Dealing With the Devil

Cancer and aging share common molecular pathways, making it tricky to treat one without triggering the other. But new research suggests a potential way around this conundrum.

When it comes to terrible tradeoffs, Doctor Faust is literature's resident expert. Armed with the science of his age, he couldn't solve the puzzle of life. So the frustrated doctor made a deal: He asked the devil to help him, with the understanding that eventually there would be hell to pay. Now, with the human genome sequence in hand, medical scientists are finding that such Faustian bargains are written into our cells. The molecules that safeguard against cancer might also drive our deterioration, delivering us into the arms of diabetes and other age-associated maladies. Because of this shared pathway between aging and cancer, medical interventions that slow one could potentially speed the other.

Early in life, when our cells are proliferating vigorously within growing tissues, a team of molecular guardians keeps an eye out for damage. Each time a cell divides, it runs the risk of making mistakes as it copies its DNA. A single cell with the right mutations can start to multiply wildly, outgrowing its neighbors and forming a tumor. "Even newborns have a surprisingly high number of mutant, precancerous cells in their blood," says Ned Sharpless, an oncologist and cell biologist at the University of North Carolina, Chapel Hill. But cancer almost never hits us in youth because certain proteins scour cells for dangerous DNA errors. They encourage impaired cells to fix themselves, and if the destruction seems beyond repair, they signal the cell to commit suicide for the good of the body.

But the same molecular mechanisms that protect us from cancer in our youth might contribute to our decline in later life. In putting a damper on cell division, the guardian proteins might deplete or destroy cells that could help us restore tissues worn out with age: blood vessels that need repairing, bone that needs bulking, or insulin-producing pancreatic cells that need replacing, for example. And if these protectors arrest the growth of stem cells, our all-purpose tissue regenerators, the whole body might head toward breakdown, says Larry Donehower, a cancer biologist at Baylor College of Medicine in Houston, Texas. A host of age-related problems--from wrinkling skin and dwindling muscles to graying hair and adult-onset diabetes--might indirectly result from the body's efforts to prevent cancer.

The most thoroughly studied of these Faustian molecules, a protein called p53, is essential for holding cancer at bay: Its loss is involved in half of all human cancers. But p53 has a dark side. In addition to killing potential cancer cells, it can order cells to retire from dividing--a condition that might underlie the process of aging. As these retired cells accumulate, worn-out tissues might lose the ability to replenish themselves. Donehower and his colleagues encountered the two faces of p53 when they engineered mice that produce more of this guardian protein than normal rodents do. These animals resisted cancer, but compared with unaltered mice their age, they possessed fewer stem cells and showed signs of accelerated aging, including wrinkled skin and brittle bones.

This hard-wired molecular link between cancer and aging has important implications for the treatment of cancer as well as for potential age-retarding therapies. We must take care that interventions aimed at reactivating our cells' innate ability to reproduce do not promote cancers, says Sharpless. Take, for example, the use of human growth hormone and other forms of hormone replacement that are advertised to stave off aging. Human growth hormone, some data suggest, might accelerate tumor formation, says Sharpless. Likewise, research shows that estrogen replacement in postmenopausal women carries an excess risk of breast cancer.

On the other hand, drugs that exploit the body's natural cancer-fighting mechanisms--by, for example, boosting p53 activity--could make us more vulnerable to the diseases of aging. For most people, the choice between developing a potentially fatal cancer and graying earlier is not difficult. In any case, cancer preferentially strikes people who are already in their golden years. But children and young adults who are cured of leukemia have a full life ahead of them, so losing decades of potential life span would be a serious side effect for them, says Sharpless.

Additional research, however, hints at a possible light at the end of this tunnel. More recent experiments with genetically engineered mice suggest that scientists can harness p53's cancer-fighting potential without shortening life span. The key, researchers find, lies in taking advantage of p53's ability to regulate its own production, ensuring that the protein is present only when needed. These mice have a normal life span with far fewer cancers. The results are preliminary, and Sharpless points out that aging and cancer work differently in mice and humans, but they suggest that cancer and aging might not be inextricably linked.

Perhaps we can turn the connection between cancer and aging to our advantage, fighting both with the same intervention. Researchers have known for decades that animals that consume 30% fewer calories than their fully fed counterparts live longer and get cancer less often. "It's the only method of cancer and aging prevention that we know works"--at least in mammals, says Sharpless. Unfortunately, this draconian diet comes with its own tradeoffs: reduced fertility, thinner bones, and an increased susceptibility to certain infections, for instance. However, many researchers are trying to tap into the benefits of calorie restriction while avoiding its drawbacks. Within 5 years, says Sharpless, studies designed to explore how cutting calories slows both cancer and aging should yield results. "Hopefully, these will show that some combination of diet and exercise does the trick." If researchers find a way to master cancer and aging in one blow, they truly will have beaten the devil at his own game.

John Bohannon is a freelance writer based in Paris, living a carefree life that he'll surely have to pay for later.