In animal models, researchers from the Keck School of Medicine of USC found that targeting the thymus can reduce age-related inflammation and improve cancer outcomes.
Chronic, low-grade inflammation in the body—a phenomenon known as “inflammaging” because it increases with age—has been linked to many of today’s leading causes of illness and death, including cancer, heart disease, metabolic conditions and neurodegenerative diseases. But scientists have struggled to understand what causes inflammaging or how to reverse its effects.
Researchers from the Keck School of Medicine of USC have now identified the thymus, a small organ behind the breastbone that plays a central role in immune system development, as a key player in inflammaging. They discovered that thymulin, a hormone produced by the organ, keeps inflammation under control. As we age, thymulin decreases and inflammation increases, allowing diseases like cancer to progress. In older mice, increasing thymulin levels improved cancer survival and made immunotherapy more effective. The study, funded by the National Institutes of Health, was just published in Nature Communications.
“This is the first evidence of a substance that is naturally produced in the thymus, declines with age, and has the power to reverse age-related inflammation,” said Fumito Ito, MD, PhD, professor of surgery and immunology and immune therapeutics at the Keck School of Medicine and lead author of the study.
Recent research has hinted that the thymus could be linked to chronic inflammation. Now, this discovery goes a step further, uncovering a biological mechanism that may actively drive that process. Thymulin could one day be tested in clinical trials as a way to treat cancer and other diseases.
“Together, these findings uncover a pathway linking aging, inflammation and cancer immunity, and suggest thymulin as a potential strategy to improve cancer immunotherapy in older individuals,” said Ito, who is also vice chair of basic and translational science in the Department of Surgery.
Finding the “youth factor”
The team’s discovery relied, in part, on an uncommon research method known as heterochronic parabiosis. In this approach, researchers surgically join an older mouse to a younger one so the two organisms share blood flow. The procedure reduced inflammation in older mice, suggesting that something in young blood may help reverse age-related decline.
To identify that factor, the researchers used both human blood samples and mouse models. They analyzed genes involved with aging and longevity, zeroing in on a shortlist linked to cytokines, signaling proteins that trigger inflammation in the body. They noticed a striking pattern: Mice missing any of these genes had problems with the thymus.
Ito and his colleagues began searching for a biological pathway involving the thymus that could explain inflammaging. Their tests revealed that thymulin, one of several hormones produced by the organ, helps regulate the body’s cytokines, keeping inflammation under control. As thymulin levels fall with age, cytokines increase.
“The thymus is best known for producing T-cells that allow the immune system to fight infections and cancer, but our findings show it also helps keep age-related inflammation in check,” Ito said.
Chronic inflammation can also interfere with the immune system’s ability to attack tumors. In older mice with cancer, adding thymulin boosted the immune response against tumors and improved overall survival. Adding thymulin also made older mice more responsive to anti-PD-1/PD-L1 therapy, a type of cancer immunotherapy.
Thymulin and inflammaging
The discovery raises new questions about thymulin’s role in cancer biology. Next, Ito and his colleagues will explore whether the hormone influences how tumors form and spread.
Beyond cancer, a range of conditions have been linked to inflammaging, including diabetes, chronic kidney disease and Alzheimer’s disease. Ito plans to investigate the role of thymulin in other chronic diseases in collaboration with experts across the Keck School of Medicine.
The work may also have broader implications for biomedical research. Insights from animal models often fail to translate into successful clinical trials, and this research may help explain why. Older mice are biologically distinct from younger mice, yet researchers often rely on younger animals because they are less expensive and easier to study.
“When using young mice, we may be underestimating the impact of age-related chronic inflammation,” Ito said. “Studying older animals may be critical for understanding diseases of aging.”
About this research
In addition to Ito, the study’s other authors are Hisashi Kanemaru, Steven Luong, Yuta Yamamoto and Yukari Mizukami from the Department of Surgery, Keck School of Medicine of USC, University of Southern California.
This work was supported by the National Cancer Institute of the National Institutes of Health [P30CA014089, R01CA255240, R01CA272827, R01CA316597] and involved the use of USC’s Flow Cytometry and Immune Monitoring Core.