The p16 Paradox:
The protein that helps prevent cancer also plays a role in aging

Aging is accompanied by a decrease in the body’s ability to regenerate new cells. Cancer, on the other hand, is the result of an overgrowth of cells and the failure of cells to die off. Yet cancer is more common in older people. Why this contradiction? Norman Sharpless, MD, assistant professor in the department of medicine and genetics at the University of North Carolina School of Medicine, and his colleagues, Sean J. Morrison, PhD, of the University of Michigan and David T. Scadden, MD, of Harvard Medical School , recently published three related studies on the topic in the September 6, 2006, issue of Nature.

Here, Dr. Sharpless answers the question: Why is there this paradox in the way cells behave as we age?

Can you provide a quick overview of this paradox?
The protein p16INK4a (p16), which is a very famous protein for its role in preventing cancer, also plays a key role in aging.

p16 is required to combat the development of would-be cancer cells. But p16, which increases in people as they get older, also causes other body cells to permanently stop dividing, which has implications in the overall aging process.  

How exactly does p16 prevent cancer?
p16 helps prevent cancer through a tumor-suppression mechanism called “cellular senescence.” When cells have divided too many times or become damaged in some way, they somehow realize this. These stresses lead to an increase in the level of p16, and the cells become senescent and stop dividing. By mediating cellular senescence, p16 stops cancer cells from reproducing before they can form a tumor. An example of p16 at work can be seen in the moles growing on our skin. Many of us have dysplastic nevi, or irregularly shaped moles. A lot of these moles have cancer-causing mutations, but they don’t cause any problems because p16 kicks in to stop the cancerous cells from growing. So those of us who have moles should be happy that p16 is at work to prevent cancer on a daily basis.

Does everyone have p16?
Everyone has p16, and studies have shown that p16 markedly increases with aging in many mammalian tissues. Some people, however, have a defective copy of p16. These people look normal and have no problems…until they come down with melanoma or another type of cancer. The strongest association between p16 malfunction and cancer is with melanoma, followed by pancreatic cancer, glioblastoma (brain cancer), myeloma (cancer of the bone marrow), and head and neck cancers. The effects of the mutant p16 are strongly influenced by the environment, however. For example, individuals with defective p16 living in non-sunny places (e.g. Ireland) have a lifetime risk of melanoma that is less than 40 percent, but genetically similar individuals with the same p16 mutation living in Australia have a lifetime risk that is greater than 80 percent. So the effects of p16 mutation are much greater when combined with exposure to carcinogens like ultraviolet sunlight.

Could p16 possibly be nature’s way of protecting people from cancer as they age?
We think the increase in p16 is important because it protects people from cancer on a daily basis. It is sort of like the police. At any moment, a police force’s activity is very important to suppressing crime; but if you have an overzealous police officer, you might not notice it on any given day. Over time, however, society will suffer because eventually the overzealous officer will have a negative impact on law-abiding citizens and beneficial activities.

So we think of p16 as behaving in a kind of good cop, bad cop way. p16 is a good cop when it cracks down on individual cancers that crop up; but at the same time, it acts like a bad cop when activation of the tumor-suppression mechanism in p16 causes self-renewing cells like stem cells and beta cells in the pancreas to become senescent. As a result, your bone marrow gets older, the beta and islet cells in your pancreas get older, and you have a tissue that cannot regenerate and repair.

Does p16 go up in all tissues as they age?
p16 accumulates in most tissues with aging. It does not increase in every cell of every tissue, however.

My colleagues and I spent several years studying rodents to examine where in the body p16 levels go up and by how much. For instance, we co-discovered with other groups that p16 increases a lot in the islets of the pancreas. In one-year-old mice (i.e., mice that are middle-aged), we found a 14-fold increase in p16 expression in the islets. This is extremely medically relevant because 20 million Americans have diabetes, which in all cases, at least in part, results from failure of the islets to make enough insulin.

