Abstract

Brain health is closely linked to bone homeostasis. Skeletal aging is characterized by inadequate bone formation and marrow adiposity, but whether the brain contributes to this imbalance remains unknown. This study shows that aged brain neurons, mainly those in the hippocampus and cerebral cortex, produce excess WD repeat and FYVE domain containing 1 (WDFY1) protein and transfer it to the bone via extracellular vesicles (EVs), leading to bone-fat imbalance and osteoporosis. Increasing brain Wdfy1 expression causes premature skeletal aging. Conversely, suppressing Wdfy1 in the whole brain, hippocampus or neurons, genetically deleting neuronal Wdfy1 , and selectively inhibiting neuronal EV release all improve bone health. Mechanistically, WDFY1 binds to the retromer complex to promote the endosome-to-Golgi recycling of cathepsin D and peroxiredoxin 2, thus inhibiting osteogenesis and augmenting adipogenesis. This study identifies the role of aged brain neuronal EVs as an important messenger in triggering bone-fat imbalance by transferring WDFY1 to bone.