Published On July 23, 2008
TO CELL BIOLOGISTS, THE 1951 DEATH of Henrietta Lacks, a 31-year-old mother of five, was a paradigm-shifting event. Until then, all human cells cultivated in the laboratory seemed to have finite life spans. For a while, cultured cells would replicate, producing exact copies right down to their DNA. But eventually the cells either stopped reproducing or died. This time, even though Lacks succumbed to cervical cancer, cells from her tumor lived on—becoming, in effect, immortal. That event, though it was decades before scientists learned what kept the tumor cells growing and dividing indefinitely, radically changed the understanding of both cancer and aging. But it seems to have created as many mysteries as it has solved.
The riddles begin at the tips of our chromosomes, in a structure known as a telomere. Chromosomes—those 23 pairs of tightly wound strands of DNA—contain our genes, and the cell has many mechanisms to safeguard their well-being. One of those is the telomere, which, like a plastic cap at the end of a shoelace, keeps chromosomes from fraying and genes from unraveling. But as we age, these tips shorten and eventually lose their protective power. When that happens, cells either undergo apoptosis (cell suicide), so they can be replaced by healthier cells, or they go into an inactive retirement called senescence. Senescent cells don’t die, but they no longer divide. In Jack W. Szostak’s laboratory at the Massachusetts General Hospital (MGH), Vicki Lundblad’s genetic studies in yeast have shown that maintaining telomere length is required to avoid cellular senescence.
Counterintuitively, this loss of protective telomeres has a protective purpose: cancer prevention. Aging cells are more likely to become malignant, so limiting the natural active life span of a cell helps the whole organism live longer. The flip side of this cancer protection, though, is the woes of aging. It’s now suspected that the accumulation of senescent cells might account for much of what we hate about getting old—sagging skin; gray hair; loss of fertility; and a weakened immune system that, paradoxically, could heighten the risk of cancer. “It’s a case of what’s good for you when you’re young can harm you when you’re old,” says Judith Campisi, who researches cancer and aging at the Lawrence Berkeley National Laboratory in Berkeley, and the Buck Institute for Age Research in Novato, Calif.
Telomere shortening explains why cultured cells before those of Henrietta Lacks, which became known as HeLa cells, stopped dividing—they entered senescence. What made HeLa cells immortal is that they, like the vast majority of tumor cells, had stepped up the activity of the enzyme that repairs telomeres, called telomerase. An increased level of telomerase allows cancer cells to escape their natural life span limits and continue proliferating into tumors.
Now researchers are trying to reconcile two intriguing but opposing therapeutic concepts. If too much telomerase in cancer cells promotes the disease, could we inhibit it to fight malignancies? Or, if having too little telomerase in normal cells leads to senescence, could we boost its levels to fight the effects of aging and—as some biotech and cosmetic companies are pursuing—remain forever young?
FOR MANY YEARS, SCIENTISTS HAD KNOWN that telomeres help a cell distinguish the natural end of a chromosome from a broken chromosome that the cell may try to stitch back together—to disastrous effect. Such would-be “repairs” prevent the cell from dividing properly, and
indeed, that’s what happens in the later stages of a cancer’s progressive malignancy. But how telomeres actually function did not become clear until Elizabeth Blackburn, a biologist at the University of California, San Francisco, her former graduate student Carol Greider (now at Johns Hopkins Medical School) and Jack Szostak, a molecular biologist at MGH and Harvard Medical School, elucidated the mechanism of telomere maintenance during the 1970s and 1980s, first in protozoa and yeast and later in mammalian cells. (The trio shared the 2006 Lasker Award as well as the 2009 Nobel Prize in Physiology or Medicine.)
Blackburn established that telomeres consist of repetitive DNA sequences and the proteins that bind them. Every time a cell divides, it copies each chromosome’s DNA except for the final few blocks of the telomere. That’s because, like a zipper, the enzymes that copy DNA cannot start at the bare end, but must begin a few teeth down. Each time the DNA is unzipped for copying, it loses the foot of the zipper and starts out shorter. So the older the person, the shorter the telomeres.
In 1984, Greider and Blackburn discovered the enzyme telomerase and worked out how it rebuilds telomeres by adding back repetitive blocks of DNA sequences to the tip, essentially extending the zipper’s foot. Normally telomerase is most active early in life, keeping telomeres in good repair while cells divide furiously to keep up with growth and development. By adulthood, most tissues need their cells to divide only occasionally, and so the cells need infinitesimal amounts of telomerase. As a rule, only reproductive cells—eggs and sperm—and stem cells, which can replenish lost cells, must maintain significant levels of the enzyme.
The exceptions to this rule are such tissues as skin, intestinal lining and bone marrow. In these, there’s rapid turnover and constant need to replenish cells damaged by ultraviolet radiation, wounds, digestive acids and infections. These self-replenishing tissues must have telomerase throughout adulthood, though at much lower levels than in early development.
