Researchers from the German Cancer Research Center (DKFZ), HI-STEM institute, and the Broad Institute have developed a new mRNA-based therapy that temporarily rejuvenates immune function in aging mice. Their findings, published in Nature, show that mRNA technology can prompt the liver to produce immune regulatory factors typically lost during aging. This process restores the formation of new immune cells and enables older mice to mount stronger immune responses and combat tumors more effectively.
As people age, their immune systems weaken due to changes in the thymus gland, which is responsible for T cell maturation. The decline of this organ leads to fewer T cells and a reduced ability to recognize antigens. "Much has already been attempted to halt or reverse the age-related involution of the thymus," said Mirco Friedrich from DKFZ, HI-STEM, and the Broad Institute. "Unfortunately, without much success so far." Working with colleagues at Feng Zhang's department at the Broad Institute in Cambridge, Massachusetts, Friedrich explored a new approach.
The team identified three signaling pathways—Notch signaling, FLT3 ligand, and interleukin-7—that decrease with age but are crucial for young T cell development. They engineered three mRNA molecules coding for these factors and delivered them into mouse liver cells using lipid nanoparticles. This temporary intervention led older mice to produce more naive T cells and improved other key immune functions.
Improvements were seen not only in T cells but also in dendritic cells and B cells. The study found that treated mice had vaccine responses comparable to those of younger animals—a significant finding given mice’s short lifespans.
Tumor response was also enhanced after treatment; more CD8 T cells infiltrated tumor tissue, leading to better outcomes with immunotherapies such as checkpoint inhibitors. In aggressive melanoma models, some tumors were completely suppressed following mRNA therapy—an effect not observed in untreated aged mice.
The researchers designed the treatment's effects to be temporary: "The mRNA is only converted into proteins in the liver for a short time, and the signaling factors produced disappear again after a while." No signs of autoimmunity or liver toxicity were reported.
Instead of trying to repair age-related damage directly within the thymus, this method generates essential maturation signals elsewhere—in this case, the liver—which is capable of releasing large amounts of protein even in old age.
"The immune system ages, but it does not irreversibly lose its abilities. If we provide it with the missing signals again, it can once more perform amazing feats," said first author Mirco Friedrich. He added that modern mRNA technologies could restore biological functions precisely and temporarily beyond their current use in vaccines.
