MOLECULAR ATLAS OF AGING. META-GROUP 22. EPIGENETIC MARKERS AND REGULATORS OF GENE EXPRESSION: THE CHRONOGRAPH OF AGING RECORDED AT THE MOLECULAR LEVEL. INTEGRATIVE APPROACH IN THE CONTEXT OF META-MEDIUM THEORY AND META-REGULATORS

Relevance. Epigenetic markers and regulators of gene expression are a chronograph of aging, recording every event of age-related degradation at the molecular level. DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs make up the epigenetic code that determines which genes are active and which are "silenced". In youth, this code ensures proper gene expression, maintaining homeostasis, regeneration, and adaptation. With age, the epigenetic landscape is distorted: DNA methylation changes chaotically (global hypomethylation and local hypermethylation), histones lose their repressive labels (H3K9me3, H3K27me3), heterochromatin is destabilized, and non-coding RNAs reprogram cells to the aging pathway. Epigenetic age, as measured by DNA methylation (Horvath epigenetic clock, PhenoAge, GrimAge), is the most accurate biomarker of biological age, surpassing chronological age in predictive power with respect to mortality and age-associated diseases. Destabilization of nucleolus heterochromatin via the ribosomal protein RPL22 accelerates human stem cell aging, and intestinal phosphatidylethanolamine induction induces reproductive aging through epigenetic regulation. Epigenetic age, as assessed by blood methylation, correlates with levels of pro-inflammatory cytokines and neurodegeneration biomarkers. Aim. To present epigenetic markers and regulators of gene expression as the twenty-second, final level of molecular aging — an integral result of all the previous 21 groups and at the same time the main target for rejuvenation, since epigenetic changes are potentially reversible. To substantiate the need for systemic restoration of the epigenetic landscape through the tuning of meta-regulators. Results. It was shown that aging is accompanied by global genome hypomethylation and local hypermethylation of gene promoters associated with DNA development and repair. Heterochromatin destabilization (loss of H3K9me3, H3K27me3) leads to transposon activation and disruption of stem cell function; RPL22 accelerates stem cell aging through the destruction of heterochromatin in the nucleolus. Sirtuin activity (SIRT1–SIRT7) decreases with age due to a drop in NAD⁺ levels, which disrupts epigenetic stability, enhances inflammation, and suppresses mitochondrial biogenesis. miR-22 increases with age, suppressing CDK6, Sp1, and SIRT1, and promotes cellular senescence; ablation of miR-22 protects against obesity-induced adipocyte aging. Epigenetic age, as measured by blood, correlates with P-tau217 levels and cytokine profiles, including IL-6 and TNF-α. A multimodal approach (Quatotron method) to the physiological restoration of the epigenetic landscape through the restoration of metabolic balance (NAD⁺, acetyl-CoA, SAM), reduction of inflammation and activation of own regulatory mechanisms is proposed. Conclusion. Epigenetic markers and regulators of gene expression are the twenty-second, final level of molecular aging – the chronograph that records all age-related changes, and the main target for rejuvenation, since their restoration can "overwrite" biological age. Their systemic recovery through the control of meta-regulators opens up new opportunities for the prevention of age-associated diseases and healthy longevity.