Cancer, although it can strike the young, is primarily a disease of aging. Understanding the complex intersection between the two is becoming increasingly important as our society ages, said Dr. John Rowe of the Mailman School of Public Health at Columbia University.

Dr. Rowe was the keynote speaker at a two-day conference on the links between cancer and aging organized by the American Federation for Aging Research (AFAR). Dr. Rowe, whose speech opened the second day of the conference, told the more than 100 scientists and academicians who gathered at the Union League Club in New York City on October 7 that as the baby boomers age, the country will not only have more elderly but also fewer young people. The cultural and economic impact of that demographic shift will be profound, Dr. Rowe said, making the need for understanding the relationship between the aging process and a pervasive and potentially devastating disease like cancer all the greater.

The conference started the day before with presentations of the five-year results by seven recipients of National Cancer Institute and National Institute on Aging grants. These grants were created by the NCI and NIA to invigorate the research community's focus on the intersection of aging and cancer. Each of the centers were to use this funding to support efforts in the Biology of Aging and Cancer; Patterns of Care; Treatment Efficacy and Tolerance; Effects of Comorbidity; Prevention, Risk Assessment, and Screening; Psychosocial Issues and Medical Effects; and Symptom Management and Palliative Care.

Dr. Richard Hodes of the NIA was the moderator.

Evolution, cancer and aging

Understanding the tradeoffs evolution has made between tissue maintenance— longevity— versus tumor suppression— cancer— is key, said Dr. Steven Austad of the Barshop Center for Longevity & Aging Studies at the University of Texas Health Science Center.

The ability to repair and regenerate tissues is an important factor that makes living a long life possible. But this ability comes at a cost: The cells that participate in tissue repair and regeneration are also susceptible to acquiring cancer-causing mutations when they are damaged. Damage comes from two main sources: environmental factors and normal cellular processes associated with breathing oxygen. “It is a trade off between the tissue’s ability to regenerate and repair, and the vulnerability of cells that make repair and regeneration to possibly acquiring mutations,” said Dr. Judith Campisi of the Lawrence Berkeley National Laboratory and Buck Institute for Age Research.

Organisms have evolved “gatekeeper” genes, which cause damaged or mutant cells to either die— apoptosis— or stop growing— cellular senescence. Both apoptosis and cellular senescence are important for keeping us from getting cancer in our youth. But both these processes can also, over time, be deleterious in older organisms. In particular, senescent cells can secrete inflammatory or growth stimulating factors. These factors can create a local tissue environment that can disrupt normal structure and function— a hallmark of aging. At the same time, they can promote malignancies, leading to cancer later in life.

Possible causes and connections

It generally takes 20 years or more for a cancer to develop. If you could prolong the latency period of the cancer, that could mean longer life and/or a greater quality of life as we age, said Dr. Lawrence Loeb of the University of Washington. Mutations accumulate as we age. Sporadic mutations in mitochondrial DNA may be caused by oxygen free radicals, reactive molecules that are produced during normal metabolic processes or externally by activities such as smoking. If we can diminish the damage of these oxygen free radicals, we might be able to delay cancer.

Studies have found that aging is not associated with a loss of stem cells but rather with changes of their function over time, changes that are related at least in part to those in the environment in which they reside and which render them less effective. It may be that by “reprogramming the environment, we can promote more healthy tissue,” said Dr. Thomas Rando of Stanford University. The Wnt signaling pathway molecules that regulate how stem cells respond to their environment are known to be involved in many types of cancer. Understanding the “surprising, unexpected role” that the Wnt signaling pathway may play in the loss of stem cell function with age may be a key to reprogramming the environment, Dr. Rando said.

Naked mole rats can live 10 times longer than similar-sized mice— up to 30 years— and don’t appear to get cancer or heart disease. In fact, researchers aren’t sure what the most common cause of death is, said Dr. Rochelle Buffenstein of the Barshop Center for Longevity & Aging Studies at University of Texas Health Science Center. That, coupled with the fact that they maintain activity, reproduction and other physiological functions well into old age, make them perfect for studying cancer and aging. Why are they so long-lived? Not because they produce fewer oxygen free radicals or have less damage from them, Dr. Buffenstein’s studies have found. In fact, naked mole rats show higher levels of oxidative damage to fats, protein and mitochondria than the short-lived mouse. Other studies by the Buffenstein lab have shown that their cells and DNA are much more resistant to toxic metals or chemotherapy agents than other mammals. A hypothesis is that naked mole rats are able to complete DNA repair without mutations because the cell has a better surveillance system and undergoes slower but more thorough repair —there is less turnover of stem cells—and/or cells are longer-lived. Dr. Buffenstein said the mechanisms involved in their resilience to oxidative damage are possibly the same as those that prevent their getting cancer.

