USC Health Now

Understanding how cancer and aging are tied together and manipulating those links to halt cancer’s progression will put time on everyone’s side.

USC Health Magazine
Fall 2005
by Lori Oliwenstein

In a scientific sense, cancer and aging seem like two completely opposite phenomena. After all, cancer is a disease of overgrowth, too much vitality, and cells that cannot or will not stop dividing. Aging, on the other hand, is about the end of growth, cells that are worn out and tired of dividing. It is about cells that are at the end of their biological and genetic rope.

And yet, cancer is so very much a disease of aging. According to the National Cancer Institute (NCI), 60 percent of newly diagnosed malignancies are found in people over the age of 65. That same age group shoulders 70 percent of cancer deaths. Overall, the elderly are 10 times more likely to get cancer, and 15 times more likely to die from cancer than are people under the age of 65.

There are certain cancers, in particular, that are linked to aging. These include colon, rectal, prostate, pancreas, lung, bladder, stomach and breast cancers. And the characteristics of some of those cancers differ according to age as well. For example, older patients with acute myelogenous leukemia are more likely to have tumors that resist treatment, and they are less likely to achieve remission than their younger counterparts.

All of this has led scientists to ponder the ways cancer and aging might be connected. Is cancer an unavoidable part of getting older? Or is it a result of some disease process associated with aging, but not linked to aging in and of itself? And is the link between the two forged at the level of DNA, or by an aging body’s influences on its cells?

“Part of the confounding thing about cancer and aging is that there’s never been a cancer genome project or an aging genome project, so we don’t really know the full spectrum of genetic changes that occur with cancer or age,” says Michael Lieber, M.D., Ph.D., the Rita and Edward Polusky Professor in Basic Cancer Research at the Keck School of Medicine of USC.

Age-related differences in people with cancer are not limited to their cells alone. There are a number of external influences—social issues, cultural issues, medical issues—that can impact the path a particular malignancy travels.

“Older cancer patients must be regarded in different ways than younger cancer patients,” notes USC University Professor Caleb Finch, Ph.D., the ARCO/William F. Kieschnick Chair in the Neurobiology of Aging at the Leonard Davis School of Gerontology. “There are usually a number of other medical difficulties to take into account, the social support issues are quite different in older patients, and complex chemotherapeutic or treatment regimes are often harder for older patients to manage.”

Researchers from the Keck School, USC/Norris Comprehensive Cancer Center and the Davis School of Gerontology recently took a first step toward addressing these issues from a cross-campus, multidisciplinary point of view. They put together a broad outline of the work already being done at USC in disparate laboratories peppered across both campuses. On this foundation, the scientists decided to pursue the idea of building a university-wide program in cancer and aging—one that might include a graduate course in the subject as well as a seminar program and a speakers’ series.

Dangers of aging

There are a number of theories that might explain why cancer rates so often increase with age. For instance, it could just be that cancer needs time to develop. Or it could be that certain cells become more susceptible to cancer-causing agents as those cells grow older.

It is possible, too, that the immune system’s ability to scan its surroundings and locate an errant malignant cell grows weaker over time. It could be that older cells have a difficult time controlling their own proliferation activities. Perhaps it has to do with a decrease, over time, in a cell’s ability to repair DNA. Or poorly repaired sites in DNA accumulate as “information scars” over time in each cell.

Lieber, head of the USC/Norris molecular genetics program and considered to be one of the leading researchers in the field of DNA repair, is studying that last explanation. He points out that cells accumulate more and more damage with each oxygen-laden breath. When cells consume oxygen to create energy, that same process also creates oxygen free radicals— highly reactive, unpaired single-electron atoms that ping around the cell looking for another electron with which to bond. And oxygen free radicals will take an electron away from any vital molecule—including DNA. In fact, Lieber says, oxygen free radicals are the source of most of the DNA damage in the human body, hitting about 20,000 sites in each genome per day.

In addition to abuse from oxygen, those same cells are bombarded by free radicals in environmental toxins such as cigarette smoke, ultraviolet radiation and asbestos, all of which can wreak havoc on their chromosomes and genes.

When a person is young, these insults—although devastating—can be borne by the cell because of the variety of methods it has developed to repair broken bits of DNA. Lieber says, “I think we have DNA breaks all the time. We go through many cycles of damage and repair. That’s part of what I think of as biological aging.”