Related experiments have also been done by us and others to suggest p16 similarly increases with aging in humans. The first was conducted at the Massachusetts General Hospital by David Louis, MD, who studied human autopsy specimens of infants to the very elderly, all of whom had died of accidental causes. Louis and colleagues found a remarkable increase in p16 expression with aging in a variety of tissues, including the islets, the brain, the liver, the spleen, and the adrenal glands.

In addition, there have been about 40 papers on the p16 increase in humans and the possible link to certain conditions, including atherosclerosis, kidney failure, heart failure, and even Alzheimer’s disease.

So there is a lot of data out there saying that p16 increases in humans, but for the most part, we don’t know the biological significance of that increase—whether it’s just a marker of old age or whether it’s causative in some way. The rodent data suggest it plays a causal role in the aging of some tissues (e.g. neural stem cells, bone marrow stem cells, and pancreatic islets), but the contribution of p16 in other organs is not established.

Is it safe to say that p16 is the sole cause of aging?
No. There is clearly aging that is independent of stem cell function, and there is stem cell aging that is independent of p16. We know this because aging is not reversed in tissues where p16 is removed or blocked. p16 causes one very specific component of aging—the decreased ability of cells to divide. Other mechanisms of aging are still being investigated.

But with that being said, I don’t want to minimize the importance of p16. In certain models, the presence of absence of the protein has a tremendous effect in animals: Its presence can, in some cases, determine whether an animal will live or die.

Is it possible that this research will lead to an anti-aging therapy?
Indirectly, yes. I think the first step toward an anti-aging therapy is the ability to test for that therapy’s efficacy. If you are going to take green tea or resveratrol for a decade, you would like to have some idea that it is working. Now that we have what we think is a biologically precise marker of aging—the p16—this might be a way to see if these anti-aging methods are working. All that’s required is a simple RNA-based test that allows us to see how much p16 is in certain cells. No drug company is going to pay for a study that shows that resveratrol prevents “aging,” but they might pay for a study that shows that resveratrol blocks some specific, surrogate marker of aging, like p16.

There has been a lot of talk in the aging research field about caloric restriction these days. How does p16 relate to caloric restriction?
As you know, caloric restriction appears to be the best way to prevent aging. It works in almost every species—rodents, spiders, flies, fish, flies—and it looks like it works in monkeys, too.

We did an interesting experiment where we looked at the p16 expression in old, calorically restricted rats. We predicted that one of two things would happen: Either caloric restriction would have no effect on p16, meaning that p16 and aging were somewhat uncoupled; or caloric restriction would block the accumulation of p16 in every tissue. We didn’t get either of those answers.

What we got was a much more complicated, but much more interesting, answer: In some tissues, such as the kidney, caloric restriction almost completely blocks the increase of p16. Calorically restricted rats have the same p16 expression in their kidneys as young rats. But in other tissues, there was little or no effect. In fact, in the uterus, the p16 expression was actually a little higher in the calorically restricted rats. We believe this means that caloric restriction slows aging in some tissues better than others, and we think p16 may in part mark this anti-aging effect. We also discovered that caloric restriction is particularly effective in certain tissues, such as the kidney.

What are the implications of your work on stem cell research?
I think this work does have some meaning for the larger ongoing stem cell debate, but only in a very peripheral way. Our work suggests that one desirable way to get around this aging/cancer paradox would be to bring in a source of young cells that haven’t suffered the ravages of aging. One source of such “young” cells would be from embryonic stem cells, so I believe our work provides additional evidence for the need for human embryonic stem cell research. We also consider further work on “adult” tissue-specific stem cells (the sort of cells we have studied) equally important.

Where is this research headed?
This research is really just beginning. The physiology of aging is exciting because it’s a really under-researched field. It’s not clear that aging is a disease in the classical sense of the word, so it’s hard to lure scientists into the field. But now, I believe in large part because of the efforts of groups like the American Federation of Aging and others, a lot of talented scientists are turning to the study of aging, and they are doing a lot of good work. So really, the field is still in its infancy, and from a scientist’s point of view, that is terribly exciting.