The hormone, thymulin, is produced by the thymus, a small immune organ located behind the breastbone. The thymus is best known for supporting the development and education of T cells, the immune cells that recognize infected or abnormal cells. Its activity declines substantially with age, a process called thymic involution. According to the USC team, thymulin levels fall alongside this structural and functional decline, while inflammatory signals rise. The researchers propose that this hormonal loss may influence the immune system far beyond T-cell production, affecting the broader inflammatory environment in which cancer develops and responds to treatment.

In a study published in Nature Communications, the scientists reported that restoring thymulin reduced inflammation and improved survival in older mice with cancer. The hormone also made immunotherapy more effective in these animals. The work is significant because it moved beyond an association between an aging thymus and inflammation, identifying a causal chain in which reduced thymulin activity contributes to an inflammatory state that can accelerate cancer progression and interfere with immune-based treatment. The findings provide a possible explanation for why many older patients respond differently to immunotherapy than younger individuals.

“Scientists have traditionally viewed the aging thymus as important mainly because of its effects on one part of the immune system—T cells,” said Fumito Ito, MD, PhD, professor of surgery and immunology and immune therapeutics at the Keck School of Medicine and principal investigator of the research. “Our findings suggest its influence is much broader, helping regulate chronic inflammation in ways that affect cancer.” The new grant will allow the team to examine how thymulin communicates with immune cells and whether that communication can be converted into a treatment strategy.

The first phase of the project will focus on the molecular mechanisms behind thymulin’s anti-inflammatory effects. Researchers will study immune cells in living mice as well as human immune cells in laboratory experiments. They plan to map the signaling pathways activated by thymulin and identify the genes whose activity changes after exposure to the hormone. These experiments could reveal whether thymulin acts directly on immune cells, alters the production of inflammatory molecules or reshapes communication among several cell types. Understanding these steps will be essential for determining how the hormone might be used safely in humans.

The researchers will then investigate how thymulin changes the tumor microenvironment, the complex network of cancer cells, immune cells, blood vessels and signaling molecules surrounding a tumor. Many cancers suppress immune activity by creating an environment that prevents T cells from entering the tumor or stops them from killing malignant cells. In aged mice with breast cancer or melanoma that respond poorly to immunotherapy, the team will test whether thymulin can reverse some of these effects. A central question is whether the hormone generates new anti-cancer immune responses, strengthens immune attacks that already exist, or performs both functions.

The project will also examine thymulin’s potential against metastatic disease. Metastasis occurs when cancer cells leave the original tumor, travel through the bloodstream or lymphatic system and establish tumors in distant organs. These secondary tumors are responsible for most cancer-related deaths and are often difficult to treat with immunotherapy alone. Ito’s group will test whether thymulin can prevent metastatic tumors from forming and whether it can slow the growth of metastases that are already established. The experiments will use aged mice carrying breast cancer or melanoma, with complementary studies conducted on human cells in the laboratory.

The investigators are particularly interested in the possibility of using thymulin as an add-on treatment for older patients receiving immune checkpoint inhibitors. Drugs targeting PD-1 or PD-L1 can restore the activity of exhausted T cells, but only a portion of patients benefit. Chronic inflammation may contribute to treatment resistance by disrupting immune coordination and creating conditions that favor tumor survival. If thymulin can reduce this inflammatory interference without suppressing anti-tumor immunity, it could potentially improve responses to existing therapies. At this stage, however, the concept remains preclinical and has not been tested as a cancer treatment in patients.

Most cancer research has historically relied on young laboratory animals, even though cancer is primarily a disease of later life. Aging affects immune-cell production, metabolism, tissue structure and the chemical signals that regulate inflammation, meaning that results from young animals may not accurately predict how older patients respond. By conducting the new experiments in aged mice, the USC team hopes to model the biology of cancer and immunotherapy more realistically. “To treat diseases of aging, we need models that reflect the biology of aging,” Ito said. “Our goal is to make what we learn in the laboratory as relevant as possible to the patients most often affected by cancer.”

Subject of Research: Thymulin, age-related chronic inflammation, cancer progression, metastasis and immunotherapy response.

Web References: Keck School of Medicine of USC; USC news release on thymulin and age-related inflammation.

References: Nature Communications study by Fumito Ito and colleagues; National Institutes of Health grant 1R01CA316597-01.

Keywords: Thymulin, inflammaging, thymus, cancer immunotherapy, immunology, aging, chronic inflammation, metastasis, breast cancer, melanoma, PD-1, PD-L1, gerontology.

Inflammaging is increasingly recognized as a central culprit behind a host of degenerative diseases such as cancer, cardiovascular disorders, and metabolic syndromes. Despite extensive study, the cellular and molecular triggers of this persistent low-grade inflammation remained elusive. Rugang Zhang, Ph.D., professor and chair of Experimental Therapeutics at MD Anderson, led the investigative team that discovered how aging cells increasingly export R-loops—exotic nucleic acid structures—from their nuclei into the cytoplasm, setting off an inflammatory cascade.

