Landmark Study in Nature Aging Uncovers How Aging Brain Neurons Drive Bone Loss

A study published bythe team from Xiangya Hospital, Central South University in the Nature Aging reveals a new mechanism by which brain aging directly leads to osteoporosis. Researchers discovered that aged neurons, particularly in regions like the hippocampus, overproduce aprotein called WDFY1. This protein is packaged into extracellular vesicles(EVs) that travel from the brain to the bone marrow. Once there, WDFY1 disrupts the function of bone marrow stromal cells (BMSCs), skewing their developmenttoward fat cells instead of bone-forming cells, thereby causing bone-fat imbalanceand bone loss.

Fig.8 b,Schematic diagram showing the aging neurons-mediated induction of skeletal aging and osteoporosis through the brain-to-bone transfer of WDFY1 protein via EVs

A Multidimensional Research Approach

The research employed a comprehensive strategy combining in vivo and in vitro models:

• EV Characterization & Tracking: Isolation of brain-derived EVs from young and aged mice, and use of reporter mice to traceneuron-derived EVs to bone tissue.

• Genetic Manipulation Models: Utilization of neuron-specific Wdfy1 conditional knockout mice and mice with impaired neuronal EV secretion to establish causality.

• Central Nervous System Targeting: Development of a rabiesvirus glycoprotein (RVG)-based delivery system to specifically silence Wdfy1 in brain neurons.

• Mechanistic Dissection: Proteomic screening,co-immunoprecipitation, and functional assays in BMSCs to delineate the downstream molecular pathway.

HySigen's AAV Vectors: A Pivotal Experimental Tool

A cornerstonefor validating the central role of brain WDFY1 was the use of AAV2-shWdfy1 and AAV2-shCon vectors, which were designed and prepared by HySigen. These custom adeno-associated virus vectors allowed the researchers to achieve precise, localized knockdown of the Wdfy1 gene specifically within the brains of aged mice. This targeted intervention was crucial for demonstrating that suppressing brain-derived WDFY1 could significantly improve bone mass, enhancebone strength, and reduce marrow adiposity, without the need for systemic inhibition. The genetic precision afforded by these tools was instrumental in confirming WDFY1 as a viable therapeutic target within this newly discovered brain-bone communication axis.

✨Key Takeaway:This study redefines osteoporosis as a condition potentially influenced by remote signals from the aging brain. It identifies neuronal WDFY1 as a key mediator and promising therapeutic target.

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‍Publication:Chen C Y, Wang Z, Hong C G, et al. Brain neuron-derived WDFY1 induces bone loss[J]. Nature Aging, 2026: 1-20.https://doi.org/10.1038/s43587-025-01032-8

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