Glow-in-the-Dark Mice Used to Track Aging, Cancer in Real-Time

Scientists have developed a strain of mice that activates a gene from fireflies when the normal p16 gene is switched on.

In a study published in the January 18, 2013, issue of the journal Cell, researchers from the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center (Chapel Hill, NC, USA) have developed a new way to visualize aging and tumor growth in mice using a gene closely associated to these mechanisms.

Researchers have known for quite a while that the gene, p16INK4a (p16), plays a role in aging and cancer inhibition by triggering an important tumor defense mechanism called cellular senescence. The UNC team led by Norman Sharpless, MD, a professor of cancer research and deputy Cancer center director, has developed a strain of mice that turns on a gene from fireflies when the normal p16 gene is activated. In cells undergoing senescence, the p16 gene is switched on, activating the firefly gene and causing the affected tissue to glow.

Throughout the total lifespan of these mice, the researchers tracked p16 activation by just monitoring the brightness of each animal. They found that old mice are brighter than young mice, and that sites of cancer formation become extremely bright, allowing for the early identification of developing cancers. “With these mice, we can visualize in real time the activation of cellular senescence, which prevents cancer but causes aging. We can literally see the earliest molecular stages of cancer and aging in living mice,” said Dr. Sharpless.

The researchers foresee instantaneous practical uses for these glow-in-the-dark mice. By providing a visual signal of the activation cellular senescence, the mice will allow researchers to evaluate compounds and exposures that promote cellular aging (gerontogen testing) in the same manner that other mouse models currently allow toxicologists to identify cancer-causing substances (carcinogen testing). Moreover, these mice are already being used by scientists at UNC and other institutions to detect early cancer development and the response of tumors to anticancer treatments.

“This work builds on previous work by the same group, as well as others, showing intriguing relationships among aging, cancer and cell senescence. It provides a valuable new tool to probe these relationships,” said Felipe Sierra, PhD, director of the Division of Aging Biology, National Institute on Aging, the National Institutes of Health (NIH; Bethesda, MD, USA).

The researchers used these mice to make several unexpected discoveries. First, the group was able to track the accumulation of senescent cells in aging mice by assessing how brightly each mouse glowed. Amazingly, the brightest animals were no more apt to die from spontaneous cancer than the less bright animals of the same age. Meaning, the number of senescent cells in the mouse did not predict its risk of dying. “The result we—and I think others—predicted is that the animals with the highest number of senescent cells would get more cancers and die sooner, but this was not the case,” said Dr. Sharpless.

Another surprise came from the discrepancies in p16 levels among the mice. The scientists examined a large group of genetically identical animals that were all kept in the same way and fed the same diet. However, in spite of the same genetic and environmental environment, the brightness of individual mice at any given age was highly variable, suggesting that factors beyond genetics and diet influence aging.

The glowing mice also provide clues into cancer formation. Expression of p16 is activated in the earliest phases of cancer formation to inhibit cancer. Usually, activation of p16 suppresses cancer, but very rarely does this tumor-suppressor process fail and tumors develop, while still triggering the p16 gene. Thus, all tumors forming in these mice strongly glowed, allowing researchers to monitor early tumor formation in a wide variety of cancer types. In contrast to expectations, the researchers also discovered that p16 was triggered not only in the tumor cells themselves, but also in healthy, neighboring cells.

“This finding suggests that activation of senescence results from an abnormal milieu within a developing cancer. Somehow, many or all the cells in a would-be tumor know they are in a bad place, and activate this tumor suppressor gene as a defense mechanism, even if they are not the would-be cancer cells themselves. This occurs really early in the cancer; we’re talking about the earliest events of neoplasia that have ever been measured in living animals,” said Dr. Sharpless.

The scientists think that similar applications to monitoring senescence can be designed to examine tumor and aging development in humans. The group is particularly interested in how cancer therapies influence human aging and patient outcome. Working with UNC oncologists, the investigators have already gauged p16 expression in several hundred patients undergoing cancer therapy. These studies, combined with research utilizing the luminescent mice, should develop more effective and tolerable patient treatment strategies based upon “molecular,” as opposed to “chronologic,” age.

Related Links:
University of North Carolina Lineberger Comprehensive Cancer Center