MOLECULAR ATLAS OF AGING. META-GROUP 18. EXOSOMES AND EXTRACELLULAR VESICLES: MESSENGERS OF AGING THAT CARRY SIGNALS THROUGHOUT THE BODY. INTEGRATIVE APPROACH IN THE CONTEXT OF META-MEDIUM THEORY AND META-REGULATORS

Relevance. Exosomes and extracellular vesicles (ECI) are nano-sized (30–150 nm) membrane particles secreted by all cell types. They are key messengers of cell-to-cell communication, transporting proteins, lipids, mRNA, and microRNAs. In youth, they provide the transmission of rejuvenating signals, the removal of cellular debris, and the regulation of the immune response. However, with age, their profile changes dramatically: they become carriers of pro-inflammatory, pro-apoptotic, and aging signals, turning local age-related changes into systemic aging. Senescence-associated secretory phenotype (SASP) exosomes, pro-inflammatory microRNAs (miR-21, miR-34a, miR-146a), damaged proteins, and mitochondrial DNA carry components SASP (SASP), pro-inflammatory microRNAs (miR-21, miR-34a, miR-146a), damaged proteins, and mitochondrial DNA, inducing paracrine senescence in healthy target cells. Aim. To present age-related dysregulation of exosomes and extracellular vesicles as the eighteenth level of molecular senescence — a system of "couriers" that turn local senescence into a systemic process and make age-related changes "contagious". To substantiate the need for systemic restoration of exosomal balance through the tuning of meta-regulators. Results. It has been shown that with age, the number of circulating exosomes increases, and their contents shift towards aging signals. Senescent cell exosomes transmit miR-34a, which suppresses SIRT1 and activates p53, and miR-21, which suppresses PTEN, which induces senescence in target cells. Exosomes carry aberrant mitochondrial DNA (mtDNA), which activates cGAS-STING and inflammation. Proteomic analysis revealed more than 1300 exosome proteins released by senescent cells, with 52 of them being SASP factors, including serine protease inhibitors (serpines), prothrombin, factor V clotting, and Reelin. Lipidomics showed a significant increase in phosphatidylcholines, phosphatidylethanolamines, and sphingomyelins in senescent cell exosomes. Senescent cell exosomes were found to be involved in extracellular matrix remodeling and the spread of inflammation to distant tissues. A multimodal approach (Quatotron technique) to physiological restoration of exosome balance through reduced cellular aging, suppression of pro-inflammatory secretion, and modulation of exosome composition was proposed. Conclusion. Exosomes and extracellular vesicles are the eighteenth level of molecular aging, a system of "messengers" that make aging systemic and transmit it from cell to cell. Their systemic recovery through the control of meta-regulators opens up new opportunities for the prevention of age-associated diseases and healthy longevity.