Abstract
The common occurrence of cognitive decline is one of the most significant manifestations of aging in the brain, with the hippocampus - critical for learning and memory - being one of the first regions to exhibit functional deterioration. BGLAP/OCN/osteocalcin (bone gamma-carboxyglutamate protein), a pro-youth systemic factor produced by the bone, improves age-related cognitive decline by boosting hippocampal neuronal autophagy. However, the mechanism by which hippocampal neurons detect BGLAP/OCN in the systemic milieu and adapt their downstream response was previously unknown. We determined that BGLAP/OCN modulates core primary cilia (PC) proteins, suggesting that this "extracellular antenna" may play a role in mediating BGLAP/OCN's anti-aging effects. Furthermore, selective downregulation of core PC proteins in the hippocampus impairs learning and memory by reducing neuronal macroautophagy/autophagy. In contrast, restoring core PC protein levels in the hippocampus of aged mice improved this phenotype and was necessary for the induction of autophagy machinery by BGLAP/OCN. Together, these findings reveal a novel mechanism through which pro-youth systemic factors, like BGLAP/OCN, can regulate neuronal autophagy and foster cognitive resilience during aging.