Thymulin Reduced Age-Related Inflammation and Improved Immunotherapy Response in Aged Mice

The same breast cancer cells behaved differently in young and aged mice. In older animals, tumors grew faster, while PD-L1 blockade—a treatment designed to release a brake on antitumor T cells—had no detectable effect on tumor growth or survival. Adding thymulin, a short peptide produced by the thymus, reduced inflammatory activity, slowed tumor growth, and made anti-PD-L1 treatment effective.

The thymus gradually shrinks with age and becomes less capable of supporting T-cell development. This study suggests that its role may extend further: the organ may also help prevent the innate immune system from remaining locked in a chronically inflammatory state.

Aging Reprograms Myeloid Cells

The authors first compared young mice aged 8–12 weeks with aged animals 65–75 weeks old. In blood from 21 young and 21 aged females, they measured cells producing four inflammatory signals: IL-1α, IL-1β, IL-6, and TNF-α. Cytokine-producing cells were more common in aged mice, particularly among monocytes and macrophages.

In two breast cancer models, AT-3 and E0771, tumors progressed faster and survival was shorter in aged mice. Their tumors also contained more inflammatory myeloid cells. A similar age-related pattern appeared in male mice with melanoma and in a separate mouse strain carrying mammary tumors.

The human findings supported an association but did not establish causation. Among 90 healthy blood donors, the frequency of inflammatory myeloid cells increased with age; in a direct group comparison, it was higher in 12 people aged 60–87 than in 21 participants aged 21–33. The researchers also reanalyzed a published single-cell dataset from 26 primary breast tumors. Their main comparison included 16 patients who had not received neoadjuvant treatment—eight younger and eight older individuals. Among 60,994 cells, myeloid cells from the older group more often showed activity in inflammatory pathways involving IL-1, IL-6, TNF, and NF-κB.

A Young Systemic Environment Calms Aged Cells

To distinguish properties intrinsic to blood-forming cells from effects imposed by the host environment, the team surgically joined young and aged mice so that they shared a circulation. After two weeks, about 40% of circulating leukocytes had exchanged between partners. In aged mice paired with young animals, inflammatory activity declined even in the aged animal’s own myeloid cells, and tumors progressed more slowly than in aged–aged pairs.

Bone marrow transplantation experiments led to the same general conclusion. Aged blood-forming cells became less inflammatory in young hosts, whereas young cells developed a more inflammatory profile in aged hosts. This pointed to a circulating signal produced outside the bone marrow.

These experiments did not identify a single molecule by themselves. The authors therefore combined pathway analysis with prior evidence on thymic factors. Thymulin emerged as the leading candidate. It is a nine-amino-acid peptide whose circulating activity declines with age.

How Thymulin Suppressed the Inflammatory Program

Treating human blood cells with thymulin for 24 hours reduced inflammatory cytokine production mainly in samples from older donors. Daily thymulin injections for one week likewise reduced inflammatory myeloid cells in aged mice, while producing little detectable effect in young animals.

The mechanism was examined in macrophages. Thymulin inhibited NF-κB, a protein complex that acts as a molecular switch for many inflammatory genes. It reduced p65 binding to DNA and blocked signaling events required to activate the pathway. When the researchers altered the NF-κB binding site in an experimental IL6 promoter, thymulin lost its inhibitory effect. This ties the peptide’s action to NF-κB signaling, although it does not rule out additional mechanisms.

In the tumor experiments, thymulin was given daily at 1.5 mg/kg, beginning one day after tumor-cell implantation and continuing for four weeks. In aged mice, it slowed tumor growth, increased interferon-γ-producing T cells, and improved survival. The combination-treatment groups contained seven animals each. Anti-PD-L1 alone did not alter tumor growth or survival, whereas the combination of thymulin and anti-PD-L1 produced stronger tumor control.

The work remains far from a human treatment. The therapeutic experiments used small groups of mice and focused mainly on breast cancer models. Group sizes were based on prior experience rather than a prospective power calculation, and the experiments were not blinded. Thymulin administration began almost immediately after tumor implantation, not after treatment of an established, clinically diagnosed cancer. The human evidence consisted of observational blood data, reanalysis of an existing tumor dataset, and short ex vivo exposure of isolated cells; no patient received thymulin. Administering the peptide also does not prove that loss of endogenous thymulin is the sole cause of age-related inflammation.

The study therefore does not present a ready cancer therapy. It adds a specific link to the biology of immune aging: thymic decline may affect not only T-cell production but also the inflammatory state of myeloid cells. Whether this pathway can be targeted safely and effectively in older patients will require further preclinical and clinical testing.