Turning eighty could have an unexpected benefit: a reduction in the risk of Lung cancer, according to two studies on mice 1, 2.

The results, published as preprints on the bioRxiv server, pinpoint specific genes that may contribute to decreasing risk and reveal a surprising connection Iron metabolism. The studies have not yet been peer-reviewed.

The results may seem counterintuitive: Cancer is a disease associated with aging, and the probability of many Cancer diagnoses peaks in a person's 60s or 70s. But afterward, rates of many of these cancers mysteriously decline.

“It's an observation we've been making for decades,” says Ana Gomes, who studies aging and cancer at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, and is not involved in the preprints. “But we really couldn’t explain why that was.”

Age accumulation

Cancer is caused by DNA mutations that accumulate over time. More years of life means more opportunities to accumulate the constellation of mutations necessary to create rogue cancer cells that grow uncontrollably. Immune responses that would once have been able to keep a tumor in check can also become quieter with age.

But the changes in tissue that come with aging can also discourage tumor growth by changing the environment in which cancer cells live. For example, older lungs tend to have more scar tissue than younger lungs. Lung cells also become less capable of regeneration and less resistant to the stressors of unregulated growth. “Structurally and functionally, the environment you have at an older age is a completely different environment than the one you have when you’re young,” says Gomes.

To learn more about how aging affects tumor growth, Emily Shuldiner, a cancer biologist at Stanford University in California, and her colleagues studied mice that have a cancer-causing mutation that the authors controlled with a genetic switch 1. The team turned on these mutated genes in the lungs of young and old mice and found that tumors in the younger mice were larger and more common than in the older mice.

The researchers also used CRISPR-Cas9 genetic engineering in mouse tumors to study the effects of inactivating more than two dozen genes that normally suppress tumor growth. On average, turning off most of these genes increased the growth rate of tumors in mice of all ages, but there were more tumors, and they grew larger, in younger mice than in older mice. This suggests that a different process may be at work to suppress cancer in older mice.

Iron grip on tumors

Another team led by Xueqian Zhuang, a cancer biologist at Memorial Sloan Kettering Cancer Center in New York City, found that aging increases the production of a protein called NUPR1 — which affects iron metabolism — in mouse and human lung cells 2. The cells then behaved as if they were low in iron, limiting their capacity for the rapid growth that is a hallmark of cancer.

To follow up on this discovery, the team used CRISPR-Cas9 genetic engineering toNupr1gene in older mice. Iron levels in the animals' lungs increased, and the mice became more susceptible to tumors, like their younger counterparts.

The authors also found that people over the age of 80 have more NUPR1 in their lung tissue than people under the age of 55, suggesting that the mechanism may be conserved between mice and humans.

The stress of cancer

The results nicely show that aging can affect the fitness of lung cancer cells in a way that prevents tumors, says Gomes. But there may be important differences in how tumors form in humans and in these mice, she adds. In humans, cancer-causing mutations usually accumulate gradually, and the seeds of a cancer can disappear decades before a tumor is detectable. However, in the mice, the tumors were initiated by suddenly switching on the cancer-causing gene when the mice were already old.

And results on lung cancer may not generalize to cancers in other tissues, says Cecilia Radkiewicz, an oncologist and cancer epidemiologist at the Karolinska Institute in Stockholm. “It's quite different between different types of cancer because they have different biological drivers,” she says.

Radkiewicz has found that for many types of cancer, the apparent decline in incidence in old age may be an artifact. When she examined how often tumors were found in autopsies, that decline often disappeared 3. This suggests that rates of various cancers often remain the same even in old age, she says, but the cancers are simply diagnosed or reported less frequently in people over 75.

One exception, she adds, was lung cancer: its incidence actually decreased in older people, even when taking autopsy data into account.

Overall, the results highlight the importance of studying cancer in old mice, says Zhuang. Such studies can be difficult, she says: It's expensive and time-consuming to breed mice into old age. But the results could reveal new ways to treat cancer in old and young people, as well as important targets for Regenerative medicine point out.

“People often think that aging is all bad,” says Dmitri Petrov, an evolutionary biologist at Stanford University and author of the preprint with Shuldiner. “But if this [work] is correct, then aging has an important role to play.”