Research on Cancer Gene Poses a Dilemma

We all get old. But getting old is more than just the passage of time. There seems to be specific genetic signals that determine how fast we age.

Norman Sharpless of the University of North Carolina in Chapel Hill has been searching for the genes related to aging. He focused on an anti-cancer gene called p16. Anti-cancer genes put the brakes on cell proliferation, so cells don't divide uncontrollably and form tumors. But he wondered whether p16 was also preventing aging organs from renewing themselves.

So Sharpless asked himself what would happen if you took p16 away. He created a strain of so-called knockout mice; they lacked the anti-cancer p16 gene.

The James Dean Phenomenon

Sure enough, the mice without p16 kept healthy, young-looking organs filled with young looking cells even as they grew older. But they didn't live any longer than normal mice.

"The good news is, you don't age as quickly," says Sharpless. "The bad news is, you get cancer. I like to think of this as the James Dean phenomenon. Live fast, die young and leave a good-looking corpse."

But even if p16 didn't make the animals live longer, it did make their cells behave like they did when they were young.

And that gives scientists a way of studying how cells behave when they age normally, and what changes when they age without the p16 gene.

Sean Morrison took up that challenge. He's a stem cell biologist at the University of Michigan in Ann Arbor. He focused on what happens to stem cells.

"You have stem cells in many different tissues that are required to generate new cells every day," he says. "You have stem cells in your bone marrow that make new blood cells every day. Stem cells in your skin that make new skin cells, even stem cells in your brain that make new brain cells. And we've always known that during aging, tissues have less capacity to grow, and less capacity repair themselves after injury."

The Secret to Cell Youth

In the current issue of the journal Nature, Morrison reports that brain stem cells missing p16 don't appear to age. They retain their capacity to grow and repair injury.

In a second paper, stem cell biologist David Scadden shows that blood stem cells also retain their youthful vigor when p16 is missing. Scadden is director of the Center for Regenerative Medicine at Massachusetts General Hospital in Boston.

He says even though p16 isn't the answer to living longer, tinkering with someone's p16 levels may make it possible to treat traumatic injuries.

"We'll have to be very careful with the way this gene is regulated," says Scadden, because shutting it off increases the likelihood of getting cancer. "But if we could modify it following a particular kind of injury, you might be able to enhance the restoration of function, and that would be a very very powerful tool."

There's another way p16 might be useful in medicine. North Carolina's Norman Sharpless, who has the third Nature paper on p16, says scientists know that p16 levels go up as humans age. But they may go up at different rates in different people. So maybe you're only as old as your molecules say you are.

"There's molecular age, and then there's chronologic age," says Sharpless. "And as a physician, I can tell you that some patients who say they're 60 look a lot older, and some patients who say they're 70 look quite spry."

Sharpless says the more spry, the better they can tolerate certain drugs.

The three new studies all seem to show that the same genetic change that makes cells stay youthful also makes you more susceptible to cancer. But Cynthia Kenyon isn't convinced that's always true.

Kenyon is director of the Hillblom Center for the Biology of Aging at the University of California San Francisco. She's been studying animals with genetic mutations that make them live longer.

"We asked what happened to tumors in these animals," says Kenyon, "and we found that all of these different genes that extend lifespan also delay tumors."

So there's a chance someday we'll all live longer, cancer-free lives.