In a tale of identities as divergent as "The Prince and the Pauper," a well-known cancer-causing gene also influences cells in a zombie-like state meant to prevent cancer.
Scientists at Sanford Burnham Prebys Medical Discovery Institute and an international team of collaborators published findings August 20, 2026, in Nature Aging unpacking this biological paradox, finding that this cell proliferation gene played a distinct role in cells that no longer proliferate. It served as a driver of chronic inflammation linked to age-related disease, marking it as a promising target for future therapies to reduce sustained inflammation and promote healthier aging.
The code for producing the protein cyclin D1 is carried by the gene CCND1. This gene made waves in the field of oncology in the early-to-mid 1990s when overexpressing it was shown to cause cancer. Normally, cyclin D1 governs the activity of signaling molecules needed to push cells along the cell cycle towards replicating their DNA and dividing to make new cells. This process goes haywire and becomes hyperactive in cancer, but it is nonexistent in zombie-like senescent cells.
"We and others had found this odd juxtaposition where this protein identified for its control of the cell cycle and links to cancer was also highly expressed in non-proliferating senescent cells," said corresponding author Peter Adams, PhD , the Jeanne and Gary Herberger Leadership Chair in Cancer Research at Sanford Burnham Prebys.
"Senescent cells are meant to prevent cancer, so why would the same protein be so active in cells with opposite functions?"
Senescent cells attempt to put the brakes on cancer in two ways. First, they become frozen in a stable phase of the cell cycle so that they can't experience unchecked growth. Then they begin to spew out inflammatory molecules to attract the attention of the immune system. Immune cells should target them for removal but become less reliable at this job as we age. This allows senescent cells to accumulate—and with them, a growing state of chronic inflammation.
The research team wanted to know if cyclin D1 had a unique role in senescent cells' inflammatory secretions separate from its function in the cell cycle. They began by checking sequencing data from 14 publicly available datasets featuring multiple senescence models and cell types. This confirmed that the CCND1 gene was elevated even more often than other genetic markers used to identify senescent cells. Follow-up experiments showed that cyclin D1 also contributed actively to sustaining senescent cells' propensity to spill out inflammatory molecules.
"It turned out that cyclin D1 and one of its partner molecules called cyclin-dependent kinase 6 reinforced these cells' inflammatory tendencies by promoting DNA damage," said lead author Adarsh Rajesh, PhD '25, a postdoctoral researcher at Cold Spring Harbor Laboratory and former member of the Adams lab.
"It was important to then see how our findings in cells in a dish compared to a more complex animal model."
The scientists observed that cyclin D1 also accumulated within the livers of mice as they aged. Mouse liver cells with overabundant cyclin D1 resembled the cells in their previous experiments. They featured a progressive increase in the expression of genes related to the release of inflammatory molecules. Known as the senescence-associated secretory phenotype, or SASP, this cellular state contributes to chronic inflammation as mice and humans age.
"At that point, we knew that cyclin D1 was an important player in age-related inflammation," said Adams, who also is director of and professor in the Cancer Genome and Epigenetics Program . "But was it necessary?"
Getting this answer required comparing normal mice to mice genetically altered to be unable to produce cyclin D1. The aged livers of mice without cyclin D1 suffered less DNA damage and contained lower expression levels of inflammatory genes. Then, the scientists demonstrated that normal mice experienced similar protective benefits when treated with a drug called palbociclib that interferes with cyclin D1 by blocking its interaction with cyclin-dependent kinase 6.
"What was very exciting is that in addition to dampening inflammation, it also suppressed frailty in the older mice and improved their function," said Rajesh. The research team assessed motor coordination by testing the ability of mice to balance on a rotating rod. Frailty was evaluated through a combined score taking into account more than 30 measurements, including the severity of gait disorders, hearing loss and vision impairment.
"The older mice on the drug do much better than older mice not on the drug," said Adams.
"That suggests that it has the ability to improve the health status and function of older mice."
Palbociclib is approved by the Food and Drug Administration as a targeted treatment for multiple indications of breast cancer.
"It's quite thrilling to think that this potentially might have some repurposing activity in humans to promote healthier aging," said Adams.
"Repositioning this and similar drugs for the treatment of age-related inflammatory diseases appears to be a promising strategy that warrants further exploration, and we're going to continue pushing this idea forward."
Additional authors include:
- Aaron P. Havas, Rouven Arnold, Kathryn Lande, Xue Lei, Kelly Yichen Li, Armin Gandhi, Angela Liou, Hiroshi Tanaka, Marcos Garcia Teneche, Michael Alcaraz, Karl N. Miller, Zoe Yao, Sviatlana Zaretski, Jessica Proulx, Andrew Davis, Laurence Haddadin, Carolina Cano Macip, Brightany Li, Nirmalya Dasgupta, Zong Ming Chua, Ceda Stamenkovic, Gabriele Guarnaccia, Rebecca A. Porritt, Alessandra Sacco and Kevin Y. Yip at Sanford Burnham Prebys
- K. Garrett Evensen and April E. Williams at the Salk Institute for Biological Studies
- Ana Catarina Franco, Seung-Hwa Woo, Anthony Lagnado and Joao Passos at Mayo Clinic
- Linshan Laux, Maggie Klaers, Jake Kircher, Jeffrey H. Albrecht and Laura Niedernhofer at the University of Minnesota
- Amirhossein Nayeri Rad at the Ludwig Boltzmann Institute for Traumatology
- Sainath Mamde, Qian Yang, Charlene Miciano, Elizabeth Smoot, Allen Wang and Bing Ren at the University of California San Diego
- Hideki Tanizawa and Ken-ichi Noma at the Hokkaido University
The study was supported by the National Institutes of Health, National Institute on Aging, National Cancer Institute, American Society of Hematology, California Institute for Regenerative Medicine, Howard and Maryam Newman Family Foundation and Helmsley Trust.
The study's DOI is 10.1038/s43587-026-01196-x .
