Extracellular Vesicles in Young Serum Contribute to the Restoration of Age-Related Brain Transcriptomes and Cognition in Old Mice

Abstract

We have previously demonstrated that 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 improve age-associated memory deficits, and that these effects are abolished after serum depletion of EVs. RNA-seq analysis of the choroid plexus demonstrates EV-mediated effects on genes involved in barrier function and trans-barrier transport. Comparing the differentially expressed genes to recently published chronological aging clock genes reveals a reversal of transcriptomic aging in the choroid plexus. Following young serum treatment, the hippocampal transcriptome demonstrates significant upregulation of the anti-aging gene Klotho, along with an abrogated effect after EV depletion. Transcriptomic profiling of Klotho knockout and heterozygous mice shows the downregulation of genes associated with transport, exocytosis, and lipid transport, while upregulated genes are associated with activated microglia. The results of our study indicate the significance of EVs as vehicles to deliver signals from the periphery to the brain and the importance of Klotho in maintaining brain homeostasis.

Neuron-type specific aging-rate reveals age decelerating interventions preventing neurodegeneration

“…We computed age-correlations of z-score normalized gene counts for all human brain regions in the GTEx dataset 33 , the Tabula Muris Senis (TMS) dataset 5 , and an additional mouse Hypothalamus aging cohort (GSE157025). Similarly, we calculated the enriched pathways for several "anti-aging" treatments like young serum injections 34 , the platelet factor PF4 35 , sport in humans 36 , and krilloil in C. elegans 37 . An unbiased clustering analysis revealed that the aging-trajectories of C. elegans, mouse, and humans cluster together.…”

Extracellular Vesicles: The Next Generation of Biomarkers and Treatment for Central Nervous System Diseases

“…EVs encapsulate a diverse array of biomolecules, reflecting the composition and physiological state of their parent cells. Proteomic, lipidomic, and nucleic acid analyses have revealed that EV cargo encompasses proteins involved in cell signaling, membrane trafficking, and cytoskeletal organization, as well as nucleic acids such as microRNAs, mRNAs, and DNA fragments [28][29][30][31][32]. Importantly, the selective packaging of cargo into EVs is governed by specific sorting mechanisms, including protein post-translational modifications, RNA-binding proteins, and lipid raft domains [33].…”