But as a person ages, those hits to the DNA become harder to repair. If the unrepaired damage is on a gene responsible for the growth or reproduction of the cell, that cell may begin proliferating out of control and become cancerous.

In addition, Lieber points out that each time the ends of a bit of DNA need to be rejoined due to damage, there is some loss of information that results in an “information scar”. And again, if the scar occurs in a key gene that controls cell growth or death, it may have an impact on that cell’s future and its mortality. That, too, can lead to malignancy.

These ideas are echoed by Lucio Comai, Ph.D., associate professor of molecular microbiology and immunology at the Keck School, who studies the genetic mistakes that cause premature aging and their link to aging-related diseases.

In particular, Comai focuses on a genetic condition called Werner syndrome, which afflicts between one and two people per million. The mutation to the Werner syndrome gene usually occurs around the time of adolescence, causing premature graying of the hair, changes in skin and its elasticity such as wrinkles and age spots, osteoporosis, atherosclerosis, diabetes, cataracts and, most relevantly, a variety of age-related cancers. A person with Werner syndrome rarely reaches the age of 50, having died of either cardiovascular disease or cancer.

Comai suggests that some of the confusion over the links between cancer and aging might be alleviated by studying the genetic changes in the cells of people with Werner syndrome.

He explains that the chromosomes in the cell nuclei of people with Werner syndrome are more likely to break or mutate than those found in people without the syndrome. In addition, those same bits of genetic destiny are hypersensitive to cancer-causing chemicals and radiation. All of this is caused by the mutation to the Werner syndrome gene, Comai says.

Unfortunately, while scientists know the location of the gene, the effects that its protein products have on cells and how that is linked to the syndrome or to the normal aging process remain a mystery. Comai speculates that it might be somehow involved in DNA repair. In fact, his laboratory has shown that the Werner protein works with or alongside one of the key parts of the DNA repair mechanism that Lieber has been studying. “These findings suggest that the Werner protein may be involved in the repair of specific chromosomal breaks, and we are currently testing this hypothesis,” Comai says.

Glimpse at gliomas

Other USC scientists, including Finch, a renowned gerontologist, reiterate the belief in the link between age-related genetic damage and cancer.

Finch’s main research interest is not in cancer, however; it is in Alzheimer’s disease and how aging impacts this degenerative brain disease.

Part of that interest lies in numbers. In the human population, Finch notes, Alzheimer’s disease is 100-fold more prevalent than gliomas, which are the most common type of primary brain malignancy.

Still, there are certain shared key characteristics between the two that Finch, along with Thomas Chen, M.D., associate professor of neurosurgery at the Keck School, find intriguing. For instance, both Alzheimer’s disease and gliomas become far more common with age, and both have a predilection for one gender over the other. Alzheimer’s is more likely to be found in women than men, while gliomas strike men more frequently.

In addition, Finch notes, Alzheimer’s disease and gliomas can coexist in a single brain, showing that gliomas are not put off by the inflammation that Alzheimer’s brings with it. This is not surprising, he says, considering that inflammation is now known to play a role in causing cancer, and it most certainly plays a similar role in the neurological deficits that characterize Alzheimer’s disease.

These connections have led Finch to suspect that there might be an actual link between Alzheimer’s and gliomas, rather than coincidental similarities. He wants to know if the presence of inflammatory processes in brains affected by Alzheimer’s disease directly alters the incidence and growth of gliomas, and if so, how this occurs.

In addition, he and his colleagues are looking at estrogen’s role in slowing age-related increases in gliomas—a finding that might explain why women, who have been under the hormone’s protective influence throughout their lives, are less likely to get this type of tumor when they get older.

Time or age

Not everyone is convinced that the link between cancer and aging is tied to the passage of time as humans measure it—in days, weeks, months and years.

Malcolm Pike, Ph.D., professor of preventive medicine at the Keck School, agrees that cancer rates rise over the years—at least up until age 75, after which the data become unreliable due to any number of factors, not the least of which is the inevitable influence of other life-threatening diseases. But, he says the issue is not the passage of time, exactly; rather, it is a question of duration.

Pike says that any link between cancer and the ticking of some external timepiece is purely incidental. Instead, he says, cancer results from the interplay between how many times a cell has divided, and how long that cell has been exposed to an environmental insult, such as oxygen or a chemical toxin or radiation exposure.

While that may seem like a point based purely on semantics, Pike believes otherwise. In his research, Pike has shown that cells, when protected from exposure to toxins and kept in a non-dividing state, start up their internal clocks only when the protection is removed. They do not immediately become cancerous, even though their never-protected brethren are dividing out of control.

