A new study proposes a novel approach to fighting immune system decline caused by thymic involution: making the liver produce proteins that support T cell development and function [1].
Bringing back the Ts
Immunosenescence, the gradual deterioration of the immune system, is a central aspect of aging. Research has tied it to increased cancer incidence, vulnerability to infections, weak vaccine responses, and so on [2]. Learning how to keep the immune system active and functional would be a huge leap towards meaningful life extension, although some recent studies suggest this would require simultaneously curbing autoimmunity, which also increases with age.
T cells, an important part of the immune system, mature in the thymus, a small organ near the heart. With age, the thymus experiences involution: the functional tissue gets replaced by fat, and the output falls dramatically. This leads to a loss of naive T cells, which are ready to be primed against a specific new pathoges, and a rise in memory and exhaustion-like T cell states, reducing immune resilience [3].
A new study by MIT researchers, published in Nature, suggests a novel approach to solving this problem. “Efforts to counter immune ageing have primarily focused on reversing thymic involution through hormones, cytokines, small molecules and heterochronic parabiosis, or by directly modulating haematopoiesis,” the paper says. “Although these strategies have provided valuable insights into immune ageing, they have been limited by effect size, toxicity or clinical feasibility.”
Instead of trying to rebuild the thymus, the team used the liver to produce factors that are usually made in the thymus and are central to T cell development.
“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,” said 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.
Increased thymic output
The authors first tried to pin down which thymic support signals actually fade with age. They profiled thymus tissue across many ages and used spatial assays to study cell–cell communication between thymocytes (immune cells maturing in the thymus) and thymic epithelial cells (TECs). The analysis pointed to age-linked weakening of Notch1/3 and IL-7 signaling programs, alongside reduced interstitial FLT3-L in aged thymus and classic involution metrics, such as a decrease in thymus weight.
Based on these findings, the researchers decided to put back the Notch ligand DLL1 in aged hosts along with FLT3-L and IL-7 to create a combined DFI treatment. They focused on the liver, because its protein-synthesis capacity is preserved at advanced ages and blood circulation, including T cells, passes through it.
The team used mRNA encapsulated in lipid nanoparticles (LNPs) to deliver “production instructions” to the liver, rather than simply flooding the blood with recombinant proteins. This was done for several reasons, including the rapid clearance of recombinant cytokines, toxicity issues associated with frequent dosing, and the fact that Notch ligands are transmembrane and normally require cell-cell contact. This means that simply putting them in the blood would not do the trick, as they must be expressed by cells on their surface, which hepatocytes can do.
The four-week DFI treatment of aged mice (~18 months) increased naive T cell counts and improved the naive-to-memory T cell ratio. Crucially, the team showed that these new cells were not just clones of a few old ones (“peripheral expansion”). Analysis of T cell receptor sequences instead supported the idea that more new T cells are being produced, signifying increased thymic output. None of the three factors alone showed the same effect.
Testing the concept
To determine if this actually makes the immune system work better, the researchers used a vaccination model based on ovalbumin, a harmless protein that the immune system can be primed against as if it were a pathogen. Aged mice normally generate fewer antigen-specific CD8+ T cells and show weaker vaccine responses.
Preconditioning with the DFI treatment improved vaccine-induced T cell responses in aged mice, increasing ovalbumin-specific CD8+ T cells significantly. It also preserved a higher naive T cell fraction post-vaccination, supporting more functional immunity.
Then came the big test: cancer. The team challenged aged mice with melanoma (B16-OVA) or colon carcinoma (MC38-OVA) cells and examined how well older animals could control tumors, including in the context of anti-PD-L1 checkpoint blockade, a current state-of-the-art immunotherapy. As expected, aged mice had faster tumor progression and worse survival, and PD-L1 blockade that controlled tumors in adults had little effect in aged cohorts.
In the melanoma model, DFI pre-treatment followed by anti-PD-L1 drove complete rejection in 40% of aged mice, while all controls died within about 3 weeks. In the colon carcinoma model, DFI pre-conditioning (with a short washout) improved endogenous tumor control, increasing spontaneous rejection rates and prolonging survival. In follow-up profiling, DFI was associated with a higher fraction of intratumoral CD8+ T cells and lower expression of exhaustion-associated markers.
Finally, the researchers checked whether DFI might increase autoimmunity. In a mouse model of type 1 diabetes, an autoimmune disease in which the immune system attacks beta cells in the pancreas, DFI didn’t raise blood sugar or make diabetes start sooner, and it didn’t increase self-reactive T cells. The team then ran tests in two additional autoimmunity models, supporting DFI’s immunological safety in those settings.
Literature
[1] Friedrich, M. J., Pham, J., Tian, J., Chen, H., Huang, J., Kehl, N., … & Zhang, F. (2025). Transient hepatic reconstitution of trophic factors enhances aged immunity. Nature, 1-9.
[2] Liu, Z., Liang, Q., et al. (2023). Immunosenescence: Molecular mechanisms and diseases. Signal Transduction and Targeted Therapy, 8(1), 200.
[3] Liang, Z., et al. (2022). Age-related thymic involution: Mechanisms and functional impact. Aging Cell, 21(8)
View the article at lifespan.io
