Researchers found that TIMP2 supports microglial function and reduces age-related cellular changes associated with inflammation in mice.
As the brain grows older, its immune cells can become less effective at clearing debris and controlling potentially harmful responses. Researchers at The Icahn School of Medicine at Mount Sinai have identified a role for TIMP2, a protein associated with youth, in helping microglia, the brain’s resident immune cells, maintain healthier function.
In research published in Nature Communications, the scientists found that removing TIMP2 caused microglia to develop several characteristics linked to aging and neurodegeneration. Restoring TIMP2 in the blood of aged mice, by contrast, improved the cells’ ability to remove debris and reduced molecular markers associated with inflammation and other maladaptive states.
The results provide insight into how factors associated with youth may influence the aging brain and indicate that TIMP2 could play a role in preserving healthy immune activity as organisms age.
Aging is the strongest known risk factor for Alzheimer’s disease and other neurodegenerative disorders, but researchers still do not fully understand the biological changes that make older brains more susceptible to disease.
Microglia help protect brain health by removing cellular debris, supporting neural circuits, and responding to injury. As they age, however, these cells can become less efficient and shift into states that may promote 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.”
Without TIMP2, microglia take on aging traits
To investigate how TIMP2 affects microglia in healthy and aging brains, the researchers, including first author Brittany Hemmer, PhD, who was a graduate student in the Castellano laboratory at the time, studied several mouse models. Some mice lacked TIMP2 throughout the body, while others had the protein selectively removed from either microglia or neurons.
The researchers analyzed gene activity with single-nucleus RNA sequencing of brain tissue and combined those data with advanced imaging, functional assays, and in vivo microdialysis, a technique used to sample molecules in the living brain.
When TIMP2 was removed, microglia developed features commonly linked to aging and brain injury. The cells showed changes in activation markers, became less capable of clearing cellular debris, and displayed molecular signatures associated with cellular senescence. In vivo microdialysis also revealed higher levels of inflammatory and stress-related proteins in the extracellular environment of the brain when TIMP2 was absent.
TIMP2 improves debris clearing in aged mice
The researchers next examined whether adding TIMP2 could counter some of these age-related changes. After administering systemic injections of TIMP2 to aged mice, they found that microglia shifted away from pro-inflammatory states and became better at clearing debris.
The findings suggest that TIMP2 helps regulate how microglia respond to challenges in the brain, supporting functions that preserve a healthy neural environment while limiting potentially damaging responses. They also point to a possible molecular connection between systemic factors associated with youth and the function of innate immune cells in the aging brain.
Whether TIMP2 benefits humans remains unknown
“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.
Because the experiments were conducted in mice, further research will be needed to determine whether the same findings apply to humans. Researchers must also establish whether TIMP2 or the pathways it controls could eventually be targeted to alter age-related changes in the brain.
Reference: “Youth-associated protein TIMP2 regulates microglial state and function in healthy and aged mice” by Brittany M. Hemmer, Sarah M. Philippi, Ana Catarina Ferreira, Samuele F. Petridis, Annie Phan and Joseph M. Castellano, 12 August 2026, Nature Communications.
DOI: 10.1038/s41467-026-74906-z
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).
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