MIT scientists find a way to rejuvenate the immune system as we age

 

As people get older, the immune system often becomes less effective. Populations of T cells shrink, and the remaining cells may respond more slowly to germs. That slowdown can leave older adults more vulnerable to many kinds of infections.

To address this age related decline, scientists from MIT and the Broad Institute developed a method to temporarily reprogram liver cells in a way that strengthens T cell performance. The goal is to make up for the reduced output of the thymus, the organ where T cells normally mature.

In the study, the team used mRNA to deliver three important factors that support T cell survival. With this approach, they were able to rejuvenate the immune systems of mice. Older mice that received the treatment produced larger and more varied T cell populations after vaccination, and they also showed improved responses to cancer immunotherapy.

The researchers say that if this strategy can be adapted for patients, it could help people stay healthier as they age.

"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," says Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT, who has joint appointments in the departments of Brain and Cognitive Sciences and Biological Engineering.

Zhang is also an investigator at the McGovern Institute for Brain Research at MIT, a core institute member at the Broad Institute of MIT and Harvard, and an investigator in the Howard Hughes Medical Institute. He is the senior author of the new study. Former MIT postdoc Mirco Friedrich is the lead author of the paper, which was published in Nature.

The Thymus and Why T Cells Decline With Age

The thymus is a small organ located in front of the heart, and it is essential for building a healthy supply of T cells. Inside the thymus, immature T cells go through a checkpoint process that helps create a diverse set of T cells. The thymus also releases cytokines and growth factors that help T cells survive.

But beginning in early adulthood, the thymus starts to shrink. This process is called thymic involution, and it reduces the body's ability to produce new T cells. By about age 75, the thymus is essentially nonfunctional.

"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 says.

Earlier efforts to rejuvenate the immune system have often focused on sending T cell growth factors through the bloodstream, but that approach can cause harmful side effects. Other researchers are investigating whether transplanted stem cells could help regrow functional thymus tissue.

A Temporary Liver Factory Powered by mRNA

The MIT team chose a different strategy. They asked whether the body could be prompted to create a temporary "factory" that produces the same T cell stimulating signals typically made by the thymus.

"Our approach is more of a synthetic approach," Zhang says. "We're engineering the body to mimic thymic factor secretion."

They selected the liver for the job for several reasons. The liver can produce large amounts of protein even in old age. It is also easier to deliver mRNA to the liver than to many other organs. In addition, all circulating blood flows through the liver, including T cells, making it a practical place to release immune supporting signals into the bloodstream.

To build this factory, the researchers picked three immune cues involved in T cell maturation. They encoded these factors into mRNA and packaged the sequences into lipid nanoparticles. After injection into the bloodstream, the nanoparticles collect in the liver. Hepatocytes take up the mRNA and begin making the proteins encoded by it.

The three factors delivered were DLL1, FLT-3, and IL-7. These signals help immature progenitor T cells develop into fully differentiated T cells.

Vaccine and Cancer Immunotherapy Benefits in Older Mice

Experiments in mice showed multiple positive outcomes. In one test, the researchers injected the mRNA particles into 18 month old mice, roughly comparable to humans in their 50s. Because mRNA does not last long in the body, the team gave repeated doses over four weeks to keep the liver producing the factors consistently.

After the treatment, T cell populations increased substantially in both size and function.

The team then examined whether the approach improved vaccine responses. They vaccinated mice with ovalbumin, a protein found in egg whites that is often used to study immune reactions to a specific antigen. In 18 month old mice that received the mRNA treatment before vaccination, the number of cytotoxic T cells targeting ovalbumin doubled compared with untreated mice of the same age.

The researchers also found that the mRNA method could strengthen responses to cancer immunotherapy. They treated 18 month old mice with the mRNA, implanted tumors, and then gave the mice a checkpoint inhibitor drug. This drug targets PD-L1 and is intended to release the immune system's brakes so T cells can attack tumor cells more effectively.

Mice that received both the checkpoint inhibitor and the mRNA treatment had much higher survival rates and lived longer than mice that received the checkpoint inhibitor drug without the mRNA treatment.

The researchers determined that all three factors were required for the immune improvement. No single factor could reproduce the full effect. Next, the team plans to test the approach in additional animal models and search for other signaling factors that might further strengthen immune function. They also want to investigate how the treatment influences other immune cells, including B cells.

Other authors of the paper include Julie Pham, Jiakun Tian, Hongyu Chen, Jiahao Huang, Niklas Kehl, Sophia Liu, Blake Lash, Fei Chen, Xiao Wang, and Rhiannon Macrae.

The research was funded in part by the Howard Hughes Medical Institute, the K. Lisa Yang Brain-Body Center at MIT, Broad Institute Programmable Therapeutics Gift Donors, the Pershing Square Foundation, the Phillips family, J. and P. Poitras, and an EMBO Postdoctoral Fellowship.

Journal Reference:

1. Mirco J. Friedrich, Julie Pham, Jiakun Tian, Hongyu Chen, Jiahao Huang, Niklas Kehl, Sophia Liu, Blake Lash, Fei Chen, Xiao Wang, Rhiannon K. Macrae, Feng Zhang. Transient hepatic reconstitution of trophic factors enhances aged immunity. Nature, 2025; DOI: 10.1038/s41586-025-09873-4 

Courtesy:
Massachusetts Institute of Technology. "MIT scientists find a way to rejuvenate the immune system as we age." ScienceDaily. ScienceDaily, 29 December 2025. <www.sciencedaily.com/releases/2025/12/251227082718.htm>. 

