ZIP9 is a member of the zinc transporter ZIP family, responsible for transporting zinc ions from the extracellular space or intracellular organelles into the cytoplasm. In recent years, studies have uncovered an additional identity for ZIP9—it functions as a membrane-bound androgen receptor. Unlike classical nuclear receptors, ZIP9 mediates rapid, non-genomic effects of androgens. In vitro experiments have implicated ZIP9 in the apoptosis of certain hormone-dependent tumors and in the formation of tight junctions in Sertoli cells. In systemic knockout mice, ZIP9 has been suggested to participate in regulating the expression of PSD95 in hippocampal neurons.
In a study published in the KeAi journal Model Organisms Research , researchers from the Department of Nutrition and Health at China Agricultural University have identified ZIP9 as a critical regulator of brain aging and lifespan, capable of linking cognitive function, gut microbiota, and lipid metabolism in an interconnected network.
The researchers generated hippocampus-specific conditional knockout (cKO) mice using the Camk2a-Cre system, in which Z ip 9 was deleted exclusively in the hippocampal region.
"We found that these animals began dying at approximately 3.5 months of age, with some succumbing even earlier, in stark contrast to the normal lifespan exceeding two years," shares corresponding author Professor Bing Fang from the Department of Nutrition and Health at China Agricultural University. "They also exhibited profound spatial memory deficits and reduced cognitive flexibility as early as 3 months of age—behavioral phenotypes very similar to those of naturally aged mice."
The researchers observed premature death in the cKO mice at just 3.5 months of age, and postulated that the underlying mechanisms likely extend well beyond cognitive regulation.
Indeed, further analysis revealed that ZIP9 deficiency led to a significant decrease in the postsynaptic density protein PSD95 in the hippocampus, alongside marked elevations in the prefrontal inflammatory cytokines TNF-α and IL-1β.
"This molecular landscape of "synaptic damage plus neuroinflammation" closely parallels the hallmarks of natural brain aging," says Fang. "Notably, ZIP9 expression itself exhibited an age-dependent decline in the mouse hippocampus, gradually decreasing from adulthood to old age. This suggests that ZIP9 loss may not represent a "disease" condition per se, but rather an accelerated manifestation of the aging process itself."
Metabolomic analyses further uncovered remodeling of lipid profiles in both the hippocampus and serum, particularly involving dysregulated cardiolipin levels—lipids that are critically important for mitochondrial energy metabolism and neuronal survival.
"Our findings show that a brain-specific genetic change can ripple outward to alter gut bacteria and lipid profiles," adds Fang. "This indicates that the brain does not operate in isolation, but rather communicates with the rest of the body through a 'brain–gut–key molecule' network."
The researchers acknowledged that the current findings are primarily correlative; the causal relationships await further validation through intervention experiments—such as fecal microbiota transplantation, antibiotic depletion, or hormone supplementation—to determine the directionality of these changes.
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Contact the author: Bing Fang, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, China, bing-fang@cau.edu.cn
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Model Organisms Research
Experimental study
Animals
Postnatal deletion of ZIP9 leads to premature mortality and hippocampal-dependent cognitive decline with disrupted brain–gut–lipid homeostasis
The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.