MIT and Broad Institute researchers used mRNA to turn the liver into a temporary immune-support “factory” in aging mice. The approach restored T cell strength, improved vaccine responses and made cancer immunotherapy work better.
A new study from MIT and the Broad Institute suggests it may one day be possible to turn back the clock on the aging immune system — not by rebuilding organs, but by briefly reprogramming the body to act like them.
In experiments with older mice, scientists used messenger RNA, or mRNA, to temporarily turn liver cells into a kind of immune-support “factory.” That boost helped aging animals produce more and better-functioning T cells, the white blood cells that hunt down infected or cancerous cells.
The treated mice mounted stronger responses to vaccines and lived longer when given cancer immunotherapy compared with untreated peers, pointing to a potential new way to help people stay healthier as they age.
The work, published in the journal Nature, started from a simple but pressing question, according to lead author Mirco Friedrich, a former MIT postdoctoral researcher.
“As we get older, the immune system begins to decline. We wanted to think about how can we maintain this kind of immune protection for a longer period of time, and that’s what led us to think about what we can do to boost immunity,” Friedrich said in a news release.
The study’s senior author is Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT, an investigator at the McGovern Institute for Brain Research at MIT, a core institute member at the Broad Institute of MIT and Harvard, an investigator in the Howard Hughes Medical Institute, and co-director of the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics at MIT.
Aging’s hidden weak spot: the thymus
The work targets a quiet but dramatic change that happens in nearly everyone: the shrinking of the thymus, a small organ in front of the heart that trains immature T cells and helps them survive.
In youth, the thymus churns out a diverse army of T cells, each tuned to recognize different threats. It also secretes growth factors and signaling proteins called cytokines that help these cells mature and persist.
But starting in early adulthood, the thymus begins to wither in a process known as thymic involution. By about age 75 in humans, it is largely nonfunctional, and the body produces far fewer new T cells. That decline leaves older adults more vulnerable to infections, less responsive to vaccines and often less able to benefit from cutting-edge cancer immunotherapies.
Previous efforts to rejuvenate immunity have tried flooding the bloodstream with T cell growth factors or regenerating thymus tissue using stem cells. Those strategies can be powerful but may carry safety risks or be difficult to deliver.
Zhang’s team took a different tack: instead of regrowing the thymus, they asked whether another organ could temporarily stand in for some of its functions.
“Our approach is more of a synthetic approach,” Zhang said in the news release. “We’re engineering the body to mimic thymic factor secretion.”
Turning the liver into a temporary immune “factory”
The researchers chose the liver as their stand-in organ. The liver is a natural protein-production powerhouse, remains active even in old age, and is relatively easy to target with mRNA delivered in tiny fat bubbles called lipid nanoparticles. It also filters all of the body’s blood, meaning circulating T cells regularly pass through it.
The team identified three key molecular signals that support T cell development and survival: DLL1, FLT-3 and IL-7. They then encoded instructions for making these factors into mRNA, similar to the technology used in many COVID-19 vaccines.
When injected into the bloodstream, the lipid nanoparticles carrying these mRNA instructions accumulated in the liver. Liver cells, or hepatocytes, took up the mRNA and briefly began producing the three immune-supporting proteins, effectively turning the organ into a temporary thymus-like “factory.”
Because mRNA molecules are short-lived, the effect is transient. In the study, the scientists gave 18-month-old mice — roughly equivalent to humans in their 50s — multiple injections over four weeks to maintain steady production of the thymus-like factors.
Immune systems in older mice spring back
After treatment, the aging mice showed a marked rebound in their T cell populations. Their T cells were not only more numerous but also functionally stronger.
To see if that translated into real-world protection, the team vaccinated the mice with ovalbumin, a protein commonly used in immunology experiments. In treated 18-month-old mice, the population of cytotoxic T cells specifically targeting ovalbumin doubled compared with untreated animals of the same age.
The researchers then tested whether the liver “factory” could help older mice fight cancer. They implanted tumors into 18-month-old mice and treated them with a checkpoint inhibitor drug that targets PD-L1, a protein that normally dampens T cell activity. These drugs, a mainstay of modern cancer immunotherapy, can unleash T cells against tumors but often work less well in older patients.
Mice that received both the mRNA treatment and the checkpoint inhibitor had higher survival rates and lived longer than mice that received the cancer drug alone, the study found.
The team also showed that all three factors — DLL1, FLT-3 and IL-7 — were required to achieve the full immune boost. No single signal could reproduce all of the benefits on its own.
A vision of healthier aging
The work is still in its early stages and has so far only been tested in mice. Much more research will be needed before any similar approach could be tried in humans, including studies in additional animal models and careful safety testing.
The researchers plan to explore whether adding other signaling molecules could further enhance immune function and to examine how the treatment affects other immune cells, such as B cells, which produce antibodies.
Still, the findings hint at a future in which aging immune systems could be periodically tuned up, rather than simply accepted as an inevitable decline.
The ultimate goal is to extend the years people can live free from disease, according to Zhang.
“If we can restore something essential like the immune system, hopefully we can help people stay free of disease for a longer span of their life,” Zhang added.
By using mRNA to briefly rewire the body’s own organs into a supportive immune “factory,” the study points to a new way of thinking about aging: not as a one-way slide, but as a process that might be nudged, at least in part, back toward youth.