 

 

 

 

The brain has a hidden language and scientists just found it

 

Scientists have developed a protein that can record the chemical messages brain cells receive, rather than focusing only on the signals they send out. These incoming signals are created when neurons release glutamate, a neurotransmitter that plays a vital role in brain communication. Although glutamate is essential for processes like learning and memory, its activity has been extremely difficult to measure because the signals are faint and happen very quickly.

This new tool makes it possible to detect those subtle chemical messages as they arrive, giving researchers access to a part of brain communication that has long been hidden.

Being able to observe incoming signals allows scientists to study how neurons process information. Each brain cell receives thousands of inputs, and how it combines those signals determines whether it produces an output. This process is thought to underlie decisions, thoughts, and memories, and studying it directly could help explain how the brain performs complex computations.

The advance also opens new paths for disease research. Problems with glutamate signaling have been linked to conditions such as Alzheimer's disease, schizophrenia, autism, epilepsy, and others. By measuring these signals more precisely, researchers may be able to identify the biological roots of these disorders.

Drug development could also benefit. Pharmaceutical companies can use these sensors to see how experimental treatments affect real synaptic activity, which may help speed up the search for more effective therapies.

Introducing a powerful glutamate sensor

The protein was engineered by researchers at the Allen Institute and HHMI's Janelia Research Campus. Known as iGluSnFR4 (pronounced 'glue sniffer'), it acts as a molecular "glutamate indicator." Its sensitivity allows it to detect even the weakest incoming signals exchanged between neurons.

By revealing when and where glutamate is released, iGluSnFR4 provides a new way to interpret the complex patterns of brain activity that support learning, memory, and emotion. It gives scientists the ability to watch neurons communicate inside the brain in real time. The findings were recently published in Nature Methods and could significantly change how neural activity is measured and analyzed in neuroscience research.

How brain cells communicate

To understand the impact of this advance, it helps to look at how neurons interact. The brain contains billions of neurons that communicate by sending electrical signals along branch-like structures called axons. When an electrical signal reaches the end of an axon, it cannot cross the small gap to the next neuron, which is known as a synapse.

Instead, the signal triggers the release of neurotransmitters into the synapse. Glutamate is the most common of these chemical messengers and plays a key role in memory, learning, and emotion. When glutamate reaches the next neuron, it can cause that cell to fire, continuing the chain of communication.

From fragments to the full conversation

This process can be compared to falling dominos, but it is far more complex. Each neuron receives input from thousands of others, and only certain combinations and patterns of activity will trigger the receiving neuron to fire. With this new protein sensor, scientists can now identify which patterns of incoming activity lead to that response.

Until now, observing these incoming signals in living brain tissue was nearly impossible. Previous technologies were too slow or lacked the sensitivity needed to measure activity at individual synapses. As a result, researchers could only see pieces of the communication process rather than the full exchange. This new approach allows them to capture the entire conversation.

Making sense of neural connections

"It's like reading a book with all the words scrambled and not understanding the order of the words or how they're arranged," said Kaspar Podgorski, Ph.D., a lead author of the study and senior scientist at the Allen Institute. "I feel like what we're doing here is adding the connections between those neurons and by doing that, we now understand the order of the words on the pages, and what they mean."

Before protein sensors like iGluSnFR4 were available, researchers could only measure outgoing signals from neurons. This left a major gap in understanding, since the incoming signals were too fast and too faint to detect.

"Neuroscientists have pretty good ways of measuring structural connections between neurons, and in separate experiments, we can measure what some of the neurons in the brain are saying, but we haven't been good at combining these two kinds of information. It's hard to measure what neurons are saying to which other neurons," Podgorski said. "What we have invented here is a way of measuring information that comes into neurons from different sources, and that's been a critical part missing from neuroscience research."

Collaboration behind the breakthrough

"The success of iGluSnFR4 stems from our close collaboration started at HHMI's Janelia Research Campus between the GENIE Project team and Kaspar's lab. That research has extended to the phenomenal in vivo characterization work done by the Allen Institute's Neural Dynamics group," said Jeremy Hasseman, Ph.D., a scientist with HHMI's Janelia Research Campus. "This was a great example of collaboration across labs and institutes to enable new discoveries in neuroscience."

A new window into brain function

This discovery overcomes a major limitation in modern neuroscience by making it possible to directly observe how neurons receive information. With iGluSnFR4 now available to researchers through Addgene, scientists have a powerful new tool to explore brain function in greater detail. As this technology spreads, it may help reveal answers to some of the brain's most enduring questions.

Journal Reference:

1. Abhi Aggarwal, Adrian Negrean, Yang Chen, Rishyashring Iyer, Daniel Reep, Anyi Liu, Anirudh Palutla, Michael E. Xie, Bryan J. MacLennan, Kenta M. Hagihara, Lucas W. Kinsey, Julianna L. Sun, Pantong Yao, Jihong Zheng, Arthur Tsang, Getahun Tsegaye, Yonghai Zhang, Ronak H. Patel, Benjamin J. Arthur, Julien Hiblot, Philipp Leippe, Miroslaw Tarnawski, Jonathan S. Marvin, Jason D. Vevea, Srinivas C. Turaga, Alison G. Tebo, Matteo Carandini, L. Federico Rossi, David Kleinfeld, Arthur Konnerth, Karel Svoboda, Glenn C. Turner, Jeremy P. Hasseman, Kaspar Podgorski. Glutamate indicators with increased sensitivity and tailored deactivation rates. Nature Methods, 2025; DOI: 10.1038/s41592-025-02965-z 

Courtesy:

Allen Institute. "The brain has a hidden language and scientists just found it." ScienceDaily. ScienceDaily, 29 December 2025. <www.sciencedaily.com/releases/2025/12/251225235950.htm>.