THE STUDIES A trilogy of papers published in the September 28 issue of Nature examine the role of a protein—cyclin-dependent kinase inhibitor p16^INK4a—in aging, healing, and cancer.
THE PROBLEM Of the 10 or 15 molecules dedicated to cell division, only one accumulates with age: p16^INK4a (p16 for short), which can be 100 times more abundant in the tissues of older people than in young people. Researchers know that the protein stops cells from dividing; without it, most large moles would probably become skin cancer. What they didn't know was whether the protein also hinders healing and regeneration as we grow older.
THE FINDINGS To look for the gene's effects, Norman Sharpless of the University of North Carolina genetically engineered mice that don't have it. Half the colony got cancer and died young. That underscored p16's role in cancer prevention. Next, to study regeneration, he selectively destroyed the mice's pancreatic cells using a particularly toxic chemotherapy drug. "Give a mouse a slug of this and 99 percent of their beta cells are killed, and they get diabetes," he explains. Within 100 days, he saw two distinctly different outcomes. If an old mouse was p16-deficient, it regrew pancreatic cells and cured itself like a normal young mouse. If it had a normal p16 gene that curbed cell division, it died of diabetes. The same pattern turned up in bone marrow studies. Sharpless lent his mice to David Scadden at Harvard, who transplanted old bone marrow from normal and p16-deficient animals into mice whose own bone marrow had been destroyed by radiation. Bone marrow from the p16-deficient mice made 3 times as many blood-forming stem cells as bone marrow from the normal mice did.
In the third paper, Sean Morrison at the University of Michigan looked for p16's effects in the brain. Normal mice with p16 had fewer neural stem cells in one part of the brain and fewer new neurons in the olfactory bulb, again demonstrating p16's ability to inhibit regeneration. But Morrison thinks a little decrepitude might be worth it: "The cells are shutting themselves down when they get old to avoid turning into cancer cells," he says. "There are trade-offs everywhere."
THE RESEARCHERS "Basically you've got a choice," says Morrison. "You can either die of aging or die of cancer. But you're gonna die either way." The three lead researchers, who ought to be in competition, collaborated closely to reach their results. "In many ways science is depicted as sterile and impersonal," Scadden says, but in this project "it was the personal dimension that ultimately contributed to the strength of the discovery."
