deterioration, says cancer geneticist Ronald DePinho of the Dana-Farber Cancer Institute in Boston. People with ataxia-telangiectasia experience neurodegeneration, cancer, and immune system disorders and usually die in their teens or early 20s.

Telomere shortening also appears to be associated with ailments in the elderly. In one study, people over 60 were more likely to die if they had shorter telomeres than if they had longer ones. And cardiologist Abraham Aviv of New Jersey Medical School in Newark finds that individuals with shorter telomeres in their white blood cells are more prone to cardiovascular disease and the forms of dementia that can accompany it. Other researchers have found that heart muscle cells from individuals with atherosclerosis appear to have shorter telomeres than do those from people without clogged arteries.

But aside from the genetic disorders, scientists don't yet know whether abbreviated telomeres cause these illnesses, make people susceptible, or merely reveal underlying disease, cautions Aviv. Perhaps shorter telomeres are a byproduct of the same molecular malfunction that's putting people at risk for heart trouble and mental ruin, he says. For example, telomeres are "exquisitely sensitive" to molecules generated when cells are under certain kinds of stress, says Aviv. Inflammation and oxidative stress--two conditions that ravage tissues with age--can also chisel away telomeres, at least in cultured cells. Aviv and his colleagues are exploring whether telomeres are a sink for stresses in the body.

Telomeres might even get hammered by psychological stress, another recent study suggests. Blackburn and her UCSF colleagues examined the chromosome caps in mothers who had taken care of their sick children for many years. The chronic caregivers sported shorter telomeres than women with more peaceful home lives, the researchers announced in early December. Emotional duress has been shown to increase cells' oxidative stress--including cells of the worn-down mothers--a burden that might have helped whittle away their telomeres. It's not clear whether the stress will cause these women to age more quickly. "Nobody had overt disease," says Blackburn. And relieving the stress might allow their telomeres to bounce back, she adds: "We don't know that it's inevitable that telomeres remain shortened."

To nail down whether short telomeres are a cause or a side effect of age-related illnesses, Aviv says that researchers need to monitor the lengths of telomeres in individuals over time to see whether folks with tinier telomeres are more prone to heart disease or dementia. Blackburn says a variety of studies are already under way to follow telomere length in people who are ill or under stress, including depressed individuals. She's curious to know whether stress interventions prevent telomere shortening over time.

Scientists have made more headway in understanding telomeres in malignancy. "Telomere dysfunction is one of the major mechanisms that contributes to age-dependent increases in cancer," says DePinho. The evidence comes primarily from studies of mice. To make mouse telomeres more like those of humans, DePinho and his collaborators knocked out the animals' telomerase gene. As the mice grew old, their telomeres dwindled. And each generation was worse off than the last: Without telomerase, the animals could not reset the telomeres in the cells that give rise to their offspring. After six or so generations, the mice started sprouting tumors in the colon, breast, and pancreas--the same tissues that fall prey to cancers in elderly humans. The results suggest that telomere shortening might pave the way to cancers in humans.

Minute telomeres don't in and of themselves cause cancer, says DePinho. But they can fuel the process. To a cell's DNA-repair mechanism, shrunken telomeres look a lot like broken DNA. Normal cells detect that kind of damage and, if the injury seems irreparable, kill themselves, says DePinho.

But not every cell in the body is normal. Every time cells divide, says Hornsby, they can accumulate little errors in their DNA. Some of these mistakes bring cells closer to being cancerous. One type of error knocks out a protein that monitors DNA for damage. Cells with such a mutation would continue to divide despite their shortened telomeres. Proliferation without protection from telomeres compounds the damage to the chromosomes. And in the fracas, some cancer cells even reawaken their sleeping telomerase gene, at which point the cells are unstoppable in their march toward malignancy.

About 80% of cancers turn on dormant telomerase. This observation led many scientists to posit that knocking down telomerase might stem the growth of cancer. At least one biotechnology company, Geron Corp., is pursuing drugs that do just that, says cell biologist Jerry Shay of the University of Texas Southwestern Medical Center in Dallas.

At the same time, other scientists are toying with the idea that turning on telomerase early in the process might keep cells from losing their chromosome caps in the first place. "Preventing telomere erosion might be a very good way to quell cancer," says DePinho, in much the same way that telomerase protects mice from the kinds of cancers that humans get.

Researchers have a way to go before they'll be testing concepts as radical as DePinho's. First they need to learn more about whether waning chromosome tips really do lead to cancer and to the deterioration of tissues in older people. But as researchers sharpen their understanding about telomeres and aging, perhaps their efforts will help dull Atropos's scissors and improve fate for all of us.

Mary Beckman is a stressed-out science writer in southeast Idaho who swears she can feel her telomeres shortening.