Age‐Dependent Regulation of Hippocampal Inflammation by the Mitochondrial Translocator Protein in Mice

The mitochondrial translocator protein (TSPO) is a biomarker of inflammation associated with neurodegenerative diseases, widely regarded to be upregulated in the aging brain. Here we investigated the interaction between aging and TSPO immunomodulatory function in the mouse hippocampus, a region severely affected in Alzheimer's Disease (AD). Surprisingly, we found that TSPO levels were decreased in brain innate immune populations in aging. Aging resulted in a reversal of TSPO knockout transcriptional signatures following inflammatory insult. TSPO deletion drastically exacerbated inflammatory transcriptional responses in the aging hippocampus, while dampening inflammation in the young hippocampus. This age-dependent effect of TSPO was linked to NF-kβ and interferon regulatory transcriptional networks. Drugs that disrupt the cell cycle and induce DNA damage, such as heat shock protein and topoisomerase inhibitors, were identified to mimic the inflammatory transcriptional signature characterizing aging in TSPO knockout mice most closely. These findings indicate that TSPO plays a protective role in brain aging. This TSPO-aging interaction is an important consideration in the interpretation of TSPO-targeted biomarker and therapeutic studies, as well as in vitro studies that cannot model the aging brain.