By Alexandra Goho
New Genetic Twist in Cancer and Aging
A gene involved in aging also helps to keep cancer at bay
By Alexandra Goho
Three recent studies have found that a critical gene which protects against cancer also controls longevity in mice. Understanding this link between cancer and aging could help oncologists better tailor therapies for their patients and minimize toxic side effects.
The gene, called p16INK4a, is among the most commonly mutated genes in cancer cells. As a person gets older, amounts of the protein encoded by this gene increase. Meanwhile, the number of cells that permanently stop dividing—called senescent cells—also increases with age. Until recently, it was unclear whether these two processes were linked. “Does the protein go up with aging because it marks aging or does it cause cells to stop dividing?” says Norman Sharpless, a medical oncologist at the University of North Carolina School of Medicine in Chapel Hill.
Seeking to answer that question, his lab and two other research groups compared normal mice with genetically engineered mice lacking the p16INK4a gene. Each team focused on cells from a different tissue: Sharpless’ group looked at the pancreas; Sean Morrison, a stem cell biologist at the University of Michigan in Ann Arbor, studied the brain; and David Scadden, a stem cell biologist at Harvard Medical School, focused on bone marrow. The three studies were reported in the Sept. 28, 2006, issue of Nature.
The results were consistent across the board. As the mice aged, p16INK4a gradually slowed the proliferation of stem cells or other self-renewing cells, which are essential for repairing and regenerating tissues. However, in mice lacking the gene, cell growth didn’t slow as much.
The aging process may have slowed down in mice missing p16INK4a, says Sharpless, but this came at a cost: The animals were more prone to developing tumors. This makes sense, he says, since cancer is a disease of excessive cell proliferation and p16INK4a shuts down cell division.
Although the findings could affect the development of anti-aging therapies, which might put patients at increased risk of developing cancer, Sharpless sees a potential benefit for cancer patients. Because levels of the protein encoded by p16INK4a strongly correlate with aging, “it’s like an odometer,” he says. Oncologists could use the levels of protein to determine the molecular age of a patient’s bone marrow prior to chemotherapy or radiation treatment.
That’s important, since patients with older bone marrow—either due to age or the stress from previous rounds of chemotherapy—might be at a greater risk for long-term side effects or toxicities. Having high p16INK4a levels and a large number of senescent cells could potentially reduce the body’s ability to make new blood cells. Using p16INK4a as a diagnostic tool could help doctors more precisely weigh the risks and benefits of a particular treatment. Sharpless and his colleagues have already begun to test the diagnostic in humans.
Scott Lowe, a cancer geneticist at Cold Spring Harbor Laboratory in New York, says the findings could also help in the development of new cancer therapies. Blocking p16INK4a temporarily during a round of chemotherapy or radiation, for instance, might help the body replace the blood cells that were destroyed during treatment, he says.
Ultimately, adds Lodovico Balducci, a geriatric oncologist at the H. Lee Moffitt Cancer Research Center in Tampa, Fla., “the control of cancer will rely, in part, on understanding the interactions between cancer and aging.” 