At its core, an R-loop is a three-stranded nucleic acid formation that arises transiently during transcription when an RNA-DNA hybrid displaces a single strand of DNA. Under normal physiological conditions, R-loops are tightly regulated and confined within the nucleus. However, Zhang’s team demonstrated that senescent cells, characterized by their permanent exit from the cell cycle, display a marked increase in exporting these R-loops to the cytoplasm. Once outside the nucleus, these R-loops bind to DNA fragments floating in the cytoplasm, mistakenly signaling an immune alarm.

This aberrant immune activation resembles a malfunctioning smoke detector that continuously blares despite the absence of fire. The immune system, triggered by these mistaken nucleic acid signals, initiates a widespread inflammatory response that persists chronically, resulting in tissue damage and functional decline often observed in aged organisms. This discovery fills a critical gap in understanding how senescent cells contribute to inflammaging at the molecular level.

Delving deeper, the study identified the two key proteins that form the molecular machinery enabling this R-loop export: DDX1 and XPO1. DDX1 acts as a shuttle by binding R-loops within the nucleus, while XPO1 functions as a gatekeeper, facilitating the translocation of this complex across the nuclear membrane. This nuclear export system, the researchers found, is a pivotal control point driving the inflammation-inducing presence of R-loops in the cytoplasm.

Intriguingly, the research team exploited existing pharmacological interventions by repurposing selinexor (KPT-330), an FDA-approved drug currently used to treat multiple myeloma. Selinexor specifically inhibits the nuclear export protein XPO1, effectively trapping R-loops within the nucleus and preventing their cytoplasmic mislocalization. Preclinical models treated with selinexor showed profound reductions in systemic inflammation, liver fibrosis, aberrant fat accumulation, and muscle wasting—hallmarks of aging pathology.

Moreover, the blockade of R-loop nuclear export not only abated inflammation but also led to a striking increase in lifespan in animal models. This finding suggests that modulating nucleic acid trafficking represents an actionable target for delaying age-associated functional decline and potentially extending healthspan. The therapeutic implications of this discovery are vast, offering a clinically translatable strategy using a drug with an established safety profile.

However, the researchers caution that the inflammatory alarm triggered by R-loop and DNA fragment interactions may also play beneficial roles, such as aiding immune surveillance against precancerous cells. Therefore, completely silencing this alarm might impair protective immune functions. Future therapeutic endeavors might benefit from selectively targeting DDX1, disrupting the R-loop shuttle without broadly shutting down nuclear export, thereby minimizing potential side effects.

This study also opens new avenues for investigating why cells escalate R-loop export as they age. Unraveling the upstream regulatory mechanisms may illuminate further insights into senescence biology and how cellular aging contributes to systemic pathologies. Detailed exploration of how DNA damage responses and nuclear architecture influence R-loop dynamics will be critical to developing refined and targeted interventions.

The convergence of molecular biology and translational medicine underscored in this research exemplifies how deep mechanistic understanding can seed innovative therapies for complex age-related conditions. The use of selinexor as a proof-of-concept therapeutic strategy heralds an era wherein aging, once deemed immutable, is approached as a modifiable risk factor through molecular precision medicine.

As the global population ages, the burden of chronic inflammatory diseases continues to rise, underscoring the urgent need for effective anti-inflammaging interventions. These findings invigorate hope for tangible clinical solutions that can improve quality of life in the elderly and reduce the health care costs associated with aging populations worldwide.

The next critical steps involve rigorous clinical evaluation of nuclear export inhibitors in aging populations while monitoring for immune competence. Furthermore, delineating the fine line between beneficial versus deleterious inflammatory signaling will refine therapeutic windows and guide patient-specific treatments.

In summary, Rugang Zhang and colleagues’ elucidation of R-loop export mechanisms driving inflammaging represents a transformative advance in aging research. Their identification of selinexor’s potential to suppress this process paves the way for repurposed drug interventions that could ameliorate the devastating effects of age-related chronic inflammation and related morbidities.

Subject of Research: Molecular mechanisms of age-related inflammation and therapeutic targeting of R-loop nuclear export

Article Title: Study identifies a new cause of age-related inflammation, suggesting promising treatment pathway

News Publication Date: 16-Jun-2026

Web References:
https://www.mdanderson.org/
https://www.nature.com/articles/s43587-026-01147-6

Image Credits: The University of Texas MD Anderson Cancer Center

Keywords: inflammaging, R-loops, aging, chronic inflammation, senescence, nuclear export, selinexor, KPT-330, DDX1, XPO1, molecular therapeutics, lifespan extension