With age, though, telomerase cannot keep up with the demands of cell division. There’s less of the enzyme just when aging cells may need more. So telomeres become shorter, germ cells lose their fertility, and stem cells lose their capacity for self-renewal. That’s the start of what Blackburn describes as a “Dr. Jekyll and Mr. Hyde” role for telomerase in the life of both the cell and the organism.
EVERY TIME A CELL DIVIDES—copying its DNA and sending one copy to each daughter cell—it risks making a mistake in replicating one or more of the 3 billion “letters,” or chemical base pairs, in the chromosomes. Some copying errors—mutations—may change the significance of a gene. Meanwhile, the wear and tear of daily living, from sunlight, infections, cigarette smoke and other toxins, further damages DNA and introduces more mutations.
During what is usually a gradual process that accelerates as we age, these mutations make genes oncogenic, or cancer promoting. When that happens, cells normally sense the danger and activate the cell-death program apoptosis to prevent the cell from becoming malignant. Occasionally, though, the mutations help the cell override apoptosis and continue dividing.
But cancer prevention is so important to an organism that it has other checkpoints, including telomere shortening, that may stem the destruction. Cancerous cells divide at a faster-than-normal pace, and their telomeres rapidly become too short to protect the chromosome. That usually sends the cells into senescence, which puts the brakes on cancer.
For cancer to continue developing, cells must bypass the telomere-shortening roadblock; the most common way to do that is to rev up telomerase activity. Blackburn notes that while telomere shortening may act to suppress tumors in early cancer stages, once that protection fails, telomerase may play an oncogenic role. Studies in cell cultures and mouse models have largely substantiated this theory, and there’s growing evidence that it also works that way in human tumors.
Such research has encouraged the notion that if telomerase is essential in allowing tumor cells to divide and flourish, a compound that blocks telomerase could potentially halt or even reverse cancer’s progress. And because restricting the enzyme should have little impact on normal adult cells—as most of them need so little telomerase—this approach might have fewer side effects than other anticancer drugs.
One potential stumbling block for telomerase interference is that it might work too slowly. But Blackburn’s research group is finding that’s not a problem. “It’s as if the tumor cells were junkies, addicted to telomerase, and they go through cold-turkey withdrawal,” she says. “So in theory, the strategy of depleting their telomerase makes sense, though we are still a long way from using this approach to cure cancer.” The first candidate compounds are in preclinical or early clinical testing.
BUT JUST AS IT HAS BECOME INCREASINGLY clear that too much telomerase promotes cancer, scientists have also discovered that too little telomerase activity in normal cells can allow other maladies of aging to develop. And one disease, a rare genetic disorder called dyskeratosis congenita, has turned out to be a perfect medium for studying the connections among telomere length, telomerase activity and aging.
Dyskeratosis congenita causes such anomalies as hyperpigmentation, prematurely gray hair and, worse, bone marrow failure; patients eventually die when their infection-fighting cells can no longer replenish themselves and their immune systems collapse. Each generation succumbs earlier, with more severe symptoms. “We see grandparents present symptoms of the disease at age 65, parents at 40 and the latest generation at 9,” Greider says.
Telomere researchers have long been fascinated by dyskeratosis congenita because even the youngest patients have abnormally short telomeres—and unusually low levels of telomerase. People with the disease all have a defective gene, inherited from one parent, that doesn’t produce any telomerase. As a result, those who are afflicted have only half the normal amount of telomerase in their cells.
In 2001, Greider and her collaborators were conducting experiments with a telomerase-deficient mouse they had developed to understand the relationship between telomerase levels, telomere length and cancer when she read a new study that identified the missing gene in dyskeratosis congenita. It happened that this gene was the same one Greider had knocked out in the mice for her cancer studies, and she decided to adapt the mice to study the genetic disorder. She crossed telomerase-deficient mice with normal ones, breeding them so that after seven generations, all the offspring had extremely short telomeres but only half had reduced levels of telomerase. If it were lack of the enzyme rather than prematurely shortened telomeres that caused dyskeratosis congenita, only half those mice would have had the disease.
But instead, they all developed the same spectrum of symptoms seen in dyskeratosis congenita. “It was really startling,” Greider says. “It told us it’s the short telomeres, rather than the amount of telomerase, that causes this disease.”
It turns out that two other diseases, aplastic anemia and pulmonary fibrosis, have the same root cause—the same defective telomerase gene that somehow ages cells throughout the body. “It’s what a physician sees first that drives the diagnosis,” Greider says. “If the symptoms first show up in skin irregularities, the diagnosis is dyskeratosis. If a patient’s immune system fails because the immune cells that fight infections go into senescence, it’s aplastic anemia. If the symptoms first affect the lungs, then it’s pulmonary fibrosis.”
