Stanford Scientists Discover Aging May Suppress Cancer, Not Fuel It

Although cancer becomes more common as people get older, individuals of very advanced age appear to face a lower threat. New research from Stanford University demonstrates this pattern in mice and investigates how later-life biological changes may offer unexpected protection.

Older laboratory mice were found to develop far fewer lung tumors, and those tumors were less aggressive compared to tumors in younger mice, according to a new study from Stanford University. This outcome challenges the long-standing belief that cancer risk simply climbs with age and instead aligns with observations in very elderly humans, whose cancer rates tend to stabilize or even drop.

“It’s a striking finding,” associate professor of genetics and of pathology Monte Winslow, PhD, said. “We would expect that older animals would get more and worse cancers, but that’s not at all what the study found. So, what is it about the molecular changes associated with aging that suppress cancer?”

Although these results hint that aging could offer unexpected protective effects, researchers have struggled to examine this idea in depth. Limited data have made it challenging to understand how a patient’s age might influence their response to cancer treatments.

“Aging is a systemic change to your body, but most cancer studies in mice are conducted on younger animals,” said former graduate student Emily Shuldiner, PhD. “When we introduced the same lung cancer-causing mutations in young and old mice, the young mice develop more, faster-growing tumors.”

Shuldiner is the lead author of the study, which was published on November 4 in Nature Aging. The senior authors of the paper are Winslow and professor of biology Dmitri Petrov, PhD.

Factoring in the age factor

It seems logical that cancer becomes more likely as we grow older. Every round of cell division carries a small risk of introducing DNA mutations that can disrupt how cells interpret signals that regulate growth and rest.

For much of adulthood, this idea appears accurate. Cancer rates in the general population climb steeply starting around age 50 and reach their highest levels between 70 and 80. However, after about age 85, the trend levels off and even starts to decline. Researchers have not known whether this drop reflects reduced screening, which would lower detection, or whether it points to a form of natural selection — maybe individuals who live to very old ages also possess immune systems that are better at recognizing and removing emerging cancers.

But the results in the mice suggest a deeper biological cause.

“The standard model of cancer is, with age, you accumulate bad things in the form of mutations,” said Petrov, the Michelle and Kevin Douglas Professor in the School of Humanities and Sciences. “And when you collect enough bad things, cancer happens. After a certain age, it should be almost inevitable, right? But that’s not what we see; after a certain point, aging appears instead to be a generic form of cancer suppression.”

Other changes also accumulate with age: For example, the patterns of chemical tags on our DNA called methyl groups that help regulate which genes are expressed and when they are expressed are altered. And the genome generally becomes more structurally unstable and vulnerable to breakage. Segments of DNA in our cells’ energy factories can duplicate and reintegrate into the genome, creating stretches of repeating sequences like identical boxcars on a train track.

Among all that genetic mayhem, however, some of these changes hamstring cancer development in a way that could be exploited for new therapies. But identifying this in animals is extremely time-consuming.

Shuldiner tackled the problem head on. The mice in her study were genetically engineered to develop fluorescently tagged lung cancers when the animals were treated with an inhaled gene delivery system. But to compare tumor formation between young (four to six months) and old (20 to 21 months) mice, she first had to wait nearly two years for the animals to age. (The average lifespan of a laboratory mouse is about two years.)

Once the animals were sufficiently long in the tooth, Shuldiner induced lung cancer formation. Fifteen weeks later, the amount of cancer in the lungs of the young mice — measured by lung weight and fluorescent imaging — was about three times that of the older mice. The young mice also had about three times as many tumors, and these tumors were significantly larger than those found in old animals.

“In every way we could measure, the younger animals had worse cancers,” Shuldiner said.

She then investigated the effect of inactivating 25 tumor-suppressor genes in the animals before triggering cancer development. These genes make proteins that block the development of cancers, and many are involved in processes associated with normal aging.

When it’s better to be old

The impact of inactivating any of several tumor suppressor genes were lessened in old mice. That is, although tumor incidence increased in the animals with inactivated tumor suppressors regardless of age, the effect was greater in younger mice. But inactivating one tumor suppressor gene in particular, PTEN, had a much greater impact than the others.

“PTEN inactivation stood out as having a much stronger effect in young mice,” Shuldiner said. “It suggests that the effect of any given mutation, or the efficacy of cancer therapies targeted at specific mutations, might be different in young versus old people.”

Shuldiner also investigated the gene expression patterns in cancer cells from old animals with either active or inactive PTEN.

“We found that patterns known to be associated with aging were still present in the cancer cells from old mice,” Shuldiner said. “This was not an obvious finding because cancer cells are rapidly dividing. It was interesting to see those signatures of aging remained. However, in old animals in which PTEN was inactivated, these aging signatures in the cancer cells were much less pronounced. They looked as young as the PTEN-deficient cancer cells from young animals, which was very surprising.”

The study is the first to conclusively show that aging represses tumor initiation and growth and that it changes the impact of inactivation of tumor suppressor genes like PTEN. It also describes how signatures of aging remain in old cancer cells, even though they are dividing rapidly. The findings illustrate the importance of developing new cellular and animal models of cancer that incorporate the effects of aging to develop new therapies.

“We develop these animal models of cancer with an eye to developing new treatments for patients,” Winslow said. “But for this to work, the models have to be correct. And this study suggests that models using young animals may not be accurately reflecting important aging-related changes.”

“The implications of this story could be huge,” Petrov said. “Maybe aging has a beneficial side to it that we could harness for better therapies.”

Reference: “Aging represses oncogenic KRAS-driven lung tumorigenesis and alters tumor suppression” by Emily G. Shuldiner, Saswati Karmakar, Min K. Tsai, Jess D. Hebert, Yuning J. Tang, Laura Andrejka, Maggie R. Robertson, Minwei Wang, Colin R. Detrick, Hongchen Cai, Rui Tang, Christian A. Kunder, David M. Feldser, Dmitri A. Petrov and Monte M. Winslow, 4 November 2025, Nature Aging.
DOI: 10.1038/s43587-025-00986-z

The study was funded by the National Institutes of Health (grants R01 CA234349, R01 CA230025, U01 AG077922, P30 CA124435 and F99/K00 CA2344962), the Canadian Institute of Health Research, the Stanford Cancer Institute, the American Cancer Society and the University of California’s Tobacco-Related Disease Research Program.

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