To further showcase the importance of duration of exposure to a cancer-causing agent—as opposed, more simply, to age and the passage of years—Pike points to the connections between hormones and women’s cancers, a topic on which he is perhaps one of the world’s leading experts.

“The thing we know about breast cancer, endometrial cancer and ovarian cancer is that if you have menopause at age 30, you won’t get any of them,” he says. “We also know that if women ovulated until the age of 70, the rates of all of these cancers would rise significantly.”

Those facts, Pike says, make it clear that the risks of getting these cancers are tied in to how long a woman is exposed to the hormones that lead to malignancy, rather than her age.

Reset the clock

Similarly, Valter Longo, Ph.D., assistant professor of gerontology at the Davis School of Gerontology, points out that interventions that increase the lifespan of rodents by slowing down their cell-turnover rates also decrease their cancer rates.

Longo and others have shown that a 30 to 50 percent decrease in caloric intake extends the lifespan of rats and mice by 30 to 40 percent. It also decreases blood glucose and insulin levels, dampens the inflammatory response and, most relevantly, decreases the numbers of tumors, even in tumor-prone rodents. In other words, even though these rodents are old, Longo says, they do not show the same dramatic increase in cancer rates—mostly because their cells do not divide as often.

Agreeing with this concept is Darryl Shibata, M.D., professor of pathology at the Keck School, who says that cancer cares nothing about age. It only cares about how many times the most basic cells—stem cells—have divided. Each division, he says, puts the next generation of cells at a higher risk of being handed down some kind of genetic mutation. Shibata notes that in 1990, now-Keck School Dean Brian E. Henderson, M.D., showed that mitotic age—the number of times a cell’s DNA has been copied—can differ from and is more important than chronological age in cancer.

The problem, Shibata says, is that measuring mitotic age accurately is almost impossible using current methods. He and his colleagues are searching for an accurate biological clock that could gauge cancer risk and target cells for therapeutic intervention. They hope to find that clock in methylation—a process by which a chemical group is added to the surface of certain genes, changing their ability to be read and translated into proteins.

Shibata points out that each time a cell divides, its methylation patterns change. “If we can use methylation patterns as molecular clocks, we will be able to figure out a cell’s molecular age by how much methylation it has undergone,” he says. And that will make it possible not only to assess a cell’s risk of becoming cancerous, but possibly to step in and stop the process—to reset the clock back to an earlier, low-risk time.

Treat the aging

Despite the fact that the burden of cancer falls so heavily on the aged, their care is generally less intense and less aggressive than care given to younger patients. Studies have shown that people over age 65 are less likely to be referred to a specialist when there are signs of malignancy, are less likely to be given early detection tests to catch cancer at the most treatable stage and receive less aggressive treatment options.

Part of the reason may be a lack of data, notes Edward Schneider, M.D., Dean Emeritus and professor of gerontology at the Davis School of Gerontology.

Schneider explains that clinical trials, which generate information on how people might respond—or not respond—to different levels and combinations of experimental drugs, are carefully designed to avoid doing more harm than good. So they include a large number of requirements that geriatric cancer patients rarely meet because they are too sick or have too many other health issues, called comorbidities. An NCI study found that 40 percent of elderly cancer patients have more than five comorbidities, with hypertension and heart disease topping the list.

Because of additional illnesses, many elderly patients take a variety of drugs that might interact with the chemotherapy agents being tested in a clinical trial, thus muddying the statistical waters and making the trial useless in terms of data reliability.

Outside the clinical trial, comorbidity and drug interaction still plague the treatment of the elderly cancer patient; add to that the fact that drug metabolism rates change as people age, so data culled from younger cancer patients are all but useless in finding the right dose for an older patient, and the result is a major conundrum.

Schneider says that while making more clinical trials accessible to elderly cancer patients is the goal, another approach would be individualized treatment for each patient’s unusual set of medical circumstances. “The use of a geriatric assessment team would be a unique approach,” he says, “so that an elderly patient has the best chance of being given a treatment that will allow a good standard of living.”

Ultimate answers

Understanding how cancer and aging are tied together is undoubtedly worth all of this effort and more. After all, the population is aging, putting more and more people at risk for age-discriminating malignancies. No matter what links are confirmed between aging and cancer, figuring out how to manipulate those links and stop cancer’s progression will ultimately put time on everyone’s side.