That cellular senescence, when a cell permanently loses the ability to divide, prevents cancer is no longer controversial, said Dr. Norman Sharpless of the University of North Carolina School of Medicine. Knock out tumor suppressor genes like p16 and p53 and mammals won’t live long because of cancer. But the dark side of tumor suppression is that certain cells lose their ability to replicate, a hallmark of aging. Decline in replicative function is in part caused by p16, and its expression increases exponentially with age. It also rises with smoking, chemotherapy and radiation and decreases with exercise. Thus, p16 may be a good biomarker of molecular age to look at the efficacy of anti-aging therapeutics, forecast future diseases or identify agents that cause aging.

Telomeres, aging and cancer

Telomeres, the caps at the end of chromosomes, play a role in both aging and cancer. Researchers have long noted that telomeres in humans and some other mammals get shorter with age and are actually a marker of age, said Dr. Jack Griffith of the University of North Carolina at Chapel Hill in a keynote presentation. When they get too short, that triggers cells to go into senescence or to die. But not all aging animals have shorter telomeres. "In some mammals the length correlates with age and others it does not," Dr. Griffith said.

His group was the first to show that telomeres in many higher and lower species and indeed plants are arranged into large loops called T-loops. These loops are a "clever way" of protecting the chromosome end from being seen as broken DNA, Dr. Griffith said. As telomeres shorten with age it may be harder and harder to form the loops. As a result, the cells senesce.

Another part of the story, Dr. Griffith said, has to do with cancer and T-circles. When telomeres are "fiddled with" genetically or are from some forms of cancer cells, the loop portion of the T-loop tends to spit out circles made of telomere DNA. These free-living circles look as though they were once part of T-loops. They can keep replicating and reattach themselves to other T-loops, making cancer cells that are immortal.

Cancer and aging: the flip side

Both cancer and aging research seek basic understanding, the first to prevent, cure or ameliorate cancer, the latter to prevent functional decline and prevent or ameliorate the diseases of aging. Tissue renewal and repair may sit at the nexus of the concept that cancer and aging are in some ways the flip sides of a coin, said Dr. Harvey Jay Cohen of Duke University Medical Center. Tissue renewal and repair may slow aging and functional decline, but the cellular proliferation involved may lead to cancer. For instance, responses to DNA damage by tumor suppressor genes such as p53 and p16 can lead to cell death, which can lead to tissue degeneration and stem cell loss. But inhibition of either gene can lead to cancer. There are a number of other targets for research, including mitochondrial function and the role of oxidative damage to cells and immune function.

The next generation

Four winners of the AFAR-GE Healthcare Junior Investigator Award for Excellence in Cancer-Aging Research highlight new paths for exploration. Dr. Hiroaki Iwasa and colleagues at Rutgers University are studying the role that EGF (epidermal growth factor) signaling plays in promoting healthy aging. Dr. Brian Onken, also of Rutgers, and colleagues are examining how Metformin, a drug used to treat Type 2 diabetes, reduces the risk of cancer. Dr. Marcela Raices of the Salk Institute for Biological Studies and colleagues are studying length regulation of telomeres, the structures that protect the ends of chromosomes, in the worm C. Elegans to better understand cancer and aging. Dr. Christina Yau at the Buck Institute for Age Research and colleagues are looking at early and late onset forms of the same human breast cancer to assess the impact of aging and oxidative stress.

The industry perspective

As we get more and more information, the challenge for industry is to put it to good use, said Dr. Steven Shak of Genomic Health in an industry roundtable discussion. He predicted that the cost of getting a personal genome sequence would fall from around $100,000 now to about $100 in five to 10 years. “This is very exciting. But what does it mean and does it matter?” he asked. How, he said, will this translate into clinical applications?

Translating information into something useful that can be used in treatment or in diagnostics often requires expensive clinical trials. Industry must ask questions, like how long does it take to design a study and is this going to pass FDA approval, said Dr. Margaret Yu of Myriad Pharmaceuticals.

