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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\u2010associated 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\u2010dependent effect of small extracellular vesicles (EVs) from plasma on the outcome following sepsis. The EVs from the young mice were cytoprotective, anti\u2010inflammatory, and reduced cellular senescence markers. MicroRNA sequencing of the EVs showed an age\u2010associated signature and identified miR\u2010296\u20105p and miR\u2010541\u20105p 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\u2010296\u20105p and miR\u2010541\u20105p showed a reparatory effect in an in vitro wound healing model and the miR\u2010296\u20105p, 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\u2010dependent. Our observation that miR\u2010296\u20105p and miR\u2010541\u20105p are plasma EV constituents that significantly reduce with age and can reduce inflammation suggests a therapeutic potential for these miRNAs in inflammation and age\u2010associated diseases.<\/jats:p>","DOI":"10.1002\/jev2.70065","type":"journal-article","created":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T09:40:16Z","timestamp":1745660416000},"source":"Crossref","is-referenced-by-count":6,"title":["Plasma Extracellular Vesicle\u2010Derived miR\u2010296\u20105p is a Maturation\u2010Dependent Rejuvenation Factor that Downregulates Inflammation and Improves Survival after Sepsis"],"prefix":"10.1002","volume":"14","author":[{"given":"Lun","family":"Cai","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Georgia Augusta University  Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parmita","family":"Kar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Georgia Augusta University  Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy Medical College of Georgia  Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaogang","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Georgia Augusta University  Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashok","family":"Sharma","sequence":"additional","affiliation":[{"name":"Center for Biotechnology and Genomic Medicine Medical College of Georgia  Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Jin","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Biotechnology and Genomic Medicine Medical College of Georgia  Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Arbab","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center Medical College of Georgia  Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4516-8654","authenticated-orcid":false,"given":"Raghavan Pillai","family":"Raju","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Georgia Augusta University  Augusta Georgia USA"},{"name":"Charlie Norwood VA Medical Center  Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,26]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009951"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13103"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOH.0b013e328345a180"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2060"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17010078"},{"issue":"20","key":"e_1_2_10_7_1","first-page":"8140","article-title":"Rapamycin Treatment Early in Life Reprograms Aging: Hyperfunction Theory and Clinical Practice","volume":"14","author":"Blagosklonny M. 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