Cancer becomes more common with age and is often harder to treat in older adults. Yet most cancer studies in mice do not reflect that reality. Fewer than 10% of mouse experiments use aged animals, with researchers typically relying on mice that roughly correspond to humans in their early 20s. That gap may help explain why many cancer therapies that perform well in laboratory studies ultimately fail in human clinical trials. It turns out a mouse in its twenties and a human in their seventies have very different ideas about how tumors should behave.
New findings from Fox Chase Cancer Center, presented at the American Association for Cancer Research annual meeting, suggest that melanoma does not behave the same way throughout the aging process. Researchers found that cancer spread was lowest in young mice, reached its highest level in middle-aged mice, and then declined again in very old mice. So the sweet spot for cancer metastasis is apparently somewhere between "I have a mortgage" and "I've stopped caring."
"The vast majority of studies are done in these very young mice that have a healthy and intact immune system," said Mitchell Fane, PhD, a cancer biologist who specializes in aging and cancer, and lead investigator of the study. "Right now, it's easy to personalize care for someone who's young and fit, who's potentially not going to experience as many toxicities; understanding how therapies affect older patients would give us more and better treatment options."
The researchers believe a specialized group of immune cells known as gamma delta (γδ) T cells may help explain the surprising pattern. These cells act as an early defense system, helping prevent cancer from spreading throughout the body. Young mice and very old mice had higher levels of these protective immune cells, and their tumors were more likely to remain dormant or spread less aggressively. Middle-aged mice told a different story. They had fewer γδ T cells, and melanoma was much more likely to spread to organs such as the lungs and liver.
The team also discovered that melanoma cells can actively weaken the immune system as animals age. In middle-aged mice, the cancer released molecules that suppressed or exhausted γδ T cells. As those defenses weakened, previously dormant cancer cells were able to become active and spread more aggressively. Additional experiments reinforced the importance of these immune cells. When researchers removed γδ T cells from young and very old mice, melanoma spread increased significantly. Conversely, blocking the signals that suppress immune activity restored protection and reduced cancer spread in middle-aged mice, although the same effect was not seen in the younger or older groups.
One reason aging studies remain uncommon is practical. Young mice are easier and less expensive to obtain, while aged mice require long-term care and breeding. Researchers must typically wait 18 to 24 months before mice reach an age suitable for aging research. To address that challenge, Fane and colleague Yash Chabra, PhD, both Assistant Professors in the Cancer Signaling and Microenvironment Research Program, helped establish an aged mouse facility at Fox Chase Cancer Center. The goal is to make older animal models more accessible and encourage scientists to test whether their findings hold true across different stages of life.
"Now we have a facility with established aged mouse colonies, which lowers the cost and time barriers to aging research," he said. "It allows us to tell colleagues, 'Your model is interesting, why not test it in aged mice?'"
Understanding how aging affects cancer could lead to more effective treatments for older adults. Fane's laboratory is particularly interested in the observation that the relationship between age and cancer does not appear to follow a simple straight line. Although cancer risk generally rises with age, rates unexpectedly decline among people over 80 to 85 years old.
"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."
The new findings suggest that changes in the immune system over the course of aging may play an important role in determining when cancer is most likely to spread. They also highlight the importance of including older animals in cancer research to better reflect the patients most affected by the disease.