Research Reveals Gaps In Standard Mouse Models

Cancer risk increases with age and is often more aggressive and harder to treat in older adults. Despite this, most preclinical cancer studies rely on young mice, roughly equivalent to humans in their early 20s. Fewer than 10% of mouse studies incorporate aged animals, a mismatch that may contribute to the high rate of failure when cancer therapies move from preclinical testing to human trials.

New findings from Fox Chase Cancer Center, to be presented at the American Association for Cancer Research annual meeting, indicate that melanoma progression varies significantly with age. Researchers observed that cancer spread was lowest in young mice, peaked in middle-aged mice, and then declined again in very old mice.

“The vast majority of studies are done in these very young mice that have a healthy and intact immune system,” said Mitchell Fane, lead investigator of the study. He added that while treatment approaches are easier to tailor for younger, healthier individuals, a better understanding of how therapies affect older patients could expand available options.

The team identified gamma delta (γδ) T cells as an important factor underlying these age-related differences. These immune cells act as early responders that help limit cancer spread. Higher levels of γδ T cells were found in both young and very old mice, where tumors were more likely to remain dormant or spread less. In contrast, middle-aged mice had fewer of these cells and showed increased metastasis to organs such as the lungs and liver.

Researchers also found that melanoma cells can actively suppress immune function with age. In middle-aged mice, tumors released molecules that exhausted γδ T cells, allowing previously inactive cancer cells to become aggressive and spread. Removing γδ T cells in young and very old mice led to increased cancer spread, reinforcing their protective role. Meanwhile, blocking immune-suppressing signals restored immune activity and reduced metastasis, but only in middle-aged mice.

One reason aged mouse models are rarely used is the time and cost required to develop them, as mice must be maintained for 18 to 24 months. To address this limitation, Fane and Yash Chabra established an aged mouse facility to improve access to more representative models. “Now we have a facility with established aged mouse colonies, which lowers the cost and time barriers to aging research,” he said.

The study also highlights that cancer risk does not increase steadily across all ages. “While risk increases steadily as people age, it abruptly decreases after ages 80-85,” said Fane, “We want to explain the mechanism of why very old patients are getting less cancer, but middle-aged patients are getting more.”