Short telomeres, the culprit in all of these rare genetic diseases of aging, have also been linked to more common disorders of old age. Richard Cawthon, a geneticist at the University of Utah, has developed a way to measure telomere length in human white blood cells, and in one study, reported in the journal Lancet, he examined DNA samples from people age 60 and older that had been taken 15 to 20 years earlier. Then he researched medical and death records to look for a correlation between telomere length and mortality. Elderly people who originally had the shortest telomeres had three times the number of deaths from heart disease, eight times the deaths from infectious diseases and higher overall mortality than people with the longest telomeres. (Cawthon and his colleagues didn’t have enough data to follow cancer risk, though that’s now being examined in a follow-up study.) “We can’t say whether short telomeres are a cause or consequence of these differences in morbidity and mortality or simply an indicator of risk,” Cawthon says. “Perhaps having to fight off more diseases shortens telomeres in immune cells more quickly. Or it could be the opposite—that having short telomeres gives you more diseases.”
BUT ANOTHER STUDY, BY CAWTHON, Blackburn and Elissa Epel, a health psychologist at the University of California, San Francisco, found evidence that life stresses can shorten telomeres and reduce telomerase. In this study, they compared women supporting a chronically ill child with a control group of women. The researchers measured the women’s stress levels through questionnaires asking how long they had been caring for their sick child and their perceptions of stress. They also tested urine for a biochemical marker, F2-isoprostane, that measures oxidative stress (the production of harmful molecules called free radicals). Those with the highest, longest-lasting stress, regardless of whether they had a sick child, proved to have shorter-than-normal telomeres, lower levels of telomerase and more oxidative stress.
“We might speculate that it’s the stress that causes shorter telomeres,” Cawthon says. Although he didn’t look at the prevalence of disease, it’s known that stress is an important risk factor for the types of diseases seen in the people with short telomeres in the earlier study. A follow-up study will look at possible connections between stress-induced short telomeres and common diseases of aging.
Other environmental factors might either weaken telomerase or shorten telomeres, influencing when pathologies of aging ensue and what tissues they affect. For example, Greider observes that patients who smoke get pulmonary fibrosis 10 to 20 years earlier than they otherwise would, probably because lung cells must constantly repair damage from smoke. Regardless of the cause and effect, though, short telomeres could be useful in predicting reduced longevity or poor health. Physicians someday might benefit from knowing their patients’ telomere lengths along with other risk factors.
THE NEWS THAT TELOMERE SHORTENING is a normal part of getting old but is exacerbated in age-linked diseases has captured the imagination of biotech and cosmetic companies. Many products— including TA-65 marketed by TA Sciences, which collaborates with Geron, and cosmetic creams advertising an “enzyme therapy” that can “reset your cell’s aging clock”—already claim to reverse the effects of aging by reactivating telomerase, though none of these products is based on research published in peer-reviewed journals. Some therapies are being promoted as “nutriceuticals” from natural products and thus don’t require FDA approval, Campisi says.
In published studies, research on the telomere link between cancer and aging is still in the early stages—and fraught with the paradoxes inherent in telomeres. For example, Maria Blasco at the Spanish National Cancer Center in Madrid elevated the telomerase in skin and hair follicles of mice. These mice had healthier skin, better wound healing and more luxuriant fur. The downside was a higher rate of skin cancer.
But because skin infections are a huge health problem for the elderly and bedridden, and because cancers often take years to develop, the benefits of an ointment that helps wounds heal might be worth the tradeoff for some patients. Likewise, the theoretical risk of cancer might not matter much to patients with dyskeratosis congenita, aplastic anemia or pulmonary fibrosis. These trade-offs boil down to the fact that there are two types of diseases of aging. One kind—encompassing heart failure, skin deterioration and immune system collapse—comes from decreased cell renewal in which telomere shortening triggers cell death. The other—cancer—comes from increased cell proliferation made possible by the restoration of telomeres, which is often attributable to telomerase reactivation.
The upshot, at least for now, is that although we may eventually be able to slow or reverse the ravages of age, it could come at the cost of increased cancer risk. And although we could be closer to finding a way to inhibit tumor growth by blocking telomerase, such therapies might carry their own risks and are likely still years away. But whatever the ultimate results, today’s research on telomeres and telomerase is expanding our knowledge of how biology works. By understanding what happens when telomeres shorten too quickly or telomerase activity levels are out of whack, we can appreciate the intricate, interlocking measures that keep us healthy not only for our reproductive life but also for many years beyond—long enough that we have the luxury to worry about things as trivial as wrinkles and gray hair.
“Telomeres and Telomerase: The Path From Maize, Tetrahymena and Yeast to Human Cancer and Aging,” by Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak, Nature Medicine, October 2006. The recipients of the 2009 Nobel Prize in Physiology or Medicine describe the interdisciplinary collaboration that led to the discovery of the structure of telomeres and the enzyme telomerase.
“The Common Biology of Cancer and Aging,” by Toren Finkel, Manuel Serrano and Maria Blasco, Nature Reviews, August 2007. A detailed review of research into how telomeres and telomerase underlie the biology of both cancer (a problem of uncontrolled cell division) and aging (one of cell senescence).