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Biomarker of Aging Renders Early Stage Cancers Visible

By Anette Breindl
Science Editor

Researchers have created a mouse with a reporter gene that appears to light up at the earliest stages of tumor development, regardless of the tissue type in which the tumor is developing.

"It really does seem to work in every malignancy we've tested," Norman Sharpless told BioWorld Today, which makes the mouse in question a broadly useful tool to study the earliest stages of tumor development.

The reporter is a luciferase gene that reports expression of the tumor suppressor p16. Sharpless, who is at the University of North Carolina at Chapel Hill, and his colleagues developed the engineered mice to study what Sharpless termed the "toxicology of aging."

"We used to say that aging is like the weather," Sharpless said. "Everyone talks about it, but no one does anything about it."

These days, though, researchers increasingly think of aging "more like cancer and diabetes – something that is not inevitable," and that can be both prevented and treated.

Studying aging, though, is still an experimental challenge, partly because of a lack of biomarkers, which means that in practice, looking at aging means doing very long studies.

P16 has the potential to be such a biomarker of aging. Earlier work in mice had shown that getting rid of aged cells that expressed p16ink4a could reverse a number of age-related diseases, extending the so-called health span – though not the life span – of the animals.

Sharpless and his team had created a p16ink4a knockout a few years ago, and those animals were more prone to developing a variety of tumors. In their new work, which appeared in the Jan. 17, 2013, issue of Cell, the scientists replaced one copy of the p16 gene with an engineered gene that is activated when regular p16 is, but produces luciferase.

That causes cells – an ultimately, mice – to glow green as luciferase-p16 was activated. The animals do, however, still have one normal copy of p16ink4a, and since protein levels are transcriptionally controlled, cells have adequate amounts of the protein.

In one sense, the reporter worked the way it was intended to. "It reports age," Sharpless said. "The older the mice get, the more they glow."

However, molecular age as assessed by luciferase-p16 levels did not predict either the likelihood that a mouse would develop cancer, nor its overall mortality risk.

Another surprise was how different the rates of aging were for different mice. How much an animal aged and when it would succumb to disease was unpredictable. "The degree of variability among genetically identical mice all fed the same thing was astonishing to us," Sharpless said.

Sharpless and his colleagues are still looking for the reason behind that variability; possibilities include that there might be differences in the bacteria the mice are exposed to. But the differences can apparently not be explained by simple things such as differences in food intake.

If the marker in broad terms did not predict a mouse's overall risk of cancer, it did make tumors visible as soon as they started growing. It works because it is not expressed in the tumor cells themselves. In fact, tumor cells downregulate p16, which at first seems like something of a paradox. "Why do these tumors still glow when they are suppressing p16?"

The answer is that the tumor cells don't glow. Instead, it is the surrounding stroma that lights up. "When a tumor develops, the whole area knows that something bad is happening."

Sharpless and his team have distributed the mouse to a number of other labs, which intend to study the molecular beginnings of tumor formation. His own team is using the animals to identify both pro-and anti-aging influences on cells.

The method certainly works for known culprits: Toxins that lead to aging, such as cigarette smoke and ultraviolet light, raise p16 levels. Sharpless said his team is now looking at the effects of "less obvious" things – toxins such as arsenic, but also diet and exercise.

Sharpless and his team are also looking at p16ink4a levels in people. Tying overall p16ink4a levels to mortality, or even disease risk, would take decades. So the team is looking at whether a person's p16ink4a level can predict how well a person can deal with pro-aging stressors, such as chemotherapy or surgery – whether such stressors, in turn, affect the levels of p16ink4a.