The public only sees the success stories. What isn’t seen are the thousands of compounds that have failed. Dr. Yu said. In oncology, for example, only 1 in 10 compounds make it to the Phase III trials. Once a compound makes it to the Phase III setting, it has a 50 percent chance of being successful. Think about the amount of money spent if a drug fails in the Phase III setting, Dr. Yu said.

So, for those of us in development, we have to think about the cost/benefit ratio of a compound, she said. Do we see enough anti-tumor activity to warrant the potential side effects? Is the administration practical? A drug that must be delivered twice a day intravenously isn’t very feasible for outpatient therapy. If your drug is a pill, does food affect the absorption of the drug? Is the compound easy to manufacture or stable enough for storage or shipment? Are there significant drug-drug interactions of your experimental drug to common drugs taken by a cancer patient? What do the competing products look like? Is there room for development of one more me-too compound? Once a compound appears strong enough to withstand the competition and is discovered to be safe, you then have to design a study that will give you an answer.

Dr. George Martin of the University of Washington School of Medicine and AFAR’s scientific director said he was “disturbed” by the trend of industry withdrawing support from "curiosity-driven” research. Dr. Martin said society in general--government, industry and the public--has been losing the "ethic" of the vital importance of supporting highly imaginative, creative scientists who simply are curious about how the world works. History, he said, has shown that many of our greatest discoveries come from such unfettered curiosity-driven research.

The poster child example from industry was the famous Bell Labs, the place where radio astronomy and the transistor were discovered. These were physicists who were pretty much left alone to do research. Recent examples from the pharmaceutical industry are the now defunct Hoffman LaRoche Institutes in Nutley, N.J., and Basel, Switzerland; basic advances in the biochemistry of neurotransmitters were made at the former and in immunology at the latter. No one knows, Dr. Martin said, where the next breakthroughs will come from.

Dr. Eric Agdeppa of GE Healthcare agreed, saying that GE is "one of the last great corporate labs" in existence. Although some discovery-based research is still done at GE’s lab, the company now "looks outward" to academia for new discoveries. One reason for attending meetings like the AFAR conference, he said, is to meet up-and- coming junior scientists. Then it’s up to the corporate lab to develop the discovery into a commercially viable technology for the best customer application. PET imaging and labeled molecules used to target cancer are examples of technologies begun in an academic lab that went on to be developed in corporate R&D.

Moderator Dr. Jean-Luc Vanderheyden of GE Healthcare said the link between basic science and industry has to be stronger. While “blue sky” research is important, he said, basic science is not translated enough into drugs or treatments that benefit people—an issue the National Institutes of Health has recognized and is trying to address in its critical path initiative to improve the efficiency of product development. Dr. Vanderheyden said he favored “a balance” between basic science research and clinical application. “The goal of all research is to impact the patient,” he said.

What was learned, what remains to be learned

The relationship between aging and cancer has been a topic of interest for many years, but has only recently begun to garner significant research interest and funding, said Dr. Richard Sprott, executive director of The Ellison Medical Foundation.

AFAR’s conference brought this increased research effort into sharp focus. From researchers’ presentations, it was apparent that great progress has been achieved from molecular and genetic research in explicating the changes that occur with aging and the relationship of those changes to cancer. Many of these new insights will have important implications for both therapy and prevention.

The major challenge that emerged in the discussion between representatives of the health care industry and the audience of academics and industry scientists was how to break through the usual barriers to collaboration, including regulatory roadblocks, issues of intellectual property protection and absence of accessible channels of communication.

A major objective of the conference was to try to stimulate a response to those challenges. “We believe that this conference, like last year’s biomarkers conference, is a positive step in that direction in keeping with AFAR’s commitment to facilitating cutting edge research on aging,” Dr. Sprott said.

Select speaker presentations available upon request. Contact info@afar.org.

AFAR is a nonprofit organization whose mission is to support biomedical research on aging. It is devoted to creating the knowledge that all of us need to live healthy, productive, and independent lives. Since 1981, AFAR has awarded more than $113 million to nearly 2,500 talented scientists as part of its broad-based series of grant programs. Its work has led to significant advances in our understanding of aging processes, age-related diseases, and healthy aging practices. AFAR communicates news of these innovations through its organizational web site www.afar.org and educational web sites Infoaging (www.infoaging.org) and Health Compass (www.healthcompass.org).

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