Plasma Extracellular Vesicle‐Derived miR‐296‐5p is a Maturation‐Dependent Rejuvenation Factor that Downregulates Inflammation and Improves Survival after Sepsis

ABSTRACT There is a progressive decline in physiological function with age, and aging is associated with increased susceptibility to injury and infection. However, several reports have indicated that the agility of youth is characterized by transferable rejuvenating molecular factors, as was observed previously in heterochronic parabiosis experiments. These experiments demonstrated a rejuvenating effect of young blood in old animals. There have been several efforts to characterize these youthful or maturation‐associated factors in the young blood. In this report, we demonstrate the resilience of young mice, at or before puberty, to polymicrobial sepsis and show an age‐dependent effect of small extracellular vesicles (EVs) from plasma on the outcome following sepsis. The EVs from the young mice were cytoprotective, anti‐inflammatory, and reduced cellular senescence markers. MicroRNA sequencing of the EVs showed an age‐associated signature and identified miR‐296‐5p and miR‐541‐5p to progressively reduce their levels in the blood plasma with increasing age. We further show that the levels of these miRNAs decline with age in multiple organs. The miRNAs miR‐296‐5p and miR‐541‐5p showed a reparatory effect in an in vitro wound healing model and the miR‐296‐5p, when given intraperitoneally, reduced mortality in the mouse model of sepsis. In summary, our studies demonstrate that EVs from very young mice have a reparative effect on sepsis, and the reparative factors are likely maturation‐dependent. Our observation that miR‐296‐5p and miR‐541‐5p are plasma EV constituents that significantly reduce with age and can reduce inflammation suggests a therapeutic potential for these miRNAs in inflammation and age‐associated diseases.