The Cancer of Dorian Gray

Is growing old an inescapable cost of averting malignancy?

Dorian Gray, the everlasting dandy of Oscar Wilde’s novel, halted aging. Rather than his body growing old, his portrait suffered the insults of time. In recent years, biologists have created real-life Dorian Grays: mice that don’t show certain signs of age. But in both the story and the lab, there were trade-offs. By remaining young, the fictional Dorian Gray became self-destructive. In the scientific plotline, the specially bred mice develop cancer and die young.

DIVIDE AND CANCER. A slice of brain tissue from an adult mouse reveals neurons (red), astrocytes (green), and cell nuclei (blue), all of which regenerate less quickly with age, as a tumor-suppressing protein becomes more abundant. Morrison/Howard Hughes Medical Inst., Univ. of Michigan

Scientists create such mice by inserting mutations in one of two important tumor-suppressing genes that mice and people share. The result has revealed a deep link between cancer and aging. Cancer depends on over-enthusiastic cell replication, whereas replication typically dwindles during aging. In a sense, according to the new findings, growing old is the flip side of fending off cancer.

“Aging itself may be part of the body’s anticancer machinery,” says Viktor Janzen, a hematologist-oncologist at the University of Tübingen in Germany. The trick in using that information against cancer or aging will be to uncouple one effect from the other.

In the nearer term, scientists may find new ways to minimize the side effects associated with chemotherapy and radiation exposure. In one strategy with that objective, they plan to temporarily neutralize one of the recently studied genes that controls cell replication.

The other gene in the studies may also have a near-term use. From measures of its activity, doctors might gauge a person’s physiological age. That assessment of vitality might tell physicians how aggressively to test or treat a person’s various ailments, says oncologist and cancer geneticist Norman Sharpless of the University of North Carolina in Chapel Hill.

A dual role

Recent experiments on one cancer-suppressing protein revealed that it’s a “double-edged sword,” says biologist Judith Campisi of the Lawrence Berkeley (Calif.) National Laboratory. “We thought p16 was an unequivocal good guy, but this protein can also shut down the proliferation of good cells.”

Sharpless and his team created two strains of mice for use in several experiments. The strains differ in their production of the protein p16, also called p16INK4a. The substance suppresses replication of cancerous cells. One of Sharpless’ mouse strains has a mutation that inactivates the gene for p16, while the other has an extra bit of DNA that enhances the gene’s activity.

Scientists had previously noted that p16 becomes more abundant with age in some types of mammalian tissue. The new experiments, reported in three papers in the Sept. 28 Nature, establish that p16 contributes directly to the age-related process called regenerative senescence, which gradually erodes cells’ capacity to replicate.

Mammals and other long-lived organisms must continually replace cells in their tissues as existing ones wear out. “Declining proliferation is a cause of mammalian aging,” says Sharpless.

In one new study, he and his colleagues examined how p16 affects the proliferation of insulin-producing islet cells, which reside in the pancreas. A shortage of islet cells is a cause of diabetes.

In normal mice, old age correlates with elevated p16 concentrations and reduced islet-cell proliferation. Mice engineered to have excess p16 have little islet-cell proliferation, even during youth, the researchers found. By contrast, in the p16-deficient strain, cell proliferation remains at a youthful level of activity into maturity.

Though the p16-deficient animals excelled at islet-cell replacement, they were prone to developing cancer. Their premature deaths made it difficult for the researchers to assess whether extra cell proliferation offered any benefit to the animals. So, they exposed the protein-deficient animals, as well as some normal mice, to a drug that kills islet cells.

The toxin caused mature, genetically normal mice to develop diabetes and die. In the p16-deficient strain, mature mice were more likely to recover.

In another set of experiments, Sean Morrison of the University of Michigan in Ann Arbor and his collaborators, including Sharpless, showed that p16 can reduce regenerative capacity in the mouse brain. For example, as mice aged, those that lacked p16 had smaller declines in neuron production in the olfactory bulb, which processes odors, than normal mice did.

A third study examined p16’s effects on blood-producing stem cells in bone marrow. The research team was led by David Scadden of the Harvard Stem Cell Institute and included Sharpless and Janzen.

Transplants of bone marrow cells can reinstate blood-cell production in people who have leukemia. In general, the marrow’s regenerative capacity declines with the donor’s age, Janzen says.

The researchers repeatedly transplanted marrow cells from one mouse to another, waiting a few weeks between transplants to see whether the cells would proliferate in their new hosts. Among aged mice, mutants that had low p16 concentrations despite their age contributed stem cells that proliferated more readily than did those in mice with a normal gene for p16. It’s as if the p16-defficient mice had marrow that was still young, Janzen says.

It makes sense that a single protein can have effects that both fight cancer and preserve cell regeneration, says neuroscientist Heidi Scrable of the University of Virginia School of Medicine in Charlottesville. Rapid cycles of cell division and growth are hallmarks of tumors, and sluggish cycles are characteristic of aged tissues.

P16 is “like a rheostat,” Scrable says. “If you turn it down, you have decreased tumor suppression, but the replicative life span is extended.”

Researchers continue to document the link between p16 and aging. For example, European researchers found that p16 was more than twice as abundant in skin cells from people 21 to 70 years old—and approximately seven times as abundant in cells from people over 70—as it was in cells of children and teenagers. In the October Aging Cell, researchers led by Meinhard Wlaschek of the University of Ulm in Germany conclude that “p16INK4a is a true and robust biomarker” of cellular aging.

