Extracellular vesicles in young serum contribute to restoration of age-related brain transcriptomes and cognition in old mice
We have demonstrated that the circulating extracellular vesicles (EVs) are essential to the beneficial effect of young serum on the skeletal muscle regenerative cascade. Here, we show that infusions of young serum significantly improved age-associated memory deficits, and the effect was abolished after serum depletion of EVs. RNA-seq analysis of the choroid plexus demonstrated EV-mediated effects on genes involved in barrier function and trans-barrier transport. Comparing the differentially expressed genes to the recently published chronological aging clocks revealed a reversal of transcriptomic aging in the choroid plexus. The hippocampal transcriptome demonstrated a significant upregulation of the anti-aging gene Klotho following young serum treatment and an abrogated effect after EV depletion. Subsequent transcriptomic profiling of Klotho knockout and heterozygous mice showed downregulation of genes associated with transport, exocytosis, and lipid transport, while upregulated genes were associated with activated microglia. The results of our study indicate the significance of EVs as vehicles to deliver signals from the periphery to brain and the importance of Klotho in maintaining brain homeostasis. Overall design: We performed RNA-seq on 1) dissected choroid plexus and hippocampus isoalted from aged mice infused with young serum; 2) 2-month-old a-Klotho knockout (Klko) and WT mice; 3) 9-month-old Klotho heterozygous (Klhet) and WT mice.