Scientists Discover How to Reverse Age-Related Immune Decline—Using Your Liver

MIT researchers have discovered a groundbreaking way to reverse age-related immune decline by temporarily reprogramming liver cells to act like a younger thymus gland. The approach doubled T-cell responses to vaccination in older mice and significantly improved cancer treatment outcomes.

How Does Age Affect Your Immune System?

As we age, our immune system naturally weakens due to the shrinking of the thymus, a small organ in front of the heart that's crucial for T-cell development. Starting in early adulthood, this process called thymic involution leads to smaller, less diverse T-cell populations that can't fight infections as effectively. By age 75, the thymus is greatly reduced in size.

"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.

What Makes the Liver an Ideal Immune Factory?

The MIT team chose the liver as their target organ for several strategic reasons. The liver maintains high protein production capacity even in old age, it's easier to deliver treatments to compared to other organs, and all circulating blood—including T-cells—flows through it. This makes it an ideal location to create a temporary "factory" that generates T-cell-stimulating signals normally produced by the thymus.

The researchers used messenger RNA (mRNA) delivered by lipid nanoparticles to program liver cells to produce three key immune factors:

• DLL1: Helps immature T-cells mature into fully functional immune cells
• FLT-3: Supports T-cell development and survival pathways
• IL-7: Promotes T-cell growth and maintains diverse immune cell populations

How Effective Was This Immune Rejuvenation Treatment?

The results were remarkable across multiple measures. In 18-month-old mice (equivalent to humans in their 50s), the treatment significantly increased T-cell population size and function. When researchers tested vaccine responses, mice that received the mRNA treatment before vaccination showed double the population of cytotoxic T-cells specific to the vaccine antigen compared to untreated mice of the same age.

The treatment also enhanced cancer immunotherapy effectiveness. Older mice receiving both the liver reprogramming treatment and checkpoint inhibitor drugs showed much higher survival rates and longer lifespans than those receiving only the cancer drug. All three factors were necessary to achieve these immune enhancements—none could accomplish the full effect alone.

This approach represents a significant departure from previous immune rejuvenation strategies. "Our approach is more of a synthetic approach. We're engineering the body to mimic thymic factor secretion," explained Zhang. Unlike delivering T-cell growth factors directly into the bloodstream, which can cause harmful side effects, this method creates a controlled, localized production system in the liver.