Youth-associated protein reverses age-related microglial changes in mice

Researchers at The Icahn School of Medicine at Mount Sinai have identified a role for the youth-associated protein TIMP2 in supporting the healthy function of microglia, the brain's resident immune cells.

In a study published August 12 in Nature Communications [https://doi.org/10.1038/s41467-026-74906-z], they found that loss of TIMP2 caused microglia to develop several features associated with aging and neurodegeneration. Conversely, restoring TIMP2 in the blood of aged mice improved the ability of microglia to clear debris and reduced molecular markers associated with inflammation and other maladaptive states.

The findings provide new insight into how youth-associated factors may influence the aging brain and suggest that TIMP2 may help maintain healthy immune function in the brain as organisms age.

Aging is the strongest known risk factor for Alzheimer's disease and other neurodegenerative disorders, yet the biological changes that make the aging brain more vulnerable to disease are not fully understood. Microglia play an essential role in maintaining brain health by clearing cellular debris, supporting neural circuits, and responding to injury. With age, however, microglia can become less efficient and adopt states that may contribute to inflammation and impaired brain function.

"TIMP2 facilitates healthy function for the brain's immune cells," said Joseph M. Castellano, PhD, Associate Professor of Neuroscience at the Ronald M. Loeb Center for Alzheimer's Disease and The Friedman Brain Institute at The Icahn School of Medicine at Mount Sinai, and corresponding author of the study. "By supporting the ability of microglia to clear debris and limit maladaptive responses, TIMP2 may help restore aspects of microglial function that become compromised with age. Since our previous work identified TIMP2 as a regulator of synaptic plasticity through the extracellular matrix, these findings suggest that this factor sits at the intersection of several processes that are critical for normal brain function."

The researchers, including first author Brittany Hemmer, PhD, who was a graduate student in the Castellano laboratory at the time, used multiple mouse models to investigate how TIMP2 influences microglial biology in healthy and aged brains. These included mice lacking TIMP2 throughout the body, as well as mice in which TIMP2 was selectively deleted from microglia or neurons. The team profiled gene expression using brain single nuclei RNA-sequencing, and also employed advanced imaging and a brain sampling technique called in vivo microdialysis, as well as functional assays to examine the effects of TIMP2 on microglial states and debris handling.

They found that deleting TIMP2 caused microglia to exhibit characteristics commonly associated with aging and brain injury. These included changes in markers of cellular activation, an impaired ability to clear cellular debris, and molecular signatures associated with cellular senescence. The loss of TIMP2 was also accompanied by increased levels of inflammatory and stress-related proteins in the brain's extracellular environment, measured using in vivo microdialysis.

The researchers then tested whether supplementing TIMP2 could reverse some of these age-related changes. They administered systemic injections of TIMP2 to aged mice and found that treatment shifted microglia away from pro-inflammatory states and improved their capacity to clear debris.

The results suggest that TIMP2 helps regulate how microglia respond to challenges in the brain, supporting functions that maintain a healthy neural environment while limiting potentially harmful responses. The findings also point to a potential molecular link between systemic factors associated with youth and innate immune cell function in the aging brain.

"While additional studies are needed, this work provides new insight into how youth-associated factors influence pathways involved in brain aging and age-related neurological disorders that may ultimately inform therapeutic strategies," Dr. Castellano added.

The researchers emphasize that the study was conducted in mice and that further research is needed to determine whether the findings translate to humans and whether TIMP2 or the pathways it regulates could eventually be targeted to modify age-related changes in the brain.

This work was supported by the National Institute on Aging (R01AG061382 (JMC), RF1AG072300 (JMC), 1F31AG079604-01A1 (BMH), T32AG049688 (BMH, SMP), R01AG061382-02S1 (JMC, SMP), and Cure Alzheimer's Fund (JMC).