Molecular Atlas of Aging. Meta-Group 11. Circulating Nucleic Acids and Microrna: The Extracellular Genome of an Aging Organism. Integrative Approach in the Context of Meta-Medium Theory and Meta-Regulators

Relevance. Circulating nucleic acids (cNAs) and microRNAs represent the extracellular genome of an organism – fragments of DNA and RNA, as well as small non-coding RNAs present in the blood, lymph and interstitial fluid. In youth, their levels are low and they perform signaling and regulatory functions. However, with age, their quantity and quality change dramatically: cDNA becomes redundant (due to apoptosis, necrosis, and cell damage), and the microRNA profile shifts towards pro-inflammatory and pro-apoptotic patterns. Excess cDNA acts as a DAMP (molecular pattern of damage), activating the TLR9 and cGAS-STING pathways, triggering inflammation and inducing cellular senescence. MicroRNAs encased in exosomes affect gene expression in target cells by inhibiting rejuvenating pathways and activating pro-inflammatory pathways. Together, they create epigenetic noise that destabilizes the transcriptome and accelerates aging. Aim. To represent circulating nucleic acids and microRNAs as the eleventh level of molecular senescence, an extracellular genomic distress signal that an old organism sends to itself, triggering a cascade of inflammation, cellular senescence, and mutagenesis. To substantiate the need for systemic restoration of the balance of cNAs and microRNAs through the tuning of meta-regulators. Results. It was shown that the concentration of cDNA and cRNA in plasma increases with age by 5–10 times, with a special role played by mitochondrial DNA (mtDNA), which contains unmethylated CpG motifs, which are powerful activators of TLR9. In a study of 672 elderly people, a positive correlation was found between the levels of ctDNA-mtDNA and pro-inflammatory markers (CRP, sTNFR1, IL-6), and high levels of long (necrosis-associated) mtDNA fragments predicted deterioration in gait and increased the risk of mortality. Circulating miR-21-5p, miR-23a-3p, and miR-26a-5p microRNAs show a progressive age-dependent increase associated with frailty, decreased arm strength, and systemic inflammation. A large population study (n=2684) identified 188 microRNAs differentially expressed with age and developed four microRNA biomarkers of biological age. cDNA from cardiovascular cells is associated with a 3.1-fold increase in the risk of fragility and accelerated epigenetic aging. A multimodal approach (Quatotron technique) to physiologically restore the balance of cNAs and microRNAs through activation of DNases, improved clearance, and normalization of the microRNA profile has been proposed. Conclusion. Circulating nucleic acids and microRNAs are the eleventh level of molecular aging — a genomic distress signal, without control over which rejuvenation is impossible. Their systemic recovery through the control of meta-regulators opens up new opportunities for the prevention of age-associated diseases and healthy longevity.