According to Sharpless, “The most immediate clinical application [of the findings] is that someone could measure the p16 level of a patient and tell [his or her] biological age.” Doctors could use such a “biomarker of age,” he says, to identify patients who are most or least likely to benefit from tests such as colonoscopy and treatments such as chemotherapy.

Scientists are also thinking about drugs that they might derive from p16, though they’re wary of the protein’s opposing effects. “A drug that will keep the tumor-suppressor part of p16 active and turn it off in the stem cells [could potentially] preserve stem cell function without the risk of cancer,” suggests Campisi.

Such a medication might “rescue the regenerative capacity” of old or damaged tissues, Janzen adds.

That may be wishful theorizing. “I think what we’re going to show is there is an inextricable link between cancer and aging,” Sharpless says.

Divisible functions

While the two major functions of p16 may be inescapably intertwined, new research suggests that scientists might tease apart the dueling effects of another potent antitumor protein, p53.

Recent studies have linked p53 to regenerative senescence and aging. For example, a 2002 study found that although mice that generate excess p53 have low incidences of cancer, they have short life spans (SN: 1/19/02, p. 47: Available to subscribers at Cancer fighter reveals a dark side).

Newer research raises the possibility that manipulating p53 might minimize the side effects of chemotherapy and radiation and permit doctors to administer more-potent treatments. “When we deliver heavy-duty chemotherapy, we could suppress p53 transiently so that toxicity is not so high,” Campisi suggests.

Radiation and chemotherapy cause DNA damage, killing cancer cells but also potentially making other cells become cancerous. P53 guards against that hazard both by triggering cells that have been moderately damaged to stop multiplying and by prompting severely damaged cells to kill themselves. These effects contribute to the toxicity associated with chemotherapy and radiation.

In one study, cancer biologist Gerard Evan of the University of California, San Francisco and his colleagues treated mice with strong gamma rays. The mice had been engineered so that researchers could turn p53 production on and off at will.

In some of the animals, the scientists suppressed p53 throughout the study. In other animals, they turned it on for just 6 days either before or after the radiation.

As the scientists expected, the animals that produced no p53 after receiving radiation developed lethal cancers. Mice in which p53 production occurred just before radiation exposure—so that they had high concentrations of the protein when they were irradiated—had severe side effects from the treatment, but the other mice didn’t.

Having high concentration of p53 at the time of radiation exposure “makes the mice very sick,” Sharpless says, but surprisingly, it “doesn’t suppress cancer much.” Scientists had assumed that the body’s short-term, pathological reaction would protect the animals against later cancers.

Furthermore, in Evan’s experiment, restoring p53 production after radiation exposure protected most mice from the gamma rays’ immediate toxicity and against later cancer. The protein accomplished the trick by killing radiation-damaged cells days after the gamma-ray exposure, an activity that p16 doesn’t share. Inhibition of cells’ normal cycle of division and growth, which both proteins can affect, leads to the side effects but plays a negligible role in preventing cancer, Evan’s team concludes in the Sept. 14 Nature.

A separate study in the same issue of Nature supports Evan’s finding. Researchers led by Manuel Serrano of the Spanish National Cancer Research Center in Madrid tested a strain of mice that has an extra copy of the gene that makes p53. They found that the protein’s anticancer effects depend primarily on biochemical reactions that are unrelated to the protein’s response to DNA damage.

The idea of dialing down p53 in a person undergoing cancer treatment is appealing, says Anton Berns of the Netherlands Cancer Institute in Amsterdam. “If you could take away the toxic effects that p53 has on normal tissues, that might let you use a higher dose of radiation or [anticancer] drugs,” he says.

Revising evolution

Evan suggests that p53’s role in side effects and its lifesaving actions are linked not by an immutable law of biology but by coincidence. “We surmise that an evolutionary accident … has cobbled together two things that don’t need to be together,” he says.

On a cellular level, the toxic side effects of radiation resemble the effects of aging, Evan and Sharpless note. “P53 is involved in pathological response to chemotherapy, radiation, and perhaps aging as well,” Evan posits.

“We are not optimized for longevity and cancer suppression. We are just sort of a half-hearted compromise,” Evan says. “It might be possible to manipulate our rather substandard evolutionary dowry … to retain all the benefits of tumor suppression and yet dispense with all the downsides of having p53.”

Conversely, researchers propose that rather than decreasing p53, they might increase the protein in a person to suppress tumors without compromising health in other ways.

“I have faith that we will find ways to … suppress cancer to a large degree without causing accelerated aging,” Campisi says. In fact, when Serrano’s team recently increased p53 activity in mice, the scientists saw successful suppression of tumors but none of the cellular signs of aging.

“While those mice don’t seem to live longer, at least they’re not aging faster,” Campisi comments. Several groups are working on a way to control p53 activity in people. In the September Nature Chemical Biology, molecular geneticist Andrei Gudkov of the Cleveland Clinic in Ohio and his colleagues describe a molecule that in mice temporarily inhibits the protein and in people might prevent radiation-related side effects.

The same sort of p53-blocking compound, taken over months or years with intermittent breaks, might combat aging. Sharpless proposes, “Maybe once a month, you’d activate p53 for a few days and wipe out all your incipient cancers.”

Would that put the ravages of time on hold, finally satisfying Dorian Gray? “It’s going to be real hard to manipulate aging,” Scrable says. “But we’ll see. Scientists are clever.”

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