As we age, the immune cells that detect and attack external intruders also decline. With fewer troops guarding the border, vulnerability to disease is inevitable. A study found that ribonucleic acid (mRNA) technology, which produced COVID-19 vaccines, can rejuvenate immune function diminished by aging. If immune rejuvenation proven in animal studies applies to people, it is expected to fundamentally resolve diseases caused by aging.
A team led by Feng Zhang at the Massachusetts Institute of Technology (MIT) said in Nature on the 18th that "if the liver produces the signaling proteins needed to make T cells in the thymus, it can reverse age-related T-cell decline and strengthen vaccine responses."
◇T-cell production signals delivered by mRNA
The thymus is a butterfly-shaped immune organ in front of the heart that produces T cells, a type of white blood cell. It grows largest at puberty and then gradually shrinks in adulthood. By age 75, the thymus effectively loses function. T cells are immune cells that encircle external intruders and call in other immune cells or directly eliminate them. Increased susceptibility to pathogens and reduced vaccine effectiveness with age occur because the thymus degenerates and T-cell production capacity declines.
Zhang's team identified three proteins essential for T-cell growth in the thymus: FLT3L (Fms-like tyrosine kinase 3 ligand), IL-7 (interleukin-7), and DLL1 (delta-like ligand). In mice 18 months old—roughly equivalent to 50 years in humans—the researchers induced production of the three T-cell growth factors in the liver instead of the thymus. The ability to attack cancer cells was restored and vaccine effectiveness increased. In other words, the immune system became young again.
The principle of immune rejuvenation is the mRNA delivery technology used in COVID-19 vaccines. mRNA copies the genetic information of deoxyribonucleic acid (DNA) and synthesizes proteins outside the cell nucleus. If DNA is the complete blueprint of a living organism, mRNA is the detailed blueprint that makes stairs or walls as needed. COVID-19 vaccines contain mRNA encoding the spike protein of the coronavirus. Once inside the body, it produces the virus's spike, triggering an immune response that induces antibodies.
The researchers loaded mRNA that synthesizes growth factors essential for T-cell production into lipid nanoparticles and injected it into the livers of mice. Because mRNA has a short lifespan, injections were given twice a week for four weeks. Mice that received mRNA shots had twice as many cytotoxic T cells that attack external intruders as other mice. Their immunity recovered.
◇Liver chosen as a temporary factory instead of the thymus
Scientists have tried various methods to restore aging immune systems whose function has declined. Most prior studies focused on delivering T-cell growth factors into the blood. Attempts were also made to regenerate thymic tissue by transplanting stem cells, the primitive cells. But they achieved little effect.
The Broad Institute of MIT and Harvard chose the liver as a temporary factory to produce T-cell growth factors instead of the thymus. The liver maintains its protein production capacity even with age, and it is easier to deliver mRNA there than to other organs. They also considered that blood containing T cells must pass through the liver.
mRNA shots also enhanced the effectiveness of immune checkpoint inhibitors, widely used in cancer treatment. Immune checkpoints are proteins that mark normal cells so immune cells do not attack them. Cancer cells disguise themselves through immune checkpoints. Checkpoint inhibitors prevent cancer cells from binding to checkpoints so they again come under attack by immune cells. In experiments, mice that received mRNA shots had much higher survival rates than mice given only checkpoint inhibitors, the researchers said.
The team said the study suggests a path to reverse aging. Zhang said, "If we can restore essential functions like the immune system, we may help people live without disease as they grow older."
Maria Mittelbrunn of the Spanish National Research Council said in Nature the same day, "T cells are among the cell types that change the most during aging, and diminished effectiveness of vaccines or anticancer drugs with age stems from this," adding, "Rejuvenating T cells could have enormous consequences."
Zhang is a star scientist in the life sciences. In 2013, he presented evidence in Science that the CRISPR-Cas9 gene scissors work in complex eukaryotic cells like those of humans, animals, and plants. The CRISPR gene scissors are an RNA–enzyme complex that cuts and corrects only the desired site in DNA.
The MIT team found that all three growth factors are necessary to boost immunity and that none alone can produce the desired rejuvenation. To achieve the same immune rejuvenation in people, studies in larger animal models are needed. The team said it will search for other signaling proteins that restore immune system function. They also plan to study how mRNA therapy affects other immune cells such as B cells, which produce antibodies.
References
Nature (2025), DOI: https://doi.org/10.1038/s